Brain Research, 178 (1979) 329-346 © Elsevier/North-Holland Biomedical Press

329

SENSORY N E G L E C T A F T E R LESIONS OF SUBSTANTIA N I G R A OR L A T E R A L H Y P O T H A L A M U S : D I F F E R E N T I A L SEVERITY A N D RECOVERY OF F U N C T I O N

DENNIS M. FEENEY and CHET S. WIER Department of Psychology, University of New Mexico, .41buquerque, N.Mex. 87131 (U.S.A.)

(Accepted April 5th, 1979) Key words:

substantia nigra - - lateral hypothalamus - - superior colliculus - sensory neglect - - attention

SUMMARY Sensory neglect was studied in cats after unilateral lesions of : lateral hypothalamus (LH); internal capsule (IC) adjacent to the LH; substantia nigra (SN) or the ventromedial hypothalamus (VMH). Special behavioral tests were employed to yield quantifiable data and also to exclude any confounding due to simple movement deficits. Lesions of SN or lC produced severe and enduring contralateral visual and somesthetic deficits and a facilitation of ipsilateral visual responsiveness. In contrast, L H lesions sparing the adjacent IC produced only weak and transient deficits and VMH lesions had no effects on sensory function. This suggests that lesions of the SN or its forebrain connections are important for producing sensory neglect and that sensory deficits after L H lesions are due to infringement on fibers of passage to or from the SN. Lesions which produced neglect often suppressed the amplitude of flash evoked responses in the ipsilateral caudate nucleus and visual and association cortex. However, these evoked potential effects were transient. There was no effect on the spontaneous E E G and this fails to support the hypothesis of a lack of hemispheric arousal in sensory neglect. The results are discussed in relation to nigrotectal projections and the process of attention. This lesion-behavior model is suggested for studies of recovery of function. INTRODUCTION Sensory neglect is a syndrome of multimodal loss of responsiveness to sensory stimuli contralateral to a brain injury which spares classical sensory pathways. Neglect has been reported in man after parietal lobe injury 16 and in animals after lesions of frontal cortexS,X0,49 diencephalonl,ll,12,25-27, aa and mesencephalon s4,aS. Recently the lateral hypothalamus (LH) and the substantia nigra (SN) have been suggested as critical structures in lesions which produce neglect~, 45. Lesions of L H usually extend into

330 the adjacent internal capsule 26 (IC) and since fibers to and from the nigra traverse these regions6,Z3,3~, 32,46 their destruction may produce the sensory neglect attributed to L H lesions. Only one report 26 has compared the syndromes resulting from lesions of LH and SN and it describes an incomplete neglect after SN lesions in contrast to a complete loss of contralateral responsiveness after unilateral LH lesions. However the results of that study cannot be clearly interpreted since the LH lesions were produced by electrolytic methods whereas the SN lesions were produced by the neurotoxin 6O H D A and so either the locus of the lesion or the method of lesion may have produced the differing results. To clarify the role of the SN and the LH in neglect it is necessary to directly compare the effects of lesions in these areas made with identical methods. Previous studies of sensory neglect have relied upon simple behavioral tests such as placing and orienting responses or blink to threat26,zT, 45. The lack of quantification in these tests makes evaluation of the severity of syndrome or recovery time difficult to compare across different lesions. Moreover, these measures cannot differentiate sensory from simple motor disordersg, 22. For example, after unilateral lesions of the L H rats fail to orient toward visual, auditory or olfactory stimuli presented to the contralateral side of the body27, 45. These animals also display ipsiversive circling and so a failure to orient may represent a disorder of contralaterally directed movement. Indeed, it is difficult to interpret a 'unilateral' olfactory deficit as anything other than a simple motor disorder. While the classification sensory or motor is artificial, this has been a useful conceptual distinction and by using appropriate behavioral methods we can ask if a deficit is 'chiefly' motor or 'chiefly' sensory is. In the experiments described below we describe the sensory deficits produced in cats by unilateral lesions confined to the SN, LH, IC or the ventromedial hypothalamus (VMH). Behavioral tests were utilized which may exclude simple movement disorders and which yield quantifiable data to compare severity and the rate of recovery from the syndrome. Additionally we report exploratory electrophysiological data on the effects of these lesions on sensory evoked potentials and the electroencephalogram. A preliminary account of this work has been presented as an abstract 5°. METHODS Subjects

A total of 55 adult cats weighing between 2.2 and 3.5 kg were used in these studies. Four different types of preparations were employed and the procedures and results are described separately below. (1) Fifteen cats were studied only with behavioral tests pre- and post-lesion. (2) Thirty-one cats were studied only with acute electrophysiological procedures to explore for remote effects of the same lesions. (3) Following up the results from the acute studies, three cats were implanted with chronic electrodes and studied with both behavioral and electrophysiological procedures preand post-lesion. (4) Additionally, six cats were studied twice with acute electrophysiological procedures immediately after and 10 days after brain lesions and also studied with behavioral methods,

