caverject vs viagra th tee Anterior teeth can viagra be used for premature ejaculation is viagra available in spain This maxillary molar has a very long clinical crown since all of the anatomic crown and much of the anatomic root are exposed due to recession of the gingiva and loss of bone. how to use viagra spray for men Lingual 3rd Buccal 3rd (facial) Middle 3rd viagra russian singers L distolingual mesiolingual mesiolingual free viagra for diabetics FIGURE 1-30. The lingual surface of an incisor shows the shallow lingual fossa and an adjacent lingual pit. FIGURE 1-29. A cross section of a mandibular molar shows an occlusal groove (white arrow), which actually has a fissure (crack-like fault) extending through the outer enamel and into the dentin. The black arrows show how the dental decay spreads out once it reaches softer dentin at the depth of the fissure. FIGURE 1-33. A. Root anatomy on a single-rooted canine. B. Bifurcated (split) root of a maxillary first premolar. v herbal viagra review hay viagra femenina Table 1-3 does viagra lower your blood pressure h does viagra cure ed 3rd Molars does viagra increase testosterone levels TRAITS TO DISTINGUISH MAXILLARY CENTRAL FROM LATERAL INCISOR: LINGUAL VIEW 54 viagra heart attack risk Central incisor Lateral incisor viagra for men in their 20s Table 2-5A biverkningar av viagra ce face viagra TRAITS TO DISTINGUISH MAXILLARY FROM MANDIBULAR CANINE: LABIAL VIEW Part 1 | Comparative Tooth Anatomy viagra competitive inhibitor 100 ritalin viagra interactions MANDIBULAR PREMOLARS (OCCLUSAL) viagra pegym viagra y alcohol yahoo ANSWER: The maxillary second premolar appears viagra headquarters photo Critical Thinking why is my viagra not working The number of lobes forming molars is one per cusp, including the cusp of Carabelli. See Table 5-1 for a summary of the number of lobes forming first and second molars. 3. CROWN TILT THAT DISTINGUISHES MAXILLARY FROM MANDIBULAR MOLARS When mandibular molar crowns are examined from the proximal views, the crowns appear to be tilted lingually on the root trunk (true for all mandibular posterior teeth), whereas the crowns and cusps of maxillary molars are centered over their roots (Appendix 8b). Also, when mandibular molars are viewed from the buccal, the considerable bulge of the distal crown outline beyond the cervix of the root, and the slope of the occlusal surface shorter on the distal, may appear as though the crown is tipped distally relative to the long axis of the root. (The greater distal crown bulge can be seen on Appendix 8g.) canadian viagra email virus Two or three buccal cusps: Mesiobuccal, distobuccal, and distal (on firsts) Both lingual cusp tips visible from buccal Two buccal grooves on most first molars Two roots (one mesial and one distal) Root trunk shorter Crown tipped distally on root Lingual groove nearly centered Mesiolingual and distolingual cusps’ size and height more equal Cervix of crown tapers less to lingual No Carabelli cusp Crown tipped more lingually over root Smallest distal cusp seen from distal on most first molars D gaditano viagra Roots more spread out, shorter trunk Roots with less distal bend Buccal cusps almost same size viagra information in urdu Table 5-4 can i take viagra with atrial fibrillation viagra after cataract surgery Part 1 | Comparative Tooth Anatomy harga obat kuat / viagra 151 Distal what happens when you take half a viagra viagra price in brazil e sleep apnea viagra M. Table 6-1A hva koster viagra viagra 25mg erfahrung 7.4 5.8 7.4 8.1 9.7 a. Support The gingiva supports the tooth by means of attachment coronal to the crest of the alveolar bone that forms a dentogingival junction from tooth to gingiva near the CEJ.5 It includes the junctional epithelium (average width just <1 mm) and the connective tissue attachment (average width slightly >1 mm) (Fig. 7-1). The more coronal band (junctional epithelium) attaches gingiva to the tooth by cell junctions (called hemidesmosomes, or half desmosomes), while the more apical band (connective tissue) attaches gingiva to cementum by several gingival fiber groups made up of connective tissue called collagen. b. Protection The gingiva protects underlying tissue because it is composed of dense fibrous connective tissue covered by a relatively tough tissue layer called keratinized epithelium.6 It is resistant to bacterial, chemical, thermal, and mechanical irritants. Keratinized gingiva helps prevent the spread of inflammation to deeper underlying periodontal tissues. However, the sulcular lining (epithelium) and junctional epithelium of the marginal gingiva and interdental papillae provide less protection. Since these areas are not keratinized, they are more permeable to bacterial products, providing only a weak barrier to bacterial irritants, and may even allow bacterial penetration in aggressive forms of periodontal diseases. Healthy gingiva is protected by ideally positioned and contoured natural teeth and well-contoured restorations. The protection provided by ideal tooth contours, including anatomic heights of contour, helps to minimize injury from food during mastication (chewing) since food is diverted away from the thin gingival margin and the nonkeratinized sulcus (recall Fig. 1-37). However, poor tooth or restoration contours, especially overcontoured restorations, contribute to the retention of bacteria-laden dental plaque that may predispose to gingival and periodontal diseases and will be described in more detail later. Ideal proximal tooth contours and contacts help prevent food from impacting between teeth and damaging the interdental papilla or contributing to interproximal periodontal disease. Be aware, however, that even ideal tooth contours do not prevent the formation of bacterial plaque and development of periodontal disease. c. Esthetics In health, gingiva covers the roots of teeth, and the interdental papillae normally fill the gingival embrasure areas between adjacent teeth (Figs. 7-2 and 7-4). how long till viagra kicks in does extenze work like viagra Edentulous people (with no teeth) who wear complete dentures or false teeth are provided with CR that coincides with MIP because they can learn to pull the mandible back and close into a stable and repeatable position of CR during jaw closure. This enables the tight occlusion of denture teeth to coincide with the repeatable centric jaw position, so the dentures will remain tightly secured against the mucosa and not rock loose when functioning. An articulator is a mechanical device that holds casts of the two arches, permitting a close duplication of the patient’s opening and closing centric jaw relations (Fig. 9-24). Notice the fit of the ball of the lower (mandibular) part fitting into a concavity on the upper (maxillary) part. This design simulates the heads of the condyles fitting into their articular fossae. It is easier to study tooth relationships with the patient’s dental arches (dental stone casts) on the articulator in your hands, rather than with your hands in the patient’s mouth. What better way is there to determine whether or not the maxillary and mandibular lingual cusps fit together tightly or properly in the maximal intercuspal relationship? prijs van viagra Premolars one side Premolars both sides Molars one side Molars both sides Molar one side; premolar one side Canine MIP = centric jaw relation (no prematurity) R generic viagra nederland norvasc viagra interaction Learning Exercise, cont. CONDITION WORKING SIDE TOOTH RELATIONSHIPS can you take viagra if you don't have erectile dysfunction taking viagra on empty stomach B. PROVIDE RETENTION FORM pfizer viagra next day delivery Mesial viagra how long before it starts to work Part 2 | Application of Tooth Anatomy in Dental Practice 383 trusted viagra sales Palatal process of left maxilla Junction of hard palate and alveolar process Transverse palatine (palatomaxillary) suture Intermaxillary suture chew viagra faster Maxillary tuberosity Hamular notch Lateral pterygoid plate of sphenoid Pterygoid hamulus of medial pterygoid plate Palatine bones (right) viagra jokes women FIGURE 14-20. viagra lymphatic malformation saudi king viagra Disc FIGURE 14-28. whats happens if a girl takes viagra Chapter 14 | Structures that Form the Foundation for Tooth Function can viagra make u last longer ANSWERS: 1—a, 2—d, 3—d, 4—e, 5—d, 6—e viagra addiction side effects SECTION IV prednisone and viagra interaction Posterior superior alveolar (PSA) nerve does taking viagra feel like buy viagra gibraltar 19 Use Figure 15-5 as a guide while studying the lips. The lips are the two fleshy borders of the mouth (an upper and a lower) that join at the labial commissure. can you buy viagra in tenerife FIGURE 15-6. can you get viagra at walmart viagra samples overnight shipping Structures of the ventral (under) surface of the tongue and floor of the mouth: Some mucosa was dissected away on one side of the tongue and floor of the mouth to reveal the sublingual salivary gland (seen on the right side of the drawing in yellow), which is located just beneath the sublingual fold (seen intact in green on the left side of the drawing). The submandibular duct (blue) passes from the submandibular gland (not visible) to the openings on the sublingual caruncles (green structures on the midline where the right and left sublingual folds join). viagra super aktiv 100 mg Facial f can viagra increase sperm count viagra wikipedia francais Distal viagra 100 mg cut in half b can i buy viagra in jakarta ARRESTED CARIES Static or stationary caries which do not show any tendency for further progression. Occurs exclusively in caries of occlusal surfaces characterised by a large open cavity which lack food retention. EBURNATION OF DENTIN : gradual burnishing of superficial softened and decalcified dentin until it takes on a hard brown stained, polished appearance. can you buy viagra in bangkok organisms celery viagra vegetable 165 Contents viagra high blood pressure risk what happens if girls use viagra 1◊◊the external intercostal, the ﬁbres of which pass downwards and forwards from the rib above to the rib below and reach from the vertebrae behind to the costochondral junction in front, where muscle is replaced by the anterior intercostal membrane; 2◊◊the internal intercostal, which runs downwards and backwards from the sternum to the angles of the ribs where it becomes the posterior intercostal membrane; 3◊◊the innermost intercostal, which is only incompletely separated from the internal intercostal muscle by the neurovascular bundle. The ﬁbres of this sheet cross more than one intercostal space and it may be incomplete. Anteriorly it has a more distinct portion which is fan-like in shape, termed the transversus thoracis (or sternocostalis), which spreads upwards from the posterior aspect of the lower sternum to insert onto the inner surfaces of the second to the sixth costal cartilages. Just as in the abdomen, the nerves and vessels of the thoracic wall lie between the middle and innermost layers of muscles. This neurovascular bundle consists, from above downwards, of vein, artery and nerve, the vein lying in a groove on the undersurface of the corresponding rib (remember— v,a,n). The vessels comprise the posterior and anterior intercostals. The posterior intercostal arteries of the lower nine spaces are branches of the thoracic aorta, while the ﬁrst two are derived from the superior intercostal branch of the costocervical trunk, the only branch of the second part of the subclavian artery. Each runs forward in the subcostal groove to anastomose with the anterior intercostal artery. Each has a number of branches to adjacent muscles, to the skin and to the spinal cord. The corresponding veins are mostly tributaries of the azygos and hemiazygos veins. The ﬁrst posterior intercostal vein drains into the brachiocephalic or vertebral vein. is there anything over the counter like viagra 19 The venous drainage of the heart (Fig. 28) legal viagra substitute tiagra viagra wall is formed by the spleen attached by the gastrosplenic and lienorenal ligaments. The right extremity of the sac opens into the main peritoneal cavity via the epiploic foramen or foramen of Winslow (Fig. 49), whose boundaries are as follows: •◊◊anteriorly — the free edge of lesser omentum, containing the common bile duct to the right, hepatic artery to the left and portal vein posteriorly; •◊◊posteriorly—the inferior vena cava; •◊◊inferiorly — the 1st part of the duodenum, over which runs the hepatic artery before this ascends into the anterior wall of the foramen; •◊◊superiorly—the caudate process of the liver. Fig. 52◊The posterior relations of the stomach; the stomach (grey tint) is superimposed upon its bed. fake viagra pics Connections between the portal and systemic venous systems prirodna viagra forum 92 viagra vector logo The splenic artery is one of the three main branches of the coeliac axis. The splenic vein is joined by the superior mesenteric to form the portal vein. (Note that the splenic vessels also provide the principal blood supply of the pancreas.) efectos secundarios del viagra en mujeres The abdomen and pelvis whats the side effects of viagra can you buy real viagra from canada The muscles of the pelvic ﬂoor and perineum internal os with the cervical canal which, in turn, opens into the vagina by the external os. The nulliparous external os is circular but after childbirth it becomes a transverse slit with an anterior and a posterior lip. The non-pregnant cervix has the ﬁrm consistency of the nose; the pregnant cervix has the soft consistency of the lips. In fetal life the cervix is considerably larger than the body; in childhood (the infantile uterus) the cervix is still twice the size of the body but, during puberty, the uterus enlarges to its adult size and proportions by relative overgrowth of the body. The adult uterus is bent forward on itself at about the level of the internal os to form an angle of 170°; this is termed anteﬂexion of the uterus. Moreover, the axis of the cervix forms an angle of 90° with the axis of the vagina— anteversion of the uterus. The uterus thus lies in an almost horizontal plane. In retroversion of the uterus, the axis of the cervix is directed upwards and backwards. Normally on vaginal examination the lowermost part of the cervix to be felt is its anterior lip; in retroversion either the os or the posterior lip becomes the presenting part. In retroﬂexion the axis of the body of the uterus passes upwards and backwards in relation to the axis of the cervix. Frequently these two conditions co-exist. They may be mobile and symptomless— as a result of distension of the bladder or purely as a development anomaly. Indeed, mobile retroversion is found in a quarter of the female population and may be regarded as a normal variant. Less commonly, they are ﬁxed, the result of adhesions, previous pelvic infection, endometriosis or the pressure of a tumour in front of the uterus (Fig. 103). first viagra commercial Abdominal aorta (Fig. 110) prescribing viagra australia The clavicle (Fig. 120) uso correcto de viagra discount brand name viagra 174 Linear aspera viagra sklep online Fig. 161◊The head and neck of the femur, showing the terminology of the common fracture sites. what does viagra taste like 228 lloyds pharmacy discount code viagra viagra pills for girls Movements of the knee old viagra commercial The lower limb danger of viagra use In the process of walking, the heel is raised from the ground, the metatarsophalangeal joints ﬂex to give a ‘push off’ movement; the foot then leaves the ground completely and is dorsiﬂexed to clear the toes. Just before the toes of one foot leave the ground, the heel of the other makes contact. Forward progression is produced partly by the ‘push off’ of the toes, partly by powerful plantarﬂexion of the ankle and partly by the forward swing of the hips accentuated by swinging movements of the pelvis. Paraplegics can be taught to walk purely by this pelvic swing action, even though paralysed from the waist downwards. When one foot is off the ground, dropping of the pelvis to the unsupported side is prevented by the hip abductors (gluteus medius and minimus and tensor fasciae latae). Their paralysis is one cause of a ‘dipping gait’ and of a positive Trendelenburg sign (see page 228). viagra generico el mejor afrodisiaco This canal leads on from the apex of the femoral triangle. Its boundaries are: •◊◊posteriorly—adductor longus and magnus; •◊◊anterolaterally—vastus medialis; •◊◊anteromedially— the sartorius, which lies on a fascial sheet forming the roof of the canal. The contents of the canal are the femoral artery, the femoral vein (which lies behind the artery), the saphenous nerve and, in its upper part, the nerve to vastus medialis from the femoral nerve. John Hunter described the exposure and ligation of the femoral artery in this canal for aneurysm of the popliteal artery; this method has the advantage that the artery at this site is healthy and will not tear when tied, as may happen if ligation is attempted immediately above the aneurysm. regex viagra The thyroid gland was kostet viagra 100mg Fig. 202◊Diagram of the palatine tonsil and its relations—in horizontal section. 337 can you buy viagra over the counter in new zealand difference between generic and brand name viagra It is continuous below, through the foramen magnum, with the spinal cord and above with the pons; posteriorly, it is connected with the cerebellum by way of the inferior cerebellar peduncles. Fig. 258◊Section through the upper pons to show the nucleus of nerve IV. is there viagra for girls The special senses different brands of viagra can i sell viagra on ebay 385 order generic viagra online overnight The vascular coat viagra tra i giovani Diastole S4 Lower teeth viagra generika mit paypal is there a generic equivalent for viagra T2 viagra loses effectiveness C6 Electrolytes puscifer v is for viagra blogspot Infection (bacterial with bacteremia, viral, TB, fungal), neoplasm (Hodgkin’s disease), drug and transfusion reactions, hypothermia, malaria herbal viagra factory Decreased: (Note: Levels <7 mg/dL [<1.75 mmol/L] may lead to tetany and death.) Hypoparathyroidism (surgical, idiopathic), pseudo-hypoparathyroidism, insufficient vitamin D, calcium and phosphorus ingestion (pregnancy, osteomalacia, rickets), hypomagnesemia, renal tubular acidosis, hypoalbuminemia (cachexia, nephrotic syndrome, CF), chronic renal failure (phosphate retention), acute pancreatitis, factitious decrease because of low protein and albumin CAPTOPRIL TEST el viagra te hace durar mas viagra 19 years old diabetic ketoacidosis, lactic acidosis, alcoholic ketoacidosis, toxins [methanol, ethylene glycol, paraldehyde], severe diarrhea, renal failure, drugs [salicylates, acetazolamide], dehydration, adrenal insufficiency) werking viagra bij vrouwen Used in the differential diagnosis of Cushing’s syndrome (elevated cortisol) In the “rapid” version of this test, a patient takes 1 mg of dexamethasone PO at 11 PM and a fasting 8 AM plasma cortisol is obtained. Normally the cortisol level should be <5.0 mg/dL [138 nmol/L]. A value that is >5 mg/dL [138 nmol/L] usually confirms the diagnosis of Cushing’s syndrome; however, obesity, alcoholism, or depression may occasionally show the same result. In these patients, the best screening test is a 24-h urine for free cortisol. After collection of baseline serum cortisol and 24-h urine-free cortisol levels, dexamethasone 0.5 mg is administered PO every 6 h for eight doses. Serum and urine cortisol are repeated on the second day. Failure to suppress to a serum cortisol of <5.0 mg/dL [138 nmol/L] and a urine-free cortisol of <30 µg/dL (82 nmol/L) confirms Cushing’s syndrome. Positive: 151 and coke is viagra meds like viagra ALB α1 α2 β Abbreviations: CBC = complete blood count; WBC = white blood cell. donde comprar viagra sin receta en barcelona • Collection: Lavender top tube The ESR is a very nonspecific test with a high sensitivity and a low specificity. Most useful in serial measurement to follow the course of disease (eg, polymyalgia rheumatica or temporal arteritis). ZETA rate is not affected by anemia. ESR correlates well with C-reactive protein levels. free viagra for unemployed what is the purpose of viagra tablets FIGURE 7–2 Lab algorithm for the identification of gram-negative organisms. (Reprinted, with permission, from: Bhushan V [ed]: First Aid for the USMLE, Step 1, Appleton & Lange, Norwalk, CT, 1999.) Amphotericin B (acutely), fluconazole Sulfisoxazole, TMP–SMX Ofloxacin and metronidazole or ceftriaxone (single dose) plus doxycycline; parenteral cefotetan or cefoxitin plus doxycycline pink viagra for men Herpesvirus Ureaplasma urealyticum C. trachomatis Gonococci Coliforms Cryptococcus (AIDS) Coliforms Coliforms, enterococci, Pseudomonas Enterobacteriaceae (E. coli) Enterococci Pseudomonas spp. Helicobacter pylori precio del viagra en panama Human granulocytic ehrlichiosis difference between brand name and generic viagra dictionary definition viagra 7 1–52 wk how much does viagra cost in new zealand chinese herbal viagra jia yi jian Distal H+ secretion kiek kainuoja viagra Differential Diagnosis viagra pour bander 56 = 24 × 56 = 56 The numbers fit. psych viagra falls wiki Cl− viagra commercial drummer Voluntary blood donation is the mainstay of the blood system in the United States. Donors must usually be >18 y old, in good health, afebrile. and weigh >110 lb. Donors are usually limited to 1 unit every 8 wk and 6 donations/y. Patients with a history of hepatitis, HBsAg positivity, insulin-dependent diabetes, IV drug abuse, heart disease, anemia, and homosexual activity are excluded from routine donation. Patients are counseled about high-risk behaviors that may risk others if they have transmissible diseases and donate blood. Donor blood is tested for ABO, Rh, antibody screen, HBsAg, antihepatitis B core antigen, hepatitis C antibody, anti-HIV-1 and 2, and anti-HTLV-1 and 2. viagra college students and those without an intact gag reflex Required feeding route when proximal (ie, oral, esophageal, or gastric) GI obstruction or impairment is present Preferred delivery site for critically ill patients Premature formulas Low osmolality Similac Special Premature infants (<1800–2000 g) who are Care 20 growing rapidly. These formulas promote Enfamil Premature 20 growth at intrauterine rates. Vitamin and Preemie SMA 20 mineral concentrations are higher to meet the needs of growth. Usually started on 20 Cal/oz and advanced to 24 Cal/oz as tolerated. Isoosmolar Similac Special Same as for low-osmolality premature formulas Care 24 Enfamil Special Care 24 Preemie SMA 24 buying viagra off craigslist best pill cutter for viagra Procedure Basics Amniotic Fluid Fern Test Arterial Line Placement Arterial Puncture Arthrocentesis (Diagnostic and Therapeutic) Bone Marrow Aspiration and Biopsy Central Venous Catheterization Chest Tube Placement Cricothyrotomy (Needle and Surgical) Culdocentesis Doppler Pressures Electrocardiogram Endotracheal Intubation Fever Work-up Gastrointestinal Intubation Heelstick Internal Fetal Scalp Monitoring Injection Techniques Intrauterine Pressure Monitoring IV Techniques Lumbar Puncture Orthostatic Blood Pressure Measurement Pelvic Examination Pericardiocentesis Peripherally Inserted Central Catheter (PICC Line) Peritoneal Lavage Peritoneal (Abdominal) Paracentesis Pulmonary Artery Catheterization Pulsus Paradoxus Measurement Sigmoidoscopy (Rigid) Skin Biopsy Skin Testing Thoracentesis Urinary Tract Procedures Venipuncture integra viagra See Right Internal Jugular Vein Approach, page 257. • • • • Fetal scalp monitoring electrode Sterile vaginal lubricant or povidone–iodine spray Spiral electrode Leg plate/fetal monitor viagra turkce Vacutainer Tubes viagra commercial actors viagra side effects yahoo 2. 3. ENTERING THE OR different types of viagra pills key ingredient in viagra 345 17 woman feeds man viagra The formal procedure for obtaining a readable ECG is given in Chapter 13, page 266. Every electrocardiogram should be approached in a systematic, stepwise fashion. Many automated ECG machines can give a preliminary interpretation of a tracing; however, all automated interpretations require analysis and sign-off by a physician. Determine each of the following: • Standardization. With the ECG machine set on 1 mV, a 10-mm standardization mark (0.1 mV/mm) is evident (Figure 19–1). • Axis. If the QRS is upright (more positive than negative) in leads I and aVF, the axis is normal. The normal axis range is –30 degrees to +105 degrees. • Intervals. Determine the PR, QRS, and QT intervals (Figure 19–2). Intervals are measured in the limb leads. The PR should be 0.12–0.20 s, and the QRS, <0.12 s. The QT interval increases with decreasing heart rate, usually <0.44 s. The QT interval usually does not exceed one half of the RR interval (the distance between two R waves). • Rate. Count the number of QRS cycles in a 6-s strip and multiply it by 10 to roughly estimate the rate. If the rhythm is regular you can be more exact in determining the rate by dividing 300 by the number of 0.20-s intervals (usually depicted by darker shading) and then extrapolating for any fraction of a 0.20-s segment. • Rhythm. Determine whether each QRS is preceded by a P wave, look for variation in the PR interval and RR interval (the duration between two QRS cycles), and look for ectopic beats. • Hypertrophy. One way to determine LVH is to calculate the sum of the S wave in V1 or V2 plus the R wave in V5 or V6. A sum >35 indicates LVH. Some other criteria for LVH are R >11 mm in aVL or R in I + S in aVF >25 mm. • Infarction or Ischemia. Check for the presence of ST-segment elevation or depression, Q waves, inverted T waves, and poor R-wave progression in the precordial leads. A more detailed discussion of each of these categories is presented in the following sections. viagra wedding night FIGURE 19–15 Ventricular bigeminy. viagra wikipedia deutsch cheap viagra vipps PVR Types of Shock the man who invented viagra viagra computer virus 1. Atrial fibrillation Atrial flutter 4. Stable monomorphic VT and/or polymorphic VT cheap viagra adelaide pele viagra commercial Clinician’s Pocket Reference, 9th Edition Standard Defibrillation Procedure (conventional device) site fiable achat viagra boots chemist viagra prices OTHER COMMON EMERGENCIES buy generic viagra brazil Amoxicillin Amoxicillin-clavulanate Ampicillin Ampicillin-sulbactam Cloxacillin Dicloxacillin Mezlocillin Nafcillin Oxacillin Penicillin G aqueous Penicillin G benzathine Penicillin G procaine Penicillin V Piperacillin Piperacillin-tazobactam Ticarcillin Ticarcillin-clavulanate Miscellaneous Agents viagra sanskrit Levonorgestrel implants Oral contraceptives monophasic (Table 22–3, pages 623–625) Oral contraceptives biphasic (Table 22–3, pages 623–625) Oral contraceptives triphasic (Table 22–3, pages 623–625) Oral contraceptives progestin only (Table 22–3, pages 623–625) Norgestrel men using viagra video Prevention and Rx of RDS in premature infants Replacement of pulmonary surfactant 100 mg/kg administered via endotracheal tube. May be repeated 3 more × q6h for a max of 4 doses/48h SUPPLIED: Suspension 25 mg of phospholipid/mL NOTES: Administer via 4-quadrant method why does viagra not work sometimes Mild to moderate pain; symptomatic relief of cough Narcotic analgesic; depresses cough reflex DOSAGE: Adults. Analgesic: 15–60 mg PO or IM qid PRN. Antitussive: 10–20 mg PO q4h PRN; max 12 mg/d. Peds. Analgesic: 0.5–1.0 mg/kg/dose PO or IM q4–6h PRN. Antitussive: 1.0–1.5 mg/kg/24h PO ÷ q4h; max 30 mg/24h SUPPLIED: Tabs 15, 30, 60 mg; soln 15 mg/5 mL; inj 30, 60 mg/mL NOTES: Most often combined with acetaminophen for pain or with agents, eg, terpin hydrate as an antitussive; 120 mg IM = to 10 mg of morphine IM viagra online indonesia Cyclobenzaprine (Flexeril) viagra essential tremor Suppression and prevention PVC Class 1A antiarrhythmic DOSAGE: Adults. 400–800 mg/d ÷ q6h for regular-release products and q12h for SR products. Peds. <1 y: 10–30 mg/kg/24h PO (÷ qid). 1–4 y: 10–20 mg/kg/24h PO (÷ qid). 4–12 y: 10–15 mg/kg/24h PO (÷ qid). 12–18 y: 6–15 mg/kg/24h PO (÷ qid) SUPPLIED: Caps 100, 150 mg; SR caps 100, 150 mg NOTES: Anticholinergic side effects (urinary retention); negative inotropic properties may induce CHF; ↓ in impaired hepatic function and renal dysfunction. (See Table 22–7, pages 631–634, for levels.) funny viagra sayings Hypertensive emergency Rapid acting vasodilator DOSAGE: Initial dose 0.03–0.1 µg/kg/min IV cont inf, titrate to effect q 15 min with 0.05–0.1 µg/kg/min increments SUPPLIED: Inj 10 mg/mL NOTES: Avoid concurrent use with β-blockers do young people take viagra can i take viagra after a heart attack Haloprogin (Halotex) Kaolin-Pectin (Kaodene, Kao-Spen, Kapectolin) how should viagra be stored Head lice, crab lice, scabies Ectoparasiticide and ovicide DOSAGE: Adults & Peds. Cream or lotion: Apply thin layer after bathing and leave in place for 8–12h (6–8 h for children, 6 h for infants), pour on laundry. Shampoo: Apply 30 mL and develop a lather with warm water for 4 min; comb out nits SUPPLIED: Lotion 1%; shampoo 1% NOTES: Caution with overuse; may be absorbed into blood; repeat in 7 d if necessary how to identify real viagra DOSAGE: SUPPLIED: cheap viagra ontario ACTIONS: COMMON USES: buying viagra in belgium Ultra Rapid Humalog (Lispro) NovoLog (Insulin aspart) Rapid Regular Iletin II Humulin R Novolin R Velosulin Intermediate NPH Iletin II Lente Iletin II Humulin N Novulin L Novulin 70/30 Prolonged Ultralente Humulin U Lantus (insulin glargine) Combination Insulins Humalog Mix (lispro protamine/ lispro) como actua el viagra en un hombre black stone viagra (continued ) REIMBURSEMENT The nature of reimbursement for chiropractic services has changed, along with the maturation of the chiropractic profession and the fact that the general population has increasingly viewed chiropractic as a viable alternative or adjunctive method of treatment. To some extent, changes in reimbursement patterns have also been driven by trends in medicine as well as social and reimbursement policy in general. Up to the 1960s, the vast majority of chiropractic treatments were provided on a feefor-service basis. One milestone in the movement away from this was the inclusion of chiropractic in the original Medicare law. This inclusion was legislated in a rather narrow fashion and with tight restrictions on issues ranging from the types of conditions to be treated and the reimbursements provided. Nonetheless, it provided some impetus towards incorporation of chiropractic services in other third-party payer systems. However, through the 1970s and early 1980s transition to third-party payment proceeded at a slow pace with inclusion of chiropractic services in worker’s compensation programs and many private insurance programs. Since chiropractors were often involved in treating patients with neck and back injuries, there was also involvement in the personal injury arena. With the more recent growth of health maintenance organizations (HMOs), there has been slowly evolving inclusion of chiropractors in many of these plans. Some have restricted access strictly on the basis of referral from primary care providers, while a growing number of plans permit self-referral, usually under a system of strict guidelines for numbers of treatments. Integration of chiropractic into the US armed services is proceeding after the conclusion of a pilot program exploring the feasibility of such involvement. Additionally, the US Veterans Administration health-care system will be incorporating chiropractors, although the precise nature of this involvement is still being established. In the early 1990s the primary sources of payment for chiropractic services included private insurance and direct payments from the patient6. Together these were estimated to comprise 60% of chiropractic payments. Worker’s Compensation and automobile accident insurance accounted for an additional 10–15% each, and Medicare represented another 8%. Other forms of payment, including Medicaid and managed care, contributed the remaining 10%. However, with the growing integration of chiropractic services into managed care, the portion related to HMOs is expected to grow significantly10. viagra cause death dosis normal de viagra 50. Cassidy JD, Thiel HW, Kirkaldy-Willis WH. Side posture manipulation for lumbar intervertebral disk herniation. J Manipulative Physiol Ther 1993; 16:96–103 51. Stern PJ, Cote P, Cassidy JD. A series of consecutive cases of low back pain with radiating leg pain treated by chiropractors. J Manipulative Physiol Ther 1995; 18:335–42 52. Cassidy JD, Kirkaldy-Willis WH. Spinal manipulation for the treatment of chronic low back and leg pain: an observational study. In Buerger AA, Greenman PE, eds. Empirical Approaches to the Validation of Spinal Manipulation. Springfield, IL: CC Thomas, 1985: 119–48 53. Ben-Eliyahu DJ. Magnetic resonance imaging and clinical follow-up: study of 27 patients receiving chiropractic care for cervical and lumbar disc herniations. J Manipulative Physiol Ther 1996; 19:597–606 54. BenEliyahu DJ. Chiropractic management and manipulative therapy for MRI documented cervical disk herniation. J Manipulative Physiol Ther 1994; 17:177–85 55. Brodin H. Cervical pain and mobilization. Manual Med 1982; 20:90–4 56. Howe DH, Newcombe RG, Wade MT. Manipulation of the cervical spine—a pilot study. J R Coll Gen Pract 1983; 33:574–9 57. Jordan A, Bendix T, Nielsen H, Hansen FR, Host D, Winkel. A Intensive training, physiotherapy, or manipulation for patients with chronic neck pain. A prospective, singleblinded, randomized clinical trial. Spine 1998; 23:311–18 58. Bronfort G, Evans R, Nelson B, et al. A randomized clinical trial of exercise and spinal manipulation for patients with chronic neck pain. Spine 2001; 26:788–97 59. Parker GB, Tupling H, Pryor DS. A controlled trial of cervical manipulation for migraine. Aust NZ J Med 1978 8:589–93 60. Nelson CF, Bronfort G, Evans R, Boline P, Goldsmith C, Anderson AV. The efficacy of spinal manipulation, amitriptyline and the combination of both therapies for the prophylaxis of migraine headache. J Manipulative Physiol Ther 1998; 21:511–19 61. Tuchin PJ, Pollard H, Bonello R. A randomized controlled trial of chiropractic spinal manipulative therapy for migraine. J Manipulative Physiol Ther 2000; 23:91–5 62. Boline PD, Kassak K, Bronfort G, Nelson C. Anderson AV. Spinal manipulation vs. amitriptyline for the treatment of chronic tension-type headaches: a randomized clinical trial J Manipulative Physiol Ther 1995; 18: 148–54 63. Bove G, Nilsson N. Spinal manipulation in the treatment of episodic tension-type headache: a randomized controlled trial. J Am Med Assoc 1998; 280:1576–9 64. Nilsson N, Christensen HW, Hartvigsen J. The effect of spinal manipulation in the treatment of cervicogenic headache. J Manipulative Physiol Ther 1997; 20:326–30 65. Davis PT, Hulbert JR, Kassak KM, Meyer JJ. Comparative efficacy of conservative medical and chiropractic treatments for carpal tunnel syndrome: a randomized clinical trial. J Manipulative Physiol Ther 1998; 21:317–26 66. Alcantara J, Steiner DM, Plaugher G, Alcantara J. Chiropractic management of a patient with myasthenia gravis and vertebral subluxations. J Manipulative Physiol Ther 1999; 22:333–40 67. Alcantara J, Heschong R, Plaugher G, Alcantara J. Chiropractic management of a patient with subluxations, low back pain and epileptic seizures. J Manipulative Physiol Ther 1998; 21:410– 18 68. Wells MR, Giantinoto S, D’Agate D, et al. Standard osteopathic manipulative treatment acutely improves gait performance in patients with Parkinson’s disease J Am Osteopath Assoc 1999; 99:92–8 69. Duncan KH, Lewis RC Jr, Racz G, Nordyke MD. Treatment of upper extremity reflex sympathetic dystrophy with joint stiffness using sympatholytic Bier blocks and manipulation. Orthopedics 1988; 11:883–6 70. Toto BJ. Chiropractic correction of congenital muscular torticollis. J Manipulative Physiol Ther 1993; 16:556–9 71. Hulse M. Cervical dysphonia. Folia Phoniatr (Basel) 1991; 43:181–96 154 what are the different doses of viagra principio ativo do viagra generico X X X X X X‡ X Table 2 Meditation trials in Hatha yoga herbal viagra philippines neurological disorder. Hence, he argued that only hysterics were susceptible to hypnosis, since both were based on weak neurological systems. He hypnotized patients in order to induce and study hysterical symptoms, and also made a case for the use of hypnosis as a diagnostic tool: because only hysterics were hypnotizable, one could differentiate hysterically based disorders from those due to structural damage by examining the impact of hypnotic suggestions on the symptoms (e.g. tics). Although many of Charcot’s assumptions about hypnosis were later shown to be wrong, the fact that such a prominent figure in medical science was studying it restored credibility to medical hypnosis. At about the same time that Charcot was promulgating the view of hypnosis as a neurological disorder, two French physicians, Ambroise Liébeault and Hippolyte Bernheim were instead championing the notion of hypnosis as a form of suggestion. Far from the public demonstrations of hypnosis and hysteria at the Salpêtrière, Liébeault and Bernheim were treating the working classes by creating a state of heightened suggestibility followed by direct suggestions for symptom alleviation. Bernheim showed that the entire range of hypnotic phenomena could be elicited in 15% of the normal population and that these responses were not limited to hysterics. The weight of research supported the Bernheim-Liebeault view, and eventually Charcot’s disease-based model lost favor. The work of Charcot and Bernheim was to leave lasting impressions, not least of which was in the development of Sigmund Freud’s theories of the unconscious. Freud studied clinical neurology under Charcot and became interested in the notion of hysteria. During his subsequent visits with Liébeault and Bernheim, he witnessed patients’ amnesia for suggestions given during hypnosis and saw firsthand how these suggestions, though they remained out of conscious awareness, were able to influence behavior. However, Freud later abandoned the use of hypnosis as a reliable method for gaining access to the unconscious. He described this in Studies of Hysteria, written with Josef Breuer in 1895. After a relative lull in the field of hypnosis, a large-scale research program devoted to the topic was launched by Clark Hull at Yale University in the 1930s7. With the contemporaneous development of statistical analysis techniques, Hull was able to take hypnosis research to a new level of sophistication. The therapeutic techniques of hypnosis were further developed during that decade by one of Hull’s students, Milton H.Erickson, who advanced the practice and acceptability of hypnosis in clinical practice. By the 1950s and 1960s, surges in hypnosis research had led to methodologically rigorous practices and ongoing development of standardized tools for assessment of the hypnotic response. la viagra te hace durar mas 13 Headache viagra after 4 hours Complementary therapies in neurology what strengths does viagra come in 282 beli viagra di apotik Neck pain (chronic) viagra koh samui viagra vulnerable + 311 buy genuine viagra no prescription 314 what does taking viagra feel like 490 generic viagra aurochem taking more than one viagra CYP2C9 is the major enzyme for celecoxib hydroxylation in vitro and the CYP2C9*3 allelic variant may be associated with markedly slower metabolism. The pharmacokinetic variations observed for both racemic and S-ibuprofen depend on a CYP2C9 polymorphism. (c) viagra cmi INFLAMMATION AND PAIN tomar viagra diariamente Basic receptor pharmacology does counterfeit viagra work BASIC SCIENCE czy viagra pomaga Ketaminea CPPa Amantidinea Dextromethorphana Phenylcyclidine Nitrous oxide buy viagra discreetly online MEASUREMENT OF PAIN IN ANIMALS buy viagra saskatoon 121 internetapotheke viagra rezeptfrei viagra definition wiki Surgery and trauma are two of the commonest causes of chronic pain. In a survey of 5130 patients attending pain clinics in North Britain, surgery was assessed as contributing to pain in 22.5% of all patients seen. It was second only to degenerative disease in the causation of pain. Surgery was commonly responsible for pain in the abdomen, perineum, anal and genital regions, but was also implicated in lower limb pain. Trauma was the third commonest cause with 18.7% of patients citing this as the cause of their pain. Patients with pain due to trauma tended to be younger and male. Nerves can be injured during medical interventions. Pain following interventions and anaesthesia can result from: direct trauma, peri-operative ischaemia, compression of nerves, scar entrapment and post-injury chronic neuralgia. The nerves most often injured are as follows: (a) (b) (c) (d) Brachial plexus. Palmar cutaneous branch of median nerve. Infra-patellar branch of saphenous nerve. Ilio-inguinal, iliohypogastric, genitofemoral and femoral nerves. (e) Accessory and greater auricular nerves. (f) Long thoracic nerve. is viagra a prescribed drug ANALGESIA IN THE INTENSIVE CARE UNIT 16 does viagra make women horney ANALGESIA IN INTENSIVE CARE UNIT se gaseste viagra in farmacii how safe is viagra for a heart patient Basic principles Neuraxial blocks viagra kya hai does viagra need to be prescribed • • • 45°C for 3 min produces a few minutes of secondary hyperalgesia. 47°C for 7 min produces stable and long-lasting hyperalgesia. viagra commercial truck • • • • viagra auf pflanzlicher basis first time viagra experience The principle of pre-emptive analgesia (i.e. analgesia given prior to the nociceptive stimulus) is one of the 3–4 products that work like viagra taking viagra to thailand and frequency of guanethidine administration and incomplete crossover. Droperidol. Atropine. Amputation of the limb – this resulted in pain relief in only two of 34 patients. Therefore, it should only be considered where there is uncontrolled infection or ischaemia. does viagra help with delayed ejaculation 2 Hurts little bit Pharmacodynamics pfizer teva viagra patent can you take viagra with antibiotics It seems wiser to avoid these hazards, especially in the elderly. Consequently, it is prudent to ensure that iatrogenic pain (e.g. postoperative) is appropriately and adequately controlled, to minimize stress to the patient and optimize recovery. viagra video game Sex steroid effects on non-genomic cellular functions are diverse. Neuroactive chemicals (and their receptors) such as gamma amino butyric acid (GABA), N-methyl-D-aspartate (NMDA), glutamate and neurokinin A can co-localise and/or be modulated by sex steroid hormones, thus providing mechanisms for sex differences within the nervous system. viagra pessaries Women report pain more frequently and of higher intensity than do men. A pain history should be sensitive to sex or genderrelated events. The response to pain may be affected by sex and gender. Analgesic efﬁcacy may be altered by sex and gender. Side effects may differ between the sexes. The classiﬁcation of speciﬁc sex disorders is under scrutiny. THE ROLE OF EVIDENCE IN PAIN MANAGEMENT women eat viagra viagra online danmark 1 In open trials the investigator and the participant know the treatment. 2 In single-blind trials the investigator knows the treatment while the participant does not. If the purpose of the trial demands it, the opposite is also possible. 3 In double-blind trials neither the investigator nor the participants know the treatment. Blinding of the data analysis is often overlooked when doing single-blind and double-blind trials. Controlled clinical trials may encompass both explanatory and pragmatic trials. A controlled clinical trial aims to make the patient’s experience a clinical setting where everything is as similar as possible, with the exception of the variable to be tested. The gold standard in clinical trial methodology is the doubleblind, randomised, controlled clinical trial (RCCT). Both complete blindness, and randomisation, is essential to minimise the possibility of introducing bias into the trial results compromising their interpretation. viagra sous prescription viagra for sale gold coast T R E AT M E N T O F PA I N Thus a number of key psychological factors have been identiﬁed: A belief that back pain is harmful or severely disabling. Fear-avoidance behaviour patterns, with reduced activity levels. Tendency to low mood and withdrawal from social interaction. Expectation that passive treatments rather than active participation will help. viagra for women philippines viagra keeps flowers from wilting Many therapies and approaches that physiotherapists use, in particular the ‘complementary therapies’ (but also many of the various manual therapies) can be associated with what Evans (2003) calls ‘crackpot theories’. He suggests that these theories promote a continuing schism between orthodox and complementary approaches. Unfortunately, doing away with the crackpot theories that provide alternative therapies with some of their appeal might actually rob them of their effectiveness, by destroying the vital belief that enables them to mobilise the placebo response. • Passive modalities may help individual patients through pain ﬂare-ups. Provided patients remain employed and active or quickly return to normal daily routines their use is warranted. But, the patient must always have a role to play, with care employed to prevent unnecessary dependence on therapy. When used strategically, selective treatment (active or passive) of identiﬁed physical impairments can provide direction to speciﬁc selfmanagement exercises. viagra tablets for sale australia The pulse duration or width is the length of time each pulse lasts, usually in microseconds (s). The common clinically useful range of adjustment is 100–200 s. T R E AT M E N T O F PA I N lansoprazole viagra miss viagra video Duration and frequency of stimulation natural viagra recipe It is tempting to think of neurosurgery for the treatment of chronic pain as being a matter of the dramatic interruption or interference with some established ‘pain pathway’. In fact, it has a great deal more to offer, both by conventional treatment of the cause of the pain (e.g. trigeminal neuralgia (TGN)) and in the area of palliative manoeuvres in malignant situations. When surgery is appropriate it can provide satisfactory relief of pain without reducing the quality of life that may result from long-term medication use. When considering surgery for the treatment of chronic pain, the most important criteria turn out to be the quality of life and its expected duration, resulting from the disease process causing the pain. Pain due to uncontrolled malignancy, with reduced physical capacity and life expectation, will demand prompt treatment, with perhaps greater acceptance of surgical risk than, will that of a sufferer from a protracted but non-life-threatening condition. Patients of advanced age might also, on the same logic, demand expedient surgery, acknowledging the risk. availability of viagra in hyderabad In the CNS it has anxiolytic actions similar to diazepam and is also expressed by dopaminergic neurones in the midbrain. There have been suggestions that abnormal Hepatic metabolism produces norpethidine (exclusively renally excreted), which can cause central excitation and convulsions. However, long-term administration of high doses is required to produce signiﬁcant amounts of norpethidine. does viagra cause cancer viagra and cold medicine drugs act synergistically, allowing the use of lower concentrations of local anaesthetic, reducing the incidence of motor block. Neuraxial opioids are capable of causing all the unwanted effects observed when administered via other routes. Pruritus and retention of urine are particular problems. These effects may be reversed by small doses of naloxone without signiﬁcant loss of analgesia. ␣2 adrenergic receptor agonists act synergistically with opioid and local anaesthetic agents and there viagra for sports enhancement Underactivity/overactivity is a behavioural pattern that is often observed in the daily activity proﬁles of chronic pain sufferers. Where movement or activity acts as a trigger for increased pain, individuals tend to engage in prolonged periods of inactivity in order to keep discomfort at bay. However, these inactive periods are interspersed with attempts to suddenly regain normal levels of activity. This may relate to: nox bitkisel viagra viagra posologia consigliata Effect of psychiatric disorders in chronic painful conditions Further reading quel est le prix du viagra en pharmacie 29 whats the side effect of viagra como fabricar viagra casero Shaw Concussion may cause a gradient of clinical syndromes that may or may not involve LOC; resolution of the clinical and cognitive symptoms typically follows a sequential course. Concussion is most often associated with normal results on conventional neuroimaging studies (Aubry, 2002). viagra generika nebenwirkungen natural food substitute for viagra .,-,:^—.^>. viagra smallest dose P...-K viagra wie lange steht er Ried, S.E., Tarkington, J.A., Epstein, H.M., and O'Dea T.J. (1971). Brain tolerance to impact in football. Surgery Gynecology and Obstetrics, 133(6), 929-936. Morrison, W.E. (1983). Calibration and utilization of an instrumental football helmet for the monitoring of impact acceleration. Ph..D. unpublished thesis, PSU, Pellman, E.J., Viano, D.C., Tucker, A.M., Casson, I.R., & Waeckerle, J.F. (2003). Concussion in professional football: Reconstruction of game impacts and injuries. Neurosurgery, 53(4), 799-814. Newman, J., Beusenberg, M., Fournier, E., Shewchenko, N., Welbourne, E., & Withnall, C. (2000). A new biomechanical assessment of mild traumatic brain injury, part 11: Results and conclusions. Paper presented at the International Research Council on the Biomechanics of Impact, Montpellier, France. Newman, J., Beusenberg, M., Fournier, E., Shewchenko, N., Withnall, C, King, A., et al. (1999). A new biomechanical assessment of mild traumatic brain injury, part I: Methodology. Paper presented at the International Research Council on the Biomechanics of Impact, Sitges, Spain. Newman, J., Shewchenko, N., & Welbourne, E. (2000). A new biomechanical head injury assessment function: The maximum power index. Paper presented at the 44th Stapp Car Crash Conference, Atlanta, GA, USA. composition chimique du viagra Robert Cantu Measuring Change on the Trailmaking Tests best viagra in melbourne Football Men's Soccer Women's Soccer Men's Ice Hockey Men's Basketball Women's Basketball Men's Lacrosse Women's Lacrosse Men's Rugby Women's Rugby Wrestling viagra nhs direct Gouvier, W. D., Cubic, B., Jones, G., Brantley, P., and Cutlip, Q. (1992). Postconcussion symptoms and daily stress in normal and head-injured college populations. Archives of Clinical Neuropsychology, 7, 193-211. Guskiewicz, K. M., Riemann, B. L., Perrin, D. H., and Nashner, L. M. (1997). Alternative approaches to the assessment of mild head injury in athletes. Medical Science and Sports Exercise, 29(Suppl. 