98
Brain Research, 541 (1991) 98-102 Elsevier
BRES 16312
Apparent unilateral visual neglect in MPTP-hemiparkinsonian monkeys is due to delayed initiation of motion K.S. Bankiewicz 1, E.H. Oldfield 1, R.J. Plunkett 1, W.H. Schuette 1, D.G. Cogan 2, N. Hogan 2, A. Zuddas I and I.J. Kopin 1. 1Surgical Neurology Branch, NINDS and 2National Eye Institute, National Institutes of Health, Bethesda, MD 20892 (U.S.A.)
(Accepted 4 September 1990) Key words: MPTP; Monkey; Neglect; Parkinson's disease; Hypokinesia
Monkeys made hemiparkinsonian by infusion of a solution of MPTP into one carotid artery appeared to ignore food presented from the contralateral side. Initial observations suggested neglect of visual stimuli presented as fruit treats by automated delivery system in the half-field contralateral to MPTP treatment. Further studies in which fruit treats were left in the 'neglected' visual field indicated that this apparent neglect, unlike neglect attending cortical lesions, was rather a marked delay in initiating movements (unilateral hypokinesia). These observations may explain apparent subcortical neglect and are consistent with the known role of nigrostriatal dopaminergic neurones in movement regulation. This is a useful animal model in which difficulties in initiation of movement (hypokinesia), a cardinal symptom of Parkinson's disease, can be studied separately from other deficits in motor performance.
INTRODUCTION
alleviates all motor deficits and reverses the direction of turning I .
Severe motor deficits which resemble closely the signs of Parkinson's disease have occurred in young drug addicts after self administration of illicit narcotics containing 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) 8'17. MPTP administered to non-human primates causes selective destruction of dopaminergic cells in the substantia nigra pars compacta and their projections to the striatum with consequent severe motor impairment characteristic of human parkinsonism 5'18. Because MPTP metabolism is rapid and its toxic metabolite does not penetrate easily from the brain into blood, we have been able, by infusing a solution of MPTP into one internal carotid artery, to produce in monkeys selective destruction of the ipsilateral nigrostriatal pathway 1. There is marked depletion of dopamine and its metabolites in the striatum on the treated side, but levels of dopamine in cortical areas are not significantly altered 3. This is attended by permanent (for at least 5 years) contralateral motor impairment; both upper and lower limbs show characteristic parkinsonian signs of bradykinesia, rigidity, cogwheeling and some tremor. Spontaneous motor activity is characterized by continuous and consistent circling towards the MPTP-treated side. Treatment with L-dopa/carbidopa or apomorphine
We noticed that these animals failed to respon to food (e.g. a piece of apple) offered from the side contralateral to the MPTP infusion. When food was presented from that side, the monkey did not reach for it until it came to or passed the midline. The lack of response was initially interpreted as hemianopia yet monkeys treated systemically with MPTP are not blind 21. Could the lack of response represent hemispatial neglect? Although visual neglect is usually associated with cortical lesions a4, its occurrence has been reported in humans with lesions involving the basal ganglia 7"~2"15 and in rats after unilateral 6-hydroxy-dopamine-induced damage of the ascending dopamine pathways 1Lx9. Mild visual neglect has also been described in association with Parkinson's Disease 4,25, particularly in patients with symptoms localized to the left (suggesting predominant right hemisphere involvement) and consistent with the concept that, in humans, the right hemisphere is dominant for attention ~4. These reports of sensory neglect associated with lesions involving dopaminergic systems encouraged us to examine in greater detail the lack of responses by the MPTP-hemiparkinsonian monkey. Our initial results in which food treats were kept in the visual field for short periods of time were consistent with
Correspondence: K. Bankiewicz, Surgical Neurology, NINDS, Bldg. 10/5D37, Bethesda, MD 20892, U.S.A.
99 unilateral visual neglect 2. In neglect there is complete failure to respond, regardless of the time of exposure to the stimulus. Further testing showed that the animals did respond to food held in the affected visual half-field, but there was a marked delay in the initiation of movements triggered from the dopamine-deficient hemisphere. It is likely that, as in patients with Parkinson's disease, there is a loss of ability to implement willed movements, but in these animals the deficit is limited to one side. The sensory-motor deficit observed in the MPTP-parkinsonian monkeys is unlike to be attributed to the loss of dopamine in the cortex, since levels of the amine were not significantly different on the two sides of various cortical brain areas 3. The neostriatum on the MPTPtreated side, however, was severely depleted of dopamine 1'3'17. The deficits, which were reversed by treatments with dopa, are probably a consequence of the striatal dopamine deficiency.