331

Behavioral tests (A) Two tests were employed to yield quantitative measures of the functional integrity of the cats visual fields before and after a lesion. The appetitive test of visual perimetry required the animal to approach a piece of food (Purina Cat Chow) directly in front of him (0 °) at a distance of 70 cm. While the cat's eyes were fixed on the food presented by one experimenter (El), a second experimenter (E2), who had restrained the cat at the start point and held the cats head oriented toward 0 °, then released the cat and from behind simultaneously presented a second piece of food at a distance of 50 cm at angles 0, 30, 60 or 90 ° to each side (see Fig. 1A). Normal cats invariably go to the closer food regardless of the angle. Cats were tested three times per week for a total of 5-8 sessions before surgery. Each session consisted of 7 trials per angle in a random sequence. In addition, 10 trials at 120 ° were interspersed to control for anticipation or olfactory cues. The cats normally fail to respond since the 120 ° is not within the field of vision. After shaping and during the baseline recording sessions, all cats achieved at least 95 ~ correct responses per angle and no responses to the 120 ° tests. A correct response was defined as the animal moving more than halfway towards the food presented at a test angle. This task is considered 'movement dependent' since in order to score a correct response, the subject must move toward the food. A total of 11 cats were tested using this procedure and it is described in more detail by Sherman ag. (B) As a second test of visual function, a Modified conditioned suppression task was used. This procedure consists of a suppression of licking by the onset of light presented at various visual angles - - the light signaling imminent foot shock. Cats were first given free access to a canned milk and water solution dispended through a licking tube in their home cage, and with subsequent food deprivation they would begin to lick from the tube in 2~, days. The cat was then placed in a test chamber 1 h per day, 5 days per week. During the test period, the cat was maintained at 80-85 ~ of ad libitum body weight. On weekends the cats were given free access to Purina lab chow and high protein formula (Nutrical). The liquid food used in the test chamber was a mixture of Gerber's Baby Beef Food, Purina Tuna Cat Food juice, and water. The test chamber is depicted in Fig. IB. White noise was played into the chamber to mask room noises. H a l f of the floor was covered with copper grid bars for delivery of foot shock. To reach the lick tube, the cat had to stand on the grid and extend his head into the opening. With his tongue on the lick tube, the animal faced a series of lights 2 m m in diameter and 8 cm from his nose. Each light was covered with translucent paper over a 12V bulb. The inside of the chamber was painted flat black to reduce reflections. The lights were positioned at 0, 30, 60 and 90 ° to each side. After extensive training, the cat positioned his body in line with the 0 ° opening. Cats displaying angledhead positions were not used. Licking responses were recorded on a Brush Oscillograph Model R D 2321, by placing an Eico Craft EC-1800 capacity operated switch in series with the lick tube and recorder. After the cats achieved a steady lick rate, conditioning commenced. In each session, the cat received a total of 28 trials, 4 randomly distributed at each angle, 5 times per week. Light duration was 1 sec, followed by a 1 sec foot shock. Trials were

332 c o n d u c t e d only against a b a c k g r o u n d o f steady lick responses, a n d variable inter-trial intervals r a n g e d from 10 to 60 sec. A c o n d i t i o n e d s u p p r e s s i o n o f licking response (CSL) was defined as the c o m p l e t e suppression o f licking in the presence o f the w a r n i n g light a n d p r i o r to the delivery o f f o o t shock. W h e t h e r the cat a v o i d e d shock by m o v i n g off the grids was inconsequential to the r e c o r d i n g o f the d e p e n d e n t variable, the cessation o f licking. However, most cats did a v o i d the foot shock. This escape m o d i f i c a t i o n o f the c o n d i t i o n e d suppression technique was necessary since with u n a v o i d a b l e shocks, the cats refused to eat. Subjects were tested until they achieved a m i n i m u m o f 75 ~ C S L s for all angles for 5 consecutive test sessions. This t o o k several h u n d r e d trials. A total o f 4 cats were tested with this procedure. (C) A s a measure o f somesthetic function, the reaction time (RT) to w i t h d r a w a p a w after its i m m e r s i o n in water was measured. E a c h cat was given one session, 5 days p e r week, a n d each l i m b was tested only once per session to avoid h a b i t u a t i o n . Baseline recordings were taken for 13-16 days. The cat was held by an experimenter, a n d with its eyes covered it was lowered until a p a w d i p p e d into a stainless steel bowl o f t a p water at r o o m t e m p e r a t u r e . The sequence o f limb testing was r a n d o m l y varied. The w a t e r bowl was connected in series with a Lafayette electric timer t h r o u g h an Eico C r a f t EC-1800 c a p a c i t y o p e r a t e d switch, so that the clock ran while the p a w was in the