7), 5213-5221. Zasler, N. (1999). Medical aspects. In S. A. a. M. Raskin, C. A. (Ed.), Neuropsychological management of mild traumatic brain injury (pp. 23-38). New York: Oxford University Press. Echemendia, R. J., and Julian, L.J. (2001). Mild traumatic brain injury in sports: Neuropsychology's contribution to a developing field Neuropsychology Review, 77(2), 69-88. Lovell, M. R., Iverson, G. L., Collins, M. W., McKeag, D., and Maroon, J. C. (1999). Does loss of consciousness predict neuropsychological decrements after concussion? Clinical Journal of Sports Medicine, 9(4), 193-198. Cantu, R. C. (1998). Second-impact syndrome. Clinics in Sports Medicine: Neurologic Athletic Head and Neck Injuries, 17(\), 37-44. Chelune, G. J., Naugle, R.I., Luders, H., Sedlak, J., and Awad, LA. (1993). Individual change after epilepsy surgery: Practice effects and base-rate information. Neuropsychology, 7(0,41-52. Iverson, G. L. and Gaetz, M. (2004). Practical Considerations for Interpreting Change Following Brain Injury. In M. R. Lovell, Collins, M.W., Echemendia, R.J., and Barth, J.T. (Ed.), Traumatic Brain Injury in Sports (Vol. 1, pp. 323-356). New York: Taylor and Francis. Mackin, R. S., Sabsevitz, D.S., Julian, L., Junco, R., Dwyer, M. and Echemendia, R.J. (1997). Stability Coefficients and Practice Effects of Neuropsychological Tests in College Athletes: Preliminary Findings. Paper presented at the Sports Related and Nervous System Injuries Orlando, Florida. Barth, J. T., Alves, W.M., Ryan, T.V., Macciocchi, S.N., Rimel, R.W., Jane, J.A., and Nelson, W.E. (1989). Mild head injury in sports: Neuropsychological sequelae and recovery of function. In H. E. H. Levin, and A. Benton (Ed.), Mild Head Injury (pp. 257-275). New York, NY: Oxford University Press. McCrea, M., Barr, W.B., Guskiewicz, K., Randolph, C.R., Marshall, S.W., Cantu, R., Onate J.A., and Kelly, J.P. (2005). Standard regression-based methods for measuring recovery after sport-related concussion. Journal of the International Neuropsychological Society, 77,58-69. Dikmen, S. S., Heaton, R.K., Grant, I., and Temkin, N.R. (1999). Test-retest reliability and practice effects of Expanded Halstead-Reitan Neuropsychological Test Battery. Journal of the International Neuropsychological Society, 5(4), 346-356. Jacobson, N. S., and Truax., P. (1991). Clinical significance: A statistical approach to defining meaningful change in psychotherapy research. Journal of Consulting and Clinical Psychology, 59(1), 12-19. Barr, W. B., and McCrea, M. (2001). Sensitivity and specificity of standardized neurocognitive testing immediately following sports concussion Journal of the International Neuropsychological Society, 7(6), 693-702. Hinton-Bayre, A. D., Geffen, G.M., Geffen, L.B., McFarland, K.A., and Friis, P. (1999). Concussion in contact sports: Reliable change indices of impairment and recovery Journal of Clinical and Experimental Neuropsychology, 27(1), 70-86. Iverson, G. L., Lovell, M.R., and Collins, M.W. (2003). Interpreting Change on ImPACT Following Sport Concussion. Clinical Neuropsychologist, 77(4), 460-467. Brandt, J., and Benedict, R.H.B. (2001). Hopkins Verbal Learning Test-Revised professional manual Odessa, FL: Psychological Assessment Resources. durex presents new viagra condoms do women like viagra men 169 do you need a prescription for viagra in costa rica 181 Miller, B.L. (1991). A review of chemical issues in IH NMR spectroscopy: N-acetyl-Laspartate, creatine and choline. NMR Biomedicine, 4(2), 47-52. Moreno-Torres, A., Martinez-Perez, I., Baquero, M., Campistol, J., Capdevila, A., Arus, C, Pujol, J. (2004). Taurine detection by proton magnetic resonance spectroscopy in meduUoblastoma: Contribution to noninvasive differential diagnosis with cerebellar astrocytomas. Neurosurgery, 55, 824-829. Ordidge, R.J., Connelly, A., B., Lohman, J.A. (1986). Image-selected in-vivo spectroscopy (ISIS). A new technique for spatially selective NMR spectroscopy. Journal of Magnetic Resonance, 66, 283-294. Panigrahy, A., Krieger, M., Gonzalez-Gomez I,, Liu. X., McComb, J., Finlay, J., Nelson, M., Gilles, F., Bliiml. S. (2005). Quantitative short echo time IH magnetic resonance spectroscopy of untreated pediatric brain tumors: Pre-operative diagnosis and characterization. AJNR American Journal Neuroradiology, in press. Pfefferbaum, A., Adalsteinsson, E., Spielman, D., Sullivan, E.V., Lim, K.O. (1999). In vivo spectroscopic quantification of the N-acetyl moiety, creatine, and choline from large volumes of brain gray and white matter: effects of normal aging. Magnetic Resonance Medicine, 41(2), 276-284. Provencher, S.W. (1993). Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magnetic Resonance Medicine, 30(6), 672-679. Purcell, E.M., Torrey, H.C., Pound, R.V. (1946). Resonance absorption by nuclear magnetic moments in a solid. Physical Review, 69, 37-38. Ricci, R., Barbarella, G., Musi, P., Boldrini, P., Trevisan, C, Basaglia, N. (1997). Localised proton MR spectroscopy of brain metabolism changes in vegetative patients. Neuroradiology, 39(5), 313-319. Ross, B.D., Ernst, T., Kreis, R., Haseler, L.J., Bayer, S., Danielsen, E., Bluml, S., Shonk, T., Mandigo, J.C, Caton, W., Clark, C , Jensen, S.W., Lehman, N.L., Arcinue, E., Pudenz, R., Shelden, C.H. (1998). IH MRS in acute traumatic brain injury. Journal of Magnetic Resonance Imaging 8(4), 829-840. Schuhmann, M.U., Stiller, D., Skardelly, M., Thomas, S., Samii, M., Brinker, T. (2002). Long-time in-vivo metabolic monitoring following experimental brain contusion using proton magnetic resonance spectroscopy. Acta Neurochir Supplement, 81, 209-212. Seymour, K.J., Bluml, S., Sutherling, J., Sutherling, W., Ross, B.D. (1999). Identification of cerebral acetone by IH-MRS in patients with epilepsy controlled by ketogenic diet. Magma, 8(1), 33-42. Shutter, L., Tong, K.A., Holshouser, B.A. (2004). Proton MRS in acute traumatic brain injury: role for glutamate/glutamine and choline for outcome prediction. Journal of Neurotrauma, 21(12), 1693-1705. Signoretti, S., Marmarou, A., Tavazzi, B., Lazzarino, G., Beaumont, A., Vagnozzi, R. (2001). N-Acetylaspartate reduction as a measure of injury severity and mitochondrial dysfunction following diffuse traumatic brain injury. Journal of Neurotrauma, 18(10), 977-991. Tallan, H.H. (1957). Studies on the distribution of N-acetyl-L-aspartic acid in brain. Journal of Biological Chemistry,224(l), 41-45. Videen, J.S. (1995). Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. Journal of Clinical Investigation, 95(2), 788793. is viagra safe for heart patients can i take 150mg of viagra Recording and Patterns of EEG Activity REFERENCES does viagra work for women too EEG Fundamentals pastilla china viagra can you get high off of viagra As the number of recording channels decreases, then the ability of quantitative EEG measures to detect the consequences of rapid acceleration/deceleration forces diminishes. Nonetheless, discriminant viagra laboratorio chile X.-" At the Vienna conference it was recognized that post-concussion neuroimaging, such as CT and MRI are usually normal (Aubry et al., 2002). Although there are no clear guidelines of when to obtain neuroimaging studies after a concussion, the Prague guidelines recommend consideration of neuroimaging if there is a prolonged duration of symptoms, development of worsening post-concussive symptoms, or a focal neurological deficit that might indicate an intra-cerebral hematoma or other structural lesion (McCrory et al., 2005). Current research is being conducted on the validity of PET scans, SPECT scans, or functional MRI modalities for postconcussion assessment (Chen, 2004). On going studies are also looking at the role of EEG in post-concussion evaluation (Slobounov et al., 2005). how many hours viagra last 388 viagra age 20 ^^Scientific Approach" to Helmetry viagra coffee mug viagra bradycardia These animals are used in laboratory research to help develop an AIDs vaccine for humans. Figure 1A is viagra allowed in islam viagra response time • Proteins help form structures (e.g., muscles and membranes) and function as enzymes. 31 • Proteins are polymers of amino acids. 32 viagra and prozac together © The McGraw−Hill Companies, 2001 Some of the polymers in starch are long chains of up to 4,000 glucose units. Others are branched, as is glycogen (Fig. 2.18). Starch has fewer side branches, or chains of glucose that branch off from the main chain, than does glycogen. Starch is the storage form of glucose inside plant cells. Flour, which we usually acquire by grinding wheat and use to bake bread and rolls, is high in starch. Glycogen is the storage form of glucose in humans. Figure 2.18 includes a micrograph of glycogen granules inside the liver. After we eat starchy foods like bread, potatoes, and cake, starch is hydrolyzed to glucose. Then the bloodstream carries excess glucose to the liver where it is stored as glycogen. In between eating, the liver releases glucose so that the blood glucose concentration is always about 0.1%. As mentioned in chapter 4, this function of the liver is an example of homeostasis. ಆ is there a legal generic viagra is there an age limit for viagra Human Organization viagra dosaggio consigliato Chapter 2 H H naturens egen viagra comprar viagra de confianza 35 buy individual viagra pills Mader: Human Biology, Seventh Edition farmacia san marino viagra 3.1 Cell Size Movement of cell mens health natural viagra nail root viagra generika wikipedia viagra price in india 2012 I. Human Organization 4.4 Homeostasis why do young people take viagra blue magic viagra Mader: Human Biology, Seventh Edition 5.5 Nutrition es seguro comprar viagra por internet Food guide pyramid: A guide to daily food choices. buy genuine viagra online uk why does viagra sometimes not work © The McGraw−Hill Companies, 2001 Mader: Human Biology, Seventh Edition generic viagra switzerland Table 6.2 Blood Plasma Solutes viagra natural peruano viagra 50 gr 119 next generation viagra The rhythmical contraction of the atria and ventricles is due to the intrinsic conduction system of the heart. Nodal tissue, which has both muscular and nervous characteristics, is a unique type of cardiac muscle located in two regions of the heart. The SA (sinoatrial) node is located in the upper dorsal wall of the right atrium; the AV (atrioventricular) node is located in the base of the right atrium very near the septum (Fig. 7.7a). The SA node initiates the heartbeat and automatically sends out an excitation impulse every 0.85 second; this causes the atria to contract. When impulses reach the AV node, there is a slight delay that allows the atria to ﬁnish their contraction before the ventricles begin their contraction. The signal for the ventricles to contract travels from the AV node through the two branches of the atrioventricular bundle (AV bundle) before reaching the numerous and smaller Purkinje ﬁbers. The AV bundle, its branches, and the Purkinje ﬁbers consist of specialized cardiac muscle fibers that efﬁciently cause the ventricles to contract. The SA node is called the pacemaker because it usually keeps the heartbeat regular. If the SA node fails to work properly, the heart still beats due to impulses generated by the AV node. But the beat is slower (40 to 60 beats per inferior minute). To correct this condition, vena cava it is possible to implant an artiﬁcial pacemaker, which automatically gives an electrical stimulus to the heart every 0.85 second. The intrinsic conduction system of the heart consists of the SA node, the AV node, the atrioventricular bundle, and the Purkinje ﬁbers. can you od on viagra Vessels and Pressure Essential Study Partner The most common type of antibody (IgG) is a Y-shaped protein molecule with two arms. Each arm has a “heavy” (long) polypeptide chain and a “light” (short) polypeptide chain. These chains have constant regions, where the sequence of amino acids is set, and variable regions, where the sequence of amino acids varies between antibodies (Fig. 8.7). The constant regions are not identical among all the antibodies. Instead, they are almost the same within different classes of antibodies. The variable regions form an antigen-binding site, and their shape is speciﬁc to a particular antigen. 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The amount of heteronymous facilitation of the H reﬂex, produced by femoral stimulation at 4 MT (ISI 0.4 ms after the onset of facilitation), and expressed as a percentage of M max , for 28 healthy control subjects, (a) 17 paraplegic patients, ((b) ‘Para’, essentially traumatic) and 18 hemiplegic patients ((c) ‘Hemi’, affected side). Each horizontal bar represents one subject and the hatched columns show the mean and 1 SEM in the three populations. Modiﬁed from Faist et al. (1994), with permission. (iv) Complete disappearance of D1 inhibition of the FCR H reﬂex was observed in two patients with tetraplegia due to a spinal cord lesion at C5–C6 (Aymard et al., 2000). Whatever the nature of the lesion, no correlation has been found between the amount of reﬂex facili- tation and the severity of spasticity. Mechanisms underlying changes in presynaptic inhibition in spastics Cerebral lesions The different effects on presynaptic inhibition of Ia afferents of thelower andupper limbs after unilateral corticospinal lesion in patients with hemiplegia are in keeping with the normal pattern of corticospinal control on PAD interneurones in the lumbar and cervical enlargements: depression of lumbar and 370 Presynaptic inhibition of Ia terminals facilitation of cervical PAD interneurones (pp. 350– 3). If the corticospinal control was normally exerted tonically, corticospinal lesions would be expected to produce a decrease in presynaptic inhibition of Ia terminals on FCR and an increase in presynaptic inhibition of Ia terminals on soleus. The former has been found consistently, but the latter has not been observed. This might reﬂect a normal tonic corti- cospinal control of PAD interneurones in the cervi- cal spinal cord, but not the lumbar cord. This would imply that the organisation of the cortical control of presynaptic inhibition in the upper and lower limbs might bedifferent not onlyinitssign(dominant facil- itation versus depression) but also in its character (tonic or not). However, this view is not supported by evidence from parkinsonian patients (p. 371). Spinal cord lesions Whatever the lesion in the spinal cord, presynap- tic inhibition is decreased on Ia terminals of the lower limb. This cannot be due to the interruption of the corticospinal tract (which, if anything, would produce increased presynaptic inhibition of Ia ter- minals in the lumbar enlargement, see above). It therefore probably results frominterruptionof other descending pathways which help maintain a tonic level of presynaptic inhibition of Ia terminals in nor- mal subjects under resting conditions (e.g. pathway  in Fig. 8.1(a) mediating descending suppression of inhibitory interneurones transmitting cutaneous inhibition of ﬁrst-order PAD interneurones). Changes in presynaptic inhibition and pathophysiology of spasticity Several ﬁndings suggest that the changes in pre- synaptic inhibition of Ia terminals observed in spas- tic patients may play little pathophysiological role in the motor disability or spasticity as assessed under resting conditions (cf. Aymard et al., 2000). (i) There is no correlation between the extent to which presynaptic inhibition is decreased and the severity of spasticity or motor impairment in the corresponding muscle(s). (ii) Although the Achilles tendon jerk was clearly exaggerated on the affected side of most hemiplegic patients, there was no evidence for decreased pre- synaptic inhibition of Ia terminals on soleus, even in patients with a lesion in the territory of the anterior cerebral artery. (iii) Presynaptic inhibition of FCR Ia afferents is also reduced, although to a lesser extent, on the ‘unaffected’ non-spastic upper limb of patients with hemiplegia in the absence of any other evidence to suggest spasticity or motor impairment. Changes in presynaptic inhibition during motor tasks in spastic patients A decrease in presynaptic inhibition of Ia terminals may not be responsible for the stretch reﬂex exag- geration which characterises spasticity measured at rest, but thelackof control of PADinterneuronesdur- ing motor tasks could still contribute to the motor disability of these patients. This has been examined during both voluntary movement and gait. Changes in presynaptic inhibition during voluntary contraction In spastic multiple sclerosis patients, presynaptic inhibition of homonymous soleus Ia terminals was decreased at rest and not reinforced at the onset of voluntary ankle dorsiﬂexion (Morita et al., 2001). Nevertheless, given the low sensitivity of the stretch reﬂex to presynaptic inhibition of Ia terminals (cf. pp. 354–5), it is probable that the absence of increase in presynaptic inhibition of antagonistic Ia ter- minals is not the main mechanism responsible for the occurrence of a stretch reﬂex in the antagonistic muscle during voluntary movement (see Chapter 12, pp. 574–5). Changes in presynaptic inhibition during gait The absence of the normal modulation of the pre- synaptic inhibition of Ia terminals could contribute to the stiff spastic gait of patients with spinal cord lesions. Modulation of the soleus Hreﬂex of patients Studies in patients 371 with spinal cord injuries has been examined during treadmill walking (Yang, Stein & James, 1991). The most commonpatternobservedwasalackof Hreﬂex modulation throughout the stance phase and slight depressionof the reﬂex inthe swingphase, consider- ably less modulation than in normal subjects under comparable walking conditions (see Fig. 8.14). The responsible abnormality is probably lack of mod- ulation of presynaptic inhibition of soleus Ia ter- minals. Innormal subjects, there is a profoundmod- ulationof thequadriceps tendonjerkthroughout the step cycle, with the reﬂex peaking in early stance andthendecreasing progressively until almost abol- ished during the swing phase. Reﬂex modulation throughout the step cycle is reduced on the affected side of hemiplegic patients, and almost completely abolished in patients with spinal lesions (Faist et al., 1999). The authors argued that these dif- ferences reﬂect differences in the modulation of presynaptic inhibition of Ia terminals on quadriceps motoneurones. Changes in presynaptic inhibition in Parkinson’s disease The depression of the soleus H reﬂex by prolonged homonymous vibrationonthe Achilles tendonis not modiﬁed withrespect to normal subjects (Delwaide, Pepin&MaertensdeNoordhout, 1993), but homony- mous vibration produces complex effects which are difﬁcult to interpret (see Chapter 12, p. 587). Others studies indicate that presynaptic inhibition is decreased in Parkinson’s disease. Upper limb Radial-induced D1 inhibition of the FCR H reﬂex is decreased in patients with Parkinson’s disease (Lelli, Panizza&Hallett, 1991). Theﬁndingof similar results for bothsides inasymmetrical patients indicates that the abnormality does not correlate with the degree of rigidity. However, inconsistent results have been reported. Only the late inhibition at ISIs of 70–100 ms was found to be reduced in the patients explored by Tsai, Chen & Lu (1997), and Nakashima et al. (1994) also found no reductionof the radial-induced D1 inhibition of the FCR H reﬂex at ISIs around 20 ms. Lower limb (i) Inhibition of the soleus H reﬂex by a het- eronymous tendon tap is reduced in parkinsonian patients, all of whom were taking dopaminergic medication(Roberts et al., 1994). Nosigniﬁcant rela- tionship has been found between the amount of presynaptic inhibition so assessed and various clin- ical variables: rigidity in limb studied, Webster rat- ing, duration of disease, duration of dopaminergic treatment. (ii) The soleus H reﬂex facilitation induced by femoral stimulation is signiﬁcantly increased in patients with Parkinson’s disease (Morita et al., 2000b). There was no correlation between the decreaseinpresynapticinhibitionandgradeof rigid- ity or disease severity on the Hoehn and Yahr scale, but the decrease in presynaptic inhibition was sig- niﬁcantly correlated with the degree of bradykin- esia and the time required to walk 10 m. Of particu- lar interest was the ﬁnding that, in those patients who were responsive to L-dopa and were exam- ined on and off the medication, the amount of presynaptic inhibition increased with L-dopa along with improvement in both bradykinesia and walk- ing speed. This suggests that a descending pathway controls tonic presynaptic inhibition of Ia terminals through a dopa-responsive mechanism (though it does not imply that the descending pathway itself is dopaminergic). Changes in presynaptic inhibition of Ia terminals in patients with dystonia Changes in radial-induced D1 inhibition of the FCR Hreﬂex Decreased presynaptic inhibition of FCR Ia terminals The co-contraction of agonists and antagonists typ- ical of dystonia suggests a breakdown of the normal 372 Presynaptic inhibition of Ia terminals pattern of reciprocal innervation between opposing muscles. Radial-induced inhibition of the FCR H reﬂex has been investigated in patients with differ- ent types of dystonia: simple occupational cramp (i.e. a task-speciﬁc focal action dystonia), dys- tonic occupational cramp (the focal action dysto- nia was also evident in other manual acts than writing), blepharospasm, spasmodic torticollis, gen- eralised dystonia and symptomatic hemidystonia related to lesions of the contralateral basal ganglia (Panizza, Hallett & Cohen, 1987; Panizza et al., 1990; Nakashimaet al., 1989). Theconsistent ﬁndingis that thesecondphaseof theradial-inducedD1inhibition of the FCR Hreﬂex was decreased in all types of dys- tonia. Themoreseverethedystoniathemoremarked was the decrease in presynaptic inhibition. An inter- esting ﬁnding of these studies is that disynaptic non-reciprocal group I inhibition was not depressed in the patients studied by the Queen Square group (Nakashimaet al., 1989; Huanget al., 2004). This sug- gests that the CNS dysfunction underlying dystonia causes a speciﬁc change inthe descending control of PADinterneurones. It is alsointerestingthat asimilar decrease in radial-induced D1 inhibition of the FCR Hreﬂex was alsoobservedinthe unaffected‘normal’ armof patients with writer’s cramp (Chen, Tsai &Lu, 1995). This is in keeping with the ﬁnding that abnor- malities of the hand representation in sensory cor- tex are more obvious in the hemisphere driving the non-dystonic limb, even though they are correlated to the severity of the dystonic limb motor impair- ment (Meunier et al., 2001). Differential effect of repetitive TMS (rTMS) on the second and late phases of radial-induced depression of the FCR H reﬂex The second phase and the late phase of the radial- induced inhibition of the FCR H reﬂex (cf. p. 344) are decreased in patients with generalised dysto- nia associated with the DYT1 gene mutation. After 20 minutes of 1 Hz rTMS over the premotor area, a signiﬁcant increase in the late inhibition occurred whereas the second phase was not modiﬁed. This result supports the hypothesis that, while the second phase is due to presynaptic inhibition of Ia terminals, the late phase may involve long-loop inhibitory connections to the brainstem (spino- bulbo-spinal) or even the cerebral cortex (Huang et al., 2004). Possible decrease in group III-induced presynaptic inhibition of ECR Ia afferents In normal subjects, electrical stimulation over the ECRtendonelicits a transient inhibitionof the ongo- ing ECR EMG activity. It has been argued that this suppression is due to slowly conducting afferents from the tendon (possibly group III) activating pre- synapticinhibitionof Iaterminals (Priori et al., 1998). This suppression is not modiﬁed in patients with simple occupational dystonia, but is decreased in patients with generalised dystonia (Lorenzano et al., 2000). The latter ﬁnding could reﬂect decreased presynaptic inhibition of Ia terminals, but this con- clusionneeds to be conﬁrmed by techniques assess- ing presynaptic inhibition more speciﬁcally. Conclusions Role of changes in presynaptic inhibition of Ia terminals in normal motor control Changes in presynaptic inhibition of Ia terminals may have little effect onthe reﬂex response toabrupt stretch. Instead, the role of changes in the presynap- tic gating during motor tasks probably lies in the modulation of physiological feedback from primary endings, i.e. in modulation of natural background Ia inputs andchanges indischargeof relativelylowrate. So far, the changes in the gating of the Ia inﬂow dur- ing movement appear to be signiﬁcant only in the lower limb. During ﬂexion-extension movements, the focused corticospinal drive produces a decrease in presy- naptic inhibition of Ia terminals to motoneurones R´ esum´ e 373 responsible for the movement. This ensures that the full feedback excitatory support from primary mus- cle spindle endings is available to active motoneu- rones. Inparallel, presynapticinhibitionis enhanced onheteronymous Ia terminals oninactive motoneu- rone pools. The corticospinal control of presynap- tic inhibition selectively ‘opening’ Ia transmission to motoneurones voluntarily activated, while ‘clos- ing’ transmission to motoneurones of relaxed mus- cle(s), increases motor contrast and contributes to the selective activation of muscles in discrete movements. Duringvoluntaryco-contractionof ankleﬂexors and extensors and during active standing, presynaptic inhibition of Ia terminals of ankle muscles is increased. This probably contributes to the depres- sion of reciprocal Ia inhibition required for co- contractions involving antagonistic muscles. Thedecreaseinpresynapticinhibitionof quadriceps Ia terminals during active standing and in the early part of the stance phase of gait ensures that excita- tory Ia feedback is available to provide a safety factor to the quadriceps contraction, whenit must support much of the body weight. At the end of the stance phase of gait, presynaptic inhibition of soleus Ia ter- minals is markedly increased, to help limit the acti- vationof ankleextensor motoneurones andallowthe body to move forward. Changes in presynaptic inhibition and pathophysiology of movement disorders Spasticity Contrary to what has long been claimed, presynap- tic inhibition of Ia terminals is not modiﬁed in the lower limb of hemiplegic patients at rest. There is a decrease in presynaptic inhibition of Ia terminals in patients with spinal cord lesions, but there is no correlation between the extent to which presy- naptic inhibition is decreased and the severity of spasticity or motor impairment in the correspond- ing muscle(s). However, the absence of modulation of presynapticinhibitionof Iaterminalstosoleusand quadriceps motoneurones probably contributes to the stiff gait of these patients. Parkinson’s disease Presynaptic inhibitionof Ia terminals is decreasedin patients with Parkinson’s disease, and this decrease is related to the severity of gait disturbance. Dystonia The CNS dysfunction underlying dystonia causes a decrease in presynaptic inhibition of forearm Ia terminals. R´ esum´ e Background fromanimal experiments Presynaptic inhibition of Ia terminals is accom- panied by primary afferent depolarisation (PAD) and reduces the size of monosynaptic Ia EPSPs in motoneurones without change in the motoneu- rone membrane or its conductance (i.e. without an IPSP in motoneurones). Presynaptic inhibition is a potent mechanism since, in the acute spinal cat, it can completely suppress the monosynaptic reﬂex. It has a long central delay (∼5 ms) and a long dura- tion (300–400 ms). The shortest pathway mediating presynaptic inhibition of Ia terminals has two inter- posed interneurones (referred to as PAD interneu- rones), the last-order being GABA A -ergic. First-order PAD interneurones are excited by Ib and (to a lesser extent) Ia afferents mainly from ﬂexor muscles, and also by projections from vestibular nuclei. They are inhibited through inhibitory interneurones onto whichcutaneous andcorticospinal inputs converge. The dominant effect of corticospinal volleys on PAD interneurones is depression, and this normally 374 Presynaptic inhibition of Ia terminals masks anopposite facilitatory effect. Last-order PAD interneurones are powerfully inhibited from differ- ent reticulospinal pathways. Methodology Discrepancy between the variations in the on-going EMGand those in the Hreﬂex It was reasoned that changes in presynaptic inhi- bition of Ia terminals should affect the H reﬂex more than the on-going EMG. However, discrepan- cies betweentheHreﬂex andtheon-goingEMGmay also result from other factors. Activating PADinterneurones by a conditioning volley to assess their excitability Underlying principle PAD interneurones mediating presynaptic inhibi- tion of Ia afferents responsible for the afferent vol- ley of the test H reﬂex are activated by a con- ditioning volley. The resulting reﬂex depression depends on the excitability of PAD interneurones, andthegreater their excitability, thegreater thereﬂex depression. Prolonged vibration of the homonymous tendon is a ﬂawed technique Application of vibration to the Achilles tendon pro- duces marked depression of the soleus H reﬂex, which reﬂects a presynaptic mechanism. It was long accepted that this mechanism was presynap- tic inhibition with PAD. However, when the con- ditioning vibration is applied on the homonymous tendon, other mechanisms contribute to the reﬂex depression: post-activation depression, evoked by repetitive activation of the Ia ﬁbre-motoneurone synapse (see Chapter 2, pp. 96–9); and elevated threshold of the Ia afferents responsible for the H reﬂex, such that a greater current is required to pro- duce the same afferent volley. Accordingly, the H reﬂex suppressionwill be causedby a number of fac- tors, and it cannot be used to estimate presynaptic inhibition of Ia terminals with PAD. Presynaptic inhibition evoked by a heteronymous group I volley Toeliminatetheproblemsassociatedwithprolonged vibration of the homonymous tendon, brief vibra- tion (train of three shocks or single tap) is applied to the tendon of a heteronymous muscle. The resulting Ia volley activates PAD interneurones and evokes a long-lasting (200–300 ms) depression of the H reﬂex due to presynaptic inhibitionof Ia afferents. Adiffer- ent technique measures the ‘D1’ inhibition of the H reﬂex elicited by an electrical volley to group I afferents in the nerve supplying muscles antagonis- tic to the motoneurone pool tested. A radial volley depresses the FCR H reﬂex at ISIs of 5–20 ms due to presynaptic inhibition of FCR Ia terminals. Similarly a stimulus to the common peroneal nerve elicits a long lasting inhibition of the H reﬂex of soleus with twophases, ‘D1’ (5–30 ms) and‘D2’ (70–200 ms), due to presynaptic inhibition of soleus Ia terminals. Limitations The amplitude of the test reﬂex is the net result of presynaptic inhibition and of a late post-synaptic facilitation; a change in the reﬂex depression in a given situation could reﬂect a change in the recruit- ment gain in the motoneurone pool; a more seri- ous drawback is that decreased vibratory or D1/D2 inhibition may reﬂect decreased excitability of PAD interneurones, but could also result from increased excitability, if there is occlusion between the condi- tioning volley and ‘natural’ excitatory inputs. Routine studies Vibration(3 shocks at 200 Hz) or single tapis applied to the tendon of the tibialis anterior or the biceps femoris 40–60 ms before the test stimulus eliciting the soleus H reﬂex. D1 inhibition of the soleus H R´ esum´ e 375 reﬂex is evoked by a train of 3 shocks (at 300 Hz, 1.2 MT) to the common peroneal nerve with the ﬁrst shock 21 ms before the stimulus eliciting the H reﬂex. D1 inhibition of the FCR H reﬂex is elicited by a radial volley (single shock, ≤1 MT) 10–20 ms before the stimulus evoking the FCR H reﬂex. Assessing monosynaptic Ia facilitation of the Hreﬂex This technique measures the on-going presynap- tic inhibition exerted on Ia terminals of the condi- tioning volley. Thus, the test reﬂex is facilitated by a monosynaptic Ia volley, generally heteronymous. During its ﬁrst 0.6 ms the reﬂex facilitation depends only on the size of the conditioning Ia EPSP. A con- stant conditioning stimulus should elicit a constant degree of reﬂex facilitation, unless there is a change in presynaptic inhibition of Ia afferents mediating the conditioning volley. The larger the reﬂex facili- tation, the smaller the presynaptic inhibition. How- ever, changes in the amount of reﬂex facilitation can also be due to a change in the recruitment gain of the motoneurone pool (see pp. 18–20). The method requires that the conditioning heteronymous volley elicits a sizeable facilitationof the test reﬂex. Inprac- tice this is usually the case for the femoral-induced facilitation of the soleus H reﬂex and for the facil- itation of the FCR H reﬂex elicited by stimulation of Ia afferents from the intrinsic hand muscles. The earliest conditioning-test interval (I 0 ) at which it is possible to elicit heteronymous Ia facilitation of the test reﬂex is ﬁrst established using 0.1–0.2 ms steps, and the ISI is then set to be 0.4–0.6 ms later than I 0 . Howto eliminate changes in the recruitment gain in the motoneurone pool (i) The only way toexclude withcertainty a change in the recruitment gain in the motoneurone pool is to conﬁrm results obtained with the compound H reﬂexinsinglemotorunits. Theﬁrst 0.6msof thepeak of homonymous or heteronymous monosynaptic Ia excitation in the PSTHs of single units contains the only unequivocally monosynaptic component of the increased probability of ﬁring. Changes inthe size of this initial part of the peak faithfully reﬂect changes inpresynaptic inhibitionof the corresponding Ia ter- minals, providedthat the ﬁring rate of the motor unit is stable. The method cannot be used during phasic contractions, in which case the H reﬂex of a single motor unit might be used (see Chapter 1, pp. 37–9). (ii) When using the compound H reﬂex, the prob- lemof a change in recruitment gain can be tested by comparing the changes inmonosynaptic facilitation of the reﬂex and those in D1 or vibratory inhibition. A change in the recruitment gain that produced an increaseintheslopeof theinput-output relationship of the motoneurone pool should enhance both the amount of heteronymous reﬂex facilitation and the amount of the D1 or vibratory suppression, whereas a decrease in presynaptic inhibition of Ia terminals should enhance the monosynaptic facilitation and decrease the D1 or vibratory suppression. Organisation and pattern of connections (i) Presynaptic inhibition is stronger on Ia termi- nals on motoneurones supplying slow-twitch units than on those innervating fast-twitch units. As a result, when presynaptic inhibition of Ia afferents is active, the probability of discharge to the monosy- naptic Ia input may be reversed in favour of fast- twitch units, i.e. the opposite of the usual order of recruitment. (ii) The pathways mediating presynaptic inhi- bition of Ia terminals are organised in subsets with regard to the target motoneurones to which Ia afferents project. Thus, presynaptic inhibition of homonymous and heteronymous Ia projections from one muscle to different motoneurone pools is mediatedthroughdifferent subsets of PADinterneu- rones with a different control of ﬁrst-order PAD interneurones. Conversely, presynaptic inhibitionof homonymous and heteronymous Ia terminals pro- jecting to a given motoneurone pool is in all like- lihood mediated through the same subset of ﬁrst- order PAD interneurones. 376 Presynaptic inhibition of Ia terminals (iii) PAD interneurones are excited from Ia affer- ents and probably from Ib afferents, and are inhib- ited by cutaneous afferents. (iv) Cortical stimulation can produce inhibition and facilitation of PADinterneurones, and the dom- inant effect is different inthe upper and lower limbs: corticospinal facilitation of PAD interneurones in the cervical enlargement and corticospinal inhibi- tion in the lumbar enlargement. The focused cor- ticospinal drive to PAD interneurones in the lum- bar enlargement suggests that the same cortical site both activates motoneurones of a given pool and depresses PAD interneurones mediating pre- synaptic inhibition of Ia terminals projecting to that pool. (v) Vestibulospinal and group I inputs converge ontocommoninterneuronesfacilitatingpresynaptic inhibition of Ia terminals in the lower limb. (vi) A stimulus that produces signiﬁcant pre- synaptic inhibition of the afferent volley of the H reﬂex barely suppresses the spinal reﬂex response to abrupt stretch. This suggests that presynaptic inhibition might effectively modulate physiological feedback signals, without interfering with compen- sation for abrupt transients. Motor tasks and physiological implications Ia terminals on lower-limb motoneurones involved in voluntary contraction At the onset of a selective voluntary contraction of one muscle, presynaptic inhibition of Ia ter- minals on motoneurones of the contracting mus- cle is decreased below its level at rest or during a tonic contraction with an equivalent level of voluntary EMG activity. This effect is highly selec- tive and of similar magnitude on both homony- mous and heteronymous Ia terminals projecting to the motoneurones responsible for the contraction (see below). The decrease in presynaptic inhibition appears 50 ms before the onset of the movement, persists unchanged during the ﬁrst half of the ramp phase of a ramp-and-hold contraction whatever the ramp duration (250–1000 ms), and then abruptly returns to its control value. The stronger the force at the end of the ramp the greater the decrease in presynaptic inhibition at the onset of the ramp. This control of presynaptic inhibition is achieved through descending control of PAD interneurones, pre-programmedbefore movement onset according to the likely strength and durationof the contraction at the end of the ramp. The focused corticospinal drive seen in experiments using cortical stimulation is a good candidate for this descending control. The resulting increase inthe gaininthe monosynaptic Ia loopassures that full feedback support fromprimary spindle endings is available to motoneurones acti- vated in the movement. At the beginning of a move- ment, before the load is known, a high gain might allow the reﬂex pathway to compensate rapidly for errors in estimation of the load. Later, the decrease in presynaptic inhibition disappears and the gain of the monosynaptic loop returns to its control value but, by that time, other mechanisms are available to maintain the desired trajectory and, in addition, the decrease in the gain is required to prevent oscil- lations from developing. Similarly, during tonic vol- untary contractions, presynaptic inhibition of Ia ter- minals on motoneurones of the contracting muscle is not decreased or is hardly so. Ia terminals on motoneurones of inactive synergistic muscles of the lower limb The decreased presynaptic inhibition of homony- mous Ia afferents seen at the onset of a selective voluntary contraction of a muscle is accompanied by increasedpresynaptic inhibitionof the collaterals of these Ia afferents to inactive heteronymous mus- cles. This increase is descending inorigin. Transjoint monosynaptic Ia connections are well developed in human subjects, probably to provide the more elab- orate reﬂex assistance required for bipedal stance and gait. However, during isolated contractions of one muscle, the Ia discharge from the contracting muscle will tend to excite motoneurones linked by Ia connections. Enhanced presynaptic inhibition of R´ esum´ e 377 heteronymous Ia terminals to other motoneurone pools prevents these pools from being activated. Ia afferents to antagonists Presynaptic inhibition is increased on Ia afferents projecting to motoneurones antagonistic to the vol- untarily activated motoneurone pool. This increase becomes signiﬁcant only when PAD interneurones are activated by the peripheral feedback. During co- contraction of antagonistic muscles, the increase in presynaptic inhibition is signiﬁcantly greater, and probably contributes to the depression of reciprocal Iainhibition, throughpresynapticsuppressionof the peripheral input to Ia interneurones. Presynaptic inhibition in the upper limb In the upper limb, there is a slight decrease in pre- synaptic inhibition of Ia terminals to motoneurones of the contracting muscle at the onset of a volun- tary contraction, but this decrease differs from that observed in the lower limb in several respects: (i) the decrease is quantitatively less prominent; (ii) there is a similar decrease during tonic contractions; and (iii) there is a decrease of similar magnitude during voluntary contractions of antagonistic muscles. The lack of speciﬁcity in this slight depression suggests reticulospinal depression. Stance and gait (i) Presynaptic inhibition of quadriceps Ia termi- nals is decreased during standing without support and in the early part of the stance phase of gait. In the early stance phase of walking, as in standing, the quadriceps contraction may need to support much of the body weight. The decreased presynaptic inhi- bitionof homonymous quadriceps Ia terminals then observed assures that the excitatory Ia feedback is available to reinforce the quadriceps contraction. (ii) Presynaptic inhibition of soleus Ia terminals is increased throughout the step cycle, particularly at the end of the stance phase and during the swing phase. During the stance phase, the triceps surae contraction resists the passive ankle dorsiﬂexion, and the triceps surae tension must be overcome to allow the body to move forward. The increased pre- synaptic inhibitionof thehomonymous Iaexcitatory feedback contributes to this. During standing with- out support, the increased presynaptic inhibition of soleus Ia terminals could contribute to the depres- sion of reciprocal Ia inhibition, through presynaptic inhibition of the Ia input to interneurones of recip- rocal Ia inhibition. Studies in patients and clinical implications Methodology Studying changes in the inhibition of a test H reﬂex elicitedbyaheteronymous tapor anelectrical stimu- lus (D1) is the simplest andmost convenient method for clinical use. There is a progressive decrease in the amount of femoral-induced facilitation and in heteronymous inhibition of the soleus H reﬂex with ageing, and this must be taken into account when investigating patients. Spasticity Over-interpretation of ﬁndings using prolonged vibration of the homonymous tendon A decrease in presynaptic inhibition of Ia terminals has long been considered one of the spinal mech- anisms underlying the stretch reﬂex exaggeration characteristic of spasticity. This conclusion is, how- ever, ﬂawed: the method used to investigate pre- synaptic inhibition was vibratory inhibition of the homonymous tendon, and the vibration-induced depression of the H reﬂex is then also caused by post-activation depression and by activity- dependent hyperpolarisationof Iaafferents. The for- mer is decreased in spastic patients (see Chapter 2, pp. 99–100). Stroke patients There is no change in presynaptic inhibition of Ia terminals in the lower limb of spastic patients with 378 Presynaptic inhibition of Ia terminals hemiplegia. In the upper limb, presynaptic inhibi- tion of FCR Ia terminals is consistently reduced on the affected side of hemiplegic patients. Patients with spinal cord lesions Whatever the lesion in the spinal cord (traumatic, multiple sclerosis, amyotrophic lateral sclerosis), presynaptic inhibition of Ia terminals is decreased in the lower limb. This reﬂects the interruption of descending pathways which help maintain a tonic level of presynaptic inhibition of Ia terminals in nor- mal subjects under resting conditions. Conclusions There is a decrease in presynaptic inhibition of Ia terminals in patients with spinal cord lesions and in the upper limb of stroke patients. This abnormality doesnot seemtoberesponsiblefor theunduestretch reﬂex exaggeration observed at rest or for the occur- rence of a stretchreﬂex during voluntary contraction of the antagonistic muscle. However, the absence of modulation of presynaptic inhibition of Ia terminals to soleus and quadriceps motoneurones may con- tribute to the stiff gait of patients with spinal cord lesions or stroke. Parkinson’s disease There is evidence for a decrease in presynaptic inhi- bition. 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Pre- synaptic inhibition, EPSP amplitude, and motor-unit type in triceps surae motoneurons in the cat. Journal of Neuro- physiology, 49, 922–31. 9 Cutaneomuscular, withdrawal and ﬂexor reﬂex afferent responses Like muscle afferents, cutaneous afferents are not homogeneous, but thereﬂex pathways fedbythedif- ferent types of cutaneous afferent have been docu- mented less well than those fed by muscle afferents. Cutaneous afferents are responsible for a wide range of sensations, but most are also capable of modula- ting motor behaviour through spinal, supraspinal and transcortical pathways. There is a tendency for clinicians to group all cutaneous afferents together, and this creates confusion, leads to the usage of dif- ferent terms for the same function and the same term for different functions, and makes the systems appear more complex than necessary. There is het- erogeneity in: (i) the type of receptor (e.g. mechano- receptor, thermoreceptor, nociceptor), (ii) the peri- pheral afferents (which range fromlarge myelinated A␤ afferents to slow unmyelinated C afferents), (iii) thespinal pathways fedbytheafferents (fewor many interneurones), (iv) their central projection (spinal, supraspinal, transcortical), (v) the importance of the cutaneous contribution (predominantly ‘private’ vs. sharedpathways), and(vi) their functional role(con- tributing to the normal usage of the limb or respon- sible for withdrawal from a noxious agent). This heterogeneity is reﬂected in the terminology: ‘ﬂexor’ or ‘withdrawal’ reﬂexes are considered noci- ceptive responses (though mechanoreceptors may play a role in their generation), whereas ‘cutaneo- muscular’ reﬂexes refer to responses involved in the control of normal movement. A thesis of this book, addressedinmany chapters, is that cutaneous afferents may have a proprioceptive role, perhaps as important for some movements as that played by muscle spindle afferents, whether that inﬂuence is mediated by a primarily ‘private’ pathway or by modulating the activity of some other system. This chapter will consider the following. Withdrawal responses These responses have a spinal pathway andare com- monly but erroneously thought to involve a ﬂexor synergy activated by a nociceptive stimulus. With- drawal reﬂexes have a speciﬁc organisation, are rea- sonablystereotyped, andareelicitedbyconvergence of noxious and tactile stimuli (cf. p. 387). Cutaneomuscular responses These responses are elicited by tactile stimuli, vary with task and contribute to the control of nor- mal movement. Their late components are generally more signiﬁcant thantheir early spinal components, but the latency of the late components is solong that involvement of transcortical pathways is likely (cf. pp. 421–4). Short-latency FRA responses These responses provide a good example of a reﬂex evoked through a multisensory system with wide convergence of many different afferents on com- mon interneurones. Because the resulting reﬂexes can be evoked by afferents which may evoke the ﬂexion reﬂex, the corresponding pathways were named FRA (ﬂexor reﬂex afferent) pathways. There are alternative pathways for these afferents, and pathways mediating short-latency FRA reﬂexes are 384 Background fromanimal experiments 385 believed to be activated during normal movements (cf. pp. 389–90). Long-latency FRA responses These responses are elicited by the same afferents as earlyFRAresponses, but thetransmissionintherele- vant pathways is inhibited by activation of pathways mediating short-latency FRA reﬂexes. The organisa- tionof long-latency FRApathways suggests that they play a role in the generation of locomotor stepping activity (cf. pp. 390–1). Contributions to ‘proprioceptive’ reﬂexes The above responses can be generated by stimu- lating cutaneous afferents in isolation. In addition, cutaneous afferents contribute toshaping the motor output through their extensive convergence on interneurones interposed in pathways fed by mus- cleafferents or corticospinal volleys (cf. Chapters 3–7 and 10), and onto PAD interneurones mediat- ing presynaptic inhibition of muscle afferents (cf. Chapters 7–8). Because of this heterogeneity, withdrawal reﬂexes (pp. 399–414), and cutaneous reﬂexes from mechanoreceptors (pp. 414–32) are treated separ- ately, except for the backgroundfromanimal experi- ments (pp. 385–91), the methodology (pp. 391–9) and the changes in patients (pp. 432–8). Background fromanimal experiments Initial ﬁndings Investigations of spinal reﬂexes received impetus from the work of Sherrington (1906, 1910) on the nociceptive ﬂexion reﬂex. He showed that, in the spinalised decerebrate animal, noxious skin stim- uli excite ﬂexors and inhibit extensors in the ipsilat- eral hindlimb (the ﬂexion reﬂex), accompanied by excitation of extensors and inhibition of ﬂexors in the contralateral limb (the crossed extension reﬂex). He proposed that the function of the ﬂexion reﬂex was ‘to withdraw the limb from injurious agents’ (Creed et al., 1932), while posture was stabilised by the crossed extension reﬂex. He had already noted that light pressure on the plantar surface of the foot elicited the extensor thrust, introducing the concept of ‘local sign’. The nociceptive withdrawal (ﬂexion) reﬂex was subsequently shown to be poly- synaptic (for references, see Hunt & Perl, 1960), and this was conﬁrmed by intracellular recordings from motoneurones (R. M. Eccles &Lundberg, 1959). The extensiveconvergenceoncommoninterneurones of cutaneous, joint and high-threshold muscle affer- ents led to the concept of multisensory FRA path- ways (R. M. Eccles & Lundberg, 1959; Holmqvist & Lundberg, 1961). Further investigations showedthat administration of DOPA in the acute spinal cat suppressed short-latency FRA responses, releasing transmission in a long-latency FRA pathway, which had a half-centre organisation, capable of gener- ating alternating activation of extensors and ﬂexors (Jankowska et al., 1967a,b). Cutaneous responses mediated through ‘private’ pathways It isoftendifﬁcult todecidewhether anactionevoked by cutaneous volleys is mediated through a largely ‘private’ pathway or by a common FRA pathway for two reasons: (i) low-threshold cutaneous afferents contribute to FRA responses, and (ii) effects medi- ated through specialised cutaneous pathways may haveapattern(ﬂexionreﬂexinthehindlimb) roughly similar to that of FRA responses. However, when cutaneous and FRA volleys elicit different effects in the same motoneurone(s), there is evidence for a specialised cutaneous pathway. Reﬂexes elicited by low-threshold cutaneous afferents The toe extensor reﬂex of the cat This is the most clear-cut example of a specialised cutaneous reﬂex. Gentle pressure on the central plantar cushion (dashed area in the sketch of Fig. 9.1(a)) elicits intheacutelyspinalisedcat astrong 386 Cutaneomuscular and withdrawal reﬂexes PL TA Bi Cortico- spinal FDB Lateral Medial Central plantar cushion Descending A B C High-Th muscle Joint Cut FRA INs D E ST MN X1 Y FRA NA Flexor Extensor Ipsilateral FRA Contralateral FRA (a) (c) (d ) (e) (b) MNs TA MN MN X2 early late Inhib IN Inhib IN Fig. 9.1. Some spinal pathways fed by cutaneous afferents in the cat. (a) Stimulation of slowly adapting mechanoreceptors from the central plantar cushion of the pad activates ﬂexor digitorum brevis (FDB), through an oligosynaptic pathway, which receives corticospinal facilitation. (b) Different receptive ﬁelds in the plantar skin of the cat for withdrawal reﬂexes in the peroneus longus (PL), tibialis anterior (TA) and biceps femoris (Bi), with areas evoking 70–100% (black), 30–70% (dark grey) and 0–30% (pale grey) of maximal responses. (c)–(e) Sketches showing presumed pathways mediating FRA responses. In these diagrams each interneurone (IN) may represent a chain of INs. (c) Sketch illustrating how, during movement, short-latency FRA pathways could provide selective reinforcement of the descending voluntary command. High-threshold muscle (High-Th muscle), joint and cutaneous (Cut) (thin dotted lines) afferents converge onto common ﬁrst-order FRA INs, which excite different chains of alternative excitatory (‘A’, ‘B’, ‘C’) and inhibitory (‘D’) INs projecting to motoneurones (MN) of the semitendinosus (ST). During movement, there is descending activation (continuous thick lines) of chains ‘B’ and ‘E’ and, through inhibitory interactions (Inhib IN), there is inhibition of transmission in the other FRA excitatory (‘A’ and ‘C’) and inhibitory (‘D’) pathways (for TA MNs only descending inhibitory pathways [‘E’] are represented). The ensuing movement gives rise to an impulse ﬂow in FRA which is channelled back into the reﬂex already activated, so that its activity is reinforced and prolonged (see p. 389). (d ) Mutual inhibition between chains of INs mediating long-latency excitation to ﬂexors and extensor MNs from ipsilateral and contralateral FRAs, respectively (see pp. 390–1). (e) Inhibition of pathways mediating long-latency FRA reﬂexes by pathways mediating short-latency reﬂexes: noradrenergic (NA) paths activated by DOPA inhibit the short-latency reﬂex pathway (‘X’), thereby releasing transmission in the long-latency reﬂex pathway (‘Y’) from an inhibitory control exerted from pathway ‘X’. The short-latency pathway ‘X’ is subdivided into ‘X1’ and ‘X2’ to accommodate the ﬁnding that the NA pathway may block the short-latency reﬂex actions on MNs when there is still an inhibitory transmission on the long-latency pathway. From data in Engberg (1964) (a), and modiﬁed from Schouenborg (2002) (b), Lundberg (1973, 1979) ((c), (d)), and Baldissera, Hultborn & Illert (1981) (e), with permission. Background fromanimal experiments 387 response in the plantar ﬂexors of the toes (i.e. the physiological toe extensors), in particular the ﬂexor digitorum brevis (Engberg, 1964). This reﬂex is due to the activation of slowly adapting mechanorecep- tors and is mediated through an oligosynaptic path- way (Egger &Wall, 1971; see the sketchinFig. 