Journal r)f Neuro~ctence Methods, 31 (1990)101-107

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Elsevier NSM 01030

Beam-walking in rats: studies towards developing an animal model of functional recovery after brain injury L a r r y B. G o l d s t e l n 1,2 a n d J a m e s N . D a v i s ~ 2,,~ : Neurology Research Laborato O, Durham Veterans Adnum~tratton Medical Center. and Departmentv of 1 : Medicine (Neurology) and 3 Pharmacology, Dul~e Umt,ersltv. Durham. ¥ C (L' S A )

(Received 4 January, 1989) (Revised version received 22 March, 26 May and 18 August 1989) (Accepted 28 August 1989)

Kel' words

M o t o r recovery: A m p h e t a m i n e ; B e a m - w a l k i n g , Brain injury: Stroke; Cortical les~on: (Rats)

While it has long been recognized that humans recover function after stroke or head mjury, the direct impact of drugs on recovery has only recently recevced attention The ablhty of rats to traverse a narrow, elevated beam has pro'¢en to be particularly useful when studying the effects of pharmacologic mampulatlons on motor recovery following cortical mjuO Hov,ever, the effect of testing conditions on the recovery of beam-walking performance has not been mvesugated Treatment with amphetamine faclhtated recovery of beam-walking following cortical lesions regardless of whether "massed' or "spaced' trials were employed Unexpectedl}, the performance of sham-operated controls dechned when tested with 'massed" trials 'Prodding' sham-operated rats by tapping on the rump abolished this dechne In performance, but resulted m enhanced recovery m lesioned amman The results indicate that testing conditions can exert a significant influence on beam-walking performance and are ~mportant to consider when interpreting the impact of pharmacoloDc agents on the recovery process

Introduction A m m a l s including m a n show a r e m a r k a b l e capacity for recovery after b r a i n injury. Such functional recovery has received c o n s i d e r a b l e attention m the past two decades. M u c h has been learned ab o u t its cellular and m o l e c u l a r basis. It is clear that m a n y of the drugs a d m i n i s t e r e d to patients after stroke or head injury have pron o u n c e d effects on n e u r o n a l f u n c t i o n and could influence the rate or extent of recovery. T h e d e m o n s t r a t i o n that a m p h e t a m i n e a d m l m s t r a t a o n accelerates the recovery of b e a m - w a l k i n g ability in rats following a cortical lesion ( F e e n e y et al., 1982) led us to investigate the effects of this drug

Correspondence Dr Larry B Goldstem, Bmldlng 16, Room 28 Durham V A Medical Center, Durham, NC 27705, U S A Tel (919)286-6956

in selected stroke patients ( C r i s t o s t o m o et al., 1988). T h e o b s e r v a t i o n that a m p h e t a m i n e had similar effects m b o t h studies rinsed the posslblhty that b e a m - w a l k m g in rats m i g h t p r o v e a useful animal m o d e l for p h a r m a c o l o g i c a l studies predictive of t h e r a p y m man. Buytendtjk (1932) an d later MaIer (1935) n o t ed that a s e n s o r y - m o t o r cortex lesion in the rat did n o t result in a d r a m a t i c m o t o r a b n o r m a l i t y when the an i m al s were o b s e r v e d on a flat field, but b e c a m e o b v i o u s when the rats were r e q m r e d to n eg o t i at e a n a r r o w elevated beam. G e n t i l e and c o - w o r k e r s (1978) e m p l o y e d c i n e m a t o g r a p h i c analysis to analyze the b e a m - w a l k i n g a b n o r m a h t y an d its s u b s e q u e n t r e c o v e r y T h e y f o u n d differences m h m d h m b m o t o r p a t t e r n s b e t w e e n lesioned an i m al s that h ad r eco v er ed b e a m - w a l k i n g ability and s h a m - o p e r a t e d controls. F e e n e y et al (1982) d e w s e d a simple system for g r a d m g the m o t o r deficit an d f o u n d that a m p h e t a m i n e , cou-

0165-0270//90/$03 50,0 1990 Elsevier Science Publishers B V (Biomedical Division)