E1 BAITS CAT HERE

7 0 :m

30 °

5Q :m

3 0°

76 cm

90 ° ~

I 90 °

j-/'" 1 2 0 • ~"

ff v 1206 E2 HOLDS CAT HERE

Fig. 1. A : appetitive visual perimetry test method. Cat is restrained by E2 with its head held by hand immobile and its nose at the intersection of the lines pointed along the 0 ° guideline. E1 would then present food at the 70 cm 0 ° point and when the animal's eyes were fixed on this bait, E2 would simultaneously present another piece of food using long forceps at one of the test angles at the 50cm marks and release the cat. Normal cats invariably go to the closer piece of food regardless of the angle. The 120° test points are out of the cat's visual field and they do not respond to these points. B: conditioned suppression of licking test apparatus. To receive liquid food the cat must put his head through the opening and lick the tube (indicated by the thick arrow). A warning light (shown retracted) would signal imminent foot shock from the grid floor. The cessation of licking in response to presentation of one of the warning lights was considered a measure of visual detection at that angle.

333 water. The cat was allowed a maximum of 5 sec to respond. Fifteen cats were tested using this procedure. An additional test was conducted to determine if cats showing a deficit in this task were capable of making the appropriate movement swiftly. The reaction time to paw shock was tested in six of the cats displaying deficits on the water immersion RT task. Each paw was lowered on to an electrified grid using a procedure identical to the water immersion task, and time to remove the paw measured. This test was conducted only once for each cat 20-60 days following the lesion. This was not d o n e m o r e frequently to avoid stimulus generalization to the water immersion test and because of the difficulty in handling the cats in this situation.

Surgery After recording the baseline behavioral data, the cat was anesthetized with Sparine (5.5 mg/kg i.p.) followed in 45 min by Nembutal (sodium pentobarbital 24 mg/kg i.p.), placed in a K o p f stereotaxic and using sterile procedures the scalp cut and a small hole was drilled in the skull to permit electrode penetration. The dura was punctured and a single stainless steel electrode, insulated except for 1 mm at the tip, was placed in one of 4 lesion sites according to the atlas of Jasper and AjmoneMarsan 19. These sites were: (LH) at A + 9 ; L 2 and 3, H - - I to H---4; the IC (adjacent to LH) at A 9, L 4, 5 and 6, H - - 3 to - - 5 ; and the SN at A + 7 , L 4, 5 and 6, H - - 4 to H - - 6 ; or V M H at A + 1 l, 11.5 and 12; L 0.5 and 1.5; H - - 4 to --6. Using a Nuclear Chicago Constant Current Stimulator, 3 mA of anodal current was passed at each 1 mm step for 30 sec. The electrode was removed and any bleeding controlled. The hole was closed with bone wax, the scalp sutured, and standard antibiotics administered. At the conclusion of testing, the cat was again anesthetized, perfused and decapitated, and the head stored in formalin for two to three weeks. The brain was blocked using the stereotaxic device and frozen 80/~m sections were cut and stained with 1 ~ thionin using standard procedures.

Electrophysiologicalprocedures (A) Acute experiments In the acute experiments the cat was initially anesthetized with ether, a catheter inserted into the femoral vein, and 50 mg/kg of alpha-chloralose suspended in propylene glycol injected and then ether was discontinued. Small amounts of chloralose were periodically readministered as necessary to maintain anesthesia. A tracheotomy was performed. Flaxedil (gallamine triethiodide) administered (1.0 mg/kg i.v.) and the animal artificially respirated. Flaxedil was readministered to maintain paralysis. The cat was placed in a K o p f stereotaxic apparatus and the pupils dilated with topical homatropine. The scalp was resected, a large bone flap removed and the brain exposed and covered with 38 °C mineral oil contained by an acrylic dam. Body temperature was continuously monitored and maintained at 36-38 °C. For recording, silver ball electrodes were placed bilaterally upon the posterior sigmoid gyrus, anterior middle suprasylvian gyrus and middle marginal gyrus.

334 Stainless steel depth recording electrodes insulated except for 1 mm at the tip were placed bilaterally according to the coordinates from the atlas of Jasper and AjmoneMarsan 19 in the following structures: caudate nucleus (A 15, L 5, H ÷ 5), mesencephalic reticular formation (A 2, L 3, H --3), red nucleus (A 5, L 2, H -t-3) and superior colliculus (A 2, L 3, H ÷ 3). Final position of the electrodes was adjusted to obtain symmetrical evoked responses of maximal amplitude. All recordings were monopolar and referenced to a silver disc embedded in neck muscle. Evoked responses were generated by binocular flash stimulation or by electrical stimulation of the optic chiasm or forepaws using a Nuclear Chicago Constant Current Stimulator. Before a lesion, control evoked potentials were obtained by photographing five superimposed responses from a Tektronix storage oscilloscope. (Evoked potential waveforms and amplitudes are relatively constant under chloralose and computer averaging was unavailable.) Unilateral lesions were made as described above in the LH, SN, IC or VMH and evoked potentials again recorded. Depression of ipsilateral evoked potentials by the SN, L H or IC lesions were followed and replicated for as long as 8 h in these acute studies. After completion of testing the cat was killed with an overdose of Nembutal; depth recording sites marked by passing 50 #A of DC current for 60 sec and the animal perfused with formalin. The brain was removed, fixed and frozen, 80 # m sections were stained with 1 ~ thionin to reconstruct the lesions and verify subcortical recording sites. Two types of chronic preparations were used to test both the electrophysiological and behavioral effects of the lesions in the same animals. The behavioral tests on these animals included both the Appetitive visual perimetry test and the limb withdrawal to water immersion.