9.1(a)). However, thepathwayis distinct fromFRApathways, since FRA volleys (from high-threshold muscle and joint afferents) evoke the usual inhibition of physio- logical extensorsinﬂexor digitorumbrevismotoneu- rones. Cutaneous reﬂexes during locomotion Cutaneousreﬂexesduringlocomotionarealsomedi- atedthroughspecialisedpathways. Inchronic spinal cats walking on a treadmill, tactile stimuli applied to thedorsumof thepawevokeshort-latencyresponses involving the ﬂexors during the swing phase, but the extensors during the stance phase (Forssberg, Grillner & Rossignol, 1975, 1977). The responses in knee muscles are stronger and have shorter laten- cies than those of ankle and hip muscles. This pat- ternandtimingof activation(i) distinguishtheabove responses from FRA-induced responses, which are stereotyped and synchronous in all ﬂexors, and (ii) appear appropriateduringgait. Isolatedkneeﬂexion early in swing is sufﬁcient to overcome the obstacle touched by the pad dorsum, whereas the increased extension during stance acts to shorten this phase and accelerate the following ﬂexion. The hindlimb ﬂexion producing this ‘stumbling corrective reac- tion’ is completedbyplantar ﬂexionof thetoes medi- ated by disynaptic pathways (see R. E. Burke, 1999). Reﬂexes in the forelimb In the forelimb of the cat, low-threshold cutaneous afferents project to segmental interneurones inter- posed in proprioceptive pathways (cf. Introduction, and Hongo et al., 1989) and to C3–C4 propriospinal neurones (cf. Alstermark &Lundberg, 1992; Chapter 10, p. 453), and also feed ‘private’ pathways. Thus, stimulation of the skin of the forefoot pad evokes highly specialised reﬂexes in digit motoneu- rones, with excitation as in the hindfoot, associ- ated with strong disynaptic inhibition of neighbour- ingmotoneurones, presumablydesignedfor discrete movements of thedifferent digits (Sasaki et al., 1996). Withdrawal reﬂexes Incontrast withtheclassical viewthat thewithdrawal reﬂexes of the hindlimb were a stereotyped ‘noci- ceptive ﬂexion reﬂex’ in which all physiological ﬂex- ors were activated while extensors were inhibited, Hagbarth (1952) demonstrated that extensor mus- cles are activated by noxious stimuli applied to the overlying andadjacent skin. This extensor activation is appropriate to avoid the stimulus. Accordingly, a speciﬁc relationship between receptive ﬁeld, acti- vated muscle(s) and the resulting reﬂex withdrawal has been revealed both in the rat and the cat (for review, see Schouenborg, 2002). (i) Each muscle or group of muscles has a separ- ate cutaneous receptive ﬁeld corresponding to the skin area withdrawn by contraction of the partic- ular muscle group. This is illustrated for the recep- tive ﬁelds for withdrawal reﬂexes involving the pero- neus longus, tibialis anterior and biceps of the cat in Fig. 9.1(b). (ii) Nociceptors and, to a lesser extent, slowly adapting low-threshold mechanoreceptors provide the afferent input to withdrawal reﬂex pathways. (iii) The dorsal horn interneurones receiving con- verging inputs fromnociceptive and tactile afferents that elicit the withdrawal reﬂex are speciﬁc for each muscle, and under differential supraspinal control. Projections to motoneurones innervating slow- and fast-twitch motor units A differentiation between FRA pathways and spe- cialised cutaneous pathways has also been pos- sible in the motoneurones innervating fast-twitch motor units of triceps surae. Their motoneurones are excited from cutaneous afferents but inhibited fromother FRAafferents, speciﬁcally joint and high- thresholdmuscle afferents (R. E. Burke, Jankowska & ten Bruggencate, 1970). 388 Cutaneomuscular and withdrawal reﬂexes Descending projections to specialised cutaneous pathways A descending action on specialised reﬂex pathways from skin has been inferred because facilitation of cutaneous effects may occur without concomi- tant changes in the FRA effects evoked from high- threshold muscle afferents. This is the case for the following. (i) Rubrospinal facilitation of low-threshold cuta- neous excitation of extensor motoneurones inner- vatingfast motor units(cf. above) (Hongo, Jankowska & Lundberg, 1969). (ii) Corticospinal facilitation of interneurones in the cutaneous reﬂex pathway to toe exten- sors (Engberg, 1964). Because of this convergence, descending excitation of the relevant interneurones may receive feedback reinforcement by impulses evokedfromtheplantar cushionduringcontact with the ground (see Fig. 9.1(a), and Lundberg, 1973). (iii) Convergence of cutaneous and corticospinal inputs on common interneurones in pathways to distal forelimb motoneurones, which occurs at two levels: cutaneous modulation of corticospinal vol- leys mediated through C3–C4 propriospinal neu- rones (cf. above), and corticospinal facilitation of cutaneous reﬂexes mediated by interneurones located in brachial segments (C7–C8). There are di- synaptic reﬂex pathways (mediating both excitation and inhibition to motoneurones) that operate only with conjoint cutaneous and corticospinal inputs (Sasaki et al., 1996). Some cutaneous receptors can be activated during movement without contact with an external object (Hulliger et al., 1979). Lundberg (1973) speculated that the information from skin receptors may play a signiﬁcant role in control- ling hand movements in primates, both by modu- lating the cortical command relayed by common interneurones and by activating segmental reﬂex pathways to motoneurones. The increased pre- synaptic inhibition of cutaneous afferents observed during the dynamic phase of wrist ﬂexion-extension movements in the awake monkey could function to gate out inappropriate reﬂex responses from peripheral receptors and sharpen the resulting exteroceptive information (Seki, Perlmutter & Fetz, 2003). FRA reﬂex pathways Characteristics of FRA pathways Flexor reﬂex afferents (FRA) FRA include group III and, in the cat, group II muscle afferents, joint afferents and low- and high- threshold cutaneous afferents. Afferents of the FRA group may use ‘private’ pathways which are not part of the common FRA system, as discussed above for specialised cutaneous pathways and in Chapter 7 for group II pathways. There are two reﬂex patterns from the FRA: the short-latency (early) reﬂexes found in the acute spinal cat, and the long-latency (late) reﬂexes, which appear in acute spinal cats after the administration of DOPA or 5-HTP. In this chapter, ‘reﬂex actions from the FRA’ denotes the former action when not otherwise stated. Grouping FRA together There are multiple reasons to group these afferents together (cf. Lundberg, 1973, 1979, 1982): (i) They have a common action on motoneurones, i.e. ipsilateral ﬂexion and contralateral exten- sion in the spinal animal. (ii) In all cases, the reﬂex actions are drawn from a widereceptiveﬁeld, which, for muscleafferents, includes both ﬂexors and extensors. (iii) Theyconvergeoncommoninterneuronesinter- posed in reﬂex pathways to motoneurones. (iv) They act together on a variety of ascend- ing spinocerebellar pathways (Lundberg, 1959), andthis maybeexplainedbecausethedescend- ing excitation of FRA interneurones (see below) requires information regarding activity in FRA pathways. (v) Transmission in all FRA pathways is simi- larly inﬂuencedby brainstemlesions. Following Background fromanimal experiments 389 intercollicular decerebration, FRA excitation of ﬂexors and inhibition of extensors is sup- pressed, and following an additional midline low-pontine lesion, stimulation of FRA evokes inhibition in both ﬂexor and extensor motor nuclei. Following spinal transection, the classi- cal ‘ﬂexor reﬂex pattern’ with facilitation of ﬂex- ors and inhibition of extensors appears. These ﬁndings strongly suggest that there are ‘alter- native’ spinal pathways to motoneurones with wide multisensory convergence from all FRAs, a concept of importance for the possible role of early FRA pathways in normal movement (cf. below). (vi) Transmission in short-latency FRA pathways is facilitated by a number of descending tracts (corticospinal, rubrospinal, vestibulospinal), and depressed by monoaminergic pathways from the brainstem. Criticism of the FRA concept The FRA concept provoked criticism (in partic- ular, see Matthews, 1972; Binder et al., 1982), mainly related to the terminology. The termFRAis probably a misnomer that has outlived its usefulness (Lund- berg, 1979), but unfortunately it has been ratiﬁed by use. Pathways mediating short-latency FRA reﬂexes New perspective on the FRA concept The FRA concept received a new dimension when Lundberg (1973, 1979) formulated the hypothesis that, during normal movement, pathways medi- ating short-latency FRAreﬂexes couldprovide selec- tive reinforcement of the voluntary command from thebrain. Thehypothesis reliedonexperimental evi- dence for the following ﬁndings. (i) There are alternative FRA pathways to the ﬂex- ion reﬂex (see above). (ii) Thereareinhibitoryinteractionsbetweenalter- native FRA pathways (‘Inhib IN’ in Fig. 9.1(c)). (iii) Muscle contraction secondary to stimulation of ␣efferentsactivatestheFRAsystem(seeLundberg, 1979). Possible functional role The hypothesis is outlined in the sketch in Fig. 9.1(c) (in which circles represent chains of interneu- rones). Lundberg postulated that the descending command activates one of the several alternative excitatory FRA pathways to motoneurones (e.g. of semitendinosus) (‘B’ rather than ‘A’ and ‘C’ in Fig. 9.1(c)). Through inhibitory interactions, trans- mission in the other FRA excitatory pathways to the same motoneurones is inhibited (‘A’ and ‘C’ in Fig. 9.1(c)), as is transmission in the inhibitory FRA pathways to the same motoneurones (‘D’ in the sketch in Fig. 9.1(c)). Movement activates muscle receptors of thecontractingmuscle, relatedjoint and surrounding skin, many of which belong to the FRA system. This sensory activity will be channelledback into the reﬂex path already activated by descending tracts (‘B’ in Fig. 9.1(c)), because transmission in the other pathways is inhibited. A diffuse feedback sys- temwithamultisensory input may thereforebeused to reinforce and prolong the descending command. The movement may have been initiated by corti- cospinal activation of motoneurones, as occurs in primates, but the feedback would help maintain the contraction, if the descending command facilitates interneurones of the FRApathway. Parallel descend- ing excitation of FRA pathways mediating inhibition to other motoneurone pools (e.g. tibialis anterior in Fig. 9.1(c)) might thenbeusedtoprevent contraction of muscles not required in a given movement. Convergence of nociceptive afferents on FRA interneurones Convergence would facilitate correction of a move- ment as it approached its limits and became harm- ful. Due to spatial facilitation the required nocicep- tive input need only be minor, so that the correc- tion could become effective before injury or pain occurred (see Schomburg, 1990). 390 Cutaneomuscular and withdrawal reﬂexes Presynaptic inhibition of FRA ThepositivefeedbackprovidedbytheexcitatoryFRA machinery requires control. Presynaptic inhibition could play a crucial role in this. The FRAs produce primary afferent inhibition of their own terminals (Eccles, Kostyuk &Schmidt, 1962), ‘which suggests a negative feedback control of transmission from the FRAs so that excess activity automatically curtails transmission’ (Lundberg, 1979). FRA-induced excitation of other pathways Strong excitatory effects from the FRAs have been described on interneurones belonging to different reﬂex pathways: reciprocal Ia inhibition (Chapter 5, p. 199), Ib(Chapter 6, pp. 247–8) andgroupII (Chap- ter 7, pp. 291–2). These ﬁndings suggest that facil- itation of impulse transmission in the FRA path- ways evoked by the active movement might have a widespread effect on spinal circuitry (Lundberg, Malmgren & Schomburg, 1987). Pathways mediating long-latency FRA reﬂexes With DOPA, short-latency FRA reﬂexes are depressed and replaced by long-latency responses Short- andlong-latency FRAreﬂexes canhave a sim- ilar pattern of excitation of ﬂexors from ipsilateral FRAs and of extensors from contralateral FRAs, with inhibition of antagonistic motoneurones. However, several lines of evidence indicate that the short- and long-latency FRA responses are mediated through different pathways (cf. Lundberg, 1979; Schomburg, 1990). (i) Primary afferent depolarisation is exerted mainly on FRA terminals before DOPA, and on Ia terminals after DOPA. (ii) Late IPSPs evoked after DOPA are mediated via interneurones of reciprocal Ia inhibition, while IPSPs evoked before DOPA are mediated via a pri- vate inhibitory pathway. (iii) Interneurones which mediate long-latency FRA responses do not respond to FRA stimulation before DOPA. Mutual inhibition between long-latency FRA pathways to ﬂexors and extensors This mutual inhibition is very effective. Thus, trans- mission of the late EPSPs evoked by the ipsi- lateral FRAs to ﬂexor motoneurones is strongly inhibited by activation of the pathway that con- veys late excitation to extensor motoneurones from the contralateral FRAs, and vice versa, as out- lined in Fig. 9.1(d). The strong mutual inhibition between neurones exciting muscles with opposite function is reminiscent of the half-centre organi- sation postulated by Graham Brown (1914) to give alternating activation of extensors and ﬂexors dur- ing locomotion. Accordingly, when DOPA is given after pretreatment by nialamide, stimulation of the FRA produces alternating ﬂexor and extensor activation, dependent on the half-centre organi- sation of the late FRA pathways (see Lundberg, 1979). There is inhibition of pathways mediating long-latency FRA reﬂexes by pathways mediating short-latency FRA reﬂexes After DOPA, prolonging a train of FRA volleys delays the onset of the long-latency response, which then appears only after the end of the stimulus train. This ﬁnding has been taken as evidence that the same FRApathwayprovides excitationof theshort-latency FRA pathway (‘X’ in Fig. 9.1(e)) and inhibition of the long-latency FRA pathway (‘Y’ in Fig. 9.1(e)). By causing release of transmitter from a noradrenergic pathway, DOPA would inhibit pathway X, thereby releasing transmission through the pathway Y (cf. Lundberg, 1979). After DOPA, short-latency reﬂex actions to motoneurones are blocked, but short- latency pathways still have an inhibitory action on the long-latency pathway, as suggested by the ﬁnd- ing that the late response only appears after the end of the stimulus train. A possible functional outcome of the inhibition of long-latency FRA pathways by short-latency FRA pathways would be the prompt interruption of locomotor activity that occurs in all phases of stepping when high-threshold cuta- neous afferents are stimulated (Viala, Orsal & Buser, Methodology 391 1978). It has been suggested (Lundberg, 1979) but so far without experimental evidence that there is also inhibition from the long-latency to the short- latency FRA pathway, so that, once the former is activated to give locomotor activity, the latter is suppressed. Conclusions Cutaneous volleys contribute to many spinal reﬂexes. (i) They modulatetransmissioninpathways which receive their main input from muscle affer- ents throughconvergence onthe interneurones intercalated in these pathways and on PAD interneuronesmediatingpresynapticinhibition of primary afferent terminals. (ii) Low-threshold mechanoreceptors may evoke specialised reﬂex responses. (iii) Withdrawal reﬂexes are evoked by nociceptive afferents but with excitatory convergence from tactileafferentsfromaspeciﬁccutaneousrecep- tive ﬁeld. Stimulation of these ﬁelds produces withdrawal of the area fromthe potentially inju- rious stimulus. (iv) The responses mediated through short-latency FRA pathways are evoked mainly fromafferents activated during normal movement, though nociceptive afferents may also contribute. These responses may provide positive feedback designedto prolong andreinforce the voluntary command from the brain. (v) The half-centre organisationof pathways medi- ating long-latency FRA responses might be responsiblefor thealternatingactivationof ﬂex- ors and extensors during locomotion. Methodology Underlying principles Although the reﬂex responses evoked by tactile and nociceptive stimuli are carried by different peripheral afferents and have different central cir- cuits, similar general principles apply to all cuta- neous reﬂexes. (i) Some reﬂexes may be documentedby recording responses when the subject is relaxed. (ii) The reﬂex effects of cutaneous volleys may be tested using the H reﬂex, the on-going EMG or PSTHs of single motor units. (iii) Cutaneous volleys may be produced by electri- cal or mechanical stimuli. (iv) Temporal summation or spatial and tem- poral summation may be required to cause the response to appear consistently. (v) Cutaneous reﬂexes are more sensitive than H reﬂexes to repetition rate, such that irregular stimuli at very lowrates are advised, particularly at rest. (vi) Spinal responses may be distinguished from transcortical responses on latency grounds, and/or because similar responses are obtained in subjects with complete spinal transection. (vii) In practice, whether the stimulus elicits a tac- tile sensation or pain is often used to docu- ment which afferents are activated and to dis- tinguish responses produced by stimulation of low-threshold cutaneous afferents from with- drawal reﬂexes. However, it must be remem- bered that an electrical stimulus sufﬁciently strong to activate nociceptive afferents will also activate mechanoreceptive afferents. Stimuli Electrical stimuli Electrical stimuli to cutaneous nerves Electrical stimuli canbeappliedtocutaneousnerves, which are generally stimulated where the nerve is superﬁcial, through bipolar surface electrodes with the cathode proximal. The more commonly stimu- lated nerves are the sural nerve behind or just below the lateral malleolus, the superﬁcial peroneal nerve on the dorsal side of the foot proximal to the exten- sor digitorum brevis, the superﬁcial radial nerve on 392 Cutaneomuscular and withdrawal reﬂexes the inferior part of the radial edge of the forearm, the digital nerves of the ﬁngers and toes using ring electrodes. Electrical stimulation may also be delivered directly to the skin Direct cutaneous stimulation may be delivered through plate electrodes placed over the skin, at a site where there is no muscle beneath the skin, to avoid stimulation of muscle afferents. Stimuli can also be delivered through pairs of needle electrodes inserted into the skin. Withdrawal reﬂexes Withdrawal reﬂexes are elicited by painful stimuli applied to a nerve or to skin. Temporal summation will facilitate the appearance of withdrawal reﬂexes (cf. Fig. 9.2(i)–(k)), but the critical parameter is the intensity of the stimulus, which must recruit small afferents (see Hugon, 1973; Willer, 1977). The inten- sity of stimulation may be expressed with respect to the threshold for perception or to the threshold for pain. The latter is the same as the threshold for the nociceptive reﬂex (see Fig. 9.2(l )–(m); Willer, Roby & Le Bars, 1984). There is a speciﬁc organisation of thewithdrawal reﬂexes relatedtothestimulatedskin ﬁeld (cf. p. 407). Cutaneomuscular responses from low-threshold mechanoreceptors These responses are produced by stimuli that pro- duce a tactile sensation. Single shocks of weak intensity may have little effect, particularly when applied to skin, and most authors use trains of stimuli applied to nerves. The trains must be short (e.g. 3–5 shocks at 300 Hz) to allow interpretation of latency measurements. The stimulus intensity is expressed as a multiple of the threshold for percep- tion ( PT) for the radiating cutaneous paraesthe- siae in the territory of the nerve. At rest, the reﬂex response is suppressed at repetition rates above 0.1– 0.2 Hz, even more so than the H reﬂex. In con- tracting muscles, the suppression is less, and rates of 1–3 Hz provide the optimal trade-off between reﬂex attenuation and the need to average more responses. Mechanical stimuli Mechanical stimuli have been used to provide infor- mation about (i) the responses elicited in forearm and hand muscles from low-threshold mechano- receptors activated under natural conditions, and (ii) the mechanisms underlying the reﬂex responses tested in routine clinical examination. Natural stimulation of cutaneous afferents from the ﬁngers Natural stimulation may be produced using a small probe to indent the skin or a controlled puff of air. An analysis of the cutaneous receptors responsi- ble for cutaneomuscular responses in hand mus- cles has been undertaken by McNulty & Maceﬁeld (2002). Rapidly adapting type I and II units (FAI, FAII) were activated by stroking across the receptive ﬁeldof theunit, whileslowlyadaptingreceptors were stimulated by constant indentation of the receptive ﬁeld of the unit. Recordings from single cutaneous afferents allowed a further characterisation of the corresponding receptors, since FAI afferents have a characteristic bursting discharge (see the inset in Fig. 9.10(f )), FAII ahighlyvariabledischargerate, and SAII aregular dischargeinresponsetosustainedskin stretch. Plantar responses Plantar responses are evoked by ﬁrm stroking of the lateral plantar surface of the foot, a stimulus that produces spatial andtemporal summationof inputs. Attention is focused clinically on the response of the toe 1 because the normal plantar ﬂexion (physiolog- ical extension) may be replaced by dorsiﬂexion to produce Babinski’s sign of pyramidal tract dysfunc- tion (cf. Fig. 9.5; pp. 433–4; Babinski, 1898; see van Gijn, 1996 for further references). Methodology 393 (a) (l ) (m) (n) (p) (q) (b) (c) (d) (e) (f ) (g) (h) (i ) ( j ) ( k) Fig. 9.2. RII and RIII reﬂexes in the short head of the biceps femoris. (a) Sketch of the presumed pathways. A␤ (dashed line) and A␦ (thin dotted line) afferents in the sural nerve activate biceps (Bi) motoneurones (MN) through different chains of interneurones (IN). (b)–(k) and (n)–(q) Reﬂexes elicited by sural stimulation in the Bi at rest. (b) RII reﬂex elicited by stimuli evoking a tactile sensation (train of 13 shocks, 400 Hz). (c) RIII reﬂex elicited by a stronger train evoking a pain sensation (the response being limited to Bi). (d )–(f ) Modulation of the RIII reﬂex ((d ), control reﬂex) by a preceding (50 ms, vertical arrows) conditioning stimulation of A␤ (e) and A␦ (f ) afferents in the sural nerve. (g), (h) Reﬂex responses recorded in the Bi after sural stimulation (train of 10 shocks, 300 Hz, 10 mA) in a control situation (g) and during ischaemia blocking large A␤ ﬁbres (h) (arrows indicate the time of stimulation). (i)–(k) Effects of lidocaine inﬁltration on sural volleys (left traces) and Bi activity (right traces) after sural stimulation (40 mA). (i) Control recordings (the arrow highlights the A␦ wave), and effects of a single (j) and a double (k) shock (100 Hz) 10 minutes after lidocaine. (l ), (m) The size of the RIII reﬂex in the Bi (l ) (as a percentage of its maximum, Max) and the intensity of the sensation (m) (on a 0–10 scale where 3 and 10 are the threshold of pain and intolerable pain, respectively) plotted against the intensity of the sural nerve stimulation (train of 10 shocks, 300 Hz). (n)–(q) Facilitation of the RIII reﬂex in the Bi by repeating the stimulation to the sural nerve (single shock, 3.5 PT) every 2 s: records show the ﬁrst (n), ﬁfth (p) and eleventh (q) reﬂex of the same series. Modiﬁed from Hugon (1973) ((b)–(f ), (n)–(q)), Willer (1977) ((g), (h)), Willer, Roby & Le Bars (1984) ((l ), (m)), and Willer, Boureau & Albe-Fessard (1978) ((i)–(k)), with permission. 394 Cutaneomuscular and withdrawal reﬂexes Abdominal reﬂexes Abdominal reﬂexes are evokedby a rapidstroke with a blunt pin on the abdominal skin, again a stimu- lus that produces spatial and temporal summation of inputs. The latency of the response increases and the amplitude decreases withrepetitiondue to rapid habituation of the reﬂex (see Fig. 9.3(l )–(n); Kugel- berg & Hagbarth, 1958). Responses recorded at rest Withdrawal reﬂexes Provided that the stimulus is painful, withdrawal reﬂexes can be recorded consistently at rest, partic- ularly in the lower limb. The electrophysiological analysis of withdrawal reﬂexes in human subjects began with Pedersen (1954). The RIII response of the short head of the biceps femoris The RIII reﬂex is elicited by a stimulus to the sural nerve that produces pain (Fig. 9.2(c); Hugon, 1973; Willer, 1977), and is a good tool for the investigation of the pathways mediating withdrawal reﬂexes in humans. The reﬂex is mediated by small myelinated A␦ afferents (see p. 400). With sural stimulation, the nociceptive response ﬁrst appears in biceps femoris (Hugon, 1973). If the stimulus intensity is sufﬁciently strong, theRIII reﬂexmaybeelicitedbyasingleshock (Fig. 9.2(i)). Lower intensities are sufﬁcient to evoke the nociceptive reﬂex when a train is delivered but they thenalsoproduce pain(Willer, Boureau&Albe- Fessard, 1978, and Fig. 9.2(j), (k)). At threshold, the response occurs with a latency of 120–130 ms, but this decreases to ∼80–90 ms when the stimulus intensity (or the number of shocks in the train) is increased. As discussed on p. 401, such a latency is compatible with a spinal reﬂex. Other withdrawal reﬂexes Withdrawal reﬂexes may be elicited in all lower limb muscles when the adequate receptive ﬁeld is stimulated (Hagbarth, 1960), and their particu- lar pattern is considered on pp. 401–7. Noxious responses are often investigated in the tibialis ante- rior to stimulation of the medial aspect of the sole of the foot at the apex of the plantar arch (Shahani &Young, 1971), or of the medial plantar nerve of the foot (Meinck, Benecke & Conrad, 1983). Here again, increases in stimulus strength result in increases in the reﬂex amplitude and duration, and decreases in latency (Fig. 9.3(b)–(e)), to as little as 50–60 ms at the higher intensities. Increases in stimulus strength also result in the appearance of a late response (Fig. 9.3(e)), the origin of which is discussed on pp. 410–11. Abdominal skin reﬂexes are considered trunk defence reﬂexes (Kugelberg &Hagbarth, 1958; p. 402). Withdrawal reﬂexes have been studied less in the upper limb than in the lower limb. Trains of tenpainful stimuli at 4–6 PTto the ﬁngers will pro- duce reﬂex responses in most muscles investigated (Floeter et al., 1998), with a latency <100 ms (Fig. 9.6(b)). Here again, habituation is prominent. Responses elicited by stimuli evoking a tactile sensation Reﬂex responses are not easily evoked at rest by stimulation of tactile cutaneous (A␤) afferents, and temporal summation is usually required. The RII response elicited in the short head of the biceps femoris by stimulation of the sural nerve This is the most consistent cutaneous reﬂex pro- duced at rest by stimulation of tactile afferents (Fig. 9.2(b); Hugon, 1973; cf. p. 414). Thereﬂexelicited by weak electrical stimulation requires the temporal summation produced by trains of 6–10 shocks. The minimal latency of the reﬂex is about 40 ms and is consistent with a spinal pathway (cf. Hugon, 1973; Willer, 1977; pp. 418–19). The RII reﬂex is not eas- ily observed unless the subject is relaxed, and better results are often obtained during a second session when the subject is familiar with the experimental conditions. Thereﬂexisverysensitivetohabituation. Methodology 395 (a) ( j ) ( k) ( l ) ( p) ( q) ( r ) ( s) ( m) ( n) (b) (c) (d) (e) (f ) (g) (h) (i ) Fig. 9.3. Withdrawal reﬂexes in the tibialis anterior and external oblique. (a) and (k) Sketch of the presumed pathways. (a) Cutaneous volleys from the sole of the foot excite tibialis anterior (TA) motoneurones (MN) through a chain of interneurones (IN). (k) Cutaneous volleys from the abdominal skin excite external oblique MNs through a chain of INs. (b)–(i) Reﬂexes are elicited in TA at rest by trains of stimuli (0.1 ms square waves, 20 ms, 500 Hz) delivered by intradermal stimulation of the medial sole (at the apex of the plantar arch). (b)–(e) Flexor reﬂexes elicited in TA by stimuli of increasing strength. (f ) Combined EMG and mechanogram (upper trace), depicting movement at the ankle produced by the ﬂexor reﬂex, in response to a supramaximal stimulus (arrow). (g)–(i) Effects of repeating the stimulus train (arrows indicate the time of the stimuli): (g) Control response; (h), (i) the responses to two trains of stimuli given 1 s (h) and 4.2 s (i) apart. (j) Excitability curve in a normal subject (●) and a patient with complete spinal transection (❍): the size of the conditioned ﬂexor reﬂex, expressed as a percentage of the conditioning reﬂex is plotted against the ISI between the two reﬂexes. (l )–(s) Abdominal reﬂexes elicited by different types of skin stimulation in the external oblique. (l )–(n) Reﬂexes following the ﬁrst (l ), ﬁfth (m) and ﬁfteenth (n) rapid stroke (thick dotted line) produced with a blunt pin, showing the habituation of the response. (p)–(s) Progressive decrease in latency and increase in amplitude following electrical stimuli of increasing strength (train of three shocks) of the abdominal skin. With the highest intensity (s), the latency is only 24 ms, implying a central delay of 3.5–5 ms. Modiﬁed from Shahani & Young (1971) ((b)–(j)), and Kugelberg & Hagbarth (1958) ((l )–(s)), with permission. 396 Cutaneomuscular and withdrawal reﬂexes Reﬂexes are rarely evoked by Aβ afferents in other muscles However, in some subjects, sural nerve stimulation has producedRII reﬂexes intibialis anterior (Hugon, 1973) andperoneuslongus(Aniss, Gandevia&Burke, 1992), and stimulation of the ulnar nerve at the wrist has produced reﬂexes attributed to cutaneous affer- ents in the ﬂexor carpi ulnaris (Fig. 9.10(b); Cambier, Dehen & Bathien, 1974). Modulation of motoneurone excitability The reﬂex effects of cutaneous afferents may be documented by recording the modulation of the monosynaptic reﬂex, the PSTHs of single units or the voluntary on-going EMG activity. Modulation of the monosynaptic reﬂex Changes produced by cutaneous volleys in the amplitude of the H reﬂex or tendon jerk allow one to distinguish between volleys without effect on the excitability of the motoneurones, those which evoke only subliminal excitation of the motoneu- rones when applied alone, and those which inhibit the motoneurones. Thus, Fig. 9.4(b)–(d) shows that painful stimulation of the sural nerve facilitates the tendon jerk of the biceps femoris at an ISI corre- sponding to the latency of the RIII reﬂex and, at the same latency, profoundly inhibits the tendon jerk of quadriceps, the soleus tendon jerk and the soleus H reﬂex (Hugon, 1973). Modulation of the on-going EMG This method allows one to record rapidly the full time course of the inhibitory and excitatory effects. Modulation of a few sweeps of on-going tonic EMG activitymaybesufﬁcient toreveal thereceptiveﬁelds of nociceptive reﬂexes (cf. pp. 404–5). Averaging the rectiﬁed on-going EMG provides reasonable tem- poral resolutionof thecutaneous-inducedresponses and has been used to document the organisation of withdrawal reﬂexes. Gassel &Ott (1970) showed that the cutaneous modulation of the rectiﬁed on-going EMG of triceps surae closely paralleled the recovery curve of the Achilles tendon jerk, and Meinck et al. (1981, 1983a, b, 1985) detailed the organisation of noxious responses in the tibialis anterior of normal subjects and spastic patients. However, the method has been used mainly to explore the relatively weak responses to tactile cutaneous inputs in the upper and lower limbs (cf. pp. 414–15). Spike-triggered averagingof theEMGagainst thedischargeof asingle cutaneous afferent requires the use of microneuro- graphy to record the discharge of a single cutaneous afferent, but it has proved possible to investigate the reﬂex effects evoked by natural stimulation of iden- tiﬁed cutaneous mechanoreceptors (see above). Modulation of the PSTHs Modulationof thePSTHsof singleunitsbycutaneous volleys is of prime importance, because cutaneous afferents have been shown to have different effects on motoneurones of different types (cf. pp. 424–7). Critique of the tests to study cutaneous effects Nature of the stimuli Mechanical stimuli With mechanical stimuli, it is possible to activate only mechanoreceptors and, with stronger stim- uli, to reproduce the conditions in which plan- tar responses or abdominal skin reﬂexes are tested in the clinical examination. Similarly, withdrawal responses may be evoked by natural stimuli such as pinch or pinprick. However, in general, the spatial and temporal summation required to produce the reﬂex responses donot allowaccurate measurement of latencies. Radiant heat Radiant heat can be a noxious stimulus that can be precisely localised and timed (cf. Ellrich, Steffens & (a) (b) (c) (d) (e) (f ) (g) (k) (l ) (m) (h) (i ) ( j ) Fig. 9.4. Pattern of cutaneous reﬂexes in the lower limb. (a) Sketch of the presumed pathways. A␤ (dashed line) and A␦ (dotted line) afferents in the sural nerve and from the skin of the anterior aspect of the thigh activate excitatory and inhibitory spinal interneurones (IN) and transcortical pathways to biceps (Bi) and quadriceps (Q) motoneurones (MN). (b)–(d) The amplitude of the tendon jerk in biceps (b), Q (c) and soleus (d ) at rest (as a percentage of the unconditioned value) is plotted after sural stimulation eliciting a tactile sensation (❍) or pain (●) against the ISI (+, soleus H reﬂex after painful stimulation). The vertical dashed line is the latency after which a A␤ volley could act through a transcortical pathway (see p. 418). (e)–(j) Modulation of the on-going voluntary EMG of the vastus medialis (VM) by noxious stimuli (black bars under records show the duration of the stimulus train). (e), Effects of trains (20 ms) from various skin areas: excitatory (÷) and inhibitory (−, silent period) responses (three to ﬁve sweeps superimposed in each record). (f )–(h) In the position indicated in (i ), effects of a short train ((f ), 30 ms) and a long train ((g), (h) the duration of which [outlasting the sweep] is determined by the withdrawal movement), in a control situation (g) and during hypnotic analgesia (h). (i), (j) Early and late responses of the VM to noxious skin stimuli on the calf and the front of the leg (arrows) in sitting (i) and standing (j) position. (k)–(m) Diagrams showing the inhibitory and excitatory responses (estimated as in (e)) for gluteus maximus (Glut Max (k)), gastrocnemius-soleus (G-S, (l )) and tibialis anterior (TA, (m)). Modiﬁed from Hugon (1973) ((b)–(d)), and Hagbarth & Finer (1963) ((e)–(m)), with permission. 398 Cutaneomuscular and withdrawal reﬂexes Schomburg, 2000), but the stimulus necessary to producewithdrawal reﬂexes areof highintensityand may damage the skin. Electrical stimuli Electrical stimuli are artiﬁcial and, when stimulat- ing a nerve trunk, other afferents are almost cer- tainly activated, e.g. joint afferents when stimulat- ing the sural or digital nerves, and muscle and joint afferents when stimulating the tibial nerve at the ankle or its distal plantar branches. Caution should be observed in interpreting the evoked responses. For example, spindle afferents from plantar mus- cles project to lower limb motor nuclei, and pro- duce strong monosynaptic Ia, non-monosynaptic group I and group II excitation in tibialis ante- rior motoneurones (cf. Table 2.1, Fig. 10.14(b), Table 7.3), a motoneurone pool which is often used to investigate cutaneous pathways in the lower limb. The RII-like response produced in fore- arm muscles by stimulation of the ulnar nerve is subject to the same criticism, because ulnar nerve stimulation also activates muscle group I and group II afferents from the intrinsic muscles of the hand, afferents that have potent excitatory projections to motoneurones of wrist ﬂexors (cf. Chapter 7, p. 305). Despite these drawbacks, electri- cal stimulation is the only method that allows accu- ratemeasurement of responselatencies andis there- fore usually preferred. Recording the responses Responses recorded at rest A recording at rest is made under conditions similar to those of the routine clinical examination. How- ever, only excitatory responses can be so disclosed. Modulation of the average rectiﬁed EMG This is the most commonly used method, because it rapidly reveals the full-time course of excitatory and inhibitory effects produced by the cutaneous volley. The temporal resolution of the method is limited, but this is of less importance here, because there are many uncertainties about the number of interneu- rones in the pathway to the motoneurone, and mil- lisecond precision is not required. The technique is suitable for comparing the reﬂex effects of cuta- neous volleys in different motor tasks, at equivalent levels of background EMG activity (cf. p. 414 and pp. 427–30). However, there are drawbacks to the technique. (i) Volition may bias the transmission in the reﬂex pathways. (ii) Cutaneous afferents may have opposite effects on slow-twitch and fast-twitch motor units (cf. pp. 424–7), so that the EMG recorded during a strongcontractionmaycontainamixtureof opposite responses. Modulation of the monosynaptic reﬂex at rest This technique does not introduce volitional bias. However, besides their effects on motoneurones, cutaneous volleys can produce changes in the excitabilityof PADinterneuronestransmittingpresy- naptic inhibitionof Ia terminals mediating the affer- ent volley of the monosynaptic reﬂex: (i) depression by low-threshold cutaneous volleys (cf. p. 420), and (ii) activation by pathways transmitting late FRA effects (cf. p. 408). Inaddition, a monosynaptic reﬂex cannot be obtained in all muscles, and plotting the recovery curve of the H reﬂex or tendon jerk reﬂex takes a long time because cutaneous effects are long lasting. This is distinctly inconvenient when investi- gating patients. Recordings of single units PSTHs of single units should be recorded because of the opposite effect of some cutaneous stimuli on slow- and fast-twitch motor units. However, it is dif- ﬁcult to keep the same motor unit recording during a withdrawal reﬂex, and no data are available on the projections of nociceptiveafferents todifferent types of motoneurones. Withdrawal reﬂexes 399 Conclusions The method should be adapted to the type of study undertaken. (i) When nociceptive reﬂexes are used to scale pain, i.e. assessingtheeffectsof otherstimuli ordrugs on pain and/or monitoring patients with pain, voli- tional biases shouldbeeliminatedandnoxious (RIII) responses should be studied at rest. (ii) Task-related changes in exteroceptive path- ways are best investigated with the modulation of the on-going EMGactivity, because this rapidly pro- vides thefull timecourseof cutaneous-inducedexci- tatory and inhibitory effects. However, such studies should be complemented by studies of the modula- tion of monosynaptic reﬂexes to estimate the extent of volitional bias and, when possible, by studies on single units to see whether the distribution of the cutaneous input is homogeneous or not among the different units in the tasks tested. Once again, this emphasises the necessity of using different methods in studies on human subjects. Organisation, connections and physiological implications of withdrawal reﬂexes Withdrawal reﬂexes are the traditional reﬂexes pro- ducedby cutaneous afferents inthe standardneuro- logical examination. The protective nature of these reﬂexes has long been appreciated. In 1899, Collier proposed that the function of the ﬂexion reﬂex of the leg was to withdraw the foot from an offending object. Pioneering EMGstudies by the Scandinavian school in the early 1960s demonstrated that the pro- tective functionof withdrawal reﬂexes was consider- ablymorereﬁnedthanhadpreviouslybeenassumed (see pp. 401–7), and recent investigations have con- ﬁrmed a modular organisation of these reﬂexes in normal humans, much as has been described in animal experiments (see p. 407). There are two classes of withdrawal reﬂexes in the lower limbs: the early reﬂexes occurring with a latency less than 100 ms, reﬂexes which are almost certainly spinal, and the long-latency responses (see Figs. 9.3(e), (f ), 9.4(f )–(j), 9.7(b)–(j)). In this chapter, ‘withdrawal reﬂexes’ denote the former when not otherwise stated. Long-latency reﬂexes are considered separ- ately on pp. 407–11. Conclusions about the path- ways underlying withdrawal reﬂexes (in particular the involvement of long-latency responses) rely on results recorded in patients with complete spinal cord transection. These latter results are therefore considered in the subsections discussing the spinal pathways mediating withdrawal reﬂexes. Afferent pathway of withdrawal reﬂexes The afferent pathway of the RIII reﬂex of the short headof the biceps femoris tostimulationof the sural nerve has been investigated in detail (Willer, 1977, 1983; Willer, Boureau & Albe-Fessard, 1978). Parallel between pain sensation and the RIII reﬂex Stimulation of the sural nerve The close parallel between pain sensation and the size of the RIII reﬂex is illustrated in Fig 9.2(l ), (m) (Willer, Roby &Le Bars, 1984), illustrating the effects of a train of ten shocks applied to the sural nerve on theareaof theRIII reﬂex of thebiceps femoris (l ) and on the sensation (m), scaled from 0 (no sensation) to 10 (intolerable pain). The reﬂex threshold and the liminal painsensation, describedas a sharppinprick localised to the point of stimulation (occurring at ∼3 on the scale sensation, Willer, 1977), occur at the same stimulus intensity (∼10 mA). Increasing stim- ulus intensity produces a continuous and almost linear increase in both the reﬂex size and the pain sensation up to a maximum, corresponding to the threshold for intolerable pain, above which further increasesinstimulusintensitynolonger enhancethe RIII reﬂex or the pain sensation. Stimuli delivered to the skin When the stimulus is delivered to the skin in the receptive ﬁeldof the sural nerve insteadof the nerve, 400 Cutaneomuscular and withdrawal reﬂexes the thresholds for the reﬂex and the pain sensation are reduced to ∼5 mA, and curves similar to those in Fig. 9.2(l ), (m) will be recorded, though shifted to the left (Willer, 1977). This shift has been attributed to an inhibitory action of low-threshold afferents in the trunk nerve on transmission in the pathway of the withdrawal reﬂex (cf. pp. 411–12). Afferent volleys involved in producing the RIII reﬂex and pain Role of Aδ ﬁbres The role of A␦ ﬁbres in the production of the RIII reﬂex has been demonstrated by Willer, Boureau & Albe-Fessard (1978), who recorded the reﬂex in the biceps femoris and the neurogramin the sural nerve (right and left traces in Fig. 9.2(i)–(k)). With single shocks of 0.5 ms duration, the ﬁrst wave to appear in the neurogram was characteristic of large-diameter fast-conducting low-threshold afferents (A␤, 55– 60 m s −1 ). At the maximal A␤ amplitude, the sen- sation was not painful and no RIII response was recorded. Pain and the RIII reﬂex appeared at high stimulus intensities of 40–50 mA, when a small delayed response could be recorded in the neuro- gram(arrowinFig. 