102

pied with motor experience, accelerated the rate of functional recovery. Brallowsky and co-workers demonstrated that the deficit m beam-walking performance could be increased by lntracortlcal infusion of gamma-amlnobutyric acid (Brallo~sk~ et al, 1986) or by the admimstration of phenytoln (Bradowsky et al., 1986) The nature of an animal's experience after brain injury exerts a significant impact on the recovery process (Finger and Stein, 1982). Prewous mvestlgattons had suggested that active experience on the beam during the period of drug intoxication was crxtacal for amphetamine-facilitated motor recovery (Feeney et al, 1982). Although a number of investigators have used beam-walking m rats to study the effects of drugs on recover~ of function, there has been no agreement on standard testing methods We undertook the present studies to characterize the effects of varying test conditions on beam-walkmg performance The first goal of these experiments was to determine the impact of altering the interval between trials on amphetamine-facilitated recovery of beam-walking ability following a sensory-motor cortical lesion. It was hypothesized that the rate of recovery was dependent on the amount of experience but independent of the interval between trmls Results obtained m these experiments then led to studies of the influence of activating stlmuh on beam-walking recovery. Taken together, these experiments provide data which allows an apprecmtlon of some of the behavioral factors wtuch may influence the effects of drugs on recovery of beam-walking ability in rats following cortical lesions

Materials and methods

SubJects Male Sprague-Dawley rats welgtung 176-200 g were obtained from Charles River Breeding Laboratories, Inc. (Raleigh, NC) and employed in all experiments. Animals were housed in a vivarium with a 12-h light-dark cycle and controlled temperature and humidity. Food (Purina Rat Chow) and water were provided ad libitum.

Drugs (+)-Amphetarmne sulphate (Sigma) was dis-

,~olved in saline (0.9% w / v NaCI) adrmnlstered b\ an mtraperitoneal reJection at a dose ol 2 m g / k g (salt weight). Control rats received saline vehicle

Surger~ Prior to surgery, the rats were weighed and anestheuzed with sodium pentobarbltal (50 nag/ kg, l.p.) Additional doses of anesthetic were admlmstered If necessary. Ammals were then positioned in a stereotaxlc apparatus Mldhne bkm mc~sLons were made from just caudal to the e)e~ to 5-10 mm caudal to the ears. In lesioned animals, a craniotomy was performed from 2 into rostral to the coronal suture to 2 mm rostral to the lambdold ~uture and from 1-2 mm lateral to the sagittal suture to the temporal ridge. The cortex underlying the cramotomy s~te was removed by gentle suction through a fine glass Pasteur pipette until the underlying white matter was visualized The skin incision was closed with surgical staples and the animal placed in a holding cage to recover from the procedure. In sham-operated ammals, skin incisions were made but a cranlotomv was not performed. In prellrmnary experiments, even slight cortical damage produced during craniotomy was found to xmpair beam-walking performance.

Behavioral apparatus All behavioral testing was carried out m a sound-proof room with subdued lighting (less than 10.76 l u m e n s / m 2, ambient light). The testing apparatus and procedures were adapted from those described by Feeney et al. (1982). The surface of a 2.5 × 122 cm wooden beam was elevated 75.5 cm above the floor by wooden supports. A 20 × 25 × 24 cm goal box with a 9.5-cm opening was located at one end of the beam. A switch-activated source of bright light (75 W tungsten bulb) and white noise (41 dB at 8000 Hz, 58 dB at 4000 Hz, 56 dB at 2000 Hz, 56 dB at 1000 Hz, 58 dB at 500 Hz, and 52 dB at 250 Hz SPL at the center of the frequency at each octave band) were located at the start-end of the beam and served as avoidance stimuli (Campbell and Bloom, 1%5: Feeney et al., 1982). The light intensity was 6 46 × 103 l u m e n s / m 2 at the start-end of the beam and fell to 0 45 × 103 l u m e n s / m 2 at the center and 0.22 lu-

103

m e n s / m 2 at the g o a l - e n d of the b e a m ( G e n e r a l Electric '~ T y p e 214 f o o t - c a n d l e meter). The noise stimulus was 80 dB SPL at the s t a r t - e n d a n d 78 dB SPL at the g o a l - e n d of the b e a m (overall, hnear scale m e a s u r e d with Bruel & K j a e r '~ T y p e 2203 s o u n d level meter with associated 1613 octave filter set)