( B) Implanted preparations Using standard procedures, subjects were anesthetized as described above using sparine and Nembutal. Recording sites were selected on the basis of effects obtained from acute experiments. Stainless steel screws were implanted in the skull bilaterally over the posterior sigmoid gyrus, anterior middle suprasylvian gyrus and the middle marginal gyrus. Depth electrodes were placed in the head of the caudate nucleus (A 15, L 5, H +5). Two monopolar lesion electrodes, separated by 1.5 mm and bared 1 mm at the tip, were placed in either the VMH, LH or IC at the center of previously used coordinates. Recording electrodes were referenced to a skull screw over the frontal sinus. The electrodes were cemented in place with dental acrylic and connected to a Winchester 18 pin female plug. The cat was treated with antibiotics and allowed 1 week to recover. Following baseline behavioral and electrophysiological tests the subject was anesthetized with a short lasting anesthetic, Ketaset (ketamine hydrochloride 7 mg/kg i.m.) and the lesions made by passing 3 mA anodal current for 60 sec. Because of the fixed electrode positions, the lesions of the previous studies could not be duplicated exactly. Following recovery from the anesthesia the cat was tested for behavioral deficits 3 times per week for 30 days. Evoked potentials and background EEG were recorded twice per week for 30 days on a Grass polygraph, recordings were always

335 taken during wakefulness. Because of the minor behavioral effects of this first lesion of this experiment on visual behavior, a second lesion was made in all cats one week after the first lesion using identical procedures but using 6 mA for 4 min. This typical implant procedure was abandoned for several reasons: First, the implant of the lesion electrodes into the LH or IC produced behavioral impairments and so we could not exclude serial lesion effects or be confident that our pre-lesion evoked potentials were in fact 'pre-lesion'. Second, the fixed electrode array prevented making lesions comparable to the previous behavioral experiments. Third, the lack of electrophysiological results suggested that the effects seen in the acute experiments could be chloralose dependent. For these reasons the following experiments were conducted.

( C) Chronic~acute preparations In experiments on 6 cats using the acute procedure evoked responses were measured under chloralose immediately, and 10 days following the various lesions and the animals behavior tested during that 10 day interval. Prior to surgery, baseline behavioral testing was conducted to previously described criteria. The animal was then anesthetized with ether and 50 mg/kg alpha-chloralose administered via a catheter in the femoral vein. Using sterile procedures, a small incision was made in the scalp and small holes drilled through the skull above the posterior sigmoid, middle suprasylvian and marginal gyrus bilaterally. Monopolar silver ball electrodes were placed on the dura. Holes were also drilled bilaterally above the caudate nucleus, superior colliculus and mesencephalic reticular formation and unilaterally over the lesion site. Depth electrodes were placed in these structures and recording and lesion procedures identical to that described for the acute preparations was followed. The electrodes were then removed, the skull holes closed with bone wax, the scalp sutured and the cat given antibiotics. Using the somesthetic test, subjects were tested 2, 5 and 10 days after the lesion and 5-10 days after the lesion using the visual perimetry test (appetite was somewhat depressed for the first few days after surgery). On day 10, the surgery and electrophysiological recording procedure was repeated. This protocol was followed to test for transient or chloralose-dependent effect of the lesions on evoked potentials and to use identical lesion procedures as in the previous behavioral study and acute experiments. Histological procedures were identical to those used in the acute experiments. RESULTS

Behavioral data (A) Appetitive visual perimetry test A total of 11 cats were studied using this procedure. However, in one cat the lesion involved the optic tract and so the data from that subject was not included. Of the remaining subjects, three had VMH lesions, three LH lesions, two with IC lesions and two with SN lesions. During baseline recording (42 trials per angle), all subjects

336 were very consistent and accurate responding correctly on 97-100~o of the trials at

each angle, with the few errors occurring at the 90 ° angle. The lesions had a dramatic effect on performance. With the exception of the V M H group which showed no apparent effects, all of the other subjects showed a dramatic loss of responsiveness to food presented in the contralateral field, especially at the periphery. As depicted in Fig. 2 this was most dramatic for the SN group which completely failed to respond to stimuli in the entire hemifield contralateral to the lesion for 19 days after the lesion. This lesion effect was also clear in the IC group. The L H group displayed a similar but less pronounced deficit during the first 9 days after the lesion but completely recovered by day 19. The IC group and the SN group did not completely recover in the 60 days of testing.