9.2(i)), indicatingtherecruitment of high-threshold A␦ ﬁbres with conduction veloci- ties of 17–28 ms −1 . That the recruitment of A␦ ﬁbres was necessary to evoke both the RIII reﬂex and pain was conﬁrmed by their disappearance after a lido- caine block of small afferents (Fig. 9.2(j)). Similarly, it is probable that the afferent ﬁbres responsible for abdominal skinreﬂexesarewithintheA␦range, since their conduction velocity has been estimated to be ∼20–30 m s −1 (Kugelberg & Hagbarth, 1958). Possible contribution of Aβ ﬁbres A␤ ﬁbres may contribute to both the RIII reﬂex and pain, provided that they are repetitively stimulated (Willer, Boureau&Albe-Fessard, 1978). Thus, 10 min after a lidocaine block of the A␦ ﬁbres, pain and the RIII reﬂex could be produced by double-shock stim- ulation activating only A␤ ﬁbres, although not by a single shock (Fig. 9.2(j), (k)). Accordingly, it was foundthat stimulationof the sural nerve by a trainat 15 mA, far belowthe electrical threshold of A␦ ﬁbres, produced both an RIII reﬂex and a pain sensation which increased with the number of pulses in the conditioning train. Central pathway of early withdrawal responses The precise number of interneurones intercalatedin polysynaptic ‘ﬂexion reﬂex’ pathways is unknown, even in the acute spinal cat, and these ‘chains of interneurones’ contrast with the well-identiﬁed oligosynaptic pathways responsible for the reﬂex effects of low-threshold muscle afferents. The prob- lemindetermining the pathway and central delay of the withdrawal reﬂex is even more acute in humans because of the length of the afferent pathway and the relatively slow conduction of human afferents compared with those of the cat. It is therefore not surprising that a crucial question about the cen- tral pathway of human withdrawal responses is the extent to which withdrawal responses are spinal reﬂexes. Central delay Superﬁcial abdominal reﬂexes Abdominal reﬂexes have been unequivocally demonstrated to be spinal. With strong stimuli their latency may be as short as 24 ms (Fig. 9.3(s)), with a minimal central delay of 3–5 ms, and this excludes a supraspinal pathway (Kugelberg & Hagbarth, 1958). The central delay of the withdrawal reﬂexes of the limbs is less well deﬁned (i) The gradual decrease in the latency of the inhi- bition of knee extensors when the nociceptive stimulus is moved up the limb has been one of the ﬁrst arguments infavour of a spinal pathway for the withdrawal response (Hagbarth, 1960). Withdrawal reﬂexes 401 Thus, Fig. 9.4(e) shows that the latency of the initial inhibition of the on-going EMG of the vastus medialis decreases from about 65 to 35 ms when the noxious stimulus train is moved from the foot to the perineal or ischial region. This would correspond to a conductionvelocity of 33–40 ms −1 , further suggesting that afferents larger thanA␦sizeareinvolvedintheproduction of withdrawal responses. When allowance was made for a period of temporal summation and the efferent conduction time, Hagbarth (1960) concludedthat thecentral delay‘canhardlyper- mit participationof pathways higher thanspinal in the basic reﬂex arcs’. (ii) The RIII reﬂex of the biceps femoris after sural nerve stimulation is the best documented with- drawal response and has a minimal latency of ∼80 ms. Given (i) the long conduction time of theslowA␦volleyover thelongdistancefromthe ankle to the spinal cord (∼40–50 ms and ∼110 cm, respectively), and (ii) the necessity for tem- poral summation at interneuronal level, such a latency is compatible witha polysynaptic spinal pathway (Hugon, 1973, Willer, 1983). However, the exact central delay remains unknown, andit could be argued that 80 ms is also the latency of transcortical responses elicitedby A␤ ﬁbres (see pp. 421–3), which may evoke the RIII reﬂex (see above). (iii) Withdrawal reﬂexes evoked in the tibialis anter- ior appear to be spinal on latency grounds. Sha- hani &Young (1971) reported a minimal latency of 50–60 ms after stimulation of the sole of the foot, but the afferent volley was not recorded, andit isconceivablethat thehighintensityintra- dermal stimulation activated afferents from plantar muscles. However, arecent investigation using weak stimulus intensities has conﬁrmed that theminimal latencyof thewithdrawal reﬂex in the tibialis anterior may be as early as 65 ms (Andersen, Sonnenborg & Arendt-Nielsen, 1999). (iv) Inthe upper limb, the latency of the nociceptive silent period in the abductor pollicis brevis is 43 ms (see Koﬂer, 2003; Fig. 9.6(g)), signiﬁcantly earlier thanthetranscortical responsemediated throughA␤ ﬁbres (see pp. 421–3), andthis is evi- dence in favour of a spinal pathway. Patients with complete spinal transection Reﬂexes with similar features can be recorded in the tibialis anterior and the biceps femoris in patients with complete spinal transection, and this is often usedas anargument for aspinal originof withdrawal reﬂexes in normal subjects (Shahani & Young, 1971; Hugon, 1973; Willer & Bussel, 1980; Roby-Brami & Bussel, 1987). The existence of such reﬂexes in these patients does demonstratethat thereis aspinal path- way capable of mediating the RIII reﬂex in humans, but the similarity of the latencies does not imply that the responses are mediated by the same pathway in normal awake subjects and spinal patients (see pp. 407–11). Conclusions It is probable that the early withdrawal responses of lower limb muscles are spinal in awake normal subjects. However, some uncertainties remain: (i) In investigations using stimulation of the tibial nerve at the ankle or of its branches, particularly the medial plantar nerve, group II muscle affer- ents probably contribute tothe responses inthe tibialis anterior (cf. p. 398). (ii) Because of the need for temporal summation, the exact central latency of these reﬂexes is uncertain, and so is the number of interneu- rones intercalated in the relevant pathway(s). (iii) The nature of these pathways (speciﬁc or FRA- like) also remains an open question, although thereis increasingevidencethat thereis ahighly specialisedmodular organisationof withdrawal reﬂex pathways (see p. 407). Functional organisation of early withdrawal reﬂexes In the 1910s, emphasis was placed on the segmental organisationof the skinwithdrawal reﬂexes (Walshe, 402 Cutaneomuscular and withdrawal reﬂexes 1914). However, as pointed out by Kugelberg (1962), EMGstudies have shown little evidence for segmen- tal boundaries (see below). It is clear that early with- drawal reﬂexes are not organised on an anatomical (segmental) basis, but onafunctional basis designed to produce rapid movement away from an offend- ing object. The ‘local sign’ is an important feature of withdrawal reﬂexes everywhere (on the trunk as well as in the limbs), and is a consequence of this protective function. Trunk skin reﬂexes Trunkskinreﬂexes areconsideredﬁrst, becausefrom theirrelativelysimpleorganisationit iseasytounder- standthegeneral functional organisationunderlying withdrawal reﬂexes. Although the abdominal skin reﬂex is regarded as a nociceptive reﬂex, the reﬂex may be elicited by stimuli of innocuous quality, such astouch, probablybecauseof theconvergenceof tac- tile and nociceptive inputs from the same skin ﬁeld onto common interneurones, much as described in the rat (see p. 387). These reﬂexes have been investi- gated in detail by Kugelberg & Hagbarth (1958) and an example of abdominal reﬂexes in the external oblique is illustrated in Fig. 9.3(l )–(n) and (p)–(s) using mechanical andelectrical stimulation, respec- tively. Abdominal skin reﬂexes show little evidence of any segmental boundaries and radiate over sev- eral segments ipsilaterally and, to a lesser extent, contralaterally, although the response with the low- est threshold and the shortest latency is conﬁned to the ipsilateral segments in the immediate vicin- ity of the stimulus. ‘A painful stimulus applied to the abdominal skin during steady contraction of the erector spinae muscles evokes a reﬂex contraction of abdominal muscles with reciprocal inhibition of the activity in the erector spinae muscles. . . . In fact, a stimulus applied at any point on the circumfer- enceof thetrunkproducesacontractionpatternwith withdrawal from the offending stimulus. Thus, the abdominal skin reﬂexes are but one manifestation of a defence mechanism of the trunk which func- tionally connects each skin area with the appropri- ate withdrawal and protection muscles’ (Kugelberg, 1962). Plantar responses Because of the clinical importance of plantar responses evoked from the sole of the foot, their reﬁnement with respect to the area of the stimu- lus, and the considerable literature devoted to them, they are considered apart fromthe other withdrawal responses in the lower limb. Involvement of the extensor hallucis longus Different results concerning the involvement of the extensor hallucis longus have been obtained using mechanical and electrical stimulation of the hollow of the foot. (i) Mechanical stimulation produced by the point of a safety-pin on the lateral plantar surface and lateral surface of the foot was used by Landau & Clare (1959) to analyse plantar responses, grading the stimulation by varying the pressure of the pin. They showed that at threshold, in normal adults, the response inthe ﬂexor hallucis brevis (a physiological extensor) appeared before that in the tibialis anter- ior (Fig. 9.5(b), (c)). Increasing the pressure caused a general ﬂexion reﬂex of the lower limb to develop, with responses in the extensor hallucis brevis, semi- tendinosus and tensor fasciae latae (Fig. 9.5(e)). The crucial point of their description was that, whatever thestimulus strength, theresponsesparedtheexten- sor hallucis longus (a physiological ﬂexor, Fig. 9.5(e), (f )), explaining the normal plantar ﬂexion of toe 1. (ii) Noxious electrical stimuli were applied to the skin of the hollow of the foot to produce a general ﬂexion reﬂex of the ankle, knee and hip by Kugel- berg, Eklund & Grimby (1960) and Grimby (1963). This ﬂexion reﬂex was accompanied by activation of muscles responsible for dorsiﬂexing toe 1 and those for plantar ﬂexion more or less simultaneously at a latency of 70–80 ms. However, the plantar ﬂexors were activated more strongly so that the net force moved the toe down. Functional organisation with respect to the receptive ﬁeld The organisation is sketched in Fig. 9.5(j)–(l ), and was investigated in detail using strong electrical Withdrawal reﬂexes 403 (a) (b) (c) (d) (e) (f ) (g) (h) (i ) ( j ) ( k) ( l ) Fig. 9.5. Responses evoked by mechanical stimulation on the lateral plantar surface of the foot. The Babinski sign. (a) Sketch of the presumed pathways. Cutaneous afferents from the lateral part of the sole of the foot activate a chain of interneurones (IN), which mediate excitation to extensor hallucis longus (EHL), tibialis anterior (TA) and ﬂexor digitorum brevis (FDB) motoneurones (MN). Transmission in the pathway to EHL MNs is normally tonically inhibited from the corticospinal tract. (b)–(g) EMG responses elicited by mechanical stimulation of the lateral plantar surface of the foot in various muscles: FHB, TA, extensor hallucis brevis (EHB), EHL, semitendinosus (ST), tensor fasciae latae (TFL). Moment of contact: vertical continuous line. (b)–(e) Responses obtained by increasing pressure in the same normal subject. (f ), (g) Responses in the FHB, TA and EHL are compared in another normal subject (f ) and in a tetraplegic patient ((g), two months after the injury). Horizontal calibration: 1s. (h)–(l ) Schematic drawing of withdrawal reﬂexes after electrical stimulation (arrows) on the ball of the great toe ((h), ﬂexion reﬂex with contraction of the EHL, TA, hamstrings [H], rectus femoris [RF], psoas [Ps], rectus abdominis [Rect Abd]), on the buttock ((i) extension reﬂex with contraction of gluteus maximus [Glut], erector spinae [Erect Sp] and FDB), and on different parts of the sole of the foot ((j)–(l )). Modiﬁed from Landau & Clare (1959) ((b)–(g)), Kugelberg, Eklund & Grimby (1960) ((h), (i)), and Kugelberg (1962) ((j)–(l )), with permission. 404 Cutaneomuscular and withdrawal reﬂexes stimuli appliedto various areas of the sole of the foot (Kugelberg, Eklund & Grimby, 1960; Grimby, 1963). As statedbyKugelberg(1962), ‘thereﬂex defencesys- tem for the plantar surface of the toes and foot is designed primarily to protect the foot when the sub- ject is in the upright position, e.g. during walking, running andjumping, whenthe chances of aninjury to the foot are the greatest’. (i) The ball of the toes is the only area for which ﬂexionof all lower limbmuscles is the adequate pro- tection movement. Accordingly, stimulation of the ball of toe 1 in a normal subject will elicit reﬂex con- tractionof boththeextensor hallucis longus andbre- vis withdorsiﬂexionof toe 1, withdrawing it fromthe offending stimulus (Fig. 9.5(j), (h)). (ii) Astimulus tothe hollowof the foot andthe sur- rounding areas produces the normal plantar reﬂex, i.e. plantar ﬂexionof thetoeswithﬂexionat theankle, knee and hip. This is the adequate movement for protection of this area. When the subject is standing upright, plantar ﬂexion of the toes would raise the sole from the ground (Fig. 9.5(k)) and so long as the toes are in contact with the ground would assist in the general withdrawal movement. (iii) Whenthe stimulus is appliedto the heel, there is a plantar ﬂexion of the toes and extension of the ankle (Fig. 9.5(l )). This pattern, combined with ﬂex- ionat the knee andhip, represents the most effective withdrawal response to protect the heel. Maturation of plantar responses In 1898, Babinski drew attention to the presence of an upward response of toe 1 in the newborn, a phenomenon that had not escaped the renais- sance artist, Botticelli (see Lance, 2002). In normal neonates, stimulation of the sole of the foot pro- duces a ﬂexion synergy with an upward response of the toes, which is much brisker than in adults. As the pyramidal system matures, the response of the toes becomes reversed at a variable age from7 months to a year or more, and the entire ﬂexion reﬂex becomes less brisk. In most normal adults all that is left is a subtle contraction of proximal muscles, particularly of the tensor fasciae latae (see vanGijn, 1996). Inthis respect, thenormal responseinclinical investigation is closer to that illustrated in Fig. 9.5(d) than that of Fig. 9.5(e), whichmay have beenproducedby a more painful stimulus. Other withdrawal responses than plantar responses in the lower limb The principles underlying the general organisation of withdrawal reﬂexes other than plantar responses in the lower limb have been established in a seminal paper by Hagbarth (1960). Noxious electrical stimuli (trains of 5–10 stimuli in 10–20 ms, at 5–10 mA, pro- ducing an intense burning sensation) were applied to different areas of the skin of the limb during weak on-going contractions of various lower-limb mus- cles. This allowed a systematic analysis of the recep- tive ﬁelds for withdrawal responses in individual muscles. Receptive ﬁelds for individual muscles Figure 9.4(e) shows the responses inthe vastus medi- alis, a pure extensor of the knee. Stimuli applied to the leg or the posterior aspect of the thigh caused an initial inhibition, while stimuli to the anterior aspect of the thigh caused an initial reﬂex discharge. The sketches of Fig. 9.4(k)–(m) show the results of similar analyses performed for the hip extensor, glu- teus maximus, the ankle extensor, gastrocnemius- soleus and the ankle ﬂexor, tibialis anterior. Skin areas which produced primarily excitation are indi- cated by ÷, and those which produced inhibition by –. It should be noted that gastrocnemius-soleus responded in a reciprocal manner to tibialis ante- rior, activated fromthose skin areas which inhibited the ﬂexor, and vice versa. These results agree fairly well withthose obtainedinthe spinal cat (see p. 387). Theweakvoluntarycontractionusedintheseexperi- ments probably did not bias the results signiﬁcantly: noxious stimuli applied to the distal part of the limb produce an early facilitation of the biceps femoris tendon jerk and inhibition of quadriceps and soleus tendon jerks at ISIs corresponding to the latencies of the excitatory and inhibitory responses in the Withdrawal reﬂexes 405 on-going EMG of these muscles (Hugon, 1973, and Fig. 9.4(b)–(d), (•)). The organisation of withdrawal reﬂexes in humans can be summarised by stating that extensor muscles are inhibited from most parts of the limb as part of the ﬂexion withdrawal, but are activatedby cutaneous stimuli over themuscleitself. There are reciprocal responses in antagonistic ﬂexor muscles. The main function of early nociceptive reﬂexes is protective The ﬂexion movement which occurs at joints prox- imal to the stimulus represents the classical ﬂexion reﬂex, andhas anavoidance capacity. The protective function of extension movements at joints distal to the stimulus is also protective if the subject is stand- ing with lower-limb joints in slight ﬂexion. Ankle extension then removes the leg from calf stimu- lation, and knee extension causes withdrawal from an offending object on the front of the thigh. Simi- larly, a stimulus tothe buttock produces extensionof the hip and contraction of the erector spinae, both of which result in withdrawal fromthe stimulus (see Kugelberg, Eklund & Grimby, 1960; Fig. 9.5(i)). Withdrawal responses in the upper limb Silent periods in intrinsic muscles of the hand The most systematic study of silent periods evoked by noxious stimuli in intrinsic muscles of the hand is the recent investigation by Koﬂer (2003), which also reviews the literature on this topic. The higher the stimulus intensity to the ﬁnger tip, the deeper the cutaneous silent period in the abductor pollicis brevis (APB) and the earlier its latency (Fig. 9.6(d)– (g)). Qualitatively similar results were found in the abductor digiti minimi (ADM) and the ﬁrst dorsal interosseous (FDI). However, in response to nox- ious stimulation (20 PT) to the index and ﬁfth ﬁn- gers, there is a clear ‘local sign’ in the silent peri- ods of the three muscles, which are supplied by the same myotome. Stimulation caused an earlier and deeper nociceptive silent period in APB and FDI when applied to the index ﬁnger than to ﬁnger V, while the reverse occurred with ADM. Again, this indicates a functional organisation of the underly- ing spinal circuitry which is not based on anatom- ical metameric boundaries, but on the functional relevance of the responses. Appropriately, there is a similar topographic organisation of tactile cutaneo- muscular reﬂexes, again suggesting convergence of tactile and nociceptive afferents from the same skin ﬁeld onto common interneurones. The ﬁnding that the H reﬂex and the MEP in the APB are similarly inhibited by noxious cutaneous stimuli indicates that the suppression is due to postsynaptic inhibi- tion of motoneurones, not to presynaptic inhibition of the contraction-associatedIa afferent activity that helps sustain the voluntary contraction (Manconi, Syed & Floeter, 1998; Fig. 9.6(h)–(m); cf. Chapter 8, pp. 343–4). Withdrawal responses elicited at rest Therehavebeenfewstudies of withdrawal responses in non-contracting muscles of the upper limb. Cam- bier, Dehen & Bathien (1974) reported that stimula- tionof A␦ﬁbres inthe ulnar nerve at the wrist evokes a RIII-like reﬂex, with a minimal latency of 60 ms in the FCU, involving biceps with higher intensi- ties. The question was revisited recently by Floeter et al. (1998) using electrical stimulation of the dig- ital nerves. Single shocks did not evoke any reﬂex at any intensity. A noxious train to the index ﬁn- ger evoked a response in all recorded muscles (Fig. 9.6(b)), but the net biomechanical result was ﬂexion of the elbow and extension of the wrist. The short- est latencies were seen in the biceps, ECR and FCR, 60–80 ms after stimulus onset. A response was not seen consistently in intrinsic muscles of the hand and, when present, occurred at a longer latency (80– 100 ms). Interestingly, the latency of the response in wrist muscles (ECR and FCR) was shortened by 20–30 ms, when noxious stimulation of the con- tralateral index ﬁnger was delivered 100 ms before the test train. This result supports the view that withdrawal responses are mediatedthrougha spinal mechanism. Changes in the location of the stimulus 406 Cutaneomuscular and withdrawal reﬂexes Deltoid Biceps Triceps ECR FCR APB 100 ms 100 µV 100 ms 100 µV Rest Grasping an object Bi. Tri. ECR APB Withdrawal INs MNs (a) (b) (c) (d) (h) (i ) ( j) (e) (g) (f ) Cut. Median TMS Cut. + median Cut. + TMS 50 ms 0.5 mV Cutaneous + H reflex Cutaneous + MEP 200 µV 100 ms 2 x PT 5 x PT 10 x PT 20 x PT Cutaneous silent period in APB ( k) ( l ) (m) Fig. 9.6. Cutaneous withdrawal reﬂexes of the upper extremity. (a) Sketch of the presumed pathways: cutaneous afferents mediating pain sensation from the index ﬁnger excite, through a chain of spinal interneurones (withdrawal IN), motoneurones (MN) innervating proximal muscles (biceps [Bi], triceps [Tri], extensor carpi radialis [ECR]), and inhibit MNs innervating intrinsic muscles of the hand such as abductor pollicis brevis (APB). (b), (c) EMG responses recorded, from top to bottom, in deltoid, Bi, Tri, ECR, FCR and APB following cutaneous stimulation to the index ﬁnger (10 pulses, 300 Hz, at 4 PT in (b) and 6 PT in (c), stimulus artefacts being redrawn and truncated). (b) Responses obtained at rest. (c) Responses during grasping an object between thumb and foreﬁnger while keeping more proximal muscles relaxed. The onset of EMG activity in proximal muscles (dotted vertical line) occurred when EMG activity was silenced in the intrinsic muscles of the hand. (d )–(m) Cutaneous silent period in the APB evoked by a single electrical shock. (d )–(g) Rectiﬁed APB EMG (20% of MVC) conditioned by increasing electrical stimulation applied to the tip of the index ﬁnger: 2 PT (d ), 5 PT (e), 10 PT (f ), 20 PT (g). The vertical line indicates stimulus onset, and horizontal lines indicate zero EMG activity. (h)–(m) Suppression by stimulation (6 PT) to the ﬁfth ﬁnger of various responses in the APB. (h), (k) Silent period in the on-going EMG. (i), (l ) Control H reﬂex (i) and MEP (l ), (j). (m) Cutaneous suppression both of the H reﬂex (80 ms ISI) and the MEP elicited by TMS (90 ms ISI). The stimulus artefacts in (i), (j) and (l ), (m) indicate the timing of the median and TMS stimuli, respectively. Modiﬁed from Floeter et al. (1998) ((b), (c)), Koﬂer (2003) ((d )–(g)), and Manconi, Syed & Floeter (1998) ((h)–(m)), with permission. Withdrawal reﬂexes 407 (ﬁnger V, palmar or dorsal side of ﬁngers II and III) didnot change the responses. Arguably, this may not represent the absence of ‘local sign’ because, what- ever the hand region stimulated, the adequate reac- tion is to withdraw it. Relationship between the nociceptive silent period in hand muscles and proximal withdrawal reﬂexes This relationshipwas exploredby deliveringthe nox- ious stimulus to ﬁngers II or V as the hand grasped anobject betweenthumbandforeﬁnger, while prox- imal muscles were relaxed (Floeter et al., 1998). As shown in Fig. 9.6(c), a silent period was produced in hand muscles at the same time as withdrawal exci- tation was evoked in forearm and arm muscles. As a result, most subjects transiently lost their grasp on theobject, sometimes tossingit away, andmovedthe arm upwards and outwards. These nociceptive responses have a protective function The combination of the withdrawal reﬂex in proxi- mal muscles and the silent period in hand muscles is appropriate for protecting the hand, opening and withdrawing it when there is an offending stimulus to the ﬁngers. The functional relevance of nocicep- tive responses is also supported by the ﬁnding that thefunctional unit whichis most intimatelyinvolved in the prehensile grasp (index and thenar) receives the most powerful inhibition from the index (Koﬂer, 2003; see above). Modular organisation of withdrawal reﬂexes The above results show a speciﬁc organisation of withdrawal reﬂexes witha‘local sign’. Recent investi- gationsusinglesspainful stimuli at 1.5painthresh- old applied to 16 different limited areas of the sole of the foot have delineated the organisation of exci- tatory and inhibitory withdrawal responses evoked in various ankle muscles (Andersen, Sonnenborg & Arendt-Nielsen, 1999; Sonnenborg, Andersen & Arendt-Nielsen, 2000). The results concerning ankle dorsiﬂexion and plantar ﬂexion seen on pp. 402–4 were conﬁrmed, and it was shown in addition that stimuli to the medial distal sole produce inversionof the foot, while those tothe lateral distal sole produce eversion. Thus, it seems that humans have a similar modular organisationof withdrawal reﬂexes as inthe rat (p. 387). Late withdrawal responses In normal subjects, late withdrawal responses, at a latency longer than 120 ms, usually follow the early responses, when the stimulus intensity is high (Figs. 9.3(e), (f ), 9.4(i), (j)). In tibialis anterior, the main mechanical component of the withdrawal movement is producedby the long-latency response (cf. upper trace in Fig. 9.3(f ); Shahani & Young, 1971). Late responses also occur in the upper limb (e.g. see the response in the ECR in Fig. 9.6(b)). Results obtained in patients with complete spinal transection (cf. below) show that humans have a pathway analogous to the long-latency FRA path- way described in the cat (cf. pp. 390–1), but whether long-latency withdrawal responses in normal sub- jectsaretransmittedthroughthispathwayisamatter of debate. Late withdrawal responses in patients with complete spinal cord transection In patients with complete spinal cord lesions, sev- eral arguments suggest the existence of a pathway transmitting long-latency responses, analogous to the long-latency FRApathway describedinthe acute spinal cat after DOPA (Roby-Brami & Bussel, 1987, 1990, 1992). Long-latency ﬂexor reﬂexes When such patients are tested more than 6 months after the initial lesion, noxious cutaneous stimuli applied to the nerves of the foot do not produce the same withdrawal responses in ﬂexor muscles as in normal subjects. 408 Cutaneomuscular and withdrawal reﬂexes (i) In tibialis anterior and, to a lesser extent, in biceps femoris, early responses with a latency less than 120 ms are rare (Fig. 9.7(c)–(f ) and (g)–(j)). (ii) Instead, long-lasting long-latency responses appear consistently in the two muscles (Fig. 9.7(c)– (j)). When both responses are present, the thresh- old for the late response is lower than that for the early response. The ﬁnding that late responses often appear without any early response in homonymous or heteronymous muscles indicates that they are neither afterdischarges (see Creed et al., 1932) nor produced by twitch-induced afferent discharges. Early FRA pathways inhibit late FRA pathways A crucial feature of late responses is their increase in latency as the stimulus intensity increases (Fig. 9.7(c)–(j)), or the stimulus train is prolonged. The latter point is illustrated in Fig. 9.7(b), which shows that the onset of the late reﬂex is delayed after the end of the stimulus train regardless of its dura- tion. This is reminiscent of the long-latency FRA response observed in the acute spinal cat injected with DOPA (see Lundberg, 1979; pp. 390–1), and the above results could be explained by inhibition of transmission in late FRA pathways by activation of early FRA pathways, even though this was insufﬁ- cient to produce an overt early FRA response. Thus, the primary change in the spinal cord following the chronic spinal lesion could be decreased excitability of pathways mediating early responses. This would account for (i) the depressionof early ﬂexionreﬂexes withrespect tonormal subjects, and(ii) the resulting release of transmission in late FRA pathways (path- way ‘Y’ inFig. 9.1(e)). However, eventhoughthe acti- vation of early FRA pathways is insufﬁcient to evoke the early ﬂexion reﬂex, the late response might still be inhibitedby activationof early pathways, andthis wouldoccur withashorter central delaythanthelate reﬂex itself. Through pathway ‘X1’ in the sketch of Fig. 9.1(e), this inhibitory effect would prevent the late reﬂex frommanifesting itself until the inhibition ceased. As a result, there would be an increase in latency of the late response when the conditioning train was prolonged, much as occurs in the DOPA- treated cat. Presynaptic inhibition of Ia terminals Stimulation of contralateral high-threshold cuta- neous afferents has complex effects on the soleus H reﬂex (Fig. 9.7 (k)). There is an early peak of facilitation at the same latency as the early ipsi- lateral response of ﬂexor muscles, corresponding to the crossed extensor reﬂex. This is followed by a late long-lasting but weak facilitation at ISIs of 200–700 ms, and then by inhibition. The late facilitation is weak, because it is the result of two opposite effects: (i) a post-synaptic excitation, which is the counterpart in contralateral exten- sors of the ipsilateral long-latency excitation of ﬂexors, and (ii) increased presynaptic inhibition of Ia terminals mediating the afferent volley of the soleus H reﬂex, demonstrated using the het- eronymous facilitation of the H reﬂex (Chapter 8, pp. 345–6). These results provide a further simi- larity to the late FRA responses observed in the DOPA-treated cat, in which there is long-latency long-lasting postsynaptic excitation of contralateral extensors, together withalong-lastingprimaryaffer- ent depolarisation of Ia terminals of both sides (Lundberg, 1979). Stimulation of contralateral high-threshold cutaneous afferents depresses the late ipsilateral ﬂexor reﬂex When stimulation of contralateral afferents condi- tions the ipsilateral reﬂex in tibialis anterior, the early ﬂexor response is not affected, while the late response disappears almost completely (Fig. 9.7(l ), (m)). This inhibition is not due to inhibition of the target motoneurones, because the tibialis anter- ior H reﬂex is not inhibited, or to presynaptic inhi- bition of cutaneous terminals mediating the ﬂexor reﬂex response, because the early response is not modiﬁed. The most parsimonious explanation is therefore mutual inhibition between the chains of interneurones mediating long-latency ipsilateral and contralateral FRA effects, much as described in the DOPA-treated cat (see Lundberg, 1979; Fig. 9.1(d)). (a) (b) (c) (g) (h) (i ) ( j ) ( k) ( l ) ( m) (d) (e) (f ) Fig. 9.7. Late ﬂexion reﬂex in paraplegic patients. (a) Sketch of the presumed pathways: ipsilateral ﬂexor reﬂex afferents (FRA) activate a chain of early FRA interneurones (INs) (thin dotted line) and a chain of late FRA INs (thick dashed line). Late FRA INs are inhibited by early FRA INs and by contralateral FRA. (b) Rectiﬁed EMG responses in tibialis anterior (TA) to stimulus trains (70 Hz, 50 mA) of increasing duration (60, 160, 260, 360 ms from top to bottom) to the tibial nerve (the stimulus artefacts being redrawn and truncated). (c)–(j) Rectiﬁed EMG responses (average of three sweeps) elicited simultaneously in TA ((c)–(f )) and biceps femoris ((g)–(j)) to stimulation of the sural nerve (trains of 10 shocks, 300 Hz) of increasing intensity: 5 mA ((c), (g)), 10 mA ((d), (h)), 15 mA ((e)–(i)), 20 mA ((f )–(j)). Vertical dotted lines in (b)–(j) highlight the increase in latencies of the late responses when the stimulus train was prolonged (b), or the stimulus intensity increased ((c)–(j)). (k)–(m) Effects of stimulation of the contralateral FRA (train of ten shocks to the sural nerve, 300 Hz, 50 mA) on the soleus H reﬂex (k) and the early and late ﬂexor reﬂexes elicited in TA by ipsilateral stimulation of the sural nerve ((l ), (m)), train of ten shocks, 300 Hz, 10 mA). (k) The size of the H reﬂex (expressed as a percentage of its unconditioned value) is plotted against the ISI. Each point is the mean of ﬁve measurements, vertical bars ±1 SEM. (l )–(m) Flexor reﬂexes in the TA in a control situation (l ) and when stimulation of contralateral FRA (m) occurs 200 ms earlier (arrow). Modiﬁed from Roby-Brami & Bussel (1987) (b), and Bussel et al. (1989) ((c)–(m)), with permission. 410 Cutaneomuscular and withdrawal reﬂexes Conclusions Several lines of evidence suggest that the human spinal cord contains a pathway analogous to the long-latency FRA pathway revealed in the acute spinal cat bytheadministrationof DOPA. Theﬁnding that, in patients with complete spinal cord transec- tion, long-latency responses only appear in patients withchroniclesions, whenearlyresponses areatten- uated or have disappeared (cf. p. 433), favours the viewthat transmissioninlong-latency pathways can be inhibitedby pathways mediating the early effects. Late responses in normal subjects are not spinal in origin The late responses seen in normal subjects do not have the characteristics of long-latency reﬂexes described in patients with spinal cord transection and they are probably not spinal. Several features suggest that they involve supraspinal pathways. Absence of characteristics of long-latency FRA-like responses (i) Late responses of normal subjects are always associated with an early response, and the threshold of the late response is higher than that of the early response (Shahani & Young, 1971; Meinck, Benecke & Conrad, 1983). By contrast, in patients with spinal cord transection, the threshold of the early response is the higher, and the depression of transmission in the pathway of the early responses seems to be a prerequisite for the long-latency responses. (ii) The latency of late responses decreases when the stimulus strength is increased (Shahani & Young, 1971). In spinal patients, increasing stimu- lus strength or the duration of the conditioning train increases the latency of the late response, a partic- ularly strong argument infavour of a transmissionof the late response thoughlong-latency FRApathways (Roby-Brami & Bussel, 1987; cf. p. 408). Plasticity of late responses Hagbarth & Finer (1963) performed experiments in which the noxious stimulus was continued up to the withdrawal movement which terminated the stimu- lus by removing the limb fromthe electrode. They so demonstrated that the avoidance capacity of with- drawal reﬂexes in a new situation depends on late not early responses. (i) In the sitting position drawn in Fig. 9.4(i), a stimulus on the calf must cause a contraction of knee extensors to move the leg away from the stim- ulus. However, according to the results shown in Fig. 9.4(e), the initial reﬂex effect of a brief calf stimu- lus is inhibition of the activity in the vastus medialis, which would allow knee ﬂexion with movement of the leg towards the stimulus (Fig. 9.4(f )). The same earlyeffect wasobservedinexperimentsinwhichthe stimulating current was continuous and the subject couldavoidit only by removing the leg fromthe elec- trodes (which initially were in contact with the skin, but not attached to it). However, when continuous stimulation was applied, there was an extension of the knee due to a strong late discharge in the vastus medialis at a latency of 120 ms (Fig. 9.4(g)). (ii) During hypnotic analgesia, the late discharge (and the resulting knee extension) disappeared, while the early inhibition was hardly inﬂuenced by suggestion (Fig. 9.4(h)). (iii) The inﬂuence of the initial position on the early and late responses of the vastus medialis to continuous noxious stimulation applied to the front of the leg and the calf was determined when the subject was sitting and standing (Fig. 9.4(i)–(j)). Whatever the posture, both stimuli produced ini- tial inhibition, an inappropriate response to calf stimulation in sitting position (i) and to stimulation of the front of the leg when standing (j) because such responses would move the leg towards the offending the stimulus. In both cases the appro- priate movement occurred because a large late response compensated for the initial inappropriate response. (iv) Trainingexperimentswereperformedinwhich the subject could turn off a continuous unpleasant stimulus only by performing a movement towards the electrodes. The sign of the late response was reversed after a few trials, but not that of the early response even after training for a month. Withdrawal reﬂexes 411 The above results showthat, while early responses are ﬁxed, withdrawal responses can adapt to a new situationby a change inthe signof the late response. It was suggested that early responses are hardwired inthe spinal cord, whereas the late responses of nor- mal subjects involve supraspinal centres and have developed largely through experience (Hagbarth & Finer, 1963). Interactions between different inputs in withdrawal reﬂex pathways Besides the inhibition of the transmission in long- latency FRA pathways by activity in early FRA pathways, and the mutual inhibition of pathways mediating ipsilateral and contralateral long-latency reﬂexes seenabove, various peripheral anddescend- ing inputs have been shown to modulate the trans- mission in withdrawal reﬂex pathways. Effects of painful homonymous cutaneous volleys The effects of repeatedstimulationare complex with facilitationat short ISIs and suppressionat long ISIs. Facilitation at short ISIs Repeated painful cutaneous volleys at intervals below 3 s facilitate the withdrawal reﬂex in biceps femorisandtibialisanterior (Hugon, 1973; Shahani & Young, 1971). Thus, when a painful electrical stimu- lus tothe sural nerve at 3.5 PTis repeatedevery 2 s, theamplitudeanddurationof theRIII reﬂexinbiceps femoris increases progressively, in parallel with the pain sensation, while its latency decreases (cf. Fig. 9.2(n)–(q) where the eleventh reﬂex of the series is larger than the ﬁfth, which is itself larger than the ﬁrst). The tibialis anterior withdrawal reﬂex elicited by stimulation of the medial aspect of the sole of the foot is similarlyfacilitated, withdecreasedlatency, by a stimulus delivered 1 ms earlier (Shahani & Young, 1971; Fig. 9.3(h)). Suppression at long ISIs At ISIs longer than 3–4 s, facilitation is replaced by suppression, withdecreasedamplitudeandduration and increased latency of the response (Shahani & Young, 1971; Fig. 9.3(i), (j)). Thereafter the response comes back to its control value by 60 s (Fig. 9.3(j)). Underlying mechanisms The mechanisms responsible for the modulation of withdrawal reﬂexes by preceding painful volleys are probably spinal, because similar results have been recorded in spinal patients with a complete spinal transection, bothinthebicepsfemoris(Hugon, 1973) and the tibialis anterior (Shahani & Young, 1971; Dimitrijevi´ c & Nathan, 1968, 1971; Hornby et al., 2003; Fig. 9.3(j)). The facilitation of the RIII reﬂex in the short headof biceps at short ISIs is not accompa- niedby a facilitationof the tendonjerk of this muscle at corresponding ISIs (Hugon, 1973). This indicates that the ‘sensitisation’ at short ISIs was exerted at a premotoneuronal level. The simplest explanation wouldbethat facilitationat short ISIsanddepression at long ISIs reﬂect post-activation facilitation and depression of transmission at the synapse of cuta- neous afferents with interneurones. Depression, at least, has been described in dorsal horn interneu- rones activated by low-threshold cutaneous affer- ents (Hammar, Slawinska & Jankowska, 2002). Effects of other peripheral inputs Depression by tactile cutaneous volleys Tactile cutaneous volleys depress the biceps femoris RIII reﬂex (Hugon, 1973), as illustrated in Fig. 9.2(d), (e), where tactile stimulation of the sural nerve at 1 PT, 50 ms before the test stimulus, suppressed the withdrawal reﬂex almost completely. Accord- ingly, before ischaemic blockade of large A␤ ﬁbres, the RIII reﬂex was small and preceded by the RII response elicited by tactile afferents, whereas after the block and the resulting disappearance of the RII reﬂex, the same stimulus evoked a much larger RIII 412 Cutaneomuscular and withdrawal reﬂexes response (Fig. 9.2(g), (h); Willer, 1977). The depres- sion of RIII by tactile afferents is maximal at ISIs of 100–300 ms and lasts for several hundreds of milliseconds (Hugon, 1973). A similar depression, though weaker and briefer, is observed after stimu- lation of tactile afferents in the superﬁcial pero- neal nerve. This depression could result from post- synaptic inhibition of interneurones mediating RIII effects by low-threshold cutaneous afferents, as has been described in the cat lumbosacral cord (Hongo, Jankowska & Lundberg, 1966). However, the long- lasting time course of the depression rather suggests presynaptic inhibitionof cutaneous terminals by the conditioning cutaneous volley, a phenomenon that is potent inthecat (Eccles, Kostyuk&Schmidt, 1962). Facilitation by non-noxious thermal stimuli Stimuli produced by a CO 2 laser and evoking a sen- sation of warmth in the skin ﬁeld of the sural nerve facilitate the RIII reﬂex of the biceps femoris. This facilitation has two peaks, at ISIs of 500 and 1100 ms, due to the convergence of A␦ and C ﬁbres ema- nating fromwarmth receptors and fromnociceptive afferents ontocommoninterneurones (Plaghki et al., 1998). Descending effects There is no direct evidence for descending control of pathways mediating withdrawal reﬂexes in humans. However, several arguments indicate the existence of descending controls. (i) The attenuation of early withdrawal reﬂexes in patients with chronic spinal cord injury, when com- pared with normal subjects (pp. 407–8), indicates that the spinal lesionhas deprivedthe relevant path- ways of atonicexcitatorydriveand/or removedtonic inhibitory control of a spinal inhibitory circuit. This could involve the monoaminergic inhibition from the brainstem described in the cat (see Lundberg, 1982; Fig. 9.1(e)). (ii) The ﬁndings that early withdrawal reﬂexes may be modiﬁed by habituation and attention, and may besusceptibletohypnotic suggestionindicatea descending control of the pathways mediating such reﬂexes in the trunk and lower limbs (Kugelberg & Hagbarth, 1958; Hagbarth & Finer, 1963). (iii) There are depressive effects of heterotopic noxious stimuli applied to a remote part of the body suchas the hand or face onearly withdrawal reﬂexes (Willer, Roby & Le Bars, 1984). These effects are not seeninpatients withcompletetransectionof thecer- vical spinal cord and could be another example of descending control of spinal withdrawal pathways (Roby-Brami et al., 1987). Changes in withdrawal reﬂexes during motor tasks Voluntary contraction Changes in withdrawal reﬂexes during voluntary contraction have been poorly documented, and would deserve to be revisited. Cutaneous reﬂexes of the trunk Thecutaneous reﬂexes of thetrunkevokedbyagiven stimulus may be altered by a change inposture or an appropriate voluntary contraction. The reﬂex alter- ation involves the latency and size of the reﬂex dis- charge, but occasionally there may be a reversal of the reﬂex effect (Kugelberg & Hagbarth, 1958). Nociceptive inhibition of the soleus H reﬂex Inhibitionof thesoleus Hreﬂex producedbynoxious stimulation of toe 1 or toe 5 has been compared at rest and during voluntary contractions of the soleus andtibialis anterior (Pierrot-Deseilligny et al., 1973). As illustrated in Fig. 9.8(b), (c), the inhibition was more marked at rest with stimulation of toe 5. Dur- ing tonic voluntary contractions of soleus or tibialis anterior, the inhibition from toe 5 was reduced (b), but the inhibition from toe 1 was not modiﬁed (c). These results indicate that changes in withdrawal responses of the distal extremity during voluntary contractions are determined more by the site of the noxious stimulus (‘local sign’) than by the muscle involved in the contraction. Given the absence of Withdrawal reﬂexes 413 (a) (b) (c) (d) (g) (h) (e) (f ) Fig. 9.8. Task-related nociceptive reﬂexes in the lower limb. (a) Sketch of the presumed pathways. Nociceptive afferents from the ball of the toes and the sole of the foot activate chains of spinal interneurones (IN) with excitatory projections to tibialis anterior (TA) motoneurones (MN) and inhibitory projections to soleus (Sol) MNs. (b), (c) Modulation of the Sol H reﬂex by noxious stimulation (10 shocks, 300 Hz, 2 PT) applied through ring electrodes to the ﬁfth (b) and the ﬁrst (c) toe. The amplitude of the test reﬂex (expressed as a percentage of its unconditioned value) is plotted against the ISI (measured from the onset of the train) at rest (❍), and during tonic contraction of either soleus (●) or tibialis anterior (). (d )–(h) Modulation of the rectiﬁed on-going TA EMG by electrical stimulation of the sole of the foot (10 shocks, 500 Hz, 1.2 pain threshold). (d )–(f ) Results are compared during bipedal stance (d ), and unipedal stance on either the ipsilateral leg (e) or the contralateral leg (d ). (g), (h) The area of the rectiﬁed TA response (expressed as a percentage of control value in bipedal stance with an interfoot distance of 10 cm) is plotted against the loading of the ipsilateral leg ((g) 100%: symmetrical bipedal stance) or the lateral distance between the two feet (h). Each symbol is the grand average of results obtained in 12 ((b), (c)) or 6 ((g), (h)) normal subjects. Vertical bars ±1 SEM. Modiﬁed from Pierrot- Deseilligny et al. (1973) ((b), (c)), and Rossi & Decchi (1994) ((d )–(h)), with permission. changes in the inhibition from toe 1, it is unlikely that the changes fromtoe 5 during contraction were produced by a speciﬁc effect of the contraction- induced afferent discharge only on the responses from toe 5. These changes are likely to result from a descending control, and can be interpreted in terms of the requirements of unilateral stance or asymmetrical loading. The lateral part of the sole of the foot, including toe 5, bears much of the load during unilateral or asymmetrically loaded stance, and postural instability is compensated for by adaptive contractions, involving soleus and tibialis 414 Cutaneomuscular and withdrawal reﬂexes anterior. Inhibition of withdrawal reﬂexes from the supporting area would prevent them from conﬂict- ing with the support role, as discussed below. Postural tasks Reﬂex responses evoked in tibialis anterior by a nox- ious stimulus applied to the medial anterior part of the sole have been explored while the subjects maintained different postures during upright stance (Rossi & Decchi, 1994). Standing on one leg resulted in a signiﬁcant decrease in the withdrawal reﬂex of the ipsilateral tibialis anterior, whereas a signif- icant facilitationwas observed whenthe subject was standing on the contralateral leg (Fig. 9.8(d)–(f )). A progressive depression of the withdrawal response was observed when the subject gradually shifted body weight from one leg to the other: the more loaded the ipsilateral leg, the smaller the response (Fig. 9.8(g)). Similar depressionwas observedinsym- metrical bilateral stance whenthe interfoot distance was increased so that the hips were more abducted, and the load was greater on the mechanoreceptors of the stimulatedarea, the medial anterior part of the sole (Fig. 9.8(h)). Thus, the withdrawal responses of tibialis anterior are suppressed when the support- ing function of the leg increases. The function of this suppression is clearly to prevent the response from jeopardising stance. It was proposed that the load to which the limb is subjected is measured from the activity of peripheral mechanoreceptors, and forms the basis on which the reﬂex is regulated at a spinal and/or supraspinal level. Organisation, connections and physiological implications of cutaneomuscular reﬂexes evoked by non-noxious stimuli The different responses Reﬂexresponses evokedbylow-thresholdcutaneous afferents can be documented by different methods (cf. pp. 394–6), but eachhas drawbacks. Apriori, only the early responses occurring with latencies com- patible with a spinal pathway fall within the ﬁeld of a book centred on spinal circuitry. However, there must be some discussion of long-latency transcorti- cal responses, in part because some have long been considered spinal reﬂexes. RII reﬂex at rest RII reﬂex The RII reﬂex elicited at rest in the short head of the biceps femoris by low-intensity stimuli to the sural nerve at the ankle (Fig. 9.2(b)) is the most consis- tent example of a cutaneomuscular reﬂex record- able at rest (see Hugon, 1973; p. 394), and in the fol- lowing ‘RII reﬂex’ refers to this particular response when not otherwise stated. A RII-like response may be occasionally recordedinother muscles (cf. p. 396; Fig. 9.10(b)). Recording these reﬂexes at rest, without volitional bias, represents the purest way to investi- gate ‘private’ cutaneous spinal pathways. However, RII-like reﬂexes suffer several drawbacks (i) They can be evoked only in some muscles. (ii) They cannot be evoked consistently in all sub- jects. (iii) They always require temporal summation (using long trains) which makes the estimation of the central delay difﬁcult. (iv) They provide no insight into the inhibitory effects of the input. Cutaneomuscular reﬂexes during voluntary contraction Modulation of the on-going EMG The technique of modulating the on-going EMG activity by tactile cutaneous volleys was introduced by Gassel & Ott (1970) for triceps surae and by Caccia et al. (1973) for hand muscles. This tech- nique has since been used extensively to investi- gate human pathways mediating effects produced Non-noxious cutaneomuscular reﬂexes 415 by low-threshold cutaneous afferents. The resulting responses are denoted in the following as ‘cutaneo- muscular reﬂexes’. They have been documented in many limbmuscles. The technique is simple andthe cutaneomuscular reﬂexes so produced are consis- tently recorded in most normal subjects. Upper-limb responses In the upper limb, the typical pattern is a tripha- sic response with a modest early (E1) excitation at a latency of ∼30–35 ms, followed by an inhibition (I1) and by a large long-latency excitation (E2). This is illustratedin9.10E, whichshows the response pro- ducedintheﬁrst dorsal interosseous(FDI) byasingle shockat 2PTtothedigital nervesof theindexﬁnger (Jenner & Stephens, 1982). Similar responses have been recorded in many hand and forearm muscles: abductor digiti minimi, extensor digitorumcommu- nis, ﬂexor digitorumsuperﬁcialis (Evans, Harrison & Stephens, 1989), forearm extensors and ﬂexors (Issler & Stephens, 1983). E1 response habituates rapidly (Harrison, Norton, & Stephens, 2000), and this could explain why it is not always seen in nor- mal subjects (Chen&Ashby, 1993; Hallett et al., 1994; Floeter et al., 1998). Lower-limb responses In the lower limb, cutaneomuscular reﬂexes have a much less stereotyped pattern. Single shocks at 2 PT to the digital nerves of toe 2 produce a consistent excitation at spinal latency (E1) only in the extensor digitorum brevis (Fig. 9.9(b)) followed by a long-latency excitation (E2), which is the only response consistently recorded in the other tested muscles (soleus, tibialis anterior, quadriceps; Gibbs, Harrison & Stephens, 1995). Sural nerve stimula- tion using ﬁve shocks at 300 Hz and 2 PT evokes quite variable short-latency responses at ∼50 ms or less in the different muscles: excitation in the per- oneus longus and the gastrocnemii, and inhibition in both the soleus and tibialis anterior (Fig. 9.9(c)– (g); Aniss, Gandevia & Burke, 1992). These early responses are followed by a long-latency excitation which, insoleus, becomesobviousonlywithstronger stimulusintensities(4PT). Earlyinhibitionandlate facilitation have also been found in tibialis anterior after stimulation of the superﬁcial peroneal nerve at the ankle (Nielsen, Petersen & Fedirchuk, 1997). Difﬁculties in interpretation Low-threshold cutaneous afferents have effects mediated through ‘private’ circuits and can modu- late the transmission in other pathways activated during the voluntary contraction (see pp. 419–21). A further difﬁculty arises because the cutaneous input has opposite effects on motoneurones innervating slow- and fast-twitch motor units (cf. pp. 424–7). Finally, the contraction introduces a voluntary bias, and there are important task-related changes in the modulation of the on-going EMG (cf. pp. 427–30). Modulation of the monosynaptic reﬂex Lower limb The dominant effect of sural nerve stimulationusing a train of 3–10 shocks at 2–2.5 PT is facilitation occurring at ISIs longer than 50 ms in all tested motor nuclei (e.g. Fig. 9.4(b)–(d), (❍)): soleus, tib- ialisanterior, quadricepsandbicepsfemoris(Hugon, 1973; Delwaide, Crenna & Fleron, 1981; Delwaide & Crenna, 1984; Nielsen, Petersen & Fedirchuk, 1997). There are, however, more modest preceding effects, which are considered on p. 419. Upper limb Mechanical stimulation of the ﬁngertip produces a biphasic modulation of the ﬂexor carpi radialis (FCR) H reﬂex, with weak short-latency inhibition appearing at 2 PT, followed some 3–4 ms later by a potent facilitation appearing just above 1 PT (Cavallari & Lalli, 1998). Qualitatively similar results were obtained whether the stimulus was applied to the skinof the palmar or the dorsal surface of the ﬁn- ger (Fig. 9.10(c)). The same early inhibition and sub- sequent potent facilitation have now been observed 416 Cutaneomuscular and withdrawal reﬂexes (a) (c) (d ) (e) (f ) (g) (b) Fig. 9.9. Cutaneomuscular reﬂexes evoked by low-threshold cutaneous afferents in the lower limb. (a) Sketch of the presumed pathways. Cutaneous afferents excite peroneus longus (PL) and gastrocnemius medialis (GM), and inhibit soleus (Sol) and tibialis anterior (TA) motoneurones (MN) through spinal interneurones (INs), and excite TA MNs through a transcortical pathway. (b)–(g) Cutaneomuscular responses evoked by stimulation of low-threshold cutaneous afferents in various muscles. (b) Modulation of the on-going EMG (contraction 20% of MVC) in the extensor digitorum brevis (EDB) by a single shock to toe 2 (2 PT, 1024 sweeps). The arrow and vertical dotted line indicate the latency of E1. (c)–(g) All responses were evoked by sural nerve stimulation (train of three shocks, 500 Hz, 2 PT), during a background voluntary contraction of the target muscle (30% of MVC). Responses are in PL ((c), 500 sweeps), TA ((d ), 500 sweeps), Sol ((e), 250 sweeps), GM ((f ), 250 sweeps), and gastrocnemius lateralis (GL, (g), 250 sweeps). Vertical calibration: 10 V (b), 250 V (c), 200 V ((d )–(g)). The vertical thick dotted line and thin dashed line in (c)–(g) indicate the onset of the stimulus train, and the limit below which the responses may be considered as spinal, respectively. Modiﬁed from Jenner & Stephens (1982) (b), and Aniss, Gandevia & Burke (1992) ((c)–(g)), with permission. inPSTHsof singleFCRunitsafter mechanical or elec- trical stimulation of the skin of the palmar side of the index ﬁnger (Fig. 9.10(d ); G. Lourenc¸o, R. Espoti & P. Cavallari, personal communication). The brief latency and short duration of the inhibition exclude apresynaptic inhibitory mechanism. Since the reﬂex inhibition occurs at rest, it presumably results from IPSPs in motoneurones. This inhibition differs from the disfacilitation that occurs with inhibition of propriospinally mediated excitation of motoneu- rones in a number of respects: (i) brief latency; (ii) the target muscle (FCR instead of ECR); (iii) the subsequent potent facilitation; and(iv) that it canbe elicited fromboth sides of the hand. Propriospinally (a) (c) (d) (b) (f ) (g) (h) (e) Fig. 9.10. Spinal reﬂex effects evoked by low-threshold cutaneous afferents in the upper limb. (a) Sketch of the presumed pathways. Cutaneous afferents through spinal interneurones (INs) excite ﬂexor digitorum superﬁcialis (FDS) and ﬁrst dorsal interosseus (FDI) motoneurones (MNs), both excite and inhibit ﬂexor carpi radialis (FCR) MNs, and both excite and inhibit FDI MNs through a transcortical pathway. (b) RII reﬂex elicited at rest in the ﬂexor carpi ulnaris (FCU) by ulnar nerve stimulation (train 10 shocks, 500 Hz, 3 mA). (c) The FCR H reﬂex (expressed as a percentage of its control value) is plotted against the ISI after mechanical stimulation of the palmar aspect (●, 3 PT) and the dorsal aspect (❍, 1.6 PT) of the index ﬁnger. The arrowat 11 ms indicates the arrival of the cutaneous volley at motoneuronal level. (d ) PSTHs of a single FCR unit after mechanical () and electrical () stimulation (2 PT) of the palmar pulp of the index ﬁnger. The zero on the abscissa corresponds to the expected time of arrival of the cutaneous volley at motoneuronal level. (e) Modulation of on-going EMG activity of FDI by a single electrical stimulus (2 PT) delivered to the index ﬁnger (1024 sweeps). (f )–(h) EMG events time-locked to the discharge of a single FAI cutaneous afferent activated by repeated indentation of the receptive ﬁeld of the afferent, as revealed by spike-triggered averaging. (f ) Autocorrelogram of the afferent discharge with inset showing the neurogram produced by three skin strokes. (g) Averaged nerve action potential. (h) Averaged EMG (9718 sweeps), which was root-mean square processed, sampling over a sliding window (5 ms). Dashed line highlights the peak of the short-latency reﬂex. Modiﬁed from Cambier, Dehen & Bathien (1974) (b), Cavallari & Lalli (1998) (c), G. Lourenc¸o, R. Espoti & P. Cavallari (personal communication) (d ), Jenner & Stephens (1982) (e), and McNully & Maceﬁeld (2002) ((f )–(h)), with permission. 