Behartoral protocol The rats were placed in the testing r o o m for 1 2 h p r i o r to the l n m a t l o n of each training or testing session F o r each trial, the rat was p l a c e d at the start-end of the b e a m o p p o s i t e to the goal b o x with its nose 15 cm from the source of light a n d noise If the a n i m a l d i d not begin to traverse the b e a m after 10 s, the light a n d noise stimuli were activated. These stimuh c o n t i n u e d for 80 s or until the rat's nose entered the goal box. T r a i n i n g consisted of 2 trials on the b e a m s e p a r a t e d by l h p e r f o r m e d on the d a y p r i o r to surgery except in the final experiment. P e r f o r m a n c e was r a t e d on a 7-point scale as d e s c r i b e d previously ( F e e n e y et al., 1982): (1) the rat is unable to place the affected h l n d p a w on the horizontal surface of the b e a m : (2) it places the affected h l n d p a w on the h o r i z o n t a l surface of the b e a m and m a i n t a i n s b a l a n c e b u t xs u n a b l e to traverse the b e a m ; (3) the rat traverses the b e a m dragging the affected h m d p a w , (4) it traverses the b e a m and once places the affected h i n d p a w on the horizontal surface of the b e a m , (5) the rat crosses the b e a m a n d places the affected h m d p a w on the horizontal surface of the b e a m to aid less than half its steps, (6) the rat uses the affected h l n d p a w to aid more than half its steps a n d , (7) the rat traverses the b e a m with no m o r e than 2 footsllps In each experiment. Trial 1 (or the ' P r e - D r u g ' trml) p r o v i d e d a baseline m e a s u r e of the rat's m o t o r ability following cortical injury This trial was p e r f o r m e d the d a y following surgery but before drugs were a d m l m s t e r e d or other interventions were p e r f o r m e d Trials 2 7 followed Trial 1 on the first p o s t - o p e r a t w e d a y The a n i m a l s then r e m a i n e d in the b e h a v i o r a l testing r o o m a n d a final trial was p e r f o r m e d 24 h after Trial 1 (shown as d a y 1 in the figures) Behavioral m e a s u r e m e n t s were p e r f o r m e d by an observer blind to the rats" operaUve a n d treat-

m e n t status. A s e c o n d observer, b l i n d to the rats' experience a n d m o t o r scores d u r i n g Trials 1 - 7 , p e r f o r m e d the ratings on d a y 1. Since 2 observers were required for each e x p e r i m e n t , a p r e l i m i n a r y s t u d y of i n t e r - o b s e r v e r a g r e e m e n t using the b e a m - w a l k i n g r a t i n g scale was p e r f o r m e d . W e i g h t e d k a p p a - s c o r e s ( L a n d i s a n d Koch, 1977: K r a m e r a n d Feinsteln, 1983) b e t w e e n 3 pairs of raters were f o u n d to be 0 93, 0.94, and 0.97 indicating ~Almost Perfect" a g r e e m e n t between obser~ ers

The effect of altering mter-trtal ;nter;,al amphetamine promoted recto,err

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F o r t y - e i g h t rats which were trained to traverse the b e a m u n d e r w e n t right cortical suction a b l a t i o n lesions. F o l l o w i n g the ' P r e - D r u g ' trial, half of the a n i m a l s (n = 24) were g w e n a single dose of ( + )a m p h e t a m i n e while the r e m a i n i n g a n i m a l s ( n = 24) received saline ,¢ehlcle. Beginning 1 h after drug a d m i n i s t r a t i o n , half of the rats m each group u n d e r , c e n t ~massed' trials on the beam. These consisted of six 90-s trials p e r f o r m e d in rapid succession over 12 rain T h e r e m a i n i n g rats underwent 6 similar trials which also began 1 h after d r u g or vehicle admlmstrat~on, b u t the trials were carried out at 1-h intervals ( ' s p a c e d ' trials) over 6 h ( a m p h e t a m i n e - t r e a t e d / ' m a s s e d ' trials, n = 12, amphetamme-treated/'spaced' trials, n = 12, sallne-treated/'massed' reals, n = 12, sahnetreated,/ ' s p a c e d ' reals, n = 12)

The effect of altering actluatmg sttmuh on the beam-walking performance of sham-operated rats tested with "massed" or "spaced" tr;a[s F o l l o w i n g training, s h a m o p e r a t i o n , a n d baseline score, 12 rats u n d e r w e n t 6 ' m a s s e d ' trmls on the beam. O n l y averslve hght a n d noise stlmuh were e m p l o y e d with one g r o u p of rats ( n = 6). The r e m a i n i n g rats (n = 6) u n d e r w e n t 6 similar trials, b u t were ~ p r o d d e d ' while a t t e m p t i n g to traverse the beam. ' P r o d d i n g ' consisted of a gentle tap on the r u m p d e h v e r e d with a pencil eraser once every 10 s b e g i n n i n g 10 s after the start of the trial. ' P r o d d i n g ' c o n t i n u e d until the a n i m a l entered the goal b o x or 90 s h a d e l a p s e d In a second experiment, the identical p r o t o c o l was emplo3,ed except the a n i m a l s were tested with h o u r l y "spaced ' trials