(B) Modified conditioned suppression task A total of 4 cats were tested using this difficult procedure: One with a lesion of the VMH, one of LH, one of IC, and one with a very large lesion involving parts of V M H , LH, and the IC (noted as VMH-LH-IC). This task was considerably more difficult for the cats, so the baseline recording was extensive, 73 trials per angle. The subjects tended to make the most prelesion errors at the 90 ° angle on one side (ranging from 37 to 56 ~ correct responses), whereas pre-lesion performance at all other angles ranged from 84 to 100 %o correct responding. The lesions were made contralateral to MEAN PERCENTAGES OF CONTROL RESPONSES

IPSI --

VMH

LATERAL

CONTRA--

LATERAL

L.

IC

2-9

12-19

22-29

37-44

52- 59

DAYS AFTER LESION Fig. 2. Results f r o m appetitive visual perimetry test. Post-lesion data as a mean percentage of pre-

lesion performance. Insert in the upper right shows cat's head being held by E2, the test angles and calibration circles. The thick lines in the other figuresJndicate mean performance per group over 8 test sessions for each angle. Testing was discontinued upon recovery or after 60 days post-lesion. Data are depicted as if lesions were all in the left hemisphere. Abbreviations: VMH, ventromedial hypothalamus; LH, lateral hypothalamus; IC, internal capsule adjacent to LH; SN, substantia nigra.

337 MEAN PERCENTAGESOF CONTROL RESPONSES

IPSI -LATERAL

VMH

CONTRA-LATERAL

LH

IC

VMHLHIC

1-5

8-12

15-19

35-39

55-59

DAYSAFTERLESION Fig. 3. Results from the conditioned suppression of licking test. Insert shows cat's head at the lick tube and data, and abbreviations as in Fig. 2. VMH-LH-IC is data from an animal in which the lesion spread across all these structures.

the subjects 'best side'. As indicated in Fig. 3, the lesion of V M H had no effect, whereas the other lesions produced a contralateral neglect. The L H cat showed a deficit on this task for only the first 5 days following the lesion, the IC subject for 12 days, and the animal with the large lesion did not completely recover in 60 days of testing. Additionally, with the IC and V M H - L H - I C subjects there was a dramatic facilitation of responsiveness to the ipsilateral 90° light. (C) Somesthetic reaction time tests A total of 10 cats were tested on the limb withdrawal to water immersion task. The sample consisted of three subjects with V M H lesions, three with L H lesions, two with IC lesions, and two with SN lesions. All of these subjects also participated in the Appetitive visual perimetry test. Before the lesions the mean latency to paw withdrawal from water immersion for all subjects was 360 msec. Following surgery, there was a dramatic slowing of water immersion RT of the limbs contralateral tothe'lesion for the SN and IC groups. A comparatively slight effect was observed in the L H group, and no effect in the V M H group. There were no apparent differences between the effects on fore- and hindlimb in severity or duration of the effect and so these data were combined and are depicted in Fig. 4. The SN and IC groups did not completely recover in the 60 days of testing. There was some suggestion of a facilitation of water immersion RT for the ipsilateral limbs of the SN and IC groups but this was not statistically significant and perhaps was limited because of'a' 'floor' effect.

338 )300

V M H ~ - - - ~o LH +,-----°

1200

IC ~----~

1100 1000

Z

900

Lu 800 Zm ,,.i

700

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soo Z

400

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300

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200

100

50

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11-2o

21-3o

31L4o

41-'5o

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DAYS AFrt~ tESION

Fig. 4. Results from the reaction time to limb immersion in water test. Data are expressed as a mean percentage (± S.D.) of pre-lesion performance. Scores are pooled for both the forepaw and hindpaw contralateral to the lesion for the various lesion groups.

To determine if subjects displaying contralateral slowing of somesthetic R T were capable of moving those limbs as quickly as before the lesion, R T to paw shock was measured. Six cats displaying pronounced slowing of contralateral slow RT to water immersion were also tested with paw shock; two with L H lesions, two with IC lesions and two with SN lesions. It was clear that the subjects only displayed asymmetry of R T in response to water immersion and not to paw shock. When tested between 20 and 60 days after the lesion, the mean RTs to paw shock for these cats was 290 msec for the limbs ipsilateral to the lesion and 318 msec for the contralateral limbs, whereas the RTs to water immersion were 318 msec and 755 msec, respectively. Clearly the subjects were capable of making the withdrawal quickly to intense stimuli. Given that the RTs to paw shock were not different from the baseline RTs to water or from the R T of the ipsilateral limb to water immersion, it is very unlikely that this response to paw shock was simply mediated by a spinal reflex and that to water by a supraspinal path.