MATERIALS AND METHODS
Animals and M P T P administration Hemiparkinsonism was produced in 3 female Cynomologus and 5 male Rhesus monkeys (4.2-8.5 kg at the time of operation). The monkeys were housed in quarters with a 12-h light/dark cycle and were fed purina monkey chow twice daily but had free access to water. As previously described1'3, the monkeys received a single infusion of 60 ml saline solution containing 0.4 mg/kg of MPTP-HC! into either the left (2 Rhesus) or right (3 Rhesus, 3 Cynomologus) internal carotid artery. The behavioral studies were performed either about 18 months (3 Cynomologus) or 2-3 weeks (5 Rhesus) after MPTP administration.
Behavioral testing Animals were examined at various intervals for behavioral changes by direct observation, by videotaping, and with an apparatus 22 designed to record the visual angle on each side at which offered food was accepted. About one week before the experiments using this apparatus, the animals were anesthetized and a metal holder bolted to the back of the skull and embedded in acrylic plastic. After the animals were chair adapted they were seated in a primate chair with its head mechanically immobilized by fixing the holder to the chair frame. The head could be fixed so that the nose was directed forward or at a 45° angle to the right or left. Round food pellets or raisins were offered in the random fashion to the animal using a computer controlled revolving arm (18 cm radius with the center of revolution above the vertex of the animal's head) which delivered the food in an eye-level circular path moving at a rate of about 15° (15 cm) per second clockwise or counter-clockwise from the back of the animal. The angle in the visual field (nose direction = 0°) at which the food was taken was recorded by monitoring, with a solid state pressure transducer, the vacuum pressure in the delivery arm which was used to take up and hold the food offering. Eye movements were videotaped during the experiment. Studies were repeated after oral administration (imbedded in an orange) of 100 or 200 mg L-dopa in combination with 10 or 20 mg carbidopa. The medication was administered while the monkey was in its home cage. After 25-35 min, when the direction of turning during spontaneous activity had reversed, the animal was placed in the primate chair for retesting. Other studies were performed to examine the possible role of akinesia in the apparent visual half-field neglect. The animals were tested for their responses to food presented and held at eye level
Visual Field Angles at Which Food Offerings were Accepted by MPTP-Hemiparkinsonian Monkeys
hfom DOPA
After DOPA
MlrrP Into Left Carotid
MPTP Into Right Carotid
Fig. 1. Angles in visual field at which MPTP hemiparkinsonian monkeys grasp food. The animals were tested in a primate chair with head movements restricted so that the nose pointed forward (or at 45° to left or right). Food was offered to the animal from either side using a device with a revolving arm so that the exact position at which the food was removed could be determined (see text). Results show mean position in the visual field where food was removed (+ S.D.). Experiments were performed before and after treatment with L-dopa in animals which had received MPTP in the left or right carotid arteries.
about 30° to the right or left of the center of the visual field. A videotape recording was used to determine the time required until a motor response (gaze direction or onset of arm motion) was initiated and to measure the interval between the initiation of the movements involved in the grasp of the food and its delivery to the mouth. Eye movements were videotaped during each experimental session and only these trials were considered in which monkeys were fixed on the object in front of them.
RESULTS
Behavioral changes The apparent lack of response by the hemiparkinsonian monkeys to food presented in the visual half-field contralateral to the MPTP-infused side was confirmed when the animals were examined in the automated device which recorded the angle at which food offerings were accepted. When animals which had received MPTP into the right internal carotid artery were tested, food presented from the left side was not taken until it was at or near the midline (4 + 20 ° to the right of the nose direction), whereas when presented from the right side, the food treats were grasped at 42 + 18° to the right of the direction of the nose (Fig. 1). Regardless of the direction from which the treat was presented, it was obtained using the right arm (ipsilateral to the MPTP infusion). The difference in the responses could not be attributed to the use of only the right arm, since similar results were obtained w h e n the h e a d was held with the
100 TABLE I Response times and movement intervals in MPTP-hemiparkinsonian and control monkeys
The time between the presentation of food and the first indication of a motor response seen on a videotape was taken as response time. The interval between this time and that for the food to be grabbed and brough to the mouth was determined from the videotape recording and recorded as movement intervals. The number of trials in three hemiparkinsonian monkeys before and after L-dopa on the 'parkinsonian side' (contralateral) and in one normal animal is indicated in parentheses.