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The effect of 'prodding" on motor recovery Forty-seven rats were trained w~th two trtals on the beam each day for a total of 5 days Following training, one group of rats (n = 23) were sham-operated and a second group of rats (n = 24) were given sensory-motor cortex lesions. Beginning 1 h after Trial 1, all of the ammals were tested w~th 6 trials on the beam with I h inter-trial intervals ('spaced' trials). One group of sham-operated ammals (n = 13) and one group of lesioned rats (n = 12) were ' p r o d d e d ' during each of these trials as described above. The r e m a m m g rats ~ere not "prodded' during the trtals (sham-operated, n = 10; cortex les~on, n = 12)

Data anal)'sl5 Performances on Trail 1 (to determine whether comparable post-surgical deficits occurred across groups) and day 1 were analyzed with the M a n n Whitney U-test in experiments with 2 groups or w~th the Kruskal-Wallis test in experiments w~th more than 2 groups. If the Kruskal-Walhs test indicated that a slgmficant difference existed between 2 of the groups, the Fisher L S D test was applied to the ranks of the data. In order to compare the rates of ~mprovement of beam-walking performance, the area under the curve formed when scores were plotted against trml n u m b e r was determined using the Trapezoidal rule (Beyer, 1981). The resulting data were then analyzed with e~ther the M a n n - W h i t n e y U-test or the KruskalWillis test a~ reqmred by the mdlvldual experiment (Ghosh et al., 1973).

tested with ' s p a c e d ' trials as compared to those tested with "massed' trials was found, but the difference was not significant (Fig 1, day 1. Fisher LSD P > 0.05)

The effect of altering acttvattng sttmuh on the beam-walking performance of sham-operated rats tested with 'massed" or "spaced" trta/s The trend towards greater Improvement m saline-treated rats tested w~th 'spaced" as compared to ' m a s s e d ' trials suggested that the mterval between trials may have mfluenced the antmals' beam-walking p e r f o r m a n c e under the testing condlttons used. Therefore, the beam-walking performance of sham-operated rats tested with ' m a s s e d ' or ' s p a c e d ' trials was lnvesttgated using an addluonal acttvatmg stimulus There was no baseline difference between 2 groups of rats to be tested w~th 'massed" trials 24 h following s h a m - o p e r a u o n (Fig. 2A, Trml 1, M a n n - W h i t n e y U = 15, P > 0.05). In the subsequent trials, rats which were not ' p r o d d e d ' had

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The effect of altering mter-trtal mterual on amphetarome promoted recover)' Twenty-four hours following surgery, all groups exhibited a similar deficit in beam-walking performance (Fig. 1; ' P r e - D r u g ' Trial, Kruskal-Wallis H = 3.048, P > 0.05). A m p h e t a n u n e treatment resulted in an improvement in m o t o r scores measured 24 h after drug adrmmstration regardless of trial interval (Fig. 1; day 1, Kruskal-Wallis H = 12.426, P < 0.05; Fisher L S D P < 0.05). A trend towards greater improvement m sahne-treated rats

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Fig 1 The effect of altenng rater-trial interval on amphetamine promoted recovery 24 h following cortical lesion surgery, the ability of rats to negotiate a narrow, elevated beam was assessed (' Pre-Drug' Trial). 6 "massed' trials (t~, amphetamine treated, n = 12, ©, saline treated, n = 12) were then performed m rapid succession over 12 nun beginning 1 h after drug admlmstratlon 'Spaced' tnals (L amphetamine treated, n = 12, e, sahne treated, n = 12) were performed at 1-h intervals over 6 h, also beginning 1 h after drug adrmmstratlon Performance was reassessed 24 h after Trial 1 (day 1) Error bars indicate SEM