418 Cutaneomuscular and withdrawal reﬂexes mediated excitation from one muscle is selectively suppressed fromthe skin ﬁeld that would encounter the target at the end of movements produced by that muscle (cf. Chapter 10, p. 478). The modulation of the H reﬂex or tendon jerk has limitations Low-threshold cutaneous volleys may alter the size of the H reﬂex (i) by altering presynaptic inhibition of Ia afferents mediating the test volley (see Chap- ter 8, p. 350), and (ii) by modifying transmission in non-reciprocal group I (Ib) pathways activated by the test volley for the H reﬂex (cf. Chapter 6, Fig. 6.7(c) and pp. 267–8). Inaddition, because of the differential effect of thecutaneous input onearlyand late recruited motoneurones, opposite effects might occur with reﬂexes of different size (cf. pp. 425–6; Fig. 9.12(h)). Afferent conduction Given the low threshold of the RII reﬂex (5 mA, Willer, 1977), there is little doubt that the respon- siblecutaneousafferentsinthesural nervearewithin the large-myelinated A␤ range. Accordingly, stimuli evoking the responses discussed in this section gen- erally require an intensity of 2–2.5 PT, and pro- duce a non-painful tactile sensation, even when a long train is delivered. The mean conduction velo- city for thefastest of theseafferents is 51ms −1 (range 45–62) in the distal lower limb (Willer, Boureau & Albe-Fessard, 1978). Afferents are faster in the upper limb (Maceﬁeld, Gandevia & Burke, 1989), where individual axons may have conduction velocities up to 80 m s −1 (see Johansson & Vallbo, 1983). Central pathway of short-latency responses occurring at ‘spinal latency’ Three questions arise concerning the central path- way of the effects produced by stimulation of low- threshold cutaneous afferents. (i) Is the response mediated through a spinal or a transcortical pathway? (ii) If spinally mediated, is it through an oligo- synaptic pathway or a long chain of interneurones? (iii) Is it mediated through a ‘private’ cutaneous pathway or does it reﬂect a change in transmission in another spinal pathway? Spinal origin of the early cutaneous- induced effects The ﬁrst point toelucidate is whether the response is mediatedthrougha spinal or a supraspinal pathway. It is argued on pp. 421–4 that RII-like reﬂexes at rest and cutaneomuscular responses occurring after dis- tal stimulation at latencies earlier than 45–50 ms in the upper limb and 70–80 ms in the lower limb may be considered spinal (Deuschl, Schenck & L¨ ucking, 1985; Nielsen, Petersen & Fedirchuk, 1997). For the modulation of the monosynaptic reﬂex, allowance for the conduction time of the test reﬂex discharge indicates a similar spinal origin for effects occurring at ISIs of ∼30 ms inthe upper limband∼55 ms inthe lower limb. On these latency grounds, the following reﬂex responses are probably spinal: RII responses evoked at rest The latency of the biceps femoris RII reﬂex is vari- able (40–80 ms) from trial to trial and from subject to subject. This variability is due to the need for tem- poral summation, which ﬂuctuates with the state of attention-relaxation of the subject and because of habituation. RII reﬂexeswithlonger latencies(80ms) fall within the same range as the earliest ISI for the late diffuse facilitation of the monosynaptic reﬂex. However, theminimal latencyof theRII reﬂexis40ms after the onset of the train (Hugon, 1973; Willer, 1977) and, at threshold, for a minimal stimulus train which would elicit the reﬂex every second trial, the latency was 35 ms after the last shock of the train (Hugon, 1973). Such an early latency clearly indi- cates a spinal reﬂex (see above). The spinal origin of the reﬂex is also suggestedby the ﬁnding that sim- ilar low-thresholdresponsesoccurringwiththesame Non-noxious cutaneomuscular reﬂexes 419 latency can be recorded in patients with complete spinal transection (Hugon, 1973). Central delay of cutaneomuscular responses The central delay has been estimated after subtrac- tion of the peripheral afferent and efferent conduc- tiontimesfromthelatencyof theresponse. Theaffer- ent conduction time was determined by recording the spinal evoked response after cutaneous stimula- tion at C7 for the upper limb and T12 for the lower limb, and the efferent conduction time was calcu- lated by halving the sum of the latencies of the M andFwaves. Usingasingleconditioningvolley, it was demonstratedthat the meancentral delay of the ear- liest excitation (E1) in extensor digitorumbrevis and the FDI was 2.3 and 4.6 ms, respectively (Figs. 9.9(b), 9.10(e); Jenner &Stephens, 1982). Such short central delays indicate transmissionthroughanoligosynap- tic spinal pathway. Short stimulus trains to the sural nerve produce excitation in the peroneus longus at a latency of 44 ms, which implies an oligosynaptic spinal pathway and, given the necessity of temporal summation, the early inhibition in tibialis anterior andsoleus is alsoconsistent withashort spinal path- way (Fig. 9.9(c)–(e); Aniss, Gandevia & Burke, 1992). Modulation of monosynaptic reﬂexes Aspinal mechanismexplains the short-latency inhi- bition (2–3 ms central delay) and following facilita- tion of the ﬂexor carpi radialis H reﬂex after stimu- lation of the ﬁngertip (Cavallari & Lalli, 1998; Fig. 9.10(c)). The dominant effect of stimulation of tac- tile cutaneous afferents in the sural nerve is a diffuse long-latencyfacilitation, whichhasbeenshowntobe supraspinal (see pp. 421–4). However, sural stimula- tion also evokes weak earlier effects with facilitation of ﬂexors (tibialis anterior andbiceps) andinhibition of extensors (soleus and quadriceps, see Fig. 9.4(c); Hugon, 1973; Delwaide, Crenna & Fleron, 1981). Againthelatencies of theseearlyeffects, whichoccur at ISIs of 25–35 ms, are those of a spinal pathway. Oligosynaptic or polysynaptic nature of spinal pathways mediating early effects Temporal summation is required to cause the RII reﬂex to appear at rest, and this renders uncer- tain speculations about the number of interneu- rones intercalated between the cutaneous terminals and motoneurones. When the cutaneomuscular response can be obtained with a single shock, a more precise estimate of the central delay is pos- sible, as short as 1–2 ms in some cases, imply- ing an oligosynaptic pathway (Jenner & Stephens, 1982). Spike-triggered averaging of the EMG against natural spike trains of single cutaneous afferents has allowed a spinal reﬂex pathway to be demon- strated at a single unit level (McNulty & Maceﬁeld, 2002). Thus, with an afferent activated from a FAI mechanoreceptor in the skin of the index ﬁnger, the latency of the response in the ﬂexor digitorum superﬁcialis was 36 ms (Fig. 9.10(f )–(h); McNulty & Maceﬁeld, 2002). This implicates a spinal pathway but, in the absence of the conduction velocity for the afferent, it does not indicate whether the path- way is oligosynaptic or polysynaptic, though the former is likely given that polysynaptic connections are more difﬁcult to deﬁne using spike-triggered averaging. ‘Private’ pathway or changes in transmission in another pathway? RII reﬂex In the case of responses recorded at rest, such as the RII reﬂex, the absence of voluntary contractionrules out the possibility that the response to cutaneous stimulation reﬂects a change in the contraction- inducedIbdischarge or inthe propriospinally medi- ated descending activation of motoneurones. The RII reﬂex is therefore probably mediated through a ‘private’ cutaneous pathway. The problem with the RII reﬂex is that, because of the necessity for tempo- ral summation, it is impossible to estimate precisely the number of interneurones intercalated in this ‘private’ spinal pathway (cf. above). 420 Cutaneomuscular and withdrawal reﬂexes Cutaneomuscular reﬂexes During voluntary contractions, a modulation of the on-going EMG could result from a reﬂex action affecting the motoneurone discharge directly (‘pri- vate’ pathway) or indirectly by actions on (i) ␥ motoneurones (Chapter 3, pp. 127–30), (ii) inter- neurones transmitting the contraction-induced Ib afferent discharge (Chapter 6, pp. 261–3), or (iii) propriospinal neurones relaying the descending command (Chapter 10, pp. 471–4). These different possibilities have been generally neglected and are considered below. (i) Reﬂex activation of ␥ motoneurones by inputs fromcutaneous mechanoreceptors has been sought without success in the lower limb of reclining sub- jects performing isometric voluntary contractions. However, whenthe subjects were reliant onproprio- ceptive cues to maintain balance during unsup- portedstanding, it waspossibletodemonstratecuta- neous activation of ␥ motoneurones (Chapter 3, pp. 127–9). This could contribute to the task- dependent changes in cutaneomuscular reﬂexes then observed (cf. pp. 429–30). However, given the delay of transmission across the ␥ loop, any effect on ␣ motoneurones resulting from cutaneous reﬂex modulation of ␥ drive would occur at long latencies, superimposedonsupraspinally-mediated effects. (ii) Cutaneous facilitation of interneurones medi- ating Ibinhibitiontovoluntarily activatedmotoneu- rones may be observed during voluntary contrac- tions (cf. Chapter 6, p. 262). The sural-induced early inhibition observed in the on-going EMG of the tibialis anterior and soleus could reﬂect cutaneous facilitation of the transmission of the contraction- inducedIbdischarge(Fig. 9.9(d), (e)). However, cuta- neous facilitation of Ib inhibition to voluntarily acti- vated motoneurones has been observed only with afferents from the skin ﬁeld that would have come into contact with an obstacle during the contraction of the corresponding muscle (cf. Chapter 6, p. 272). This is not the case for the lateral side of the foot innervated by the sural nerve during contraction of the tibialis anterior or soleus. (iii) Cutaneous inhibition of the propriospinally mediated component of the descending command for movement is responsible for the inhibition of the on-going EMG of wrist extensors and arm muscles occurring with a 4–6 ms central delay after stimula- tionof cutaneous afferents fromthedorsal sideof the hand (Chapter 10, pp. 471–4). However, this mech- anism cannot account for the inhibition (I1) follow- ing the early excitation (E1) in the intrinsic muscles of the hand, because there are no signiﬁcant pro- jections of C3–C4 propriospinal neurones to these muscles (Chapter 10, p. 460). Nor could this mech- anism explain the inhibition of the FCR H reﬂex at rest (pp. 415–18). It also cannot account for the inhi- bitionof thetibialisanterior or soleusdocumentedin Fig. 9.9(d), (e), because there is no evidence for cuta- neous inhibition of lumbar propriospinal neurones (Chapter 10, p. 496). Presynaptic inhibition of Ia terminals Depression of presynaptic inhibition of Ia terminals mediating the afferent volley of the test reﬂex can be produced by low-threshold cutaneous afferents in the upper and lower limbs (cf. Chapter 8, p. 350), and this would facilitate the monosynaptic reﬂex. Parallel cutaneous inhibition of motoneurones and depression of presynaptic inhibition of Ia termi- nals would explain why sural stimulation produces profound suppression of the on-going EMG in the tibialis anterior and soleus (Fig. 9.9(d), (e); Aniss, Gandevia & Burke, 1992) but not the H reﬂex, which is facilitated in the tibialis anterior and only mod- estly inhibited in the soleus (Delwaide, Crenna & Fleron, 1981). In contrast, the long-lasting facilita- tion of the ﬂexor carpi radialis following the ini- tial short-latency inhibition has been reproduced in the PSTHs of single units (Fig. 9.10(c), (d)), and may be ascribed to a postsynaptic facilitation of the motoneurones. Conclusions Short-latency cutaneomuscular reﬂexes are prob- ably mediated through ‘private’ spinal pathways. Non-noxious cutaneomuscular reﬂexes 421 Cutaneous inhibition of propriospinal neurones may account for the inhibition of the on-going EMG evoked in wrist extensors and arm mus- cles, but not for the inhibition in hand and leg muscles. Divergent results obtained with the modulation of on-going EMG and the H reﬂex may be due to the cutaneous depression of PAD interneuronesmediatingpresynapticinhibitionof Ia terminals. Central pathway for long-latency effects Theconclusionthat long-latencyresponsesinvolvea long-looppathway relies on: (i) latency, (ii) studies in patients with various lesions in the central nervous system, (iii) studies in children at various stages of the maturation of the pyramidal tract, and (iv) cuta- neous modulation of the responses evoked by corti- cal stimulation. Latencies of late responses Pattern of the long-latency facilitation of monosynaptic reﬂexes Stimulation of the sural nerve evokes long-latency facilitation of the soleus and tibialis anterior H reﬂexes, starting at ISIs longer than 50 ms and peak- ing at ∼80–100 ms (Delwaide, Crenna & Fleron, 1981). The absence of reciprocal organisation of this facilitation argues against a spinal mechanism, and this view is supported by further ﬁndings (Delwaide & Crenna, 1984). (i) Sural-induced facilitation of monosynaptic reﬂexes was seenat anearlier latency inarmmuscles than in leg muscles, and at an even earlier latency in the masseter. (ii) When comparing the effects on the soleus H reﬂex of cutaneous stimuli appliedtovarious nerves, the closer the stimulus to cerebral cortex, the earlier the facilitation. Themost parsimonious explanationfor thesedata is a common supraspinal centre responsible for the reﬂex activation of the muscles in a rostrocaudal sequence. Latencies of late responses are compatible with a transcortical pathway The nature of this supraspinal pathway is discussed below. Jenner & Stephens (1982) suggested that it could be transcortical, a requirement being sufﬁ- cient timefor conductionof thevolley tothecerebral cortex and back. The afferent and efferent conduc- tiontimes ina transcortical pathway may be inferred from the latencies of the cerebral somatosensory evoked potential and of the MEP following cortical stimulation. Such estimates have been the basis of several investigations: (i) The difference in the latencies of the short- and long-latency excitatory components in FDI could represent conduction in central pathways to and from cortex. It was 3.5–8.5 ms longer than the mini- mal time for impulse conduction along a pathway travelling through the dorsal columns to cerebral cortex and returning by way of the corticospinal tract. This extra delay above the sum of estimated afferent and efferent conduction times could rep- resent the time for processing in the sensorimo- tor cortex. In addition, it was found that the dif- ference in time delay between short- and long- latency excitation in FDI and extensor digitorum brevis muscles was, on average, 12 ms, and this ﬁts well with estimates of the afferent and efferent conduction times for central pathways between the T12 and C7 spinal segments (Jenner & Stephens, 1982). (ii) More precise investigations have allowed the time for processing in the sensorimotor cortex to be measured. Such studies have (i) conﬁrmed that the timing of the late excitation is compatible with a transcortical pathway, and (ii) assessed accu- rately the minimal time required for a mediation througha transcortical pathway. This is illustratedin Fig. 9.11(b)–(d) (Nielsen, Petersen & Fedirchuk, 1997). The difference between the latency of the sural-induced excitation of the on-going tibialis anterior EMG and the sum of the afferent and effer- ent conduction times leaves ∼13 ms for process- ing in the cerebral cortex (cf. legend of Fig. 9.11(b)– (d )). Accordingly, the onset of the sural-induced 422 Cutaneomuscular and withdrawal reﬂexes (a) (c) (d) (e) (f ) (g) (h) (i ) ( j ) ( k) (b) Fig. 9.11. Evidence for transcortical mediation of long-latency excitation in tibialis anterior to sural nerve stimulation. (a) Sketch of the presumed pathways. A␤ cutaneous afferents mediate, through spinal interneurones (INs), a short-latency inhibition and, through a transcortical pathway, a long-latency excitation of tibialis anterior (TA) motoneurones (MNs). (b)–(d) Calculations of afferent and efferent conduction times for a possible transcortical reﬂex. Sural stimulation (three shocks, 300 Hz, 2.5 PT) evokes in the rectiﬁed on-going TA EMG (average of 100 traces) a late facilitation at 83 ms (b), and a somatosensory-evoked cerebral potential at a latency of 38 ms (c), while TMS produced a MEP in TA at a latency of 32 ms (d ). Vertical calibration: 20 V (b), 2 V (c), 500 V (d ). The 13 ms difference (83 −[38 ÷32]) between the latency of the late sural-induced facilitation and the sum of the minimal afferent and efferent conduction times represents the maximal central delay of the late excitation. (e), (f ) Effects of sural stimulation (three shocks, 300 Hz, 2 PT) on the TA H reﬂex at the earliest ISI (50 ms) with sural-induced facilitation when using a stronger (2.5 PT) stimulation, are compared when conditioned by TMS ((e), 50% of the stimulator output, −4 ms ISI with respect to CPN stimulation) or electrical stimulation of the motor cortex ((f ), 25% of the stimulator output, −3 ms ISI with respect to CPN stimulation): control reﬂex (), effects of separate sural (dotted), separate cortical (grey), and combined () stimulation. (g)–(k) PSTHs of a single TA unit (after subtraction of the background ﬁring, 1 ms bin width). Effects produced by separate sural (g), separate transcranial magnetic (h) and transcranial electrical (j) stimulation (same parameters of stimulation as in (e), (f ), and combined stimulation ((i), (k)). Modiﬁed from Nielsen, Petersen & Fedirchuk (1997), with permission. Non-noxious cutaneomuscular reﬂexes 423 facilitationof theresponseevokedbyTMSwas found at the 50 ms ISI, i.e. 12 ms after the arrival of the cuta- neous volleyat cortical level (38ms, Fig. 9.11(c)). This corresponds to the central delay of ∼10 ms previ- ouslyreportedfor cutaneomuscular responses inthe upper limb(Deuschl et al., 1989). Overall, it has been found that the minimal latencies of transcortical cutaneomuscular responses in tibialis anterior after sural stimulation and in the thenar muscles after superﬁcial radial stimulation are ∼85–90 and 50– 55 ms, respectively (Nielsen, Petersen & Fedirchuk, 1997; Deuschl et al., 1989). Observations in patients Latency measurements are a necessary criterion but insufﬁcient by themselves to establish transcortical mediation of the late responses. An additional com- plementaryapproachhasbeenprovidedbythestudy of patients withestablishedneurological lesions that abolished or attenuated the E2 response, but not the spinal E1 response. Studies in patients with suprasegmental lesions These studies have shown that the late E2 excitatory cutaneomuscular response requires the integrity of the dorsal columns, the sensorimotor cortex and the corticospinal tract. The E2 response in the FDI mus- cle is reduced and often delayed in patients with dorsal column lesions, absent in patients with dam- age to motor cortex, and reduced in amplitude and often delayed in patients with corticospinal tract abnormalities due to upper motor neurone disease (Jenner & Stephens, 1982). Similarly, late E2 responses in the extensor digitorum brevis and tib- ialis anterior muscles may be absent inpatients with lesions of the corticospinal tract (Choa & Stephens, 1981; Rowlandson & Stephens, 1985b). Studies in patients with mirror movements Studies in patients with X-linked Kallmann’s syn- drome and mirror movements (Mayston et al., 1997) have provided further evidence for the transcortical origin of the E2 component, and showed in addition that the inhibitory I1 component, whichwas initially thought to be spinally mediated, may also be trans- mittedthroughatranscortical pathway(seealsoCarr et al., 1993). In these studies, unilateral stimulation of the digital nerves produced a unilateral E1 spinal response but bilateral I1 andE2 responses inthe ﬁrst dorsal interosseous. The bilateral responses were attributed to the novel branched projections from the ipsilateral motor cortex, characteristic of these patients. Maturation Short- (E1) and long- (E2) latency responses to cuta- neous stimulation have been studied in forearm ﬂexors and extensors and in lower limb muscles of children of different ages (Issler & Stephens, 1983; Rowlandson & Stephens, 1985a). The main ﬁnd- ings are illustrated in Fig. 9.13(n)–(r) for the fore- arm extensors: (i) initially, there is only a large E1 response, and this decreases progressively over the ﬁrst year of life (n)–(p); (ii) E2 appears in the sec- ond year of life; and (iii) during the school years, E2 increases still further in size at the expense of E1 (q)–(r). These changes parallel the maturation of the corticospinal tract and the acquisition of motor skills, andprovidefurther evidencethat long-latency cutaneous reﬂexes haveatranscortical originandare important in the acquisition of motor skills. Which supraspinal pathway? Alternative possibilities to transcortical pathways The above ﬁndings argue that the late excita- tory cutaneomuscular reﬂex is mediated through a suprasegmental pathway, but there were originally questions about the nature of the pathway. Different alternative hypotheses had been proposed. (i) The possibility of an effect mediated through long propriospinal pathways linking upper and lower limb motor nuclei (Kearney &Chan, 1979) did not takeintoaccount themodulationinthemasseter or data in patients. 424 Cutaneomuscular and withdrawal reﬂexes (ii) Data from patients also argue against a role for a spino-bulbo-spinal pathway, which has been described in the cat (Shimamura, Mori & Yamauchi, 1967). Such a pathway had been raised by Meier- Ewert et al. (1973) to account for the modulation of the on-going EMG of different muscles in a rostro- caudal sequence after stimulation of the skin of the forehead or of the ﬁngers. (iii) Delwaide&Crenna(1983, 1984) suggestedthat the response was similar to a startle response after, e.g. an auditory stimulus, a view that has been chal- lenged by Nielsen, Petersen & Fedirchuk (1997). Deﬁnitive evidence for a transcortical pathway This evidence has come from experiments using motor cortex stimulation, as illustrated in Fig. 9.11(e)–(k) (Nielsen, Petersen & Fedirchuk, 1997). The effects of a sural volley were compared on the facilitation evoked in the H reﬂex and in the PSTHs of single units of the tibialis anterior by magnetic or electrical stimulation of the motor cortex. Sural stimulation, adjusted to be insufﬁcient by itself to facilitate tibialis anterior motoneurones, increased the facilitation of the H reﬂex produced by TMS (e) and the peak of cortical excitation evoked by TMS in the PSTHs (i), but did not enhance the facilitation evoked by electrical stimulation of the motor cortex ((f ), (k)). Adifferential effect of the sural volley onthe responses evoked by magnetic and electrical stimu- lationimplies that motor cortex excitability has been affected by the conditioning cutaneous stimulation (Chapter 1, p. 44). Similarly, a superﬁcial radial volley increases the facilitation evoked from motor cortex ontheﬂexor carpi radialis HreﬂexonlywithTMSand not withtranscranial electrical stimulation(Deuschl et al., 1991). Conclusions Measurements of afferent and efferent conduction timesandof thecentral delayof thelateexcitationare compatible with a transcortical pathway. Observa- tions in patients have shown that the late excitation requires transmission of afferent impulses through the dorsal columns, a relay in the sensorimotor cortex and then descending transmission along the corticospinal tract. Finally, cutaneous facilitation of the responses evoked by TMS, but not of those pro- duced by electrical stimulation, has demonstrated a transcortical pathway for the late responses. How- ever, it must be emphasised that the above demon- stration of a transcortical pathway does not exclude the possibility that spinal pathways also contribute totheseresponses. Indeed, inpatientswithcomplete spinal transection, reﬂexesinthetibialisanterior and biceps femoris evoked by weak sural stimuli at short latency, withthe characteristics of RII reﬂexes innor- mal subjects, may have a long duration overlapping withthe latency of transcortical responses innormal subjects (Hugon, 1967, 1973). Similarly, a contribu- tionof spino-bulbo-spinal pathways cannot beruled out. Projections of cutaneous afferents to different types of motoneurones Evidence for a different effect on motoneurones of different type In the cat, stimulation of the sural nerve produces IPSPs in small motoneurones of triceps surae, i.e. those with a high input resistance (type S motoneu- rones), and EPSPs in large motoneurones with a low input resistance (type F motoneurones) (R. E. Burke, Jankowska & ten Bruggencate, 1970; R. E. Burke, 1981). The ﬁndings in humans are consistent with the cat data, i.e. of cutaneous effects of oppo- site sign on early-recruited motoneurones innervat- ing slow-twitch motor units (inhibition) and late- recruited motoneurones innervating fast-twitch units (facilitation). First dorsal interosseous (FDI) conditioned by electrical stimuli Differential effects of low-thresholdcutaneous affer- ents on low- and high-threshold motor units of human subjects were ﬁrst shown by J. A. Stephens and colleagues in the FDI, using long trains of non-painful cutaneous stimuli delivered through Non-noxious cutaneomuscular reﬂexes 425 ring electrodes to the digital nerves of the index ﬁnger. The stimulation had opposite effects on motor units recruited at small and large contraction forces (low- and high-threshold units, respectively) during slowly increasing ramp contractions. Cuta- neous stimulation raised the recruitment thresh- old of units normally recruited at low contrac- tion strengths and reduced the threshold of units normally recruited at high contraction strengths (Fig. 9.12(b), (c); Stephens, Garnett & Buller, 1978; Garnett &Stephens, 1981). This result was conﬁrmed by showing that the mean interval between sin- gle motor unit spikes in low-threshold units was increased by a similar stimulation, while it was reduced in high-threshold units (Fig. 9.12(d), (e); Datta & Stephens, 1981). Cutaneous afferents from the index ﬁnger can therefore shift the weighting of synaptic input associated with a voluntary contrac- tion to favour the recruitment of the more powerful fast-twitch units in FDI. FDI conditioned by natural stimuli The results of Stephens and colleagues were con- ﬁrmed and extended by Kanda & Desmedt (1983), using natural cutaneous stimulation, and this is of greater functional relevance. The ﬁndings are illus- tratedinFig. 9.12(f ), (g). Duringastandardisedramp contraction, one motor unit (MU1) was recruited at a lower threshold than the other (MU2). However, when the distal phalanx of the thumb was ﬂexed so that there was skin contact between ﬁngertips and the subject made slight to-and-fro palpation move- ments, motor unit 2 ﬁred in isolation, even though the contraction force was barely at threshold for the ﬁrst unit during rampcontraction. Impressive as this ﬁnding is, it is possible that the role of FDI was dif- ferent in the two tasks, and that this might have required a change in descending drives and spinal circuitry. Effect of sural stimulation on tibialis anterior motoneurones Sural nerve stimuli below pain threshold pro- duce inhibition in the PSTHs of early-recruited motoneurones and excitation in the PSTHs of late-recruited motoneurones of tibialis anterior (Fig. 9.12(i),(j); Nielsen & Kagamihara, 1993). Because of these opposite effects on early- and late-recruitedmotoneurones, unconditionedtibialis anterior Hreﬂexes of small amplitudewereinhibited by sural stimulation, whereas those of large ampli- tude were facilitated (Fig. 9.12(h)). Changes in recruitment gain Nielsen&Kagamihara(1993) alsodemonstratedthat sural nerve stimulation, that was adjustedtohave no effect by itself, signiﬁcantly increased the amount of heteronymous monosynaptic Ia facilitation of the tibialis anterior Hreﬂex produced by femoral stimu- lation. However, the sural stimulation did not affect the peak of monosynaptic Ia excitation produced by femoral stimulation in the PSTHs of single motor units intibialis anterior. Thus, this represents a good example (actually the only one yet described) where the increased monosynaptic reﬂex facilitation could not be attributed to depression of presynaptic inhi- bitionof Ia terminals mediating the femoral volley. A change in the heteronymous monosynaptic Ia exci- tationof the Hreﬂex without a parallel change inthe monosynaptic Ia excitation of individual motoneu- rones is characteristic of a change in the recruit- ment gain of the reﬂex (see Chapter 8, pp. 346–7): the skewed distribution of cutaneous inputs within the tibialis anterior motoneurone pool, illustratedin Fig. 9.12(h)–(j), compresses the range of functional thresholds in the motoneurone pool and thereby increases the slope of the input-output relationship of the test reﬂex (Chapter 1, pp. 18–20; Fig. 1.9). Functional implications Signiﬁcant decreases in the recruitment threshold of high-threshold motor units can be produced by artiﬁcial stimuli but also occur during the natural stimulation involved in precision grip and active manipulation (see above). The net result is that pre- hension and manipulation are assisted and made more reliable: contact of appropriate skin regions (a) (b) (c) (e) (g) (i ) ( j ) (h) (f ) (d) Fig. 9.12. Different projections of cutaneous inputs to low- and high-threshold motor units. (a) Sketch of the presumed pathways. A␤ cutaneous afferents inhibit small motoneurones (MN) supplying slow-twitch motor units (MUs) and excite large MNs supplying fast-twitch MUs of the ﬁrst dorsal interosseus (FDI). (b), (c) Time course of the changes in recruitment threshold observed for a low-threshold (b) and a high-threshold (c) MU in the FDI during continuous electrical stimulation (4 PT, horizontal bar, Cut. on) of the digital nerves of the index ﬁnger (control situation: dotted line). (d ), (e) Histograms of the interspike intervals of a low-threshold ((d), recruitment threshold <1.5 N) and high-threshold ((e), recruitment threshold >1.5 N) MU are compared in a control situation (thin line) and after cutaneous stimulation (thick line) applied to the digital nerve of the index ﬁnger (3 PT) timed to arrive at the spinal cord 5–15 ms after the onset of the measured interspike interval. (f ), (g) Action potentials of single MUs (1 and 2, upper trace) and abduction force (lower trace). (f ) During a ramp contraction, MU 1 is recorded at a lower threshold (horizontal dotted line) than MU 2. (g) The contact of the thumb with index tip in natural palpation (dashed horizontal line) facilitates the recruitment of MU 2, while the force is barely at threshold of MU 1. (h)–(j) Effect of sural nerve stimulation (train of three shocks, 333 Hz, 2.5 PT) on tibialis anterior (TA) MNs. (h) Changes in the TA H reﬂex (conditioned – control reﬂex, expressed as a percentage of M max , 11 ms ISI) at the onset of voluntary dorsiﬂexion are plotted against the size of the unconditioned test reﬂex. (i), (j) Changes in the PSTHs of a low- (i) and a high- (j) threshold MU, recruited at 1 and 25% of MVC, respectively. Abscissa: latency with respect to homonymous monosynaptic Ia latency. Modiﬁed from Garnett & Stephens (1981) ((b), (c)), Datta & Stephens (1981) ((d ), (e)), Kanda & Desmedt (1983) ((f ), (g)), and Nielsen & Kagamihara (1993) ((h)–(j)), with permission. Non-noxious cutaneomuscular reﬂexes 427 with an object will excite high-threshold motoneu- rones, and thereby make a greater contribution to grip force. Similarly, during locomotion, the cuta- neous feedback evoked by foot contact might act to strengthen the on-going motoneuronal activity by changing the recruitment gain within the motoneu- rone pool(s). This could explain why the EMG activ- ity during gait may only be mimicked by strong tonic contractions (∼50% of MVC). However, while these changes will favour the recruitment of high- threshold motor units, the increased slope of the input-output relationshipwill decrease the ability to make small changes in force in discrete movements, whether in response to descending drives or periph- eral feedback. Pattern and functional role of early responses Some responses at rest suggest placing reactions RII response in the biceps femoris The primary function of the short head of the biceps femorisisnot toﬂexthekneebut toproduceanexter- nal rotation of the leg and foot, and Hugon (1973) therefore did not consider the RII response a ‘ﬂexion reﬂex’. In contrast with a withdrawal response, the RII reﬂex evoked by low-threshold cutaneous affer- ents fromthe lateral aspect of the foot would tend to increase the contact with the stimulus, much as in a ‘placing reaction’. In this respect, it may be pointed out that, in the cat, activation of hair receptors in the sural ﬁeld has been found to evoke polysynap- tic excitation of motoneurones of the tenuissimus (Hunt, 1951), which is embryologically homologous to the short head of the biceps. Early response in peroneus longus Similarly, a response in the peroneus longus may also be observed occasionally at rest after sural nerve stimulation (Aniss, Gandevia & Burke, 1992). Here again the resulting eversion and abduction of the foot would tend to increase the contact with the stimulus on the lateral side of the foot, and this response may also be considered a placing reaction. Cutaneomuscular responses in the upper limb Organisation of cutaneomuscular responses The absence of reciprocal organisation in spinal cutaneomuscular responses is attested by the ﬁnd- ing that inall muscles tested(intrinsic muscles of the hand, long ﬂexors and extensors of the ﬁngers and ﬂexors and extensors of the wrist), the early spinally mediated response is excitation (see p. 415). In addi- tion, spike-triggered averaging has revealed that the excitatory input from single cutaneous afferents in the hand is sufﬁciently strong to be able to drive motoneurones in hand muscles and in the ﬂexor digitorumsuperﬁcialis throughspinal pathways that probably contain few interneurones (see p. 419). Task-related changes in cutaneomuscular responses Theamount of cutaneous facilitationof theon-going EMG activity of a given muscle varies with the task that the subject is performing (Evans, Harrison & Stephens, 1989). The main variations involve the transcortical E2 component. Thus, as illustrated in Fig. 9.13(b)–(i) for cutaneomuscular reﬂexes elicited in the FDI by a cutaneous stimulus to the index ﬁnger, E2 was signiﬁcantly larger when the sub- ject carried out an isolated ﬁnger manoeuvre than during grip. On the other hand, during ﬁnger tap- ping, whatever the involved ﬁnger, the E2 response was smaller, probably reﬂecting gating of the affer- ent volley within the sensory cortex (Turner, Harri- son & Stephens, 2002). In contrast, the amplitude of the spinal E1 response remained relatively con- stant, except for the ball gripwhere E1 was increased (Fig. 9.13(g)). Similarly, in the extensor digitorum communis, E2 was large during an isolated volun- tary extension of the ﬁnger, while E1 was somewhat increased during a power grip (Fig. 9.13(k)). 428 Cutaneomuscular and withdrawal reﬂexes MFEDC RFFDS ECR Tripod grip Ball grip Power grip Writing Index Abduction Spread fingers Index support Hand support Power grip Extend MF Flex RF Power grip 7 months 9 months 20 months Adult 50% 10% 10% 10% 50 ms 50 ms 50 ms FDI Cutaneous 20% modulation background EMG (a) (b) (f ) (g) (h) (i ) (c) (d) (e) ( j ) ( k) ( l ) ( m) (n) ( p) ( q) ( r ) Spinal INs FDI MN Fig. 9.13. Task-related changes in cutaneous reﬂex responses in the upper limb and reﬂex maturation. (a) Sketch of the presumed pathways. A␤ cutaneous afferents (thick dashed line) from the skin of the index ﬁnger produce a triphasic effect, with early facilitation mediated through spinal interneurones (IN), and inhibition and late excitation, both mediated through a transcortical pathway. (b)–(r) Modulation of the on-going EMG activity elicited by a single cutaneous volley (2 PT) delivered via ring electrodes attached on either side of the proximal interphalangal joint of the index ﬁnger for the ﬁrst dorsal interosseus (FDI), the middle ﬁnger for middle ﬁnger extensor digitorum communis (MFEDC), ring ﬁnger for ring ﬂexor digitorum subliminis (RFFDS), and on index and ring ﬁngers for the ECR. For (b)–(m), vertical calibrations represent a 20% modulation of mean background EMG level. (b)–(m) Changes in the cutaneous reﬂexes recorded in the FDI during various tasks in which the same level of EMG activity (∼10–20% MVC) was maintained. (b)–(e) Relatively isolated ﬁnger manoeuvres: (b) index abduction; (b) spread ﬁngers; (d ) index supporting the weight of the arm; (e) all ﬁngers supporting the weight of the arm. (f )–(i) Different grips: (f ) tripod grip (holding a pen); (g) ball grip; (h) power grip (holding a cylinder); (i) writing. (j), (k) Responses in the MFEDC during extension of the middle ﬁnger (j), or power grip (k). (l ), (m) Responses in the RFFDS during ﬂexion of the ring ﬁnger (l ) or power grip (m). (n)–(r) Modulation of the ECR EMG is compared in normal infants of different age: (n) 7 months; (p) 9 months; (q) 20 months; (r) adult (32 years). Modiﬁed from Evans, Harrison & Stephens (1989) ((b)–(m)), Issler & Stephens (1982) ((n)–(r)), with permission. Functional implications The pattern of cutaneous facilitation of different distal upper limb motor pools would reinforce the grip after contact with an object, and this sug- gests that spinal cutaneomuscular reﬂexes evokedby tactile afferents prevent grasped objects from slip- ping fromthe hand. The use of excessive force could then be minimised by the transcortical inhibition (I1), which immediately follows the initial spinally mediated facilitation. Non-noxious cutaneomuscular reﬂexes 429 100 µV 10 µV 50 µV 10 µV TA Sol Bi VL 60 ms 20 ms TA E1 E2 Spinal INs TA MN Sural nerve (a) (b) (c) (d) (e) Toe-down tilt 10 µV Fig. 9.14. Task-related changes in cutaneous reﬂex responses in the lower limb. (a) Sketch of the presumed pathways from afferents in the sural nerve to tibialis anterior (TA) motoneurones (MN). A␤ cutaneous afferents (thick dashed line) produce a biphasic response, with early facilitation and inhibition mediated through spinal interneurones (INs), and a late transcortical facilitation. (b)–(e) Effects evoked in the rectiﬁed on-going EMG by a train of ﬁve shocks (300 Hz) to the sural nerve producing intense paraesthesiae belowpain threshold, at a level 2–4 PT. (b) Responses in TA, soleus (Sol), biceps femoris (Bi) and vastus lateralis (VL) during bipedal stance tilted toe-down. (c)–(e) Comparison of the results obtained in TA during bipedal stance toe-up (c), voluntary contraction during unipedal stance on the contralateral leg, with the ipsilateral leg held in ﬂexion (d ), standing on an unstable support (pedals of an exercise bicycle (e)). Background EMG levels were 108, 128 and 132 V. Vertical dotted lines indicate the latencies of the early (E1) and late (E2) excitations. Modiﬁed from Burke, Dickson & Skuse (1991) ((b)–(e)), with permission. Cutaneomuscular responses in the lower limb The pattern of the early cutaneomuscular responses in the lower limb is difﬁcult to interpret In most voluntarily activated muscles, cutaneous volleysfromthedigital nervesof thesecondtoeor the sural nerve evoke a response at transcortical latency (E2), followed by an even later excitatory response (Gibbs, Harrison&Stephens, 1995; Burke, Dickson& Skuse, 1991; Aniss, Gandevia & Burke, 1992). Early responses (E1) at spinal latency (∼50 ms) are illus- trated in Figs. 9.9 and 9.14(b): there is excitation in the extensor digitorum brevis, peroneus longus and the gastrocnemii, and inhibition in tibialis anter- ior, soleus, biceps femoris and vastus lateralis. An early inhibition of the soleus H reﬂex has been pro- duced by pressure applied to the sole of the foot and attributed to the activation of slowly adapting cuta- neous receptors (Knikou & Conway, 2001). During gait, this inhibition of ankle extensors will be max- imal prior to the initiation of swing (toe off ), and it could contribute to the timing of the transition fromstance toswing during walking (cf. Abbruzzese, Rubino & Schieppati, 1996). Task-related changes in cutaneomuscular responses Here again, the more prominent changes involve the E2 responses, which are signiﬁcantly smaller dur- ing postural tasks than during voluntary contrac- tion (Gibbs, Harrison & Stephens, 1995). Thus, the sural-induced E2 response seen in the tibialis anter- ior when standing on the contralateral leg with the ipsilateral leg voluntarily ﬂexed (Fig. 9.14(d )) dis- appears when standing toe-up on a tilted platform (Fig. 9.14(c)). However, there are also changes in 430 Cutaneomuscular and withdrawal reﬂexes the early responses during postural tasks (Burke, Dickson & Skuse, 1991). (i) With unstable stance, an early E1 excitatory response appeared at a latency of ∼50 ms inthe ipsi- lateral tibialis anterior (Fig. 9.14(e)). This ﬁndingsug- gests that anexcitatoryspinal mechanismis released froma descending inhibitory control when stance is unstable. (ii) During bipedal stance tilted toe-up, the inhibi- tion of the ipsilateral tibialis anterior is accompan- ied by facilitation in the contralateral muscle. This seems intuitivelyreasonable: inbipedal stance, there would need to be compensatory changes in one leg to support the body as reﬂex actions occurred in the other. Functional implications Tilting the platform changes the background activ- ity in soleus and tibialis anterior, and the extent to which stable stance depends on the reﬂex responses in the two muscles. The changes in E1 and E2 of tibialis anterior in Fig. 9.14(c)–(e) represent a shift from a long-latency transcortical response (E2) to a spinal response (E1) as stance becomes more unsta- ble. These ﬁndings imply that the spinal component (E1) is functionally important in maintaining bal- ance and that the later components are insufﬁcient to achieve this when the motor system is not ﬁrst primed by the E1 response. Gait Reﬂex responses produced by stimulation of the tibial nerve could be due to activation of mus- cle afferents from plantar muscles (p. 398). Thus, only the results obtained with stimulation of purely cutaneous nerves (sural, superﬁcial peroneal) are considered below. Cutaneous responses evoked during the swing phase The modulation during gait of the reﬂex responses evoked by low-threshold cutaneous afferents has beenextensivelyinvestigatedbySteinandcolleagues (for review, see Zehr & Stein, 1999) and Duysens and colleagues (e.g. Van Wezel, Ottenhoff & Duy- sens, 1997). From these studies, it has emerged that stimuli tothesural or superﬁcial peroneal nerves can evoke excitatory responses inﬂexor muscles (tibialis anterior and hamstrings). These responses occur with a latency of ∼80–85 ms and have a duration of ∼30ms, but arenot closelyrelatedtothebackground EMG activity in any of the nerve/muscle combina- tions (Van Wezel, Ottenhoff & Duysens, 1997). In striking contrast withthe responses tostretch, which are mainly observed during the stance phase of gait (Chapter 11, p. 549), these responses are seenmainly during the swing phase. Local sign The reﬂex responses depend on the stimulated nerve, as would be expected if the location of the stimulus is important for the response (Van Wezel, Ottenhoff &Duysens, 1997). Whilestimuli toboththe sural and peroneal nerves produce large facilitatory responses in hamstrings, they have a different effect on the tibialis anterior. Thus, Fig. 9.15(b) shows the excitatory response evoked by sural nerve stimula- tion on the on-going EMG of tibialis anterior during the early swing phase, 600 ms after heel strike. The time course of this response during the step cycle shows that the excitation appears at the onset of the swing phase (or at the transition from stance to swing), peaks early in swing phase and is replaced by inhibition (cutaneous reversal) at the end of the swing phase (Fig. 9.15(d)). Incontrast, stimulationof the peroneal nerve suppresses tibialis anterior EMG activity, even in early swing phase. Evidence for a transcortical response The onset latency of the excitatory response is ∼85 ms, much the same latency as the similar, though smaller, response evoked during voluntary tonic dorsiﬂexion in the sitting position (Fig. 9.11(b)). The latter depends on a transcortical pathway p. 424, and the question then arises whether the Non-noxious cutaneomuscular reﬂexes 431 (a) (b) (c) (d ) (e) (f ) (g) Fig. 9.15. Sural modulation of the on-going EMG of tibialis anterior during walking. (a) Sketch of the presumed pathways. A␤ cutaneous afferents in the sural nerve activate, through spinal interneurones (IN) and/or transcortical pathways, excitatory and inhibitory INs projecting to ipsilateral tibialis anterior (TA) motoneurones (MNs). (b) Effect of sural stimulation (3 shocks, 300 Hz, 2 PT), triggered 600 ms after heel strike (early swing) on the on-going TA EMG. (c) Background activity of TA throughout the step cycle. (d ) Modulation by sural stimulation (5 shocks, 200 Hz, 2 PT) of the on-going TA EMG, measured within a window80–110 ms after stimulation, throughout the step cycle (mean data from ten subjects). Horizontal continuous and dotted lines indicate the times of ipsilateral and contralateral stance, respectively. (e)–(g) Effect of sural stimulation (three shocks, 300 Hz, 2.5 PT, 600 ms after heel strike) on the on-going TA EMG (e), the MEP elicited by TMS ((f ), 60 ms ISI) and by electrical stimulation of the motor cortex ((g), 63 ms ISI): averaged (20 sweeps) control (continuous thick line) and conditioned responses (dotted thin line) are superimposed. Modiﬁed from Nielsen & Sinkjær (2002) ((b), (e)–(g)), and Van Wezel, Ottenhoff & Duysens (1997) ((c), (d)), with permission. sural-induced excitation of tibialis anterior during the early swing phase of gait uses the same path- way. The effects of sural stimulationontibialis anter- ior MEPs elicited by magnetic or electrical stimu- lation of the motor cortex at the time when the cutaneous volley had reached the cortex were used to investigate this possibility (Christensen et al., 1999, and Fig. 9.15(e)–(g), see also Pijnappels et al., 1998). The sural volley facilitatedthe MEPelicitedby TMS, but did not modify the MEP elicited by elec- trical stimulation. Such a differential effect implies that motor cortex excitability was affected by the 432 Cutaneomuscular and withdrawal reﬂexes conditioning cutaneous stimulus (Chapter 1, p. 44), and provides evidence for a transcortical contribu- tionto the sural-inducedexcitation. However, again, it must be emphasisedthat theabovedemonstration of a transcortical pathway does not exclude the pos- sibility that other supraspinal (spino-bulbo-spinal) or even spinal pathways also contribute to these responses (cf. p. 424). Functional implications It has been suggested that the sural facilitation of ﬂexors is involved in lifting the foot over an obstacle (Yang & Stein, 1990; Duysens et al., 1990). When the foot strikes an obstacle in the transition fromstance to swing, it would be useful for an automatic mech- anism to help withdraw the limb from the ground through actions at ankle, knee and hip. Later in the swing phase, this response would be inappropriate, as the weight is shifting from the other leg. Then facilitation of tibialis anterior activity is replaced by inhibition, and this would help to place the foot on the ground to avoid stumbling (see Zehr & Stein, 1999; Christensenet al., 2000). Ontheother hand, the dorsumof thefoot innervatedbytheperoneal nerveis most likelytoencounter anobstacleduringtheswing phase. Theresultingsuppressionof thetibialis anter- ior EMGcombinedwiththe excitationof hamstrings is then adequate to clear the foot from the obstacle andprepare the legtostepover it, thus enablingcon- tinuationof anon-goingwalkingpattern. Cutaneous reﬂexes are also evoked in contralateral muscles. It seems therefore that cutaneous reﬂexes are used during gait, whether running or walking, tomove the perturbed leg away from the stimulus, with the gen- eral constraint of preserving both the cadence and balanceduringthestepcycle(Tax, VanWezel &Dietz, 1995; Van Wezel, Ottenhoff & Duysens, 1997). Why a transcortical component to the response? Similar reﬂex responses have been described in the spinalised cat during walking, and could play a sim- ilar role (see p. 387). Christensen et al. (2000) sug- gest that ‘the ease with which the balance may be endangered in bipedal gait by too large or too small responses tocutaneous stimulationhas made it nec- essary to integrate the reﬂex response at a corti- cal level rather than or in addition to a spinal level in human subjects. In this way, an inappropriate responsemay besuppressed, or theinformationcar- ried out by the cutaneous afferents may be used by the structure responsible for subsequent voluntary corrections of the movement’. Hopping During hopping, there is a sural-induced facilita- tion of the tibialis anterior at the end of the stance phase, as during gait, but no inhibition at the end of the swing phase. This ﬁnding indicates that the end-stance facilitation is not speciﬁc for alternating gait, and the absence of the end-swing suppressive reﬂexes may be related to the absence of heel strike in hopping (Hauglustaine et al., 2001). Conclusions Cutaneomuscular reﬂexes evoked through ‘private’ cutaneous pathways prevent grasped objects from slipping from the hand. In the lower limb, spinally mediatedplacing reactions tendtoincrease the con- tact with the ground, while supraspinally mediated excitatory responses appear in ﬂexor muscles dur- ing the swing phase of gait and are involved in lift- ing the foot over an obstacle. However, the main role of cutaneous afferents in motor control is prob- ablytomodulatethetransmissionin‘proprioceptive’ pathways (cf. Chapters 3–10). Changes in patients and clinical implications Changes in cutaneous reﬂexes, in particular in with- drawal reﬂexes, are of clinical importance in the examination of patients with upper motor neurone disorders. The exaggerationof ﬂexor reﬂexes andthe Studies in patients 433 release of ﬂexor spasms may, in addition, contribute to the discomfort of these patients. Complete spinal transection Early responses are replaced by long-latency withdrawal reﬂexes These long-latency responses are mediated through pathways analogous to those transmitting long- latency FRA responses in the DOPA-treated cat. Threephases canbedistinguishedintheevolutionof reﬂexes inthese patients (Hiersmenzel, Curt &Dietz, 2000): (i) During the initial phase of spinal shock, with- drawal reﬂexes are abolished. (ii) Then, during a ‘transition phase to spasticity’, early withdrawal responses of the same amplitude as in normal subjects reappear. There are no long- latency responses. (iii) Finally, some2–6months after theinitial injury when the lesion is chronic, the pattern described by Roby-Brami & Bussel (1987) appears, with sup- pression of early responses and their replacement by long-latency responses (cf. pp. 407–8). The ear- liest plantar response after stimulation of the sole of the foot is then recorded in the extensor hallucis longus where it appears witha latency similar to that of long-latency withdrawal responses (Roby-Brami, Ghenassia & Bussel, 1989). Receptive ﬁeld Incontrast tothemodular organisationof earlywith- drawal reﬂexes in normal subjects (see p. 407), late responses in patients with a chronic spinal cord injury have an invariant pattern of ﬂexion, regard- less of thestimulus locationonthefoot or leg(Schmit et al., 2003). The ﬁnding that similar responses occur with stimulation of the sural and posterior tibial nerves (Roby-Brami & Bussel, 1987) is of methodo- logical interest: it is not possible to grade the stimu- lus intensity with respect to the perception (or pain) threshold in these patients, but stimulation of the tibial nerve can be graded with respect to motor threshold, andresults soobtainedmay thenbe com- pared across different subjects. Afferents contributing to the ﬂexion reﬂex In these patients, they include cutaneous affer- ents, since the responses are evoked by sural nerve stimulation (Roby-Brami & Bussel, 1987), but also probably high-threshold muscle afferents (Schmit, McKenna-Cole & Rymer, 2000), much as in FRA- induced reﬂexes in the spinal cat (see pp. 388–9). Upper motoneurone lesions other than those due to a complete spinal transection Upper motoneurone lesions other than those due to acompletespinal transectionproducecharacteristic changes in cutaneous reﬂexes. Abolition of normal cutaneous reﬂexes Some cutaneous reﬂexes are abolished by upper motoneurone lesions. The disappearance of cuta- neous reﬂexes on the affected side of patients with hemiplegia was recognised by Jastrowitz in 1875 for the cremasteric reﬂexes and by Rosenbach in 1876 for the abdominal reﬂexes (cited by van Gijn, 1996). When the Babinski response is manifest (see below), this is in part because the normal downward move- ment of the hallux, which is a segmental cutaneo- muscular reﬂex involving the ﬂexor hallucis brevis, disappears after upper motoneurone lesions (cf. van Gijn, 1996). The disappearance of these cutaneous responses after upper motoneurone lesions implies that the relevant pathways normally receive tonic descending excitation from the corticospinal tract. The Babinski response The replacement of the normal plantar ﬂexionof toe 1 by dorsiﬂexion constitutes the Babinski response, a major sign of an upper motor neurone lesion. 