(D) Other behavioral observations In the cats with IC or SN lesions there were dramatic but transient effects on spontaneous m o t o r behavior. Ipsiversive circling when placed in an open field lasted

339 an average of 18 days and the contralateral forepaws were splayed for an average of 34 days. The cats with LH lesions showed ipsiversive circling for an average of 9 days and forepaws were splayed for 12 days. There was no ipsiversive circling or splayed paws in any of the VMH lesion subjects. The VMH cats did display some hyperactivity and increased aggressiveness. This was most dramatic in one VMH cat that reliably displayed rage when petted on the side contralateral to the lesion whereas ipsilateral stroking rarely evoked rage. The subjects with contralateral visual deficits, shortly before recovery would display transient head orientations toward stimuli presented in the contralateral field on the appetitive perimetry test but fail to approach that piece of food.

Electrophysiological data Acute experiments Five of the 31 subjects were excluded because of mortality or misplaced lesions. Thirteen animals received LH lesions, six IC lesions, five SN lesions and three VMH lesions. The lesions of VMH had no effects on any of the evoked potentials. However, the lesions of the other sites had a similar and occasionally dramatic suppressive effect on evoked potentials recorded from the ipsilateral hemisphere. The most reliable effects of the lesions were a depression of the amplitude of flash evoked potentials recorded from the ipsilateral middle suprasylvian gyrus and the ipsilateral caudate nucleus. This effect on caudate was observed in 33-50 % of the experiments and the depression of ipsilateral association cortex responses to flash or optic chiasm stimulation was observed in 29 % of the experiments. The responses of the posterior sigmoid gyrus to paw shock and the superior colliculus to flash or optic chiasm stimulation were only occasionally depressed. The flash evoked response in the mesencephalic reticular formation was never affected by any of the lesions. The depressions of evoked potentials when they occurred were often dramatic, in that the response on the ipsilateral hemisphere was reduced by 70-80% of the prelesion amplitude whereas the response from the contralateral hemisphere was unchanged.

Chronic experiments The electrode implant alone produced surprising behavioral deficits which have been noted previouslyS,29,30. In all of the animals there was some ipsiversive circling (toward the side of the array of electrodes implanted for the lesion), and some slowing of RT to water immersion of the contralateral paws. However, there were no visual deficits in any of the subjects. Behavior returned to baseline before any electrolytic lesions were made. Following the first electrolytic lesion in the VMH subject, there was no visual deficit, a slowing of contralateral RT for one day and some increase in aggression and hyperactivity. There was no apparent effect on the background EEG or evoked responses. One week later the second lesion was made through the same electrodes.

340 This larger lesion resulted in 11 days of ipsiversive circling and 11 days of slowed RT of the contralateral paws. There were no visual deficits. There were also no apparent changes in the background EEG or evoked responses. Following the first electrolytic lesion in the LH, the subject showed ipsiversive circling and slowed contralateral water immersion RTs but no visual deficits. Following the second larger lesion, the animal had to be force fed for 11 days. When testing resumed this cat showed ipsiversive circling and dramatic contralateral visual and somesthetic neglect similar to that described for the previous subjects. This syndrome persisted for the 30 days of testing. There were no apparent effects on background EEG or evoked potentials. The first electrolytic lesions of the IC animal produced the entire syndrome of contralateral visual and tactile neglect and ipsiversive circling, but these behavioral effects were not as striking as seen in the previous behavioral study. However, following the second larger lesion, the behavioral effects were as dramatic as reported above. There was no apparent effect on the background EEG or on the flash evoked potentials.

Acute~chronicpreparations This group consisted of two cats with LH lesions, two with IC and two with SN lesions. The results with these animals for the immediate effects of the lesions on evoked responses were similar to those seen in the acute subjects--dramatic but inconsistent suppressions of the evoked potential amplitude. Following the lesion, one of the two LH cats showed a suppression of the ipsilateral visual cortex response and both animals showed visual and somesthetic neglect until terminal measures were taken 10 days after the lesion. However, when the electrophysiological measures were repeated on day 10, the evoked responses had recovered and were of symmetrical amplitude. Following the IC lesions one of the two subjects showed an immediate suppression of the flash response in ipsilateral visual cortex and middle suprasylvian gyrus. Both subjects showed dramatic visual and somesthetic neglect for the 10 day test period; however, the evoked responses returned to symmetrical amplitudes after 10 days. After the SN lesions, one of the two subjects showed a suppression of the amplitude of the flash response in the ipsilateral middle suprasylvian gyrus and caudate nucleus. Both cats displayed dramatic visual and somesthetic neglect over the 10 day test period. However, by day 10, the depressed caudate response had returned to the prelesion bilateral symmetry. The depression of evoked potentials is depicted in Fig. 5.