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Trnal Fig 2 The effect of 'prodding' on the beam-walking performance of sham-operated rats tested wnth 'massed' or 'spaced" trials 24 h following sham surgery, the ablhty of rats to negouate a narrow, elevated beam was assessed (Tnal l/ In one experiment (A), 12 rats were tested with 6 'massed' trials performed m rapid successmn over 12 min (Trials 2-7) 6 of the rats were 'prodded" (t-a) dunng the trials. The remalmng 6 rats were not "prodded" (w) In a second experiment (B), 12 rats were tested w~th 6 "spaced" trials performed at l-h intervan over 6 h (Trials 2-7) 6 of the rats were 'prodded" (,,-a) during the trials and the remaining 6 rats were not "prodded' (w) In each experiment, performance was reassessed 24 h later (da~ 1) by an observer bhnd to the rats" treatment group and motor scores dunng Trials 1-7 Error bars indncate SEM

slgntficantly lower scores than rats which were ' p r o d d e d ' (Fig. 2 A , T r i a l s 2 - 7 , M a n n - W h i t n e y U = 0, P < 0.002). T w e n t y - f o u r h o u r s l a t e r , t h e difference between the groups was not significant ( F i g 2 A : d a y 1, M a n n - W h i t n e y U - - 12, P > 0 05) Two similar groups of rats were tested with " s p a c e d ' t r i a l s xn a s e p a r a t e e x p e r i m e n t . T h e r e w a s n o d i f f e r e n c e b e t w e e n t h e g r o u p s 24 h f o l l o w i n g s h a m - o p e r a U o n ( F i g . 2 B : T r i a l 1, M a n n - W h i t n e y ( U = 15, P > 0 . 0 5 ) . In the subsequent 'spaced' trials, r a t s w h i c h w e r e n o t ' p r o d d e d ' h a d l o w e r scores than rats which were 'prodded', but the d i f f e r e n c e w a s n o t s i g n i f i c a n t ( F i g . 2B, T r i a l s 2 - 7 , Mann-Whitney U = 12, P > 0.05). T w e n t y - f o u r h o u r s later, t h e d i f f e r e n c e b e t w e e n t h e g r o u p s r e m a i n e d i n s i g n i f i c a n t (Fig. 2B; d a y 1, M a n n W h i t n e y U = 15, P > 0.05).

In other experiments with rats tested with ' m a s s e d ' trials, i n c r e a s i n g t h e n u m b e r o f t r a i n i n g trials or decreasing the time interval between the start of a trial and the activation of the aversive (light and white noise) stimuli did not significantly i n f l u e n c e t h e f i n a l ( d a y 1) score. H o w e v e r , t h e s e changes in training or testing condIttons dtd result i n i m p r o v e d p e r f o r m a n c e s in T r i a l s 2 - 7 ( d a t a n o t shown),

The effect of 'prodding' on motor recove O' Twenty-four hours after surgery, rats with c o r t e x l e s i o n s e x h i b i t e d a s i g n i f i c a n t d e f i c i t in b e a m - w a l k i n g s c o r e s as c o m p a r e d w i t h s h a m - o p e r a t e d c o n t r o l s ( F i g . 3, T r i a l 1, M a n n - W h i t n e y ' U = 18,5, c = - 6 . 0 1 5 , P < 0.001). L e s i o n e d r a t s which were 'prodded' recovered faster than lesion rats which were not 'prodded' (Trials 2-7, K r u s k a l - W a l h s H = 38.392, P < 0.01: F i s h e r L S D ,

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Fig 3 The effect of 'prodding' on beam-walking recovery_ One group of rats were sham-operated and the ~econd group sensoEy-motor cortex lestons, 24 h following surgery, the ablhty of the rats to traverse the beam was assessed (Trial 1) The ammals were then tested wnth 6 "spaced" trials at 1-h intervals (Trials 2-7) Half of the sham-operated rats and half of the rats with sensory-motor cortex lesions were 'prodded' dunng these trials (m, sham-operated/'prodded', n = 13, cl sham-operated/not" prodded', n = 10, o, cortex lesion/" prodded', n = 12, O, cortex lesion/not 'prodded', n = 12) Performance v, as rea,sessed 24 h later (day 1) by an observer blind to the rats" treatment group and motor scores during Trials 1-7 Error bars mdncate SEM

11t6 P < 0 . 0 5 ) . In these ' s p a c e d ' trials, there was no difference between s h a m - o p e r a t e d a m m a l s which were ' p r o d d e d " as c o m p a r e d with those which had not been ' p r o d d e d ' (Trials 2 - 7 . F i s h e r L S D P > 0 05)