MPTP-treated side (13) Contralateral (15) After DOPA (6) Normal monkey (8)
Response time (s)
Movement interval (s)
0.73 + 0.37 12.3 + 8.3 0.37 + 0.16 0.44 + 0.07
1.7 + 0.6 1.8 + 1.0 0.88 + 0.18 0.86 + 0.05
nose directed 45 ° to the right or to the left of the frontal plane. Similarly, in animals which had received MPTP into the left carotid artery, food presented from the right side was not taken until it passed about 23 + 21 ° to the left of the midline, but when presented from the left it was taken at 44 + 14° to that side (Fig. 1). There were no differences in the performance of monkeys treated 2 weeks or 18 months prior to testing. Effects o f L-dopa treatment After treatment with dopa-carbidopa the deficits in response were largely reversed (Fig. 1). In animals treated with MPTP on the right, food pellets were taken at 19 + 12° to the left of the midfine when presented from the left, representing an improvement of 23 °. A somewhat greater improvement in angle of response (from -23 to 24 °) was found after treatment of the left-side MPTP-treated animals (Fig. 1). Generally, the arm ipsilaterai to MPTP treatment continued to be favored for grasping the food, although after dopa treatment motor functions in the arm contralateral to MPTP-treated side returned to normal. In monkeys that preferred use of 'parkinsonian' arm after L-dopa treatment this arm was restrained and the tests were done with the same arm as prior to dopa administration. Reaction and m o v e m e n t time When food was presented and held in place on the side contralateral to the MPTP infusion, there was a marked delay (6-32 s) in the initiation of the responses compared to presentation on the opposite side (Table I). Once movement was initiated there was no difference between stimulus sides in the time required (movement interval) to grasp the food treat and to deliver it to the mouth (Table I). This might be expected, since the same arm,
ipsilateral to the MPTP-treated side, was used to obtain the food treat. The animals appeared to be unable to use the arm contralateral to M P T P treatment for grasping the food even when the ipsilateral arm was restrained for up to 1 min. The mean m o v e m e n t intervals in the hemiparkinsonian monkeys were greater than in the normal animals, but variations were large and the differences from normal or after dopa treatment were not significant. After treatment with dopa-carbidopa the responses were as rapid as recorded in the normal monkey. The mean response times to treats presented ipsilaterai to the MPTP-treated side were slightly prolonged (0.73 + 0.16 vs 0.44 + 0.07 s in the normal monkey) (Table I). DISCUSSION Neglect assumed to result from inattention to sensory stimuli on one side of the body can be also attributed to unilateral akinesia. Watson et al. 24 trained monkeys to respond to leg tactile stimuli with movements of the contralateral arm. After a unilateral frontal arcuate lesion the monkeys appeared to show contralateral neglect, but they responded normally to tactile stimulation of the neglected side while failing to respond when stimulated on the side ipsilateral to the lesion. However, the response time for these tasks were increased on both sides 26. These results were attributed to defective volitional motor responses to a perceived stimulus. Similarly, in rats trained to respond to unilateral stimulation, apparent neglect was seen after unilateral lesions of the lateral hypothalamus 16 or after unilateral dopamine depletion of the caudate induced by 6-hydroxydopamine infusion 6. In MPTP-hemiparkinsonian monkeys, visual stimuli presented in the visual half-field ipsilateral to MPTP treatment elicited immediate responses, whereas the same motor responses, performed with equally rapid movements, were markedly delayed in onset when the stimuli were presented in the visual half-field contralateral to the dopamine-deficient striatum. The food, which appeared to be ignored when passing across the visual half-field contralateral to MPTP treatment, evoked an immediate response when it passed the midline (Fig. 1) into the opposite visual half-field. The motor deficit in these MPTP-hemiparkinsonian monkeys cannot be attributed to hemianopia. When the food stimulus was held in place in the affected visual half-field the animals did respond, but only after a mean interval of 12.3 s (Table I). A motor response controlled by the untreated hemisphere could be triggered by a visual image projected to either hemisphere, but only after a long delay when the stimulus was projected to the contralateral MPTP-treated side. When the desired object reached a point in the visual field where it was projected to the
101 intact hemisphere, an appropriate motor response was initiated immediately. MPTP-induced selective destruction of the nigrostriatal dopaminergic system in monkeys has provided a remarkably faithful model of Parkinson's disease. The striking decrease in dopamine content of the caudate nucleus on the MPTP-treated side was not attended by significant asymmetry in the dopamine contents of the cerebral cortex 3. Although there is some depletion of dopamine in the prefrontal cortex, it is bilateral and it appears unlikely that any MPTP-induced functional deficits can be attributed to depletion of dopamine in the cerebral cortex 3. Monkeys with MPTP-induced parkinsonism have increased reaction times due predominantly to delayed activation of muscle 23 and many parkinsonian patients have abnormally long reaction times independent of slow performance of movements 1°'13. However, the prolongation of such reaction times, which are the intervals between awaited stimuli and predetermined responses, are less than 0.5 s. This is more than an order of magnitude less than the delays in volitional responses seen in our hemiparkinsonian monkeys or which characterize the disabling hypokinesia in severe Parkinson's disease. Although patients with parkinsonian akinesia are
aware of their difficulty in effecting willed actions, it is not possible in animals to determine the level of awareness of this m o t o r deficit. It is evident, however, that in the MPTP-hemiparkinsonian monkey, the side of the brain with a dopamine deficient striatum has difficulty in