434 Cutaneomuscular and withdrawal reﬂexes The abnormal dorsiﬂexion response has been documented in EMG recordings Using natural mechanical stimuli, Landau & Clare (1959) stated that ‘the unique feature of the patho- logical extensor responseis therecruitment of exten- sor hallucis longus into contraction’ (see Fig. 9.5(g)). However, using electrical rather than mechanical stimuli, Kugelberg, Eklund & Grimby (1960) found that the response involves both dorsiﬂexors and plantar ﬂexors of toe 1 in normal subjects and in patients with pyramidal lesions, but that the dom- inant response is in dorsiﬂexors in the patients so that the toe moves up. The differences in these stud- ies may be due to the different method of stimula- tion – electrical stimulation is artiﬁcial, quite unlike the situation when neurologists test the reﬂex. In accordance with Landau & Clare (1959), van Gijn (1996) recommends observation of the tendon of theextensor hallucis longus whentestingtheplantar response. Pathophysiology of the Babinski response The pathophysiology of the Babinski response involves the suppression of the normal segmental cutaneomuscular reﬂex (cf. above) and disinhibi- tion of the ﬂexion withdrawal reﬂex, with expansion of the receptive ﬁeld to include the skin of the lat- eral side of the sole, in addition to the ball of toe 1. Accordingly, the upward response of toe 1 will be accompanied by activation of other muscles of the ﬂexor synergy (see vanGijn, 1996). The Babinski sign is thus an indication of withdrawal of supraspinal control of ﬂexor reﬂexes in the lower limb. Absence of the downward response of toe 1 is not pathologi- cal, unless there is a marked difference between the two sides. The Babinski response can be equated with transient or permanent dysfunction of the upper motor neurone The function of the pyramidal tract may be dis- turbedbystructural lesions(of myelinsheaths, axons or both), by epileptic seizures (Babinski, 1898) or by metabolic factors, such as hypoglycaemia. The absence of an expected Babinski sign or an equiv- ocal response is often due to the technique used to elicit the response. A pressure palsy of the peroneal nerve will, of course, weaken dorsiﬂexion of toe 1. In other cases there may be temporary inexcitabil- ity of the segmental reﬂex pathway. This may be the case in the ‘spinal shock’ following an acute trans- verse lesion of the cord, but can also be observed after acute brain lesions such as a large infarct (see van Gijn, 1996). Withdrawal (ﬂexor) reﬂexes in the lower limb Alterations of lower-limb withdrawal reﬂexes in spasticity These alterations can be summarised as follows. (i) Breakdown of the adapted modular organisa- tion of withdrawal reﬂexes, with appearance of a ﬂexion response whatever the site of stimulation (Kugelberg, Eklund & Grimby, 1960; Dimitrijevi´ c & Nathan, 1968; Bathien & Bourdarias, 1972; Fisher, Shahani & Young, 1979). (ii) Irradiationinto muscles normally not involved (Meinck, Benecke&Conrad, 1983) with, for example, widespreadirradiationof activityfromstimulationof the unaffected side in hemiplegic patients (Dimitri- jevi´ c, 1973). (iii) Decreased threshold in patients with incom- plete spinal cord lesions and hemiplegic patients (Shahani & Young, 1971; Dimitrijevi´ c, 1973). (iv) Delay or suppression of early reﬂex compo- nents (Dimitrijevi´ c, 1973; Fisher, Shahani & Young, 1979; Meinck, Benecke & Conrad, 1983). (v) Dishabituation of reﬂex activity (Dimitrijevi´ c & Nathan, 1971) and abnormal sensitivity to temporal facilitation (Meinck et al., 1983b). Flexor spasms Flexor spasms are due to an overly vigorous reﬂex response of the isolated spinal cord to segmental inputs. AccordingtoShahani &Young(1973), theyare extremely variable, ranging from the brief repetitive ﬁring of single units without any visible contraction Studies in patients 435 inthe limbtosustainedﬁring of many motor units in many muscles with massive movements. They have the same clinical and physiological properties as do evoked ﬂexor reﬂexes in the same patients. Spon- taneous ﬂexor spasms may therefore be considered labile or heightened ﬂexor reﬂexes, the stimuli for which are not immediately apparent. They occur characteristically following more rostral spinal cord lesions. Electrical stimulation of the medial plantar nerve Such stimulation produces a ﬂexor reﬂex in the tib- ialis anterior, and has been used in the electrophys- iological investigations in spastic patients (Meinck et al., 1983a, b, 1985). Reﬂex pathways activated by the conditioning volley are complex, because the stimulation activates not only cutaneous affer- ents but also group I and group II muscle afferents from plantar muscles, and these muscle afferents have strong projections totibialis anterior motoneu- rones (cf. p. 398). However, these investigations are of interest because they involve a large number of patients with lesions at various level of the corti- cospinal tract. With weak stimuli, the early synchro- nised response observed in normal subjects was not seen; insteadlong-latencydesynchronisedactiv- ity occurred. With stronger stimuli, the desynchro- nised activity increased in amplitude and duration, and its latency shortened. These ﬂexor reﬂexes dif- feredfromnormal responses: (i) the inhibitory reﬂex components were replaced by excitation, (ii) the overall reﬂex discharge was greater, (iii) the reﬂex responses became grossly desynchronised, and (iv) phasic reﬂex activity was replaced by tonic activ- ity. Such abnormalities were seen in 98% of the 148 patients investigated (Meinck et al., 1983b), regard- less of whether the lesion was at the cerebral, brain- stem or spinal level. Withdrawal reﬂexes during gait in stroke patients Studies during gait have revealed three abnor- malities: (i) an expansion of the receptive ﬁeld of tibialis anterior, (ii) a decrease in the reﬂex activity in soleus and biceps femoris, and (iii) absence of reﬂex modulation during the step cycle (Spaich, Arendt-Nielsen & Andersen, 2004). Inhibition of the soleus H reﬂex Inhibition of extensors by noxious stimuli to the skin of the foot is the counterpart of the activation of ﬂexors in normal withdrawal reﬂexes of the foot (cf. pp. 404–5). Inhibition of the soleus H reﬂex by noxious stimulation to toe 5 has been compared in normal subjects and hemiplegic patients with lesions of the corticospinal tract at various levels of the neuraxis (Pierrot-Deseilligny, Bussel & Morin, 1973). The normal inhibition peaks at 50–70 ms in normal subjects (Fig. 9.8(b)) but was reduced in all patients, to a variable degree, according to the site of the lesion. The inhibition disappeared in patients with lesions of the paracentral lobule, was markedly decreased in patients with hemispheric lesions, and moderately decreased in patients with brainstem lesions. Withdrawal reﬂexes in the upper limb In stroke patients, Cambier, Dehen &Bathien (1974) described changes in the nociceptive reﬂex elicited by stimulation of the ulnar nerve at the wrist, resembling those described in the lower limb: a lower threshold for the reﬂex which appeared in the biceps, and spread of the response to involve ﬂexors of other limb segments. A recent investiga- tion by Dewald et al. (1999) has revealed further abnormalities. (i) As in the lower limb, the onset latencies of the responses were delayed. (ii) The normal proximal-to-distal sequence of activation of upper limb muscles after noxious stim- ulation of the ﬁnger was systematically changed, because the responses were more delayed at the shoulder than at the elbow. (iii) The normal patternof shoulder extensionwas changed into shoulder ﬂexion. 436 Cutaneomuscular and withdrawal reﬂexes Cutaneomuscular responses Lower limb Late E2 responses in the extensor digitorum brevis and tibialis anterior muscles are absent in patients with lesions of the corticospinal tract (Choa & Stephens, 1981; Rowlandson & Stephens, 1985b). In addition, during the stance phase of gait in stroke patients, superﬁcial peroneal stimulation suppresses triceps surae and quadriceps EMG, a change that does not occur innormal subjects (Zehr, Fujita & Stein, 1998). Upper limb Cutaneomuscular responses in the ﬁrst dorsal interosseous to stimulation of the digital nerves of the index ﬁnger undergo changes previously dis- cussed in patients with upper motoneurone lesions: the late E2 excitation may be abolished and, when present, is attenuated and delayed, the I1 inhibitory response is also attenuated, and the spinally medi- ated E1 excitation is generally increased (Jenner & Stephens, 1982; Chen et al., 1998). These changes produce a pattern similar to the cutaneomuscular responses observed in the neonate before the pyra- midal tract has reached maturity (cf. p. 423). They providesomeof theevidencefor atranscortical path- wayfor thelateE2excitation, andraisethepossibility that corticospinal drive normally exerts tonic inhibi- tion on the oligosynaptic spinal pathway mediating the E1 response. Grasp reﬂex Whether the grasp reﬂex observed in patients with frontal lobe lesions depends on cutaneous or mus- cle afferent inputs had been the subject of debate until Seyffarth & Denny-Brown (1948) showed that it was due to the summation of two local reﬂexes: an early cutaneous reﬂex (catching phase) followed by a stretch reﬂex of ﬁnger ﬂexors (holding phase), the latter being ineffective in the absence of the former. Cutaneous participation in the grasp reﬂex was indicated by the ﬁnding that the RII reﬂex evoked in the ﬂexor carpi ulnaris to stimulation of tactile afferents in the ulnar nerve was increased in a patient with a grasp reﬂex (Shahani, Burrows & Whitty, 1970). This result was conﬁrmed further in an investigation showing that the RII reﬂex is increased not only inthe ﬂexor carpi ulnaris but also in the biceps, and that, unlike RII in normal sub- jects, it is not prone to habituation (Cambier, Dehen &Bathien, 1974). The lack of habituation reﬂects the difﬁculty observed in these patients in inhibiting a response to tactile stimulation of the palmar side of the hand. In normal subjects, sustained vibra- tion of the skin of the ﬁngers at 100 Hz can pro- duce a reﬂex contraction of the long ﬁnger ﬂexor muscles, a response that nerve block experiments indicated due to activation of rapidly conducting cutaneous afferents (Eklund, Hagbarth & Torebj ¨ ork, 1978). Accordingly, the appearance of a grasp reﬂex in patients represents pathological accen- tuation of an intrinsically normal reﬂex response, not the development of a completely different reﬂex. Parkinson’s disease Withdrawal reﬂexes Withdrawal reﬂexes produced by noxious stimuli in the lower limb of patients with Parkinson’s disease differ from those in normal subjects in ﬁve respects. (i) The threshold of the early component is reduced. (ii) The normal reciprocal relationships in antag- onistic leg motoneurones are disturbed and a great deal of ‘co-contraction’ is seen, such that stimuli which normally produce reﬂex activity in extensors (cf. pp. 404–5) now also produce reﬂex activity in ﬂexors. (iii) Cutaneous silent periods (cf. Fig. 9.4(e)) are abnormally brief or virtually absent. (iv) Habituation is less evident than normal. (v) These abnormalities are largely, though not completely, reversed by the administration of DOPA Studies in patients 437 (Shahani & Young, 1971; Young, 1973; Delwaide, Schwab & Young, 1974). Early transcortical inhibition The early inhibitory component of the cutaneomus- cular response (I1) in the ﬁrst dorsal interosseus is decreased in parkinsonian patients (Fuhr, Zefﬁro & Hallett, 1992). Giventhat the I1component probably uses a transcortical pathway (cf. p. 423), this reduc- tion of I1 inhibition is in keeping with the effects of cutaneous volleys on the MEP evoked by TMS in the abductor pollicis brevis (Delwaide & Olivier, 1990). Innormal subjects cutaneous volleys fromthe index ﬁnger produce aninhibitionof the MEP at ISIs 18–22 ms, possibly the result of cutaneous inhibition of cortical neurones. This inhibition was reduced and even reversed to facilitation in parkinsonian patients. Both effects (depression of I1 and of the inhibition of the MEP) were partially reversed with dopaminergic treatments. This mechanism could contribute to parkinsonian rigidity. Peripheral neuropathies Sural-induced facilitation of the tibialis anterior and biceps femoris EMG observed in normal subjects during the swing phase of gait (see pp. 430–2) is sig- niﬁcantly reduced in patients with a sensory neu- ropathy producing a deﬁcit restricted largely to the loss of large-myelinated A␤ ﬁbres and not A␦ ﬁbres. The abnormally large variability in step cycle dura- tion and the gait impairment seen in these patients has been related to this loss of reﬂex activity from low-threshold cutaneous afferents (Van Wezel et al., 2000). Diagnostic uses Some clinically important tests in the standard neu- rological examination, suchas theBabinski response and the abolition of cutaneous abdominal reﬂexes, can provide evidence for dysfunction of the cor- ticospinal tract. An understanding of cutaneous reﬂexes and their supraspinal control is critical for understanding these tests. However, this section has focussed on the clinical relevance of electrophysio- logical investigations. Spinal responses These reﬂex responses can allow the integrity of different peripheral and segmental pathways to be investigated in tests that complement H reﬂex stud- ies. While the afferents responsible for the H reﬂex have the same segment as the innervated motoneu- rones, this is usually not so with the cutaneomus- cular responses, and reﬂex studies can be useful in differentiating between peripheral nerve and seg- mental pathologies. For example, stimulating dif- ferent digits of the hand can create inputs that traverse C6, C7 and C8 to the same motoneurone pool. Lesions of the transcortical pathway Abnormality can be manifest in patients with cen- tral lesions as attenuation of the E2 and I1 com- ponents and/or by prolongation of the interval between the short- and long-latency components. However, the selective involvement of long-latency transcortical responses sparing short-latency spinal responses has not proved a reliable ﬁnding in diag- nostic tests onindividual patients withquestionable lesions. Nociceptive reﬂexes may be of value in monitoring the effects of medication for pain Because of the strong correlation between the sural- induced RIII reﬂex in the biceps femoris and the pricking pain in the receptive ﬁeld of this nerve (p. 399; Fig. 9.2(l ), (m)), the RIII reﬂex provides an objective method to assess treatments in patients with pain (Willer, 1983). 438 Cutaneomuscular and withdrawal reﬂexes Rehabilitation The ability to activate the lower-limbﬂexionsynergy may be of value in helping restore locomotion in patients with incomplete spinal cord injury (see Barbeau et al., 1999). Conclusions Apart from their role in sensation, cutaneous affer- ents arealsocapableof modulatingmotor behaviour through spinal, supraspinal and transcortical path- ways. They may play a ‘proprioceptive’ role of paramount importance, whether that inﬂuence is mediatedbyprimarily‘private’ pathwayor bymodu- lating the activity of spinal pathways fed by muscle afferents and/or descending inputs. Role of cutaneous reﬂexes in motor control Withdrawal reﬂexes Early withdrawal reﬂexes, i.e. responses occur- ring with a latency of less than 120 ms in the lower limb, are the only responses that are unequiv- ocally mediated through spinal pathways in nor- mal subjects. They are organised to produce rapid movement away from the offending object. The ‘local sign’ is an important feature of withdrawal reﬂexes everywhere, on the trunk as well as the limbs, and is a consequence of this protective function. Late withdrawal reﬂexes are recorded in patients withcompletespinal transection, inwhomtheyhave a latency of more than 120 ms and a lower thresh- old than early withdrawal reﬂexes. Several features of these late reﬂexes, in particular that their latency increases as stimulus intensity is increased or the stimulus train prolonged, are reminiscent of the late FRA responses seen in the acute spinal cat treated with DOPA. Cutaneomuscular reﬂexes evoked by non-noxious stimuli Cutaneomuscular reﬂexes evoked through ‘pri- vate’ cutaneous pathways associate modest early responses mediated by oligosynaptic spinal path- ways withlargelong-latencytranscortical excitation. Inthe upper limb, the early spinally mediatedexcita- tion(E1) isdistributedmainlytodistal muscles, with- out reciprocal organisation, and is increased during power grip. These features and the ﬁnding that tac- tilecutaneous volleys favour therecruitment of high- threshold motor units suggest that reﬂexes evoked bytactileafferents prevent graspedobjects fromslip- ping fromthe hand. Inthe lower limb, spinally medi- ated placing reactions tend to increase the contact withtheground, whiletranscorticallymediatedexci- tatory responses appear inﬂexor muscles during the swingphaseof gait andareinvolvedinliftingthefoot over an obstacle. A major role of cutaneous afferents in motor control is to modulate the transmission in ‘pro- prioceptive’ pathways. This role is made possible because of their extensive convergence onto various spinal pathways. For example, the exteroceptive vol- ley evoked when the moving limb meets an obsta- cle helps curtail a movement through: (i) activation of inhibitory Ib interneurones transmitting the Ib feedback from the contracting muscle, and (ii) inhi- bition of cervical propriospinal neurones mediating the descending command. Changes in cutaneous reﬂexes in patients Patients with complete spinal transection When the lesion is chronic, early withdrawal reﬂexes more or less disappear and are replaced by late withdrawal responses with a stereotyped pat- tern of ﬂexion. Dishabituation is usual and may lead to ﬂexor spasms. Other upper motoneurone lesions produce char- acteristic changes in cutaneous reﬂexes: (i) replace- ment of the normal ﬂexion of toe 1 (physio- logical extension) by dorsiﬂexion (Babinski sign); R´ esum´ e 439 (ii) abolition of normal cutaneous responses, such as the abdominal and cremasteric reﬂexes. The RIII reﬂex produced by sural stimulation in the biceps femoris provides an objective method for monitoring the effects of medication for pain. R´ esum´ e Cutaneous afferents converge on interneurones intercalated in pathways fed by muscle afferents and descending tracts and on PAD interneurones mediating presynaptic inhibition of muscle affer- ents. Through this extensive convergence, extero- ceptive volleys help an appropriately timed termi- nation of the movement when the moving limb meets the target or an unexpected obstacle. Cuta- neous receptors can be activated during movement even without contact with an external object, and thereby modulate the motor output. This role is considered in detail in the other chapters. Cuta- neous afferents may also act in isolation and are capable of modulating motor behaviour through spinal, supraspinal and transcortical pathways. This chapter deals with such effects, which include two main types of response: withdrawal reﬂexes mediated by A␦ afferents and cutaneomuscular responses mediated by non-nociceptive cutaneous afferents. Background fromanimal experiments Private cutaneous pathways Reﬂexes elicited through private pathways are dif- ﬁcult to distinguish from FRA (ﬂexion reﬂex affer- ent) responses, but may be when cutaneous and FRA volleys evoke different responses in the same motoneurones. This is the case for (i) the toe exten- sor reﬂex, and (ii) the stumbling corrective reaction evoked fromthe dorsumof the foot in ﬂexors during the swing phase and in extensors during the stance phase of locomotion. Withdrawal reﬂexes evoked by noxious stimuli have for long been equated with the classical ﬂexionreﬂex. Theyare, infact, morereﬁned, with a modular organisation where each muscle has a separate cutaneous receptive ﬁeld activated from nociceptors and, to a lesser extent, slowly adapting mechanoreceptors. FRA pathways Flexion reﬂex afferents (FRA) include cutaneous, group II and group III muscle afferents and joint afferents. All of these afferents may evoke the ipsi- lateral ﬂexion reﬂex with contralateral extension (short-latency FRA responses) in the acute spinal animal. They have been grouped together, because: (i) they converge on common interneurones inter- posed in reﬂex pathways to motoneurones; (ii) they act together on a variety of ascending tracts; (iii) transmission of their effects is similarly inﬂuenced by brainstemlesions; and (iv) they are similarly con- trolled fromdescending tracts. There are alternative pathways from these afferents, and the term FRA is therefore a misnomer that may have outlivedits use- fulness, but it has been ratiﬁed by use. Lundberg (1979) formulated the hypothesis that, during normal movement, pathways mediating FRA reﬂexes could provide selective reinforcement of the voluntary command from the brain. The hypothe- sis relied on experimental evidence that: (i) there are alternative FRA pathways to the ﬂexion reﬂex, (ii) there are inhibitory interactions between alter- native FRA pathways, and (iii) muscle contraction produced by stimulation of ␣ efferents activates the FRA system. With DOPA, long-latency FRA responses replace short-latency FRA reﬂexes, which are depressed. Short- andlong-latencyresponseshaveasimilar pat- ternof excitationof ﬂexors fromipsilateral FRAs and of extensors fromcontralateral FRAs, withinhibition of antagonistic motoneurones, but they are medi- ated through different pathways, and short-latency FRA pathways can inhibit or delay the transmission in long-latency FRA pathways. There is mutual inhi- bition between long-latency FRA pathways to ﬂex- ors and extensors, and this half-centre organisation might be responsible for the alternating activationof ﬂexors and extensors during locomotion. 440 Cutaneomuscular and withdrawal reﬂexes Methodology General principles Some principles apply to all cutaneous reﬂexes: (i) some reﬂexes may be documented by recording responses when the subject is relaxed; (ii) otherwise the reﬂex effects of cutaneous volleys may be tested using the H reﬂex, the on-going EMG or PSTHs of single motor units; (iii) temporal summation or spa- tial and temporal summation is generally required to cause the response to appear consistently; (iv) cutaneous reﬂexes are very sensitive to repetition rate; and (v) spinal responses can be frequently dis- tinguished from transcortical responses on latency grounds. Stimuli (i) Electrical stimuli may be applied to cutaneous nerves or delivered directly to the skin. Withdrawal reﬂexes areelicitedbypainful stimuli andthethresh- old for pain is the same as the threshold for the nociceptivereﬂex. Cutaneomuscular responsesfrom low-threshold mechanoreceptors are produced by stimuli that can evoke tactile sensations. (ii) Mechanical stimuli may reproduce the stim- uli of natural situations. Natural stimulation of cuta- neous afferents from the ﬁngers may be produced using a small probe to indent the skinor a controlled puff of air. In routine clinical examination plantar responses are evoked by ﬁrm stroking of the lateral plantar surface of the foot, and abdominal reﬂexes by a rapid stroke with a blunt pin on the abdominal skin. Responses recorded at rest (i) The RIII withdrawal response of the short head of thebicepsfemorisisconsistentlyevokedbyastim- ulus to the sural nerve producing pain, and there is a correlation between reﬂex size and the sensation. If the stimulus intensity is sufﬁciently strong, the RIII reﬂex may be elicited by a single shock, but lower intensities are sufﬁcient to evoke the nociceptive reﬂex when a train is delivered. Noxious responses are also often investigated in the tibialis anterior to stimulation of the medial aspect of the sole of the foot at the apex of the plantar arch, or of the medial plantar nerve of the foot. Trains of tenpainful stimuli to the ﬁngers will produce reﬂex responses in most upper limb muscles investigated. (ii) RII Reﬂex responses are not easily evoked at rest by stimulation of tactile cutaneous (A␤) affer- ents, and temporal summation is always required. The RII response elicited in the short head of the biceps femoris by stimulation of the sural nerve at the ankle is the most consistent cutaneous reﬂex so produced at rest. Modulation of motoneurone excitability (i) Changes produced by cutaneous volleys in the amplitude of the H reﬂex or tendon jerk allow one to distinguish between volleys without effect on the excitability of motoneurones, those which evoke only subliminal excitation of motoneurones when applied alone, and those which produce inhibition of motoneurones. (ii) Averaging the rectiﬁed on-going EMG pro- vides reasonable temporal resolution of cutaneous- inducedresponses. The methodallows one torecord rapidly the full time course of the inhibitory and excitatory effects, and has been used extensively to explore the relatively weak responses to tactile cuta- neous inputs. (iii) Investigations of the cutaneous modula- tion of motoneurone discharge in PSTHs are very important, because cutaneous afferents have been shown to have different effects on different types of motoneurones (innervating slow- and fast-twitch motor units), andnoother technique canreveal this. Critique of the tests to study cutaneous reﬂexes (i) Nature of the stimuli. Mechanical stimuli do not allow accurate measurement of latencies and, for this reason, electrical stimuli, although artiﬁ- cial, are usually preferred. When stimulating a nerve trunk, cautionshouldbeobservedininterpretingthe evokedresponses because other afferents are almost certainly activated, even when stimulating a ‘pure’ R´ esum´ e 441 cutaneous nerve (e.g. joint afferents in digital nerves). (ii) Recordingtheresponsesat rest allowsonlyexci- tatory responses to be disclosed. (iii) Modulation of the average rectiﬁed EMG is suitablefor comparingthereﬂexeffects of cutaneous volleys indifferent motor tasks, but volitionmay bias the transmission in the reﬂex pathways. (iv) Modulation of the monosynaptic reﬂex at rest is not subject to volitional biases, but cutaneous vol- leys can produce changes in presynaptic inhibition of Ia terminals mediating the afferent volley of the monosynaptic reﬂex. (v) PSTHs of singleunits areimportant, but it is dif- ﬁcult to keep the same motor unit recording during a withdrawal reﬂex. Withdrawal reﬂexes Withdrawal reﬂexes are the reﬂexes produced by cutaneous afferents used most in the standard neu- rological examination. There are two classes of with- drawal reﬂexes in the lower limbs: early reﬂexes occurring with a latency less than 120 ms, and long-latency responses. In this chapter, ‘withdrawal reﬂexes’ denotes the former when not otherwise stated. Afferent pathway Small diameter, slowly conducting (17–28 m s −1 ) A␦ ﬁbres convey the afferent input for withdrawal reﬂexes and pain sensation. However, there is some evidence that A␤ ﬁbres can contribute to both the RIII reﬂex and pain, if they are repetitively stimulated. Central pathways of early withdrawal responses Because of the slow conduction velocity of A␦ afferents and the length of the afferent pathways after distal stimulation, the latency of withdrawal responses is often the same as that of transcor- tical responses mediated by A␤ ﬁbres. The ﬁnd- ing that responses of the same latency and pattern may be recorded in patients with complete spinal transection must be interpreted with caution (see below, long-latency withdrawal responses). Super- ﬁcial abdominal reﬂexes have been unequivocally demonstrated to be spinal, because their minimal central delay is 3–5 ms. The central delay of the with- drawal reﬂexes of the lower limb is less well deﬁned. However, after allowance for the peripheral conduc- tion time, the gradual decrease in the latency of the inhibition of knee extensors when the nociceptive stimulus is moved up the limb is best explained by a spinal mechanism. The RIII reﬂex of the biceps femoris after sural nerve stimulation, the best docu- mented withdrawal response, has a minimal latency of ∼80 ms, again compatible with a polysynaptic spinal pathway. In the upper limb, the latency of the nociceptivesilent periodintheabductor pollicis bre- vis is 43 ms, a latency that favours a spinal pathway. Functional organisation of early withdrawal reﬂexes Early withdrawal reﬂexes are organised on a func- tional basis designed to produce rapid movement away fromthe offending object. The ‘local sign’ is an important feature of withdrawal reﬂexes everywhere (in the trunk as well as in the limbs), and is a conse- quence of this protective function. (i) Trunk skin reﬂexes are regarded as nociceptive reﬂexes, even though they may be elicited by stimuli of innocuous quality, suchas touch, thoughthis may be because of the convergence of tactile andnoxious afferents on common interneurones. (ii) Plantar responses evoked from the sole of the foot are considered separately because of their clin- ical importance. Stimulation of the ball of the toe evokes a general ﬂexion reﬂex of the lower limb, including toe 1 dorsiﬂexion. Astimulus tothe hollow of the foot and the surrounding areas produces the normal plantar reﬂex, i.e. plantar ﬂexion of the toes (physiological extension) with ﬂexion at the ankle, knee and hip, a response that represents the appro- priate withdrawal movement. 442 Cutaneomuscular and withdrawal reﬂexes (iii) Other withdrawal responses in the lower limb also have a protective function. The ﬂexion move- ment at joints proximal to the stimulus represents the classical ﬂexion reﬂex, while extensor muscles are activatedby stimuli tothe overlying andadjacent skin. (iv) In the upper limb, the combination of the withdrawal reﬂex in proximal muscles and the silent period inhand muscles is appropriate for protecting the hand, opening and withdrawing it when there is an offending stimulus to the ﬁngers. (v) The protective function of withdrawal reﬂexes is very reﬁned with a modular organisation where eachmuscle has a separate cutaneous receptive ﬁeld activated from nociceptors and, to a lesser extent, slowly adapting mechanoreceptors. Late withdrawal responses These reﬂex responses occur at latencies above 120 ms after distal stimulation of the lower limb. In patients with complete spinal transection, they have a lower threshold than early withdrawal reﬂexes. Several features of these late reﬂexes are reminiscent of the late FRA responses disclosed in the acute spinal cat treated with DOPA: (i) their latency increases as the stimulus intensity is increased or the stimulus train prolonged; (ii) they are accompaniedby a prolongedpresynaptic inhibi- tion of Ia terminals; and (iii) they are inhibited from contralateral FRA. Lateresponses observedinnormal subjects donot have the characteristics of late FRAreﬂexes, because their thresholdishigher thanthat for earlyresponses, andtheir latencydecreases whenthestimulus inten- sity is increased. In addition, it has been shown that these late withdrawal responses can adapt to a new situation by a change in sign when appropriate, sug- gesting that they involve higher centres. Interactions between different inputs in withdrawal reﬂex pathways (i) Repeated painful cutaneous volleys facilitate withdrawal reﬂexes at short ISIs (below 3 s) and suppress them at long ISIs, the response coming back to its control level by 60 s. This facilitation- suppression is due to a spinal mechanism, possibly post-activation facilitation and depression of trans- mission at the synapses of the cutaneous afferents with interneurones. (ii) Tactile cutaneous volleys depress the biceps femoris RIII reﬂex. The depression of RIII responses by tactile afferents is maximal at ISIs of 100–300 ms and lasts for several hundred milliseconds. (iii) The existence of descending controls is sug- gested by: the attenuation of early withdrawal reﬂexes in patients with chronic spinal cord injury, the ﬁnding that they are susceptible tohypnotic sug- gestion, and the depressive effects of heterotopic noxious stimuli applied to a remote part of the body such as the hand or face. Changes in withdrawal reﬂexes during motor tasks These are poorly documented. (i) The cutaneous reﬂexes of the trunk evoked by a given stimulus are not invariant, and may be altered by a change in posture or an appropriate voluntary contraction. (ii) Standing on one leg results in a signiﬁcant decrease in the withdrawal reﬂex of the ipsilateral tibialis anterior, whereas a signiﬁcant facilitation is observed when the subject is standing on the con- tralateral leg. The functional signiﬁcance of this sup- pressionwould be to prevent the reﬂexes frominter- fering with the supporting action of the lower limb. (iii) The inhibition of the soleus H reﬂex pro- ducedbynoxious stimulationof toe5is reducedwith respect torest during tonic voluntary contractions of soleus or tibialis anterior. Cutaneomuscular reﬂexes evoked by non-noxious stimuli The different responses (i) The RII reﬂex evoked in the short head of the biceps femoris by low-intensity stimuli to the sural R´ esum´ e 443 nerve is the most consistent example of a cutaneo- muscular reﬂex recordable at rest. (ii) Cutaneomuscular reﬂexes can be recorded by modulating the on-going EMG activity during a vol- untary contraction by tactile cutaneous volleys. In theupper limb, withvolleysappliedtotheﬁngers, the typical pattern is a triphasic response with a modest early excitation (E1) at a latency of ∼30–35 ms, fol- lowedbyaninhibition(I1) andbyalargelong-latency excitation (E2). Such responses have been recorded in many distal, hand and forearm, muscles. In the lower limb, cutaneomuscular reﬂexes have a much less stereotyped pattern. Excitation at spinal latency (E1) is rarely seen (extensor digitorum brevis, pero- neus longus), and inhibition appears in both the soleus and tibialis anterior after stimulation of the sural nerve. These early responses are followed by a long-latency excitation in all muscles. (iii) Monosynaptic reﬂex modulation: In the lower limb, the dominant effect of sural nerve stimulation at 2–2.5PTisfacilitationof themonosynapticreﬂex occurringat ISIs longer than50ms inall testedmotor nuclei. In the upper limb, mechanical stimulation of the ﬁngertip produces a biphasic low-threshold modulation of the FCR H reﬂex, with weak short- latency inhibition, followed some 3–4 ms later by a potent facilitation. Afferent conduction Giventhe lowthresholdof the RII reﬂex (5 mA), there islittledoubt that theresponsibleafferentsarewithin the large-myelinated A␤ range (mean conduction velocity of 51 m s −1 ). Accordingly, stimuli evoking these responses generally require an intensity of 2–2.5 PT, and produce a non-painful sensation of touch, even when a long train is delivered. Central pathway of short-latency responses occurring at ‘spinal latency’ RII-like reﬂexes at rest and cutaneomuscular responses occurring after distal stimulationat laten- cies earlier than 45–50 ms in the upper limb and 70– 80 ms in the lower limb are probably spinal. For the modulation of the monosynaptic reﬂex, allowance for the conduction time of the test reﬂex discharge indicates a similar spinal origin for effects occurring at ISIs of less than ∼30 ms in the upper limb and ∼55 ms in the lower limb. Thus, on these latency grounds, transmission through spinal pathways is probable for: (i) the RII reﬂex of the biceps femoris; (ii) the early cutaneomuscular responses, whether E1 inthe upper limb or early inhibitioninthe tibialis anterior and soleus; (iii) the short latency inhibition and following facilitation of the FCR H reﬂex after stimulation of the ﬁngertip. Temporal summation is required to cause the RII reﬂex to appear at rest, and this makes uncertain speculations about the number of interneurones intercalated between the cutaneous terminals and motoneurones. When the cutaneomuscular response canbe obtainedwith a single shock, a more precise estimate of the central delay is possible. This may be as short as 1–2 ms in some cases, implying an oligosynaptic pathway. ‘Private’ pathway or changes in transmission in another pathway? (i) The RII reﬂex recordedat rest is probably medi- ated through a ‘private’ pathway. (ii) Cutaneomuscular reﬂexesrecordedduringvol- untary contractions could result from the modula- tion of the transmission in other pathways. Given the delay of transmission through the ␥ loop, any effect on ␣ motoneurones resulting from a change in the ␥ drive would only occur at long latencies. Cutaneous facilitation of interneurones mediating Ib inhibition to voluntarily activated motoneurones has been observed only with afferents from the skin ﬁeld that would have come into contact with an obstacle during contraction of the corresponding muscle, and this is not the case for the lateral side of the foot innervated by the sural nerve during con- traction of tibialis anterior or soleus. (iii) Depression of presynaptic inhibition of Ia ter- minals mediating the afferent volley of the test reﬂex can be produced by tactile afferents. This would explain why sural stimulation produces profound suppression of the on-going EMG in tibialis anter- ior and soleus but not of the soleus H reﬂex. 444 Cutaneomuscular and withdrawal reﬂexes Central pathway of long-latency effects The conclusion that long-latency responses have a supraspinal pathway relies on several arguments. (i) Thepatternof thelong-latencyfacilitationof the monosynaptic reﬂex suggests mediation through a supraspinal centre with reﬂex activation of the mus- cles in a rostrocaudal sequence. (ii) Thelatenciesof lateresponses, whencompared to the sum of the afferent and efferent conduction times to and from the cortex, are compatible with a transcortical pathway. (iii) Observations in patients with established neurological lesions have shown that the late E2 cutaneomuscular response requires the integrity of the dorsal columns, the sensorimotor cortex and the corticospinal tract. The ﬁnding that uni- lateral stimulation of the digital nerves produces bilateral I1 and E2 responses in the ﬁrst dorsal interosseous in patients with X-linked Kallmann’s syndrome and mirror movements provides further evidence for a transcortical origin of the I1 and E2 components. (iv) The development of E2 responses in infants parallels the maturation of the corticospinal tract, and provides further support for the view that long- latency cutaneous reﬂexes have a transcortical ori- gin. (v) Deﬁnitive evidence for a transcortical path- way has come fromexperiments using motor cortex stimulation. It has been shown that cutaneous vol- leys facilitate, at the appropriate latency, the MEP and the peak of cortical excitation in the PSTHs, when the cortical stimulation is magnetic, but not when it is electrical. Projections of cutaneous afferents to different types of motoneurones Cutaneous afferents from the index ﬁnger can shift the weighting of synaptic input associated with a voluntary contraction to favour the recruitment of the more powerful fast-twitch motor units in the ﬁrst dorsal interosseous. Similarly, sural nerve stim- uli below pain threshold produce inhibition in the PSTHs of early-recruited motoneurones and excita- tion in the PSTHs of late-recruited motoneurones of tibialis anterior. As a result, unconditioned tib- ialis anterior Hreﬂexes of small amplitude are inhib- ited by sural stimulation, whereas those of large amplitude are facilitated. The skeweddistributionof cutaneous inputs within the tibialis anterior motoneurone pool compresses the range of func- tional thresholds in the motoneurone pool and thereby increases the slope of the input-output rela- tionship of the test reﬂex, i.e. it produces a change in the recruitment gain of the reﬂex. Pattern and functional role of early responses (i) The RII reﬂex evoked at rest inthe short head of the biceps femoris tends toincrease the contact with the stimulus, much as in a ‘placing reaction’. (ii) In all tested upper-limb muscles, the early spinally mediated cutaneomuscular response is an excitation (E1). The diffuse pattern of excitation of distal muscles, the ﬁnding that it is increased during power grip, and the fact that natural tac- tile cutaneous volleys favour the recruitment of the more powerful fast-twitch units suggest that the reﬂex responses evoked by tactile afferents help prevent grasped objects from slipping from the hand. (iii) Inthe lower limb, apart fromplacing reactions which tend to increase the contact with the ground, an excitatory response appears at spinal latency in tibialis anterior when stance is unstable. During the swingphaseof gait, excitatoryresponses arerevealed in ﬂexor muscles. They might be involved in lifting the foot over an obstacle. However, there is increas- ing evidence that they are mainly transcortically mediated. Studies in patients and clinical implications Complete spinal transection During spinal shock, withdrawal reﬂexes are abol- ished. Then, during a ‘transition phase to spasticity’, References 445 early withdrawal responses of the same amplitude as in normal subjects reappear. Finally, some 2– 6 months after the initial injury when the lesion is chronic, early responses are suppressed and re- placed by long-latency responses. In patients with a chronic spinal cord injury, withdrawal responses have aninvariant patternof ﬂexion, regardless of the stimulus location on the foot or leg. Upper motoneurone lesions These produce characteristic changes in cutaneous reﬂexes: (i) Abolition of normal cutaneous reﬂexes, such as the abdominal and cremasteric reﬂexes. (ii) Appearance of the Babinski response, i.e. the replacement of the normal plantar ﬂexion of toe 1 by dorsiﬂexion. With mechanical stimuli, the patho- logical responseinvolves therecruitment of extensor hallucis longus. The pathophysiology of the Babin- ski response involves the suppression of the nor- mal segmental reﬂex plantar ﬂexion and disinhibi- tion of the ﬂexion withdrawal reﬂex, with expansion of the receptive ﬁeld to include the skin of the lat- eral side of the sole, in addition to the ball of toe 1. Accordingly, the upward response of toe 1 will be accompanied by activation of other muscles of the ﬂexor synergy. The absence of an expected Babin- ski sign may be due to a pressure palsy of the pero- neal nerve. There may be temporary inexcitabil- ity of the segmental reﬂex pathway in the ‘spinal shock’ following an acute transverse lesion of the cord. (iii) Alterations of lower limb withdrawal reﬂexes can be summarised as follows: breakdown of the adapted modular organisation of withdrawal reﬂexes, irradiation into muscles normally not involved, decreased threshold, delay or suppression of early reﬂex components, and dishabituation of reﬂex activity. (iv) Flexor spasms are due to an overly vigorous reﬂex responseof theisolatedspinal cordtosegmen- tal inputs, andhavethesameclinical andphysiologi- cal properties as doevokedﬂexor reﬂexes inthesame patients. Grasp reﬂex The grasp reﬂex observed in patients with frontal lobe lesions is due to the summation of two local reﬂexes: an early cutaneous reﬂex followed by a stretch reﬂex of ﬁnger ﬂexors, the latter ineffective in the absence of the former. The RII reﬂex evoked in wrist and elbow ﬂexors by cutaneous afferents from the palmar side of the hand is increased and, unlike the case in normal subjects, is insensitive to habituation. 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Progress in Neurobiology, 58, 185–205. Zehr, E. P., Fujita, K. &Stein, R. B. (1998). Reﬂexes fromthesuper- ﬁcial peroneal nerveduringwalkinginstrokesubjects. Jour- nal of Neurophysiology, 79, 848–58. 