Discussion The central findings in the p r e s e n t s t u d y are' (1) a m p h e t a m i n e t r e a t m e n t f a c i h t a t e d recovery of b e a m - w a l l ~ n g p e r f o r m a n c e regardless of interval between trials; (2) s h a m - o p e r a t e d a n i m a l s h a d a s~gniflcant decline in p e r f o r m a n c e when tested with ' m a s s e d ' trials; (3) the decline in perform a n c e of s h a m - o p e r a t e d rats tested with ' m a s s e d ' trials was e h m m a t e d by ' p r o d d i n g " a n d was red u c e d by m a n i p u l a t i o n of other testing variables; a n d (4) ' p r o d d i n g ' alone e n h a n c e d the rate of b e a m - w a l k i n g recovery in rats with a s e n s o r y - m o tor cortex lesion Pre- a n d post-lesion e n v i r o n m e n t a l e n r i c h m e n t a n d d e p r i v a t i o n influence b e a m - w a l k i n g recovery following s e n s o r y - m o t o r cortex injury ( H e l d et al., 1985) The c a p a c i t y of a m p h e t a n u n e to increase the rate of recovery of b e a m - w a l k i n g m the rat ( F e e n e y et al., 1982), b e a m - w a l k i n g In the cat ( H o v d a a n d Feeney, 1984), a n d stereopsls in the cat ( F e e n e y and H o v d a , 1985) d e p e n d s on the a m m a l s ' experience d u r i n g the p e r i o d of drug lntoxicatton A l t h o u g h both drugs a n d experience Influence the recovery process, the m e c h a m s m s by which a m p h e t a m i n e a d r m n i s t r a t i o n or ' p r o d d i n g ' accelerate the rate of recovery of b e a m - w a l k i n g p e r f o r m a n c e remains speculative. ' M o t i v a t i o n ' m a y be one factor. ' P r o d d e d ' rats m a y a t t e m p t to take m o r e steps on the b e a m a n d t h e r e b y o b t a i n m o r e task-specific experience t h a n ' n o n - p r o d d e d ' controls. A m p h e t a m a n e m a y act m a m a n n e r s m u l a r to ' p r o d d i n g ' m that the d r u g increases l o c o m o t o r activity m b o t h n o n - l e s i o n e d ( S w e r d l o w et al., 1963) a n d lesioned rats ( L y n c h et al., 1969). T h e o p p o s i t e effect m a y occur when rats are tested with "massed' r e a l s . S h a m - o p e r a t e d rats h a d a d e c h n e m p e r f o r m a n c e when tested with ' m a s s e d ' trials which could be e l i m i n a t e d b y ' p r o d d i n g ' a n d influenced b y the m a n i p u l a t i o n of other testing

condlt~ons. Thus, u n d e r certain testing clmd~tton~. the failure of some rat~ with cortex les~on~ to cros~ the b e a m (~cores of '1' or '2') m a y be the result of a lack of m o t i v a t i o n a n d not a failure ,,1 recover\ An a p p r e c i a t i o n of the mapact of testing c o n d i tions is m a p o r t a n t for the i n t e r p r e t a t i o n of the effects of p h a r m a c o l o g i c a l agents on rccovcr,, ol b e a m - w a l k i n g p e r f o r m a n c e after ~ensor~-tnotor cortex les~ons U n d e r the training and te,qlng cond m o n s e m p l o y e d m the final e x p e r i m e n t I Ftg 3~, s h a m - o p e r a t e d rats h a d n o r m a l b e a m - w a l k i n g perf o r m a n c e s a n d rats w~th cortical lesk,n~, had a c o n s i s t e n t b e a m - w a l k i n g deficit The a~aflabfllty of a well u n d e r s t o o d , r e p r o d u c i b l e a m m a l model of functional recovery wtll bc i n v a l u a b l e lor e~entual s t u & e s of the effects of p h a r m a c o l o g i c m a n i p u l a t i o n s m h u m a n p a t i e n t s following stroke a n d b r a i n t r a u m a . B e a m - w a l k i n g m rats may prove useful m p r e d i c t i n g d r u g effect~ in man since p r e l i m i n a r y evidence suggests that a m p h e t a m i n e m a y accelerate recover) of m o t o r f u n c m m after stroke ( C n s o s t o m o et al., 1988).

Acknowledgements The a u t h o r s are i n d e b t e d to G e r a l d Miller. K a t h e r i n e W a l t o n a n d N a n c y Cress for excellent t e c h m c a l assistance. This work was s u p p o r t e d by the Veterans A d m i n i s t r a t i o n , a n d the N I.H. (NS 06233 a n d N S 01162). A p r e h m l n a r y r e p o r t of a p o r t i o n of this w o r k was p r e s e n t e d at the 16th a n n u a l P r i n c e t o n C o n f e r e n c e on C e r e b r o v a s c u l a r Disease. M i a m i , F L , in M a r c h , 1988.

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