Histology Examination of histological material indicated that the lesions were similar within the different groups except for the two subjects already noted. The VMH lesions extensively damaged the Ventral Medial Nucleus and the posterior hypo-

341 PRELESION

~;f

P.M.

i

~,~.

POSTLESION

....

/ilC

M.Ss.

Fig. 5. Flash evoked potentials from acute/chronic preparations. Post-lesion data were taken immediately after lesions of the SN or IC and the depressed amplitudes (lower traces) in the hemisphere ipsilateral to the lesion recovered by 10 days. Abbreviations: P.M., posterior marginal gyrus; M.Ss., middle suprasylvian gyrus; Cd. N., caudate nucleus. Calibrations 200/~V and 50 msec.

thalamic area. The L H lesions additionally involved the zona incerta, the stria terminalis and the fields of Forel including the thalamic fasciculus (Ht), the lenticular fasciculus (H2), and the prerubral field (H). Larger LH lesions infringed upon the basal thalamus and medial portions of the internal capsule. The IC lesions involved the internal capsule adjacent to the lateral hypothalamus, the subthalamic nucleus and the lenticular fasciculus. Larger IC lesions infringed on the thalamic reticular nucleus, and the rostral portion of the nigra. The SN lesions involved the substantia nigra and the underlying cerebral peduncle. Larger SN lesions also infringed on the medial geniculate. In one subject designated VMH-LH-IC the lesion was spread laterally infringing on all of these structures. In the implanted subjects the lesions were approximately twice as large as the lesions in the corresponding animals studied only with behavioral or acute electrophysiological methods. The lesions illustrated in Fig. 6 are from animals in the behavioral experiment and show the small lesions of SN, IC, and L H that produced clear behavioral effects and the VMH lesion is typical for the subjects in that group.

342

SN

IC

LH

VMH

Fig. 6. Thionin stained sections of SN and IC lesions which produced clear and enduring sensory neglect. The LH lesion produced a very mild and transient neglect and the VMH lesion did not produce sensory deficits. DISCUSSION It is clear from this study that unilateral lesions of the nigra or along the path of its forebrain connections produce a severe and enduring syndrome of contralateral sensory neglect. Comparable lesions of the L H sparing adjacent IC produce a very mild and transient neglect. This suggests that cell bodies of the L H are not involved in the neglect syndrome and that fibers passing through the adjacent IC going to or from the SN are of primary importance for perceptual function. This conclusion is reinforced by the recent observations of the effects of kainic acid injections into L H 15. This procedure destroys cell bodies but spares fibers of passage and produces aphagia and adipsia but no sensory deficits. The data from these experiments could support the proposal that sensory neglect appears following interruption of the nigrostriatal path 4~ or some other forebrain-nigra path, such as the striato-nigral fibers, which course through the IC. However, in other work11,12 we have observed that lesions of the basal forebrain also produce a profound sensory neglect in cats. Perhaps other nigraforebrain or forebrain-nigra interconnections traversing 1C, such as those with nucleus accumbens32, 48, are of importance for perceptual function. This general conclusion is

343 compatible with the recent conceptions of the importance of the basal ganglia in modulating afferent responsiveness 42,47. An explanation of sensory neglect as due to trauma or edema to the optic tract and ventral basal thalamus seems unlikely. The VMH lesions were closer to the optic tract than the SN lesions and only the latter lesion produced visual neglect. Additionally, contralateral visual and somesthetic neglect is observed after unilateral basal forebrain lesions which are quite anterior to the ventrobasal thalamus or any somesthetic projections11, lz. Also, our results do not support the hypothesis of a critical role of hypothalamic projections from the amygdala in sensory neglect44. The SN lesions which produced neglect spared these structures and, furthermore, neglect has not been observed after lesions of the amygdala sparing the IC~L The results o J" this study indicate that visual and somesthetic neglect is not a result of a simple inability to organize a required movement. This is indicated by the data from the modified conditioned suppression task on which the identical motor response, a cessation of licking, was required regardless of the locus of a warning light. Cats displaying neglect only failed to stop licking to lights presented in visual fields contralateral to lesions which produced neglect. Thus the failure to respond did not represent an inability to perform the required movement, a problem that has confounded the interpretation of previous studies. Similarly the neglect of contralateral somesthetic stimuli is not a simple movement deficit. Subjects with unilateral lesions displayed a dramatic increase in the latency to withdraw the contralateral limbs from water but when tested with stronger stimulation (paw shock) the ipsilateral and contralateral latencies were not different. This indicates that the subjects displaying neglect were capable of performing the required movement swiftly. The effects of these lesions on paw immersion reaction time cannot be attributed to infringement on the neighboring pyramidal tract, since lesions of the pyramids do not affect simple reaction time in cats 24. The effectiveness of stronger stimulation in evoking responses from the neglected sensory fields and the presence of the deficit on tasks specifically designed to exclude movement bias clearly indicates that in Jacksonian terms is the syndrome is 'chiefly sensory'. The observation of a facilitation of behavioral responsiveness to stimuli presented in the ipsilateral visual fields concurrently with contralateral neglect further supports the sensory aspect of the syndrome. Facilitation was only observed on the conditioned suppression task which was the only test on which pre-lesion performance was not at a 'ceiling' level and so could improve. The combination of ipsilateral facilitation with contralateral neglect suggests a shifting of relative response thresholds. A parallel neurochemical observation has been made after unilateral SN lesions in the cat; ipsilateral caudate dopamine release is reduced but contralateral caudate dopamine release is increased ~3. Thus sensory neglect may represent only half of a perceptual imbalance. The electrophysiological experiments do not support the hypothesis that sensory neglect is a result of reduced hemispheric arousal z5,~5. We could not confirm the early report a5 that neglect is accompanied by EEG sleep spindles in the ipsilateral cortex of the behaviorally waking animal. More significant is that in other experiments11, x~ we