10 Propriospinal relay for descending motor commands The most important motor function of the spinal cord is to transmit the command for movement from higher centres to spinal motoneurones. In pri- mates, there are monosynaptic cortico-moto- neuronal projections, whereas, in the cat, the corticospinal command to forelimb motoneurones is transmitted exclusively through oligosynaptic pathways with intercalated spinal interneurones. Some are located at each segmental level (segmen- tal interneurones). Others are rostral to motoneu- rones and are referred to as propriospinal neurones in the following (although the term ‘propriospinal’ has a more general meaning: that of an intrinsic spinal cord neurone, the axon of which terminates in remote spinal cord segments). The presence of a signiﬁcant contribution of the cervical propriospinal system to the control of upper limb movement in higher primates has been debated, but there is mounting evidence that, in macaque monkeys (Sasaki et al., 2004) and in humans (Pierrot-Deseilligny, 2002), a substantial part of the cortical commandfor movement is trans- mitted to motoneurones through a ‘propriospinal’ relay locatedrostral tomotoneurones. The existence of a functional propriospinal system in human sub- jects is of particular interest. Indeed, because of the extensive convergence onto cervical propriospinal neurones of descending and peripheral inputs, the major role of the propriospinal system is proba- bly to enable integration of the descending com- mand en route to the motoneurones with the affer- ent feedback fromthe moving limb. This provides an example of the integrative action of spinal circuitry, such that the cortical command can be updated at a premotoneuronal level to take into account changes in the internal and external environment. The cervical propriospinal system Background fromanimal experiments The propriospinal systemin the cat The only premotoneuronal system for which both connections andfunctionare knownis the systemof C3–C4 propriospinal neurones in the cat, described by Lundberg and his group (for review see Alster- mark & Lundberg, 1992; Lundberg, 1999). Connec- tions have been established using classical intracel- lular recordings from motoneurones and interneu- rones. Behavioural studies on the effects of selective spinal lesions have elucidated the functional role of the system. Thus, this systemcan transmit descend- ing commands for target-reaching movements, and theextensiveconvergenceontoC3–C4propriospinal neurones of descending excitation and inhibition and of peripheral inputs (mainly inhibitory) from the moving limb allows the cortical command to be updated at that premotoneuronal level. Excitatory projections to and from propriospinal neurones Multi-excitatory convergence onto propriospinal neurones Corticospinal volleys evoke oligosynaptic EPSPs in feline forelimb motoneurones through both 452 Background fromanimal experiments 453 propriospinal neurones and segmental interneu- rones. Propriospinally mediated disynaptic EPSPs disappear after sectionof thecorticospinal tract at C2 but persist after its section at C5. This indicates that propriospinal neurones are located in C3–C4 (Illert, Lundberg &Tanaka, 1977), where they are in the lat- eral parts of laminae VI and VII. Other descending pathways (rubro-, tecto- and reticulo-spinal) and, to a much lesser extent, peripheral afferents also have monosynaptic excitatory projections onto pro- priospinal neurones (Illert et al., 1978) (Fig. 10.1). Projections from propriospinal neurones Propriospinal axons are located inthe ventral part of the lateral funiculus (whereas the corticospinal tract runs in its dorsal part), and project monosynapti- cally to motoneurones, to interneurones mediating reciprocal Ia inhibition(not showninFig. 10.1), or to both. Individual propriospinal neuronesmayproject to motoneurones of various muscles acting at differ- ent joints. This creates a hard-wired network in the cervical spinal cord to subserve complex motor syn- ergies in which muscles operating at different joints are co-activated (Alstermark et al., 1990; Chapter 11, pp. 529–30). Inhibitory mechanisms in the propriospinal system There is a wealth of inhibitory actions (Fig. 10.1) in the propriospinal system, mediated through inhibitory interneurones also located rostral to motoneurones (Alstermark, Lundberg & Sasaki, 1984a, b, c). (i) Inhibitory C3–C4 propriospinal neurones (not shown in Fig. 10.1) projecting monosynaptically to motoneurones andfeedforwardinhibitoryinterneu- rones projecting to propriospinal neurones have the same excitatory connections from higher centres as the excitatory propriospinal neurones and are interspersed among the propriospinal neurones in the lateral part of lamina VII. They are presumably used to focus excitation to the muscles required for PN LRN Corticospinal Rubrospinal Tectospinal Reticulospinal Feedforward inhibitory IN Feedback inhibitory IN Peripheral afferents MNs C3 C4 C5 C6 C7 C8 Fig. 10.1. The connections of the C3–C4 propriospinal system in the cat. In this and subsequent ﬁgures, segmental cervical levels are indicated on the left in italics, excitatory synapses are represented by Y-shaped bars and inhibitory synapses by small ﬁlled circles, excitatory interneurones by open circles and inhibitory interneurones by large ﬁlled circles. An individual propriospinal neurone (PN) projects to motoneurones (MNs) innervating different forelimb muscles and receives monosynaptic excitation from corticospinal (thick continuous line) and rubro-, reticulo- and tecto-spinal tracts (thick dashed line) and, to a much lesser extent, from peripheral afferents (thin dotted line). Note that there are no monosynaptic cortico-motoneuronal projections in the cat. Feedback inhibitory interneurones (IN) projecting to PNs receive monosynaptic excitation from peripheral and corticospinal inputs, while feedforward inhibitory INs projecting to PNs receive only monosynaptic excitation from the same descending tracts as PNs. The thick dotted line indicates that the feedback to inhibitory INs is stronger than to PNs. Axons of PNs have ascending collaterals to the lateral reticular nucleus (LRN). Projections of PNs to INs mediating reciprocal Ia inhibition, and inhibitory PNs projecting to MNs and their ascending collaterals to the LRN are not represented. Neither are the ascending collaterals of feedback inhibitory interneurones to the LRN represented. Sketched to illustrate data in Alstermark & Lundberg (1992) and Lundberg (1999). 454 Cervical propriospinal system the particular movement (in a manner analogous to lateral inhibition in sensory pathways). (ii) Feedback inhibitory interneurones, which project to propriospinal neurones, are excited from peripheral afferents in the moving limb, and are located medially in the laminae V and VI. They are usedtoregulatetheforceandspeedof themovement and contribute to its termination: whereas transect- ing the dorsal columns in C2 produces a moderate ataxia easily compensated by visual control, sup- pressing the afferent input to feedback inhibitory interneurones by transecting them in C5 results in marked hypermetria that cannot be corrected, sug- gesting that the command centres take feedback inhibitionfor granted(Alstermark et al., 1986). Feed- back inhibitory interneurones are alsoexcitedby the corticospinal tract so as to adjust the gain in the feedback inhibitory loop. Ascending projections Excitatory propriospinal neurones Theseneurones haveascendingcollaterals tothelat- eral reticular nucleus (LRN, seeFig. 10.1) (Alstermark et al., 1981a). Antidromic volleys produced by stim- ulationof the projections inthe LRNproduce mono- synaptic EPSPs in motoneurones, and their size can be used as a measure of the strength of the projec- tionof propriospinal neurones tomotoneurones. Via these ascending collaterals, the LRN, which projects tothe cerebellum, receives mirror informationof the motor commandthat reaches motoneurones via the propriospinal neurones, i.e. a perfect efference copy (see Lundberg, 1999). This may allowthe cerebellum to take corrective measures witha minimal delay, for which purpose it has at its disposal the rubro- and reticulo-spinal tracts whichproject directly toC3–C4 propriospinal neurones. Inhibitory propriospinal neurones and feedback inhibitory interneurones Unlike feedforward inhibitory interneurones, these interneuronesalsohaveascendingprojectionstothe LRN, and antidromic volleys produced by stimu- lation of their projections elicit monosynaptic IPSPs in motoneurones and in propriospinal neu- rones, respectively (Alstermark, Lundberg & Sasaki, 1984a, b). Function of the propriospinal system Behavioural studies on the effects of selective spinal lesions have been performed using a test consist- ing of reaching to a tube and retrieving food from it. These experiments have shown that the command for target-reaching is mediated by propriospinal neurones, whereas that for object-takingis transmit- ted by cortico- and rubro-spinal activation of seg- mental interneurones (Alstermark et al., 1981b). The extensive convergence (descending and peripheral) onto propriospinal neurones suggests that a motor command initiated in higher centres and relayed through motor cortex could be reshaped en route to motoneurones by integration in the propriospinal system. This would confer the ability to react to sud- den unforeseen changes in the internal or external environment that have occurred during the devel- opment of the motor commandandits transmission down to the spinal cord level (‘updating hypothesis’, see Illert et al., 1978). Conﬂicting results in the monkey Scarcity and weakness of propriospinally mediated EPSPs under control conditions In upper limb motoneurones of the macaque mon- key, indirect propriospinally mediated corticospinal EPSPs evokedby strong stimulationof the pyramidal tract are rare andweak, andsotooare monosynaptic EPSPs evoked antidromically by stimulation of the projections of propriospinal neurones to the LRN (Maier et al., 1998). Intermediate results between the cat and the macaque monkey were obtained in the squirrel monkey, in which hand dexterity is less advanced than in the macaque monkey. As a result it was argued that there was a positive Methodology 455 correlationbetweenhanddexterityandmonosynap- tic corticospinal projections across species, and a negative correlation between this function and the strength of the propriospinal system (Lemon, 1999; Nakajima et al., 2000; Kirkwood, Maier & Lemon, 2002). Disclosure of strong propriospinally mediated EPSPs after reduction of inhibition Effects after reduction of the inhibition When the post-synaptic inhibition mediated by feedback and feedforward inhibitory interneurones in propriospinal neurones has been reduced by intravenous strychnine, large corticospinal pro- priospinally mediateddisynaptic EPSPs canbe read- ily demonstrated in most upper limb motoneurones in the macaque monkey (Alstermark et al., 1999). This also applies to monosynaptic EPSPs elicited by stimulation of the LRN(which, under control condi- tions, are probably partially maskedby IPSPs elicited in motoneurones by stimulation of the ascending projections of inhibitory propriospinal neurones). Finally, intracellular recordings from identiﬁed C3–C4propriospinal neurones byAlstermarkandIsa have documentedtheir projections directly to upper limb motoneurones and the LRN in the macaque monkey (see Rothwell, 2002). Selective chronic lesions of the pyramidal tract Recent experiments performed after selective chro- nic lesion of the pyramidal tract in C4–C5 further support the view that a functional propriospinal system does exist in higher primates (Sasaki et al., 2004). (i) Propriospinally mediated disynaptic EPSPs could be induced even without strychnine in half of the forelimb motoneurones, occasionally even by a single stimulus. It was postulated that the strength of the inhibition had decreased so that C3–C4 propriospinal neurones mediating disynap- tic EPSPs were more readily activated after a chronic corticospinal lesion. (ii) Despite the lesion interrupting both cortico- motoneuronal excitationandexcitationviasegmen- tal interneurones monkeys could grasp a morsel of food using independent ﬁnger movements, though there was a deﬁcit in force between the index ﬁnger and the thumb. Conclusions The species difference might therefore be that in higher primates there is stronger inhibitory control of propriospinal neurones through feedforward and feedback inhibitions, in order to focus the descend- ing command more accurately than in the cat, not that evolution has caused the propriospinal system to disappear (Alstermark et al., 1999; pp. 467–8). Methodology Activation of propriospinal neurones may be inves- tigated by assessing (i) the excitation evoked by peripheral volleys in motoneurones, or (ii) the cuta- neous suppression of the descending command passing through the propriospinal relay. In both cases, theﬁndingthat themorecaudal themotoneu- rone, the longer the central delay of the effect sug- gests that the relevant neurones are located rostral to the cervical enlargement. Propriospinally mediated excitation produced by peripheral volleys Underlying principles Propriospinal neurones are activated by a volley applied to a peripheral nerve, and the resulting exci- tation of upper limb motoneurones is assessed as a change in (i) the PSTHs of single motor units, or (ii) compound EMG responses. The characteristics of this excitation of motoneurones are a long cen- tral delay, a low threshold, and disappearance when the stimulation is increased, and they allow it to be distinguished from an effect mediated through seg- mental interneurones. (f ) (g) (h) Facilitation of the MEP Facilitation in the PSTH of a single unit 10 15 20 25 30 -4 4 Latency (ms) M E P hayat devam ediyor viagra krizi t r i g g e r s ) 0 5 10 0 50 100 0 5 10 (c) (d) (e) (f ) FCR C4 C5 C6 C7 C8 C4 C5 C6 C7 C8 0 10 20 30 40 50 Fig. 10.7. Strength of corticospinal excitation of propriospinal neurones projecting to early and late recruited motoneurones. (a), (c) Sketch of the presumed pathways to ﬂexor carpi radialis (FCR, (a)) and extensor carpi radialis (ECR, (c)) motoneurones (MN) (monosynaptic corticospinal projections have been omitted). (a) Corticospinal excitation is more potent on propriospinal neurones (PN) projecting to large (‘fast’) MNs (thick line) than on PNs projecting to small (‘slow’) MNs (thin line), whereas monosynaptic Ia projections are more potent on small (thick dotted line) than on large (thin dotted line) MNs. (c) Different subsets of PNs transmit excitation from ECR and biceps afferents to ECR MNs, and during selective ECR contraction only the subset fed by ECR afferents receives corticospinal excitation. (b) The amount of facilitation of the FCR H reﬂex (conditioned–unconditioned reﬂex, as a percentage of M max ) is plotted against the size of the unconditioned reﬂex (as a percentage of M max ), which recruits small motoneurones before large. Propriospinally mediated excitation elicited by musculo-cutaneous (MC) stimulation (●, 0.75 MT, 4 ms ISI) and heteronymous monosynaptic Ia excitation elicited by stimulation of the ulnar nerve at the wrist (❍, 1 MT, 5.5 ms ISI), both effects tested at the onset of a selective biceps voluntary contraction. Each symbol is the mean of 20 measurements. (d)–(f ) The size of the peak of non-monosynaptic (d) and monosynaptic (e) excitations elicited by stimulation of the radial nerve and of non-monosynaptic excitation elicited by MC stimulation (f ) in the PSTHs for single ECR motor units (MU). Each symbol is the size of the peak in one MU (expressed as a percentage of the number of triggers) plotted against the background EMG activity (as a percentage of the EMG recorded during MVC) at which each MU was recruited (i.e. from slow to fast units). Oblique lines represent the regression line for the excitation. Modiﬁed from Marchand-Pauvert et al. (2000) ((b)–(e)), and J. Nielsen & E. Pierrot- Deseilligny (unpublished results) (f ), with permission. Motor tasks – physiological implications 471 maintaining the voluntary ﬁring of the motor unit required for the PSTHs. As expected (Chapter 2, pp. 79–81), homonymous monosynaptic Ia excita- tion was most marked in the lower-threshold units (Fig. 10.7(e)). In contrast, homonymous propriospi- nally mediated excitation was evenly distributed across units (Fig. 10.7(d)). However, this was no longer the case when the conditioning stimulus was applied to afferents of a non-contracting muscle (J. Nielsen & E. Pierrot-Deseilligny, unpublished data). Thus, Fig. 10.7(f ) shows that propriospinally medi- ated excitation elicited by musculo-cutaneous stim- ulation is preferentially distributed to ECR units in the low-threshold range during selective ECR con- tractions, i.e. when propriospinal neurones medi- ating musculo-cutaneous excitation are not facili- tated from descending tracts (see p. 476). Conclusions The above results are compatible with the ﬁnd- ings in the cat (Alstermark & Sasaki, 1986): the pro- jections of propriospinal neurones themselves, like most inputs to motoneurones, are distributed pref- erentially to early recruited units, as revealed when the tested propriospinal neurones do not receive descending excitation. However, recruitment of pro- priospinal neurones by descending inputs favours those projecting to high-threshold motoneurones and, as a result, propriospinal excitation is then preferentiallydistributedtolate-recruitedmotoneu- rones (see the sketch in Fig. 10.7(a)). This could account for the ﬁnding that at rest TMS may recruit ECR motoneurones in a sequence different fromthe orderly recruitment of the H reﬂex (Nielsen et al., 1999; Chapter 1, p. 45). Motor tasks and physiological implications The rationale for an integrative centre near but dis- tinct fromthemotoneuronelies inthefact that trans- mission of descending commands can be mixed and modulated without altering the excitability of the motoneurone pool. Intense suppression (or intense activity) of the motoneurone pool couldren- der it transiently less able to respond to further inputs, and there are therefore advantages in having these processes located elsewhere so that only the updatedcommandwouldimpinge onthe motoneu- rone. In human studies, two different experimen- tal paradigms have been employed to elucidate the extent to which the propriospinal system is used in natural movement: (i) cutaneous suppression of the on-going voluntary EMG, and (ii) facilitation of the propriospinally mediated excitation of the H reﬂex during voluntary contraction. Evidence for propriospinal transmission of a part of the descending command Underlying principles The effects upon the voluntary motoneurone dis- charge of a peripheral volley known to inhibit pro- priospinal neuroneshavebeenexplored(Burkeet al., 1994). The rationale behind these experiments was that, if a signiﬁcant part of the descending command passed through the propriospinal relay, the inhibitory volley would interrupt it and thus suppress the voluntary EMG (see the sketch in Fig. 10.8(a)). In these experiments superﬁcial radial volleys were used to inhibit propriospinal neurones projecting to wrist extensors, biceps and triceps motoneurones. Evidence for disfacilitation Suppression of the on-going ECR EMG while the H reﬂex is spared Asingle superﬁcial radial volley suppresses the tonic on-going ECR EMG activity, with a central delay of 4 ms (Fig. 10.8(b) and its legend). In contrast, the same cutaneous volley has little effect on the ECR H reﬂex recorded during a similar voluntary con- traction, and this indicates that the inhibition is not exerted directly on motoneurones. Instead, it is (a) (b) (c) (d ) (e) (f ) Fig. 10.8. Evidence for transmission of a component of the descending command for movement through the propriospinal relay. (a)–(c) Cutaneous suppression of the propriospinally mediated descending command for tonic extensor carpi radialis (ECR) voluntary contraction. (a) Sketch of the presumed pathways. Cutaneous volleys in the superﬁcial radial nerve (SR) activate feedback inhibitory interneurones (IN) which inhibit propriospinal neurones (PN) projecting to ECR motoneurones (MN). (b) Effects of a cutaneous stimulus to the SR (single shock, 3 PT) on the ongoing EMG activity (average of 300 sweeps, ●), the motor evoked potential (MEP elicited by TMS, ▲) and the H reﬂex (❍) of the ECR (mean ±SEM of 20 responses). Conditioned responses (as a percentage of unconditioned responses) plotted against the central latency, i.e. zero on the abscissa corresponds to the synchronous arrival of conditioning and test volleys at the segmental level of the MN pool (▲, and ❍), or to the arrival of the cutaneous volley at that level (●, estimated from the latency of the ECR H reﬂex and the difference in afferent conduction times of the cutaneous and Ia volleys). (c), (d) Mean MEP responses elicited by TMS in the ECR (20 sweeps, control, thick lines; conditioned, thin lines) are conditioned by SR stimulation ((c), 3 PT, 11 ms ISI) and median nerve stimulation ((d), 1 MT, 3 ms ISI). (e), (f ) Descending facilitation of the propriospinally mediated excitation from the musculo-cutaneous nerve (MC) to ECR. (e) Sketch of the presumed pathways (monosynaptic corticospinal projections have been omitted). It is assumed that the same subset of PNs, activated by biceps (Bi) group I afferents, projects to Bi and ECR MNs. Presynaptic inhibition of MC group I afferents synapsing with PNs is represented (see p. 475). (f ) Changes in the ECR H reﬂex amplitude after stimulation of the MC nerve (as a percentage of control values) are plotted against the ISI at rest (❍) and at the onset of a selective biceps voluntary contraction (●), the hand being in pronation. Modiﬁed from Burke et al. (1994) (b), Mazevet, Pierrot-Deseilligny & Rothwell (1996) ((c), (d)), and Mazevet & Pierrot-Deseilligny (1994) (f ), with permission. Motor tasks – physiological implications 473 presumably exerted on ‘premotoneurones’ which transmit a part of the voluntary drive to the ECR motoneurone pool, and the suppression is due to disfacilitation of motoneurones. (Such a disfacilita- tionbearsnorelationshiptotheshort latency–2ms– cutaneous inhibitionof theFCRHreﬂexevokedfrom both sides of the ﬁngers, see Chapter 9, pp. 415–18). Complex effects of disfacilitation The effects of disfacilitation are complex because a withdrawal of excitation must affect the excitabil- ity of the motoneurone pool. Nevertheless, disfacil- itation is not the equivalent of inhibition because it is not accompanied by a conductance change, which is the major factor suppressing motoneurone discharge with postsynaptic inhibition (Chapter 1, p. 27). Disfacilitation does reduce the monosynap- tic part of the peak of Ia excitation slightly (see p. 464) and accordingly, during contraction, it would prevent the less excitable motoneurones ﬁring inthe control reﬂex from being recruited by the test vol- ley. However, this would be offset (at least in part) by the availability for the H reﬂex of motoneurones no longer engaged in the contraction, now the most excitableof thesubliminal fringe. Inother words, dis- facilitation will produce a decrease in excitability for eachindividual motoneurone, but theHreﬂexwould be modiﬁed only slightly because the reﬂex can now access motoneurones no longer active in the con- traction, thus compensating for the failure to recruit less excitable motoneurones. Parallel suppression of the on-going EMG and of the MEP Disfacilitation at premotoneuronal level is also sup- ported by the ﬁnding that the superﬁcial radial vol- ley suppressed the MEP elicited by TMS or elec- trical stimulation of the motor cortex to a simi- lar extent as the on-going EMG (Fig. 10.8(b); Burke et al., 1994; Mazevet, Pierrot-Deseilligny &Rothwell, 1996). The cutaneous suppressionlargely spared the initial part of the MEP due to the monosynaptic cortico-motoneuronal volley (Fig. 10.8(c); Mazevet, Pierrot-Deseilligny &Rothwell, 1996). Again, this ini- tial sparingis consistent withdisfacilitation, because inhibition exerted on motoneurones should affect the entire corticospinal response, as occurs with median-induced disynaptic “reciprocal” inhibition of ECR motoneurones (Fig. 10.8(d)). Site of disfacilitation Cutaneous depression of the corticospinal excita- tion reaching the motoneurone pool could occur through three mechanisms: depression of motor cortex excitability (Maertens de Noordhout et al., 1992); presynaptic inhibition of the terminals of corticospinal axons with motoneurones; depression of interneurones in the corticospinal pathway. The ﬁrst alternative can be excluded on latency grounds (Burkeet al., 1994). Thesecondalternativeis unlikely because the available evidence indicates that corti- cospinal terminals on motoneurones are not sub- jected to presynaptic inhibition (Nielsen &Petersen, 1994). This leaves only the third alternative, depres- sion of premotoneurones interposed in the corti- cospinal pathway. Two arguments favour the view that the relevant premotoneurones are located ros- tral tomotoneurones: (i) the central delay of the sup- pressionof theon-goingEMGis longer themorecau- dal the motoneurone pool (see p. 459); and (ii) the central latency of the cutaneous suppression of the MEP is compatible with inhibition of premotoneu- rones located 1–2 ms rostral to the motoneurones (Mazevet, Pierrot-Deseilligny & Rothwell, 1996). Cutaneous suppression of the corticospinal command to various motor nuclei Superﬁcial radial stimulation suppresses the volun- tary EMG recorded during tonic and phasic con- tractions of wrist extensors (Pierrot-Deseilligny & Mazevet, 1993; Burke et al., 1994). Suppressionof the on-going voluntary EMGof biceps andtriceps by the same cutaneous volley has also been observed dur- ing tonic and phasic contractions of these muscles. Here also parallel depression of the MEP with the same central delay as that of the on-going EMG but 474 Cervical propriospinal system the absence of parallel modiﬁcation of the tendon jerkduringcontractionareinfavour of disfacilitation interrupting the descending excitation at a premo- toneuronal level (cf. Pierrot-Deseilligny, 1996). Quantiﬁcation of transmission of the descending command via the propriospinal relay Amount of suppression Cutaneous suppression of the ECR MEP is often profound: it is maximal at the 8–9 ms ISIs when using TMS (Marchand-Pauvert et al., 1999a), and the mean suppression is 32% (Nicolas et al., 2001). The amount of suppression of the on-going tonic EMG activity (difference between conditioned and control EMG, expressed as a percentage of control EMG), at the latency where it is maximum, is on average 38% in the ECR (Burke et al., 1994) and can reach up to 70% in the triceps brachii (Fig. 10.9(b); Pierrot-Deseilligny, Mazevet & Meunier, 1995). The maximal suppression is, not surprisingly, greater than the mean suppression over 10 ms given above (p. 459). Limitations The greater the component of the descending com- mand passing through the propriospinal relay, the more profound will be the cutaneous disfacilitation. However, this does not imply that the percentage of EMG suppression reﬂects the percentage of the voluntary command transmitted to motoneurones through the propriospinal relay. The corticospinal response is produced by spatial summation at the motoneurone pool of the propriospinally mediated andmonosynapticcorticospinal EPSPs, andremoval of either could have a large effect. Conversely, the amount of cutaneous inhibition also depends on the cortical drive on feedback inhibitory interneu- rones. If this cortical drive is weak (e.g. at the onset of movement, see p. 478), a single cutaneous vol- ley may not recruit all feedback inhibitory interneu- rones. The resulting inhibition would silence only some propriospinal neurones, and the component of the descending command relayed by the pro- priospinal relay, as assessed by this method, would be underestimated. Conclusions The relationship between the cutaneous suppres- sion of descending excitation at the propriospinal level and the resulting disfacilitation of motoneu- rones is complex, and the percentage of the corticospinal drive that is relayed through this indi- rect system cannot be measured in isolation. How- ever, it is safe to conclude that this oligosynaptic component makes a substantial contribution to the contraction. Propriospinally mediated facilitation of motoneurones during voluntary contraction Reﬂex facilitation at the onset of voluntary contraction Changes in transmission across propriospinal neu- roneshavebeenexaminedduringvoluntarycontrac- tions. Monosynaptic reﬂex testing has been used to compare these data with data at rest. The test reﬂex was the H reﬂex for FCR and ECR, or the tendon jerkfor biceps andtriceps. Conditioningvolleys were applied to group I afferents in the ulnar, musculo- cutaneous or triceps nerves. The resulting group I facilitation of the reﬂex had all the characteristics of apropriospinallymediatedeffect (longcentral delay, low threshold, and disappearance when the stimu- lation was increased, see p. 457). The central ﬁnd- ing of these studies, illustrated in Fig. 10.8(f ) for the musculo-cutaneous facilitation of the ECR H reﬂex, was that asmall or absent effect at rest became much larger at theonset of aselectivevoluntarycontraction of the muscle innervated by the nerve stimulated to Motor tasks – physiological implications 475 (a) Corticospinal Feedback inhibitory IN PN Tri MN Superficial radial (b) (c) (d ) Triceps 0 7 14 -50 -25 0 0 7 14 Train 1 shock -80 -60 -40 -20 0 20 0 5 10 15 20 25 30 Onset Offset Onset Offset Central l atency (ms) A m o u n t how long does viagra make you last food alternatives to viagra CLINICAL DRUG THERAPY puscifer v is for viagra zip Canada and its provinces have laws and standards that parallel those of the United States, particularly those related to controlled substances (see Appendix D). American Drug Laws and Amendments viagra makes my face red viagra hologram (4) Give most oral drugs with a full glass (8 oz) of water or other ﬂuid. Most studied and used to treat anxiety, stress, emotional excitability and restlessness; additional claims include treatment of depression, insomnia, asthma, pain, rheumatism, muscle spasms, and promotion of wound healing viagra met alcohol The reticular activating system is a network of neurons that extends from the spinal cord through the medulla and pons to the thalamus and hypothalamus. It receives impulses from all parts of the body, evaluates the signiﬁcance of the impulses, how many times a day can i take viagra Basal Ganglia avigra viagra difference film pfizer viagra Drugs affecting the CNS, sometimes called centrally active drugs, are broadly classified as depressants or stimulants. CNS depressant drugs (eg, antipsychotics, opioid analgesics, sedative-hypnotics) produce a general depression of the CNS when given in sufﬁcient dosages. Mild CNS depression is characterized by lack of interest in surroundings and inability to focus on a topic (short attention span). As depression progresses, there is drowsiness or sleep, decreased The client will: • Experience relief of discomfort with minimal adverse drug effects • Experience increased mobility and activity tolerance • Inform health care providers if taking aspirin or an NSAID regularly • Self-administer the drugs safely • Avoid overuse of the drugs • Use measures to prevent accidental ingestion or overdose, especially in children • Experience fewer and less severe attacks of migraine can you buy viagra over the counter in hong kong viagra 0nline Nonaspirin NSAIDs are widely used and preferred by many people because of less gastric irritation and GI upset, compared with aspirin. Many NSAIDs are prescription drugs used primarily for analgesia and anti-inﬂammatory effects in arthritis and other musculoskeletal disorders. However, several are approved for more general use as an analgesic or antipyretic. Ibuprofen, ketoprofen, and naproxen are available by prescription and OTC. Clients must be instructed to avoid combined use of prescription and nonprescription NSAIDs because of the high risk of adverse effects. NSAIDs commonly cause gastric mucosal damage, and prolonged use may (3) Hypertension (4) Hypersensitivity reactions—local edema and pruritus, anaphylactic shock 4. Observe for drug interactions a. Drugs that increase effects of aspirin and other NSAIDs: (1) Acidifying agents (eg, ascorbic acid) (2) Alcohol (3) Anticoagulants, oral (4) Codeine, hydrocodone, oxycodone viagra e prescrizione medica Dosage and Administration 200 mg viagra too much viagra and hot tubs Withdrawal symptoms have been reported with sudden discontinuation of most antidepressant drugs. In general, symptoms occur more rapidly and may be more intense with drugs having a short half-life. As with other psychotropic drugs, these drugs should be tapered in dosage and discontinued gradually unless severe drug toxicity, anaphylactic reactions, or other life-threatening conditions are present. Most antidepressants may be tapered and discontinued over approximately 1 week without serious withdrawal symptoms. For a client on maintenance drug therapy, the occurrence of withdrawal symptoms may indicate that the client has omitted doses or stopped taking the drug. The most clearly deﬁned withdrawal syndromes are associated with SSRIs and TCAs. With SSRIs, withdrawal symptoms include dizziness, nausea, and headache and last from several days to several weeks. More serious symptoms may include aggression, hypomania, mood disturbances, and suicidal tendencies. Fluoxetine has a long half-life and has not been associated with withdrawal symptoms. Other SSRIs have short half-lives and may cause withdrawal reactions if stopped abruptly. Paroxetine, which has a half-life of approximately 24 hours and does not produce active metabolites, may be associated with relatively severe withdrawal symptoms even when discontinued gradually, over 7 to 10 days. Symptoms Phenytoin (prototype; Dilantin) my viagra not working viagra transdermal Toxicity of Antiseizure Drugs: Recognition and Management RATIONALE/EXPLANATION These drugs increase activity of hepatic drug-metabolizing enzymes, thereby decreasing blood levels of carbamazepine. Reduce absorption of gabapentin. Gabapentin should be given at least 2 hours after a dose of an antacid to decrease interference with absorption. Valproic acid inhibits the liver enzymes that metabolize lamotrigine, thereby increasing blood levels and slowing metabolism of lamotrigine. As a result, lamotrigine dosage must be substantially reduced when the drug is given in a multidrug regimen that includes valproic acid. These drugs induce drug-metabolizing enzymes in the liver and thereby increase the rate of metabolism of themselves and of lamotrigine. These drugs induce drug-metabolizing enzymes in the liver and thereby increase the metabolism and hasten the elimination of oxcarbazepine. May increase plasma levels of phenobarbital as much as 40%, probably by inhibiting liver metabolizing enzymes. Inhibits drug-metabolizing enzymes, thereby slowing elimination from the body and increasing blood levels of valproic acid Displace valproic acid from binding sites on plasma proteins, thereby increasing the serum level of unbound valproic acid These drugs induce drug-metabolizing enzymes in the liver and thereby increase the metabolism and hasten the elimination of zonisamide. These drugs are benzodiazepines, discussed in Chapter 8. comprar viagra online seguro SECTION 2 DRUGS AFFECTING THE CENTRAL NERVOUS SYSTEM can you cut viagra pills in half Halothane (Fluothane) viagra pas d'effet generic viagra walmart pharmacy CHAPTER 15 SUBSTANCE ABUSE DISORDERS donde puedo comprar viagra generico Alcohol detoxiﬁcation; benzodiazepine withdrawal Alcohol withdrawal; opiate withdrawal acheter viagra feminin • Record weight at least weekly. • Promote nutrition to avoid excessive weight loss. • Provide information about the condition for which a stimulant drug is being given and the potential consequences of overusing the drug. norvasc and viagra interaction Hypertension Hypertension Hypertension viagra for runners SECTION 3 DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM melon d'eau viagra Anticholinergic drugs, also called cholinergic blocking and is viagra only available on prescription administration. reliable source viagra uk retention can i take half a viagra pill 350 dr. ed viagra Tachycardia Increased cardiac output Increased blood volume Increased systolic blood pressure Cardiac dysrhythmias Congestive heart failure buying viagra manila (2) Parathyroid hormone decreases effects. g. Drugs that decrease effects of phosphate salts: Antacids containing aluminum and magnesium 4. 5. 6. abra 100 viagra All of the currently available types of oral agents (alphaglucosidase inhibitors, biguanide, glitazones, meglitinides, and sulfonylureas) have been used successfully with insulin. viagra and sleep apnea (6) Rotate injection sites systematically, within the same anatomic area (eg, abdomen) until all sites are used. Avoid random rotation between the abdomen and thigh or arm, for example. viagra til piger donde comprar viagra chino Jane Smily, an adolescent, calls the clinic because she forgot to take her birth control pill yesterday. What effect will this have on the therapeutic effects of the birth control pills? How should you advise her? What teaching can you provide that will help her remember to take her birth control pills regularly? How Can You Avoid This Medication Error? comprare viagra senza ricetta medica when did viagra first come out • viagra first time experience 1. Review functions and food sources of essential vitamins. 2. Differentiate between maintenance and therapeutic doses of vitamins. 3. Identify clients at risk for development of vitamin deﬁciency or excess. 4. Delineate circumstances in which therapeutic vitamins are likely to be needed. como tomar viagra masticable Critical Thinking Scenario You have been asked to speak with a group of senior citizens, living independently in a retirement community, about vitamins and health. You have a group of approximately 25 who signed up for this talk as part of a general education series on “Staying Fit and Healthy After 65.” Reﬂect on: ᮣ Teaching strategies that might enhance learning, considering the size of the group and the age of the participants. ᮣ Review important vitamins, their beneﬁts, and Recommended Dietary Allowances (RDAs). ᮣ Review dietary sources to meet daily requirements. ᮣ Problem-solve which nonprescription vitamins are indicated and cost-effective. ᮣ Review potential problems in megadosing. Deﬁciency States Causes Signs and Symptoms GI problems (stomatitis, glossitis, enteritis, diarrhea) Central nervous system problems (headache, dizziness, insomnia, depression, memory loss) With severe deﬁciency, delusions, hallucinations, and impairment of peripheral motor and sensory nerves may occur. Causes Excess States Signs and Symptoms can you buy viagra legally in uk the king of eastern viagra Assess each client for current or potential vitamin disorders during an overall assessment of nutritional status. Specific assessment factors related to vitamins include the following: • Deﬁciency states are more common than excess states. • People with other nutritional deﬁciencies are likely to have vitamin deﬁciencies as well. • Deﬁciencies of water-soluble vitamins (B complex and C) are more common than those of fat-soluble vitamins. • Vitamin deficiencies are usually multiple and signs and symptoms often overlap, especially with B-complex deficiencies. • Vitamin requirements are increased during infancy, pregnancy, lactation, fever, hyperthyroidism, and many illnesses. Thus, a vitamin intake that is normally adequate may be inadequate in certain circumstances. • Vitamin deﬁciencies are likely to occur in people who are poor, elderly, chronically or severely ill, or alcoholic. • Vitamin excess states are rarely caused by excessive dietary intake but may occur with use of vitamin drug preparations, especially if megadoses are taken. viagra funny cartoon Vitamin E viagra package insert pdf Magnesium oxide or hydroxide may be given for mild hypomagnesemia in asymptomatic clients. Magnesium sulfate is given parenterally for moderate to severe hypomagnesemia, convulsions associated with pregnancy (eclampsia), and prevention of hypomagnesemia in total parenteral nutrition. Therapeutic effects in these conditions are attributed to the drug’s depressant effects on the central nervous system and smooth, skeletal, and cardiac muscle. Oral magnesium salts may cause diarrhea; their uses as antacids and cathartics are discussed in Chapters 60 and 61, respectively. Magnesium preparations are contraindicated in clients who have impaired renal function or who are comatose. Oral preparations of magnesium oxide or hydroxide act in 3 to 6 hours, are mini- can you drink alcohol after taking viagra Dosage viagra 100mg preis apotheke chapter 34 Beta-Lactam Antibacterials: Penicillins, Cephalosporins, and Others compuesto quimico del viagra How Can You Avoid This Medication Error? William Howles, 82 years of age, has been receiving gentamicin for the last 3 days to treat a serious wound infection. Peak and trough blood levels have been drawn and you receive the following results: peak 7 mcg/mL and trough 4 mcg/mL (normal: peak 5 to 8 mcg/mL and trough < 2 mcg/mL). How will you interpret these results, and what, if any, action will you take? other antimicrobials to provide broad-spectrum activity. In critical care units, as in other settings, there is increased use of once-daily dosing. Because critically ill clients are at high risk for development of nephrotoxicity and ototoxicity with aminoglycosides, guidelines for safe drug usage should be strictly followed. Because ﬂuoroquinolones may be nephrotoxic and hepatotoxic, renal and hepatic function should be monitored during therapy. Fluoroquinolones are usually infused IV in critically ill clients. However, administration orally or by GI tube (eg, nasogastric, gastrostomy, or jejunostomy) may be fea- viagra on wedding night viagra urdu information Blood dyscrasias (potentially serious and life-threatening) have occurred in clients taking chloramphenicol. Irreversible bone marrow depression may appear weeks or months after how does viagra work wiki stopped and not resumed if enzyme levels are higher than ﬁve times the upper limit of normal in an asymptomatic person, are higher than normal range if symptoms of hepatitis are present, or if a serum bilirubin is above normal range. Rifampin daily for 4 months. This regimen is used mainly for clients who cannot tolerate INH or pyrazinamide. Special Populations 1. Pregnant women. The preferred regimen for treatment of LTBI is INH, administered daily or twice weekly for 9 or 6 months. Pregnant women taking INH should also take pyridoxine supplementation. For HIV-positive women with higher risks of progression to active TB, treatment should not be delayed; for those with lower risks, some experts recommend waiting until after delivery to start treatment. In general, INH, rifampin, and ethambutol have good safety records in pregnancy. Pyrazinamide and streptomycin are contraindicated during pregnancy. 2. Children and adolescents. INH daily or twice weekly for 9 months is recommended. Infants and children under 5 years of age with LTBI are at high risk for progression to disease. They are also more likely than older children and adults to develop life-threatening forms of TB, including meningeal and disseminated disease. INH therapy appears to be more effective for children than adults, and the risk for INH-related hepatitis is minimal in infants, children, and adolescents, who generally tolerate the drug better than adults. Routine administration of pyridoxine is not recommended for children taking INH, but should be given to breast-feeding infants, children and adolescents with pyridoxine-deﬁcient diets, and children who experience paresthesias when taking INH. Although few studies have been done in infants, children, and adolescents, rifampin alone, rifampin with INH, and rifampin with pyrazinamide have been used to treat LTBI with effectiveness. Although the optimal length of rifampin therapy in children with LTBI is unknown, the American Academy of Pediatrics recommends 6 months. There have been no reported studies of any regimen for treatment for LTBI in HIV-infected children. The American Academy of Pediatrics recommends INH for 9 months; most experts recommend routine monitoring of serum liver enzyme concentrations and pyridoxine administration. 3. Contacts of patients with drug-susceptible TB and positive skin-test reactions (>5 mm) should be treated with one of the recommended regimens described above, regardless of age. 4. Contacts of patients with INH-resistant, rifampin-susceptible TB should generally be given rifampin and pyrazinamide for 2 months. For patients with intolerance to pyrazinamide, rifampin alone for 4 months is recommended. If rifampin cannot be used, rifabutin can be substituted. 5. Contacts of patients with multidrug-resistant (MDR)-TB who are at high risk for developing active TB are generally given pyrazinamide and ethambutol or pyrazinamide and a fluoroquinolone (levofloxacin, ofloxacin, or sparfloxacin) for 6 to 12 months. Immunocompetent contacts may be observed without treatment or treated for 6 months; immunocompromised contacts (eg, HIV-infected persons) should be treated for 12 months. For children exposed to MDR-TB, pyrazinamide and ethambutol are recommended for 9 to 12 months if the isolate is susceptible to both drugs. If these drugs cannot be used, two other (continued ) SELECTED REFERENCES does viagra make you stay hard Nick, a 19-year-old college student, is diagnosed with genital herpes at the student health center. Acyclovir 200 mg q4h is prescribed for 10 days. In addition, acyclovir 400 mg is ordered bid to control recurrence of symptoms when lesions appear. What client teaching will Nick need at this time? buy generic viagra melbourne viagra sleep apnea Drugs at a Glance: Selected Antifungal Drugs fake viagra australia CHAPTER 40 ANTIFUNGAL DRUGS can you travel with viagra 667 pfizer viagra price in malaysia tacrolimus may have stronger immunosuppressant activity than cyclosporine. By inhibiting helper T cell proliferation and cytokine expression, these three drugs reduce the activation of various cells involved in graft rejection, including cytotoxic T cells, natural killer cells, macrophages, and B cells. Consequently, they have become a mainstay of heart, liver, kidney, and bone marrow transplantation. Cyclosporine is used to prevent rejection reactions and prolong graft survival after solid organ transplantation (eg, kidney, liver, heart, lung), or to treat chronic rejection in clients previously treated with other immunosuppressive agents. The drug inhibits both cellular and humoral immunity but affects T lymphocytes more than B lymphocytes. With T cells, cyclosporine reduces proliferation of helper and cytotoxic T cells and synthesis of several cytokines (eg, IL-2, interferons). With B cells, cyclosporine reduces production and function to some extent, but considerable activity is retained. Transplant rejection reactions mainly involve cellular immunity or T cells. With cyclosporine-induced deprivation of IL-2, T cells stimulated by the graft antigen do not undergo clonal expansion and differentiation, and graft destruction is inhibited. In addition to its use in solid organ transplantation, cyclosporine is used to prevent and treat GVHD, a potential complication of bone marrow transplantation. In GVHD, T lymphocytes from the transplanted marrow of the donor mount an immune response against the tissues of the recipient. Absorption of cyclosporine is slow and incomplete with oral administration. The drug is highly bound to plasma proteins (90%), and approximately 50% is distributed in erythrocytes, so drug levels in whole blood are signiﬁcantly higher than those in plasma. Peak plasma levels occur 4 to 5 hours after a dose, and the elimination half-life is 10 to 27 hours. Cyclosporine is metabolized in the liver and excreted in bile; less than 10% is excreted unchanged in urine. Because the drug is insoluble in water, other solvents are used in commercial formulations. Thus, it is prepared in alcohol and olive oil for oral administration and in alcohol and polyoxyethylated castor oil for IV administration. Anaphylactic reactions, attributed to the castor oil, have occurred with the IV formulation. Neoral is a microemulsion formulation of cyclosporine that is better absorbed than oral Sandimmune. The two formulations are not equivalent and cannot be used interchangeably. Neoral is available in capsules and an oral solution; Sandimmune is available in capsules, oral solution, and an IV solution. Nephrotoxicity is a major adverse effect. Acute nephrotoxicity commonly occurs and, in some cases, progresses to chronic nephrotoxicity and kidney failure. Sirolimus is used to prevent renal transplant rejection. It acts by inhibiting T-cell activation. It is given concomitantly with a corticosteroid and cyclosporine. It may have synergistic effects with cyclosporine because it has a different mechanism of action. However, the two drugs are metabolized by the same cytochrome P450 3A4 enzymes and cyclosporine increases blood levels of sirolimus, possibly to toxic levels. Consequently, the drugs should not be given at the same time; venta de viagra online sin receta 12 hours and the drugs should not be taken more frequently. If additional bronchodilating medication is needed, a shortacting agent (eg, albuterol) should be used. Isoproterenol is a short-acting bronchodilator and cardiac stimulant. When used for treatment of bronchospasm, iso- viagra for women for sale ireland Pseudoallergic drug reactions resemble immune responses (because histamine and other chemical mediators are released) but they do not produce antibodies or sensitized T lymphocytes. Anaphylactoid reactions are like anaphylaxis in terms of immediate occurrence, symptoms, and life-threatening severity. The main difference is that they are not antigen– antibody reactions and therefore may occur on ﬁrst exposure to the causative agent. The drugs bind directly to mast cells, activate the cells, and cause the release of histamine and other vasoactive chemical mediators. Contrast media for radiologic diagnostic tests are often implicated. Drugs at a Glance: Commonly Used Antihistamines (continued ) viagra prescription only drug unsteady gait, and paradoxical CNS stimulation in older adults. These effects, especially sedation, may be misinterpreted as senility or mental depression. Older men with prostatic hypertrophy may have difficulty voiding while taking these drugs. Some of these adverse reactions derive from anticholinergic effects of the drugs and are likely to be more severe if the client is also taking other drugs with anticholinergic effects (eg, tricyclic antidepressants, older antipsychotic drugs, some antiparkinson drugs). Despite the increased risk of adverse effects, however, diphenhydramine viagra sale ph 1. Describe several factors that cause histamine release from cells. 2. What signs and symptoms are produced by the release of histamine? 3. How do antihistamines act to block the effects of histamine? 4. Differentiate between H1 and H2 receptor antagonists in terms of pharmacologic effects and clinical indications for use. 5. In general, when should an antihistamine be taken to prevent or treat allergic disorders? 