344 have found the opposite effect - - a suppression of sleep spindles in the ipsilateral cortex after basal forebrain lesions which produce dramatic and enduring sensory neglect. Thus, these ipsilateral EEG manifestations and behavioral neglect are not causally related. Our present observations of transiently depressed evoked responses in ipsilateral caudate nucleus and visual and association cortex deserve further study. The evoked potential amplitude was depressed only by lesions which produced neglect but the amplitude recovered rapidly whereas the behavioral effects were very enduring. The amplitude recovery is not totally unexpected since visual cortex evoked responses recover to pre-lesion amplitude even after lesions of 9 5 ~ of the optic tract a:3. However, these transient effects in caudate and cortex point to structures that should be examined using more refined techniques which may yield information regarding where sensory input fails to engage normal responses. Such data could account for the syndrome of neglect and perhaps suggest how recovery takes place. The similarity of behavioral deficits after lesions of the SN and of the superior colliculus cannot be overlooked. Unilateral lesions of either structure produce contralateral neglect ~5,41 and a facilitation of ipsilateral visual responsiveness 4~. Ipsiversive circling follows both lesions 25. The amphetamine reinstitution of ipsiversive circling a month after SN lesions 45 also occurs after superior colliculus lesions (unpublished data). Aphagia and adipsia do not follow lesions of the cotliculus and there are some other slight differences in the pattern of deficits 25; however, the overall sensory deficit syndrome is very similar. In the cat, the SN pars reticulata projects to the intermediate gray of the ipsilateral superior colliculus14,36, 48 and terminates in a highly systematic pattern 14. A large proportion of SN neurons which project to the superior colliculus bifurcate and send an axon branch to the ventral medial thalamus '~ and so may influence both visual and somesthetic input. Also, the occulogyric crises which occur in Parkinson's disease 8,37 suggest a functional link between SN and the superior colliculi in man. The anatomical projection to the colliculus could account for the similarities of the behavioral syndromes following lesions of these structures and would place both the superior colliculi and the SN in position to account for the multimodal sensory deficit which may more generally be described as an attentional loss. Finally, lesions caudal to the SN or superior colliculus may only produce sensory neglect if they infringe on descending projections of the superior colliculus ~4. There are several other lines of work that may represent interactions between the basal ganglia and attention, perhaps mediated via the SN projections to superior colliculus. The administration of amphetamine to decorticate cats will restore visual placing responses 28 and similarly will restore black-white discriminations in rats with visual cortex ablations 2°. Amphetamine has a powerful action on pars compacta neurons of the SN, mediated by striato-nigral fibers of the IC 6, which then may affect visual function via a pars reticulata projection to the superior colliculus. Additionally some of the symptoms of schizophrenia have been attributed to a disorder of attention 4,7 and this would fit with a dopaminergic hypothesis of schizophrenia 4°. The eye movement dysfunctions that have been reported in schizophrenics 17,42 may be related to the attentional disorder and perhaps reflect pathological basal ganglia

345 f u n c t i o n a n d c o n s e q u e n t a b n o r m a l nigral o u t p u t . F u t u r e e x p e r i m e n t a l w o r k m a y clarify these speculative relationships. ACKNOWLEDGEMENTS S u p p o r t e d b y funds f r o m T h e R e s e a r c h A l l o c a t i o n s C o m m i t t e e o f the U n i v e r sity o f N e w M e x i c o a n d N I H research g r a n t NS13684-01A1. W e t h a n k M a r i l y n A l e x a n d e r for assistance with some o f the b e h a v i o r a l testing a n d surgery a n d G o r d o n H o d g e for critical readings o f early drafts o f the m a n u s c r i p t .

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Sensory neglect after lesions of substantia nigra or lateral hypothalamus: differential severity and recovery of function.

Brain Research, 178 (1979) 329-346 © Elsevier/North-Holland Biomedical Press 329 SENSORY N E G L E C T A F T E R LESIONS OF SUBSTANTIA N I G R A OR...
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