6. Compare and contrast the first- and second-generation antihistamines. stamina rx viagra alternative Upper respiratory infections with nasal congestion, sore throat, cough, and increased secretions are common in children, and viagra price in pakistan lahore viagra falls imdb 752 betabloccanti e viagra Nursing Notes: Apply Your Knowledge 806 how much does viagra cost at boots Routes and Dosage Ranges Generic/Trade Name Adults IV infusion, add 200 mg to 250 mL of 5% dextrose or 0.9% sodium chloride solution (concentration 2 mg/3 mL) and infuse at a rate of 3 mL/min. Adjust ﬂow rate according to blood pressure, and substitute oral labetalol when blood pressure is controlled. Calcium Channel Blocking Agents PO 5–10 mg once daily Amlodipine (Norvasc) PO 60–120 mg twice daily. Diltiazem (sustained release) Extended-release tablets; swallow whole, do not (Cardizem SR) crush or chew. PO 5–10 mg once daily. Felodipine (Plendil) Extended-release tablets; swallow whole, do not crush or chew. PO 2.5–5 mg twice daily Isradipine (DynaCirc) PO 20–40 mg three times daily; sustained-release, Nicardipine (Cardene, Cardene PO 30–60 mg twice daily; IV infusion 5–15 mg/h SR, Cardene IV) Sustained-release only, PO 30–60 mg once daily, Nifedipine (Adalat, Procardia, increased over 1–2 wk if necessary Procardia XL) PO, 20 mg once daily initially, increased by 10 mg/wk Nisoldipine (Sular) or longer intervals to a maximum of 60 mg daily. Average maintenance dose, 20–40 mg daily. Adults with liver impairment or >65 y, PO, 10 mg once daily initially Immediate-release, PO 80 mg 3 times daily; Verapamil (Calan, Calan SR, sustained-release, PO 240 mg once daily; IV, Isoptin SR) see manufacturer’s instructions Other Vasodilators Fenoldopam (Corlopam) Children viagra effective duration 809 viagra australia fake viagra doping sports Use in Hepatic Impairment viagra spam email example 832 SECTION 9 DRUGS AFFECTING THE CARDIOVASCULAR SYSTEM viagra rezeptfrei kaufen auf rechnung c. With nicotinic acid, ﬂushing of the face and neck, pruritus, and skin rash may occur, as well as tachycardia, hypotension, and dizziness. 4. Observe for drug interactions a. Drugs that increase effects of lovastatin and related drugs: (1) Azole antifungals (eg, ﬂuconazole, itraconazole) skinner viagra uso correcto del viagra How Can You Avoid This Medication Error? side effects of too much viagra Lactulose is a disaccharide that is not absorbed from the GI tract. It exerts laxative effects by pulling water into the intestinal lumen. It is used to treat constipation and hepatic encephalopathy. The latter condition usually results from alcoholic liver disease in which ammonia accumulates and causes stupor or coma. Ammonia is produced by metabolism of dietary how long does it take for 100mg viagra to work A ﬂuoroquinolone (See Chap. 35) generic viagra securetabs 900 jake gyllenhaal viagra movie The drugs may cause obstruction of the gastrointestinal (GI) tract if swallowed in a dry state. They may combine with and inactivate other drugs. buy viagra in phoenix az OVERVIEW NORMAL AND MALIGNANT CELLS pfizer viagra cheap prices dove posso comprare viagra online Nursing Notes: Ethical/Legal Dilemma 930 importation of viagra into australia 1. Topical application is the most common route of administration for ophthalmic drugs, and correct administration is essential for optimal therapeutic effects. 2. Systemic absorption of eye drops can be decreased by closing the eye and applying pressure over the tear duct (nasolacrimal occlusion) for 3 to 5 minutes after instillation. 3. When multiple eye drops are required, there should be an interval of 5 to 10 minutes between drops because of limited eye capacity and rapid drainage into tear ducts. (text continues on page 943) viagra bestellen 24 stunden Clinical Indications generic viagra vs regular viagra • Observe for improvement in skin lesions and symptoms. • Interview regarding use of measures to promote healthy viagra for sale winnipeg acquisto viagra all'estero Answer: Many drugs given to the mother are excreted into breast milk. An increasing number of studies are being conducted to try to quantify drug effects during lactation, so use current resources to get the most up-to-date information. To determine possible effects on her son, the mother should consult her pediatrician regarding any medications she is taking. At times, it is best for the mother to pump her breast and discard the milk until she is no longer taking medication. Antihistamines, which often are found in cold remedies, may dry up milk production and cause drowsiness in the infant. 48 street value of viagra 50mg EXPERIMENTAL CASE STUDY 2–1: Neuromaging Diaschisis-Related Recovery self prescribing viagra PNS Neurons Sensory, axon regeneration do u need a prescription for viagra in canada viagra pribalovy letak 100 106 buy viagra pharmacy ireland results may produce misinformation. Unrecognized subconscious processes may be at work during the activation task. For example, anterior language areas can be activated merely by preparation for speech, in the absence of articulation. The investigator often cannot be sure that the subject is carrying out the process of interest, such as silent speech or no intended speech to engage the intended network. For motor tasks, greater physical effort may produce subtle mirror movements that cause activation, usually in the hemisphere of the unaffected limb, when none is expected57 or produce overflow movements with associated head motion artifacts. These problems are managed by configuring the task in a way that lessens the effort required of the subject. Motor and cognitive activations may change with aging, perhaps related to changes in strategies or effort and associated with degenerative changes over time such as dopaminergic cell loss. Thus, healthy subjects and patients must be carefully matched for age, since aging alters cerebral responses during performance. For example, an fMRI study compared performances during a reaction time task in which subjects under the age of 35 years and over age 50 years pressed one of four buttons to a visual stimulus.57a The older subjects had relatively larger regions of activation in the contralateral S1M1, lateral premotor area, SMA, and ipsilateral cerebellum. In addition, ipsilateral S1M1, bilateral putamen, and contralateral cerebellum were activated. Relatively larger and more bilateral frontal activations are found in older subjects performing the same cognitive tasks as younger people as well, especially in the dorsal and lateral prefrontal cortices. Recruitment of additional regions does not necessarily imply any decline in task performance, however. Indeed, when younger subjects attempt more demanding motor or cognitive tasks, similar bilateral motor or frontal regions may also be activated. Prescribed medications may alter excitation and inhibition of functional activations (Color Figure 3–9 in separate color insert). Ovarian steroids that vary with the menstrual cycle more clearly do this. TMS studies show greater excitatory responses when estradiol is high and inhibition when progesterone increases.57b These hormones act on a variety of neurotransmitters. The entry criteria in Table 3–3 mention other potentially important variables, viagra super fluox-force Neuroscientific Foundations for Rehabilitation is it illegal to bring viagra into australia viagra and scuba diving Neuroscientific Foundations for Rehabilitation what does it feel like to take viagra ter robot was engineered by observing the movements of the lobster under many circumstances and recreating its actions with an electronic system that parallels the lobster’s nervous system. Electronic command neurons, coordinating neurons, central pattern generators, and sensory feedback allow software to manage a remarkably modest number of circuits to mimic all locomotor activities. Such neurocreations may extend the reach of the disabled. Intelligent wheelchairs and lightweight exoskeletons with sensors and tiny actuators worn under clothes and powered without leaden battery packs could also serve a robotic function. An ankle-foot orthosis, for example, is a passive device that is not as compliant as an ankle, does not adapt over time to the changing needs of its user, and cannot reproduce biologic behaviors. The U.S. armed forces have funded research for the development of tiny joint actuators built into exoskeletons that aim to enable a soldier to leap over walls and run at great speeds. These exoskeletons may find their greatest benefit in helping the mobility and self-care activities of the disabled. For rehabilitation at present, the most successful robotic efforts have been simple devices designed to enhance the retraining of movement. The International Conference on Rehabilitation Robotics (ICORR) presents biannual updates on robotic devices that replace or augment diminished physical and cognitive capabilities. in the early 20th century. In addition, these approaches were first formulated from the founding advocate’s observations of children with cerebral palsy and adults with hemiplegic stroke. The approaches involve hands-on interaction between the therapist and the patient. The interventions utilize sensory stimuli and reflexes to facilitate or inhibit muscle tone and patterns of movement. Therapy aims to elicit individual and whole limb muscle movements, but schools vary in whether they try to initially elicit mass flexor or extensor patterns of movement called synergies. Therapists may try to activate or suppress a stretch reflex, the asymmmetric and symmetric tonic neck reflexes, the tonic labyrinthine reflex, and withdrawal and extensor reflexes. They use stimuli that include muscle or tendon vibration, joint compression, skin stroking, and other sensory inputs that elicit reflexive movement and positive and negative supporting reactions. Neurodevelopmental Techniques Most schools have emphasized a progression in the sequence of therapies reminiscent of the neurodevelopmental evolution from reflexive to more complex movements. Neurodevelopmental techniques (NDT) call for reproducing the developmental sequence shown by infants as they evolve motor control. Based on handson experience with children with cerebral palsy, practitioners believe that normal movement requires normal postural responses, that abnormal motor behaviors are compensatory, and that the quality of motor experiences helps train subjects for normal movement. Practitioners emphasize normal postural alignment prior to any movement. Mobility activities proceed in a developmental pattern from rolling onto the side with arm and leg flexion on the same side, to extension of the neck and legs while prone, to lying prone while supported by the elbows, and then to static and weight-shifting movements while crawling on all four extremities. These mat activities are followed by sitting, standing, and, finally, walking. Different schools vary in their attempts to activate or mimimize reflexive movements and to train functional movements during ordinary physical activities. One of the potential problems with NDT is the delay of standing and walking until the patient has achieved relative control of proximal can i take viagra with citalopram Blocked and Random Practice Blocked practice, the mass repetition of a drill, improves performance during the phase of acquisition. Random schedules of practice, in which several motor or verbal tasks are given so that the same task is not practiced on successive trials and repetition of any one task is widely spaced, will degrade success during acquisition. The term contextual interference describes distractors involved when a subject carries out more than one activity within a training session. In normal subjects, random schedules of practice enhance retention over the long run and can improve performance in contexts other than those evident during training.57 This finding suggests that random practice adds difficulty for the learner during acquisition, but prevents superficial rehearsal. Unlike blocked practice, it forces the learner to design or retrieve a different strategy for each trial. Practice at performing a task along a single dimension, such as tossing beanbags into a basket at one distance or walking only on a smooth flat surface, produces better accuracy during acquisition than variable practice, in which a person tosses bags at different distances or walks on a variety of surfaces. Variable practice, however, seems to force a change in behavior from trial to trial that improves performance on tests of long-term retention of the motor skill and generalizes the skill to other settings.55 Variable practice, then, strengthens the processes or rules between the outcome of a goaldirected movement and the parameters for that movement, such as postural adjustments, the sequence of movements, firing rates of agonist and antagonist muscles, and error-detection. How much practice is needed to master a new skill? A strong relationship exists between performance and the time spent on deliberate practice.58 For example, by age 20 years, the best professional musicians have practiced for more than 10,000 hours, nearly twice as much as less accomplished groups of expert musicians and 8000 hours more than amateur musicians of the same age. Deliberate practice is sustained for 3 to 5 hours every day for years in elite performers. Only approximately 50 hours of training is typically needed to achieve effortless performance of everyday activities such as learning to drive a car. Even this amount of practice at a particular activity is unlikely to be achieved during rehabilitation for herbal viagra singapore ing items led to better retention over time compared to blocked practice.67 Despite the contextual interference of intermixing other tasks such as pointing and touching during learning in the random-practice group, both groups acquired their learning within the same number of trials. Thus, random practice did not impede the rate of gains, and still increased retention. Patients whose brain injury involves the hippocampus, cerebellum, or basal ganglia may not learn as quickly or fully as the subjects involved in these two studies of motor learning, however (see Chapter 1). Studies are still needed that enter subjects in the first several weeks after stroke or head injury and that provide as much practice as may be needed to show differences in acquisition and retention for contextual learning compared to errorless practice. In addition, the types of learning that can be transferred from one hand to the other, such as the timing of a movement rather than the forces exerted,68 and the value of bimanual task training under various practice conditions69,70 need further assessment in patients. The overall evidence suggests, however, that drill-sergeant therapists who try to stamp in retention with blocked practice and constant attention to the details of performance need to reconsider their approach to training. If a task requires minimal variations under constant conditions, say relearning to use a toothbrush to brush the teeth, it is probably best trained with little variation. Practice designed to promote active involvement of subjects in solving the demands of goal-directed actions, however, ought to take a more open approach. Training Techniques One of the first formalized physical therapy techniques to draw upon the literature of motor learning marks the transition from the neurophysiologic to a task-oriented approach by therapists.71,72 Carr and Shepherd offered a model of therapy that trains functional actions in a task-specific and context-specific manner. Patients practice the action to be learned with many repetitions to strengthen muscles and to optimize learning of the target action. Their use of learning principles was initially less well developed. Physiotherapists and other rehabilitationists are, however, developing interventional strategies around these notions of task- pfizer viagra 50mg tablets 234 wie oft viagra einnehmen gloria viagra wikipedia At least 1 in 3 early survivors of an acute stroke or serious traumatic brain injury has dysarthric speech or aphasia. The dementias, brain tumors, meningoencephalitides, and other neurologic diseases also affect language. The prevalence of aphasia is uncertain, but given the frequency of all of these entities, an annual incidence of 200,000 cases in the United States seems likely. Articulatory disorders and oropharyngeal dysphagia are even more common, can you take viagra and antibiotics tients, an AFO in 5° of dorsiflexion increases walking speed, increases the duration of heelstrike and midstance, and improves the knee flexion moment in midstance.58 An AFO for hemiparetic patients should increase step length and swing time, and improve stance time for the affected leg. The orthotic may increase walking speed. By aiding toe clearance, the risk of falls decreases. Many patients are concerned that an AFO will reduce the likelihood of improving ankle movement. In patients with a drop foot from peripheral causes and in healthy subjects, an AFO initially decreases mean EMG by 7% and 20% in early stance, respectively, but after 6 weeks of use, total EMG activity did not differ from initial levels.61 Thus, wearing an AFO may not particularly limit gains for ankle dorsiflexion during gait training and everyday walking. Stepping practice without an AFO, however, at least during BWSTT, may decrease cutaneous and proprioceptive inputs associated with the gait cycle that contribute viagra generico farmacias del ahorro Sensorimotor Impairment Scales Walks 10 feet without help Maintains stance Maintains sitting position No sitting balance viagra gel bestellen viagra available saudi arabia GENERAL TOOLS The Sickness Index Profile (SIP)176 provides 136 statements grouped into 12 categories around physical and psychosocial dimensions. The statements are weighted for scoring that reflects dependence, distress, and social isolation. The SIP primarily assesses the negative impact of disability, including the impact on work, recreation, and eating. The Functional Limitations Profile is a British version. The SIP-NH (Nursing Homes) is a 68-item scale drawn from the items in the SIP. This SIP-68 eliminates unnecesary components and has good reliability.177 The SIP has been used in studies of stroke, TBI, SCI and other neurologic diseases. It may be more responsive to group than to individual changes.8 A 30-item version of the SIP that retained the SIP’s physical and psychosocial dimensions had similar construct, clinical, and external validities as the full version for patient with stroke.178 Using a format similar to the SIP, the Nottingham Health Profile8 asks about emotions more directly than does the SIP and has good reliability and validity in some populations. The Health Status Questionnaire179 grew out of the Medical Outcomes Study (MOS) questionnaire and another study by the RAND Corporation aimed at constructing scales sensitive to changes in functioning associated with changing health. This health-related QOL survey has taken the form of 12, 20,180 36, and 74 questions that cover all domains with a progressively greater number of dimensions.181 The Short Form (SF)-12 generates the physical and mental component summary scores of the SF-36 in some groups of patients after a stroke.182 The SF-36 version (a 39-item version includes 3 items that screen for depression) has received much support for its ability to distinguish between ill herbal viagra reviews uk A trial of three graded levels of dysphagia therapy during inpatient stroke rehabilitation randomized 115 subjects to one of three interventions:64 1. The therapist explained the results of MBS and gave recommendations regarding food consistency and compensatory techniques; patient and family then made their own decisions. 2. The same as above, but a therapist reassessed the diet every other week. No single approach can be recommended for the treatment of a pressure ulcer.72 Many concoctions have been smeared on reddened skin. Table 8–5 shows commonly used skin treatments. Iodine and hydrogen peroxide should be avoided. Polyurethane films and gauze can damage new epithelium when they are removed. Debridement by one of many methods and topical antibiotics are most important for stage 3 or stage 4 ulcers. Consultation with a plastic surgeon is usually necessary. The clinical evaluation for osteomyelitis that has developed beneath a pressure sore is less accurate than a percutaneous needle biopsy of bone taken for aerobic and anaerobic cultures. Growth factors might be of value in promoting healing. Myocutaneous and other types of protective flaps must be accompanied by patient and family education regarding flap care and pressure sore prevention. Neuropathies may predispose to foot ulcers. Shear forces and repeated trauma during walking on an insensate foot, along with muscle atrophy and accompanying foot deformities, make neuropathies the most frequent cause of foot ulceration.74 Rest, orthoses to shift pressure points, wound care, surgical correction of deformities, evaluation for vascular insufficiency, and assessment for osteomyelitis with a bone scan or MRI with gadolinium may be indicated. natural alternatives viagra uk 341 se puede comprar viagra sin receta en argentina viagra online kaufen ohne kreditkarte Naϩ channel blockade viagra dos and don'ts Studies of the efficacy of aphasia therapy after a stroke have usually set out to learn whether nonspecific approaches improve language functions. Most studies suffer from the methodological shortcomings found in clinical trials of stroke rehabilitation interventions for mobility and self-care. Design problems include the lack of randomized controls, failure to stratify subjects by particular aphasia syndromes, inadequate assessment of the extent of the cortical and subcortical lesion or of the presence of a contralateral lesion that might affect compensation, and assessment and outcome tools of uncertain precision and reliability. In addition, studies include wide variations among patients in the time since onset of stroke, in age and education, and in comorbidities that affect cognition and learning. The investigators may not specify the type, intensity, or duration of language therapy. Also, aphasia assessment tests often do not reflect changes in functional communication with family and friends. By reporting an overall outcome score, investigators may not detect clinically important gains in language and nonlanguage subskills. Table 9–13 summarizes some of the better designed, large clinical trials of aphasia therapy for stroke. Treatments averaged 45 to 60 minutes, provided up to 3 times a week in most instances. Dropouts were due to illness, death, disenchantment with the program, or satisfaction with the level of recovery. Overall, subjects showed average gains of 20% in scores on the Functional Communication Profile (FCP) and a 10–20 percentile change on the PICA. Aphasics improved on test scores spontaneously and with nonspecific, traditional interventions. Gen- 448 how long do you stay hard with viagra Rehabilitation of Specific Neurologic Disorders legality of buying viagra online 482 cheapest authentic viagra 24. 25. 26. young guy taking viagra Rare case reports describe patients who recovered spontaneously several years after onset of PVS, but these patients were probably at least minimally conscious. INTERVENTIONS Interventions to reverse coma or PVS either early or late after onset have generally not been successful. A few reports have claimed recovery of consciousness using bromocriptine, amphetamine, electrical stimulation of the reticular formation and its connections, and in association with sensory stimulation programs. Families and clinicians often try sensory stimulation employing tasks from the Western Neurosensory Stimulation measure.80 Bromocriptine, 2.5 mg twice a day, was associated anecdotally with greater gains than the investigators expected in five patients with PVS during inpatient rehabilitation.81 Programs for coma stimulation aim for input to the reticular activating system and try to enrich the environment for the sensory deprived patient. Electrical stimulation of the nonspecific thalamic nuclei and of the high cervical spinal cord with implanted electrodes was used in six patients for 12 hours a day at 30% of the film viagra pfizer can you safely buy viagra online had what appeared to be a dementia secondary to the trauma. An interaction between having early Alzheimer’s disease or a vascular dementia and even mild TBI may manifest underlying cognitive impairments that had not previously been recognized by patients and families. It is not uncommon to find a greater decline than expected in elderly patients admitted for inpatient rehaiblitation or evaluated as outpatients after TBI. Some of that change is reversible, but the baseline dementia remains apparent. Postdischarge support is especially necessary for many of the elderly who return home. Help is often needed for bathing, housework, shopping, and pain and medication management. With cognitive dysfunction, some elderly patients require full-time supervision. pfizer viagra 100mg review 136. Powell J, Heslin J, Greenwood R. Community based rehabilitation after severe traumatic brain injury: A randomised controlled trial. J Neurol Neurosurg Psychiat 2002; 72:193–202. 137. Granger C, Hamilton B. The Uniform Data System for Medical Rehabilitation report of first admissions for 1992. Am J Phys Med Rehabil 1994; 73:51–55. 138. Powell J, Machamer J, Temkin N, Dikmen S. Selfreport of extent of recovery and barriers to recovery after traumatic brain injury: A longitudinal study. Arch Phys Med Rehabil 2001; 82:1025–1030. 139. Katz D, Alexander M, Klein R. Recovery of arm function in patients with paresis after traumatic brain injury. Arch Phys Med Rehabil 1998; 79:488–493. 140. Wolman R, Cornall C, Fulcher K, Greenwood R. Aerobic training in brain-injured patients. Clin Rehabil 1994; 8:253–257. 141. Bates E, Reilly J, Wulfeck B, Dronkers N, Opie M, Fenson J, Kriz S, Jeffries R, Miller L, Herbst K. Differential effects of unilateral lesions on language production in children and adults. Brain Lang 2001; 79:223–265. 142. Heinemann A, Sahgal V, Cichowski K. Functional outcome following traumatic brain injury rehabilitation. J Neuro Rehabil 1990; 4:27–37. 143. McLean A, Dikmen S, Temkin N. Psychosocial recovery after head injury. Arch Phys Med Rehabil 1993; 74:1041–1046. 144. Gray J, Shepherd M, McKinlay W. Negative symptoms in the traumatically brain-injured during the first year postdischarge. Clin Rehabil 1994; 8:188– 197. 145. Schwab K, Grafman J, Salazar A, Kraft J. Residual impairments and work status after penetrating head injury. Neurology 1993; 43:95–105. 146. Brooks N, McKinlay W, Simington C, Beattie A, Campsie L. Return to work within the first 7 years of severe brain injury. Brain Inj 1987; 1:5–19. 147. Cifu D, Keyser-Marcus L, Lopez E, Wehman P, Kreutzer J, Englander J, High W. Acute predictors of successful return to work 1 year after traumatic brain injury: A multicenter analysis. Arch Phys Med Rehabil 1997; 78:125–131. 148. Rao N, Kilgore K. Predicting return to work in traumatic brain injury using assessment scales. Arch Phys Med Rehabil 1992; 73:911–916. 149. Wagner A, Hammond F, Sasser H, Wiercisiewski D. Return to productive activity after trauamtic brain injury: Relationship wiht measures of disability, handicap, and community reintegration. Arch Phys Med Rehabil 2002; 83:107–114. 150. Yasuda S, Wehman P, Targett P, Cifu D, West M. Return to work for persons with traumatic brain injury. Am J Phys Med Rehabil 2001; 80:852–864. 151. Sohlberg M, Mateer C. Cognitive Rehabilitation. New York: Guilford Press, 2001. 152. Stuss D, Winocur G, Robertson I. Cognitive neurorehabilitation. Cambridge: Cambridge University Press, 1999. 153. Alexander M, Benson D, Stuss D. Frontal lobes and language. Brain Lang 1989; 37:656–691. 154. Dikmen S, Machamer J, Temkin N, McLean A. Neuropsychological recovery in patients with moderate to severe head injury: Two years’ follow-up. J Cin Exp Neuropsychol 1990; 12:507–517. 155. Ben-Yishay Y, Diller L. Cognitive remediation in is viagra available in saudi arabia 246. 247. can viagra be bought over the counter in canada 558 Clinical Trials safe place to order viagra online como se administra el viagra Traditionally, the body has been divided into many systems, according to speciﬁc functions. The ultimate purpose of every system, however, is to maintain a constant cell environment, enabling each cell to live. Fluid surrounds every cell of the body, and all systems are structured to maintain the physical conditions and concentrations of dissolved substances in this ﬂuid. The ﬂuid outside the cell is known as the extracellular ﬂuid (ECF), and the ﬂuid inside the cell is known as intracellular ﬂuid (ICF) (see Figure 1.2). The extracellular ﬂuid inside the blood vessel is known as the intravascular ﬂuid, or plasma. The ﬂuid outside of the cells and the blood vessels is known as the interstitial ﬂuid. Because the interstitial ﬂuid surrounds the cells, it is known as the internal environment; the condition of constancy in the internal environment is called homeostasis. In short, all systems maintain homeostasis by regulating the volume and composition of the internal environment. Each system continuously alters its active state to maintain homeostasis. The maintenance of homeostasis can be compared to the working of a baking oven. When the temperature is set, the heating element (the effector) is switched on—indicated by a red light—to heat the oven. When the desired temperature is reached, the heating element is switched off and the light goes out. When you open the oven door (without switching off the oven, of course) to check the food that is baking, the light comes on again—have you noticed that? When you open the oven door, the heat escapes and the temperature drops slightly. This drop in temperature is detected (receptor) and conveyed to the thermostat (the control center) in the oven and the heating element is switched on. Similarly, the body has various detectors to detect changes in speciﬁc elements. Let’s take, for example, the oxygen content in the blood. If the detectors (receptors) ﬁnd the level of oxygen becoming lower, they stimulate the system(s) that bring oxygen into the body—the respiratory system works harder until the oxygen level reaches the normal range. Imagine many similar detectors located all over the body—monitoring calcium, hydrogen, and sodium levels; volume of blood; blood pressure; hormone levels; and body temperature. Can you picture each of these regulators monitoring speciﬁc elements and bringing about an appropriate action or change in various systems—all at the same time! You expect chaos. Instead, the body is orchestrated so beautifully that all systems work in harmony with one aim—to maintain homeostasis. When a person is ill, therefore, the body must be treated as a whole and cheap herbal viagra pills Atoms can interact in three ways; therefore, there are three types of chemical bonds—ionic bonds, covalent bonds, and hydrogen bonds. Ionic Bonds Some atoms may lose or gain an electron when bonding with another atom. In the ﬁrst case, this atom has one electron less than the number of protons, meaning that there are more positive than negative charges. This atom is referred to as a cation (posi- shell needs another electron to be complete. Therefore, one hydrogen atom shares its electron with another hydrogen atom, completing their energy levels and forming a molecule. This is how hydrogen normally exists—in pairs, and is referred to as hydrogen molecules. A hydrogen molecule is symbolized as H2. Similarly, many different elements may bond together. Carbon dioxide gas has one carbon atom and two oxygen atoms bonded covalently (CO2). Water has two hydrogen atoms and one oxygen atom bonded covalently (H2O). Elements may share one, two, or three electrons. In the human body, covalent bonds are the most common. When covalent bonds are formed, the electrons may be shared equally or unequally between the speciﬁc atoms. When shared equally, these bonds are known as nonpolar covalent bonds. Sometimes, one atom attracts the shared electron more than the other atom. In this case, the atom that attracts the electron to a greater degree would be slightly more negatively charged than the other atom. The other atom will be slightly more positively charged. These charges are represented with the symbol ␦ϩ or ␦- (see Figure 1.13). These covalent bonds are known as polar covalent bonds. Hydrogen Bonds Other than ionic and covalent bonds, other weak attractions may be present between atoms of the same molecule or compound or between atoms in other molecules. The most important of these weak attractions are hydrogen bonds, in which a hydrogen atom involved in a polar covalent bond is attracted to oxygen or nitrogen involved in a polar covalent bond by itself. This attraction is important. Although molecules are not formed through the hydrogen bonds, this bonding can alter the shape of the molecules. For example, it is this weak attraction that holds water together and makes it form a drop. We refer to this force as surface tension (see Figure 1.14). At the dissolving viagra under tongue brane. Channels in the nuclear membrane control the movement of substances in and out of the nucleus. The nucleus contains a denser structure called the nucleolus, in which ribosomes (containing RNA) are assembled. The nucleus contains all the information required for the cell to function and controls all cellular operations. The nucleus has the information needed for the manufacture of more than 100,000 proteins. It also controls which proteins will be synthesized and in what amounts in a given time. The information required by the cell is stored in DNA strands. The DNA strands are found in threadlike structures known as chromosomes. Each human cell has 23 pairs of chromosomes. DNA is actually a double-helix strand, with the two strands held together by hydrogen bonds (see Figure 1.16). The genetic code in the DNA is in the sequence of nitrogenous bases. The nitrogenous bases adenine, thymine, cytosine, and guanine are arranged in different ways to form the genetic code. Three of the bases, arranged in a speciﬁc way, code for a speciﬁc amino acid. In this way, the DNA has viagra patent expiration date 2012 Anatomic Term Condyle Crest Facet Fissure Fossa Foramen Description smooth, rounded end that articulates with another bone prominent ridge small, ﬂat surface that articulates with another bone long cleft shallow depression small, round passage through which nerves/blood vessels pass in and out or through the bone expanded end low ridge canal leading through the substance of a bone narrowed part closely related to an expanded end projection or bump extension of a bone that makes an angle to the rest of the structure chamber within the bone, usually ﬁlled with air pointed process narrow groove large, rough projection pulleylike end of bone that is smooth and grooved smaller, rough projection viagra generika per nachnahme bestellen Chapter 3—Skeletal System and Joints zenerx vs viagra where can i buy viagra over the counter in glasgow The ﬁbula (Figure 3.30) is slender and is located lateral to the tibia. The proximal end is widened into the head. The head of the ﬁbula articulates with the tibia, just inferior to the lateral condyle of the tibia. Along the shaft, a thin ridge, the interosseous crest, marks the surface that gives attachment to the strong connective tissue interosseous membrane. The interosseous membrane bridges the gap between the tibia and the ﬁbula along the two shafts, stabilizing the bones and increasing the anterior and posterior surface area for attachment of muscles. The lower end of the ﬁbula widens to form a prominence called the lateral malleolus. The bony projection on the lateral aspect of the ankle is the lateral malleolus that articulates with the talus bone. Although the upper Amphiarthroses is viagra safe during pregnancy Atlas buy viagra honolulu viagra building in canada ACROMIOCLAVICULAR JOINT Articulating Surface and Type of Joint Lateral medexpress viagra buy herbal viagra nz with the apex moving posteriorly, while the iliac bones approximate and the ischial tuberosities move apart. Such a movement occurs when walking and when bending forward (ﬂexion) and backward (extension). During walking, the movement of the sacrum is determined by the forces from above, while the movement of the ilium is determined by the femur. taking viagra diabetic When assessing this joint, it is important to take a good history that includes history of trauma and abnormal stress to the region. Typically, the pain arising from this joint is unilateral, increased by walking, getting off the bed, and climbing stairs, etc. Examination of this joint should be done in conjunction with the hip joint and lumbar spine as the pain may be referred to this joint from those areas. Description of individual tests used for assessing this joint is beyond the scope of the book. The gait, posture, alignment of bony structures, difference in leg length, and passive and active movements should be tested, and treatment aimed at normalizing the stresses on the lumbopelvic complex should be based on the ﬁndings. Patella viagra sudden death best fake viagra TIBIOFIBULAR JOINT (PROXIMAL AND DISTAL) Fill-In Refer to page ••. Case Studies Case 1. This is an important topic for bodyworkers. See page •• for formation of bone; page •• for the role of parathyroid gland; vitamin D (page ••); calcitonin (page ••); and estrogen (page ••) on calcium metabolism; page •• for age-related changes in musculoskeletal system; and page •• for menopause. Case 2. See page •• for the anatomy of humerus; page •• for the muscles attached to this region; and page •• for different types of fractures and healing of fracture. is viagra covered by obamacare Coloring Exercise prix du viagra 50 mg en pharmacie can you take viagra with blood pressure medication Sarcolemma buy viagra chandigarh Although the contractile mechanism is the same, muscle characteristics are modiﬁed in many ways to enable the body to adjust force and speed of contraction and direction and range of motion. At the microscopic level, variations in contraction duration exist between muscles. Macroscopically, variations in fascicle arrangement and size of motor units are present. Together, structural and functional variations allow us to execute both crude and intricate, movements. is viagra prescription only in australia The Massage Connection: Anatomy and Physiology viagra l368 Chapter 4—Muscular System getting viagra over the counter Fulcrum F viagra patent india ISOTONIC AND ISOMETRIC CONTRACTIONS Sensory fiber gnc viagra substitute TrPs are identiﬁed as localized spots of tenderness in a nodule or a palpable taut band of muscle ﬁbers. Patients complain of aching pain characteristic of deep tissue pain. The pain is often referred to a site some distance from the TrP that is speciﬁc to individual muscles. It is interesting to note that there is a high degree of correspondence between published locations of TrPs and classical acupuncture points for the relief of pain. Pressure on the nodule elicits the familiar pain sensation. Because of pain, there is resistance to passive stretch of muscle. TrPs are believed to be caused by dysfunction of the motor endplate. The dysfunction results in an abnormal increase in production and release of ACh at rest. This results in depolarization of the sarcolemma with release of calcium from the sarcoplasmic reticulum and sustained shortening of sarcomeres (taut band). The shortening of muscle ﬁber compresses the local blood vessels, reducing the nutrient and oxygen availability. This, in turn, results in release of substances that sensitize pain receptors (pain). TrPs are responsive to stretch therapy used in massage. By lengthening the sarcomeres and reducing the overlap between actin and myosin molecules, the energy consumption of the local tissue is reduced. Blood ﬂow to the muscle ﬁbers is also restored when the muscles are relaxed by stretch. spironolactone viagra can you buy viagra in qatar These muscles (see Figures 4.20A and 4.21) depress the mandible, tense the ﬂoor of the mouth, control the position of the larynx, and help provide a stable foundation for the muscles of the tongue and pharynx. The points of attachment of these muscles include the hyoid bone, the cartilages of larynx, the clavicle, and sternum. viagra distributors canada Rectus capitis: Anterior Lateralis viagra till kvinnor Origin Insertion do i need a prescription to buy viagra in the us Flexor digitorum profundus yahoo mail virus viagra Adductor and Iliopsoas Strains C4–C8 is viagra kosher Longissimus capitis (considered part of erector spinae) Longissimus cervicis (considered part of erector spinae) Levator scapulae viagra dosage difference O viagra cubano ppg can you break viagra in half The Massage Connection: Anatomy and Physiology Table 4.13 viagra prank video The neurons may be also classiﬁed according to function. These are the sensory, motor, and interneurons, or association neurons. Those that take impulses to the CNS are known as the sensory neurons or afferent ﬁbers. Of the sensory neurons, the visceral afferents innervate the organs, and the somatic afferents carry impulses from the surface of the body. Sensory neurons may be named according to the type of information they sense. Those afferents that sense information in the external environment are called exteroceptors. Afferents sensing changes in the inside of the body are called interoceptors. viagra ulcerative colitis viagra doziranje Chapter 5—Nervous System Perception of one point of touch average cost per pill viagra generic viagra 5 pills From receptors of fine touch, proprioception, vibration, pressure Pons counterfeit viagra dangers Olfactory Nerve Problems can a female take male viagra viagra einfuhr nach deutschland This nerve has two major divisions: the vestibular nerve and the cochlear nerve. The vestibular nerve conveys sensations from the vestibular apparatus (described on page ••). This organ is stimulated by linear and rotational accelerations of the body and is responsible for equilibrium and balance. After the nerve reaches the medulla, it has extensive connections with the cerebellum. Its connections with cranial nerves III, IV, and VI help the body adjust eye movements according to the position of the body. Its other connections help the body increase or decrease the tone of different muscle groups to maintain balance. The cochlear branch carries hearing sensations. The cochlea has many receptors, each stimulated by a speciﬁc wavelength. In this way, the pitch of the sound is detected. The intensity of the sound is determined by the number of action potentials produced in each receptor. The neurons from the cochlea synapse with others in the medulla, and the impulses ultimately reach the temporal lobe where sound is interpreted. Similar to the representation of the body in the primary sensory and motor cortex, there is a representation in the temporal lobe for various tones. viagra use after heart attack Execute viagra permanent damage 365 A amerikan viagra yan etkileri viagra caricature The Massage Connection: Anatomy and Physiology kubwa herbal viagra Positive feedback The scrotum (see Figure 7.2) consists of a thin layer of skin and underlying fascia. The fascia has a layer of smooth muscle known as dartos, which is responsible for the wrinkles seen in the skin. Deep to the dermis, there is a layer of skeletal muscle known as the cremaster muscle. The contraction of this muscle causes the testis to be pulled closer to the body when cold. Relaxation of the muscle causes the testis to move away from the body. Thus, the temperature of the testis is maintained about 1.1°C (34°F) below that of the body—the temperature required for normal sperm production. Internally, the scrotum (see Figure 7.3A) is divided into two chambers. The division can be seen on the external surface as a thickening in the midline. A testis lies in each of these chambers or cavities. Due to the partition, infection or inﬂammation in one cavity does not easily spread to the other. The testis is separated from the inner surface of the scrotum by a space lined by serous membrane. The membrane, known as the tunica vaginalis, is a remnant of the peritoneum through which the testis pushed during development. The tunica vaginalis reduces the fric- bill kaulitz viagra good viagra tablets in india Changes in the Vagina This section gives an overview of fetal development, the maternal changes that occur during pregnancy, and the physiology of labor and lactation. instrucciones para tomar viagra Breast-feeding reﬂexively inhibits the secretion of GnRH from the hypothalamus and gonadotropins from the pituitary and, thereby, ovulation. Breastfeeding can be considered a natural form of contraception. However, it is not an effective form of contraception in those who breast-feed infrequently, with wide intervals between feedings. During lactation, the mother’s diet has to be adequate because she uses large amounts of fat and protein to produce milk. In addition, if her calcium intake is insufﬁcient, her parathyroid glands stimulate the absorption of calcium and phosphates from her bones, weakening them. posologie viagra 100mg does viagra stop you from ejaculating Importance of Blood Grouping II red viagra side effects viagra naturel forum Rheumatic Fever does viagra help delayed ejaculation B 498 buy viagra online norway bruk av viagra The Massage Connection: Anatomy and Physiology viagra jelly sachet uk Major systemic arteries. Label the major arteries indicated by leader lines. is viagra covered by health insurance 2012 Chapter 9—Lymphatic System Bone marrow maturation taking viagra before eating pate in cell-mediated immunity in which the cytotoxic T cells and natural killer cells recognize virus infected cells and foreign antigens. Helper T cells also induce the macrophages and monocytes to ﬁght infection. Another type of T cell, the suppressor T cell, suppresses the immune reaction by inhibiting both B and T cells. Memory T cells remember the antigenic properties and respond quickly and vigorously if the same antigen is reintroduced into the body. The T cells are responsible for transplanted organ and tissue rejection. When tissue from another individual is transplanted into the body, the T cells recognize the antigens on the transplanted cells as foreign and produce an immune reaction that kills the foreign tissue—rejects it. This reaction is observed even when the tissue is from a close relative, unless the tissue is from an identical twin. viagra femenino mapuche Passive Immunization taking viagra for performance anxiety viagra 25 mg efectos Genitourinary Tract viagra 24 std lieferung The Massage Connection: Anatomy and Physiology secretly taking viagra Case Studies 1. A, The swelling is a result of the pressure put on the veins in the back of legs as one sits. Lymph ﬂow relies on muscle movement. When seated on the plane, it was unlikely that Mrs. Albright could move freely. The effects of gravity also play a part in reducing venous return. As a result, plasma hydrostatic pressure increases, resulting in edema. B, She can be massaged, provided that she is not at risk for venous thrombosis. C, Massage, especially manual lymphatic drainage, would be helpful. D, The therapist should rule out all other causes of edema by taking careful history. 1. A, Filariasis is a parasitic infection transmitted by the bite of an infected mosquito. B, The swelling is a result of inefﬁcient lymphatic drainage. The ﬁlarial worm lodges in the lymph nodes, producing an inﬂammatory reaction. This reaction, in turn, affects drainage in the local area. The accumulation of ﬂuid, together with the protein in the interstitial compartment, is responsible for the viagra exercise performance 539 Having learned that the muscles involved in respiration are skeletal muscles, one might wonder how we are able to breathe rhythmically and regularly on a continuous basis. At the same time, it is fascinating to consider the many ways the rate and depth of respiration is altered in everyday activity. how to get viagra without going to a doctor Beriberi (muscle weakness; nervous and cardiovascular problems) Epithelial and mucosal deterioration Pellagra (CNS, GI, epithelial and mucosal degeneration) Growth retardation; CNS abnormalities Growth retardation; anemia; epithelial changes, convulsions Growth retardation; anemia; GI disorders; deﬁciency during pregnancy; CNS abnormalities Pernicious anemia Fatigue; muscle pain Scurvy (epithelial and mucosal deterioration) plavix and viagra interaction 3. The activities of the digestive system are controlled by , , and . 4. The feeding center and the satiety center are located in the . 5. Of the various nutrients, are constituents of muscles, enzymes, and antibodies. are the main source of energy, and are needed for formation of steroid hormones. 6. The process of swallowing is known as . 7. The elimination of waste products from the GI tract is known as . 8. The end product of carbohydrate digestion is . 9. The end product of protein digestion is . 10. The end product of fat digestion of is and . found husbands viagra effects of male viagra on women ﬂuid retention resulting from kidney malfunction. Because edema can be an early sign of kidney problems, it must be ensured that edema is not caused by kidney disease. Kidney infections often present as tenderness, pain, or swelling in the back, just below the costal margin and adjacent to the vertebrae. Problems with the organs of the urinary system may present as pain that is referred to other areas of the body (see page ••). Polycystic kidney is one condition in which the kidney is enlarged, with or without functional problems. Abdominal massage is contraindicated in this condition. Floating and movable kidneys are relatively common. Care should be taken when the abdomen is massaged. (It is beyond the scope of this book to give details of the various kidney disorders, and the student is encouraged to refer to pathology textbooks.) Individuals on dialysis, or those who have had kidney transplants, are usually prescribed antibiotics and drugs that suppress immunity. Care should be taken to prevent these clients from being exposed to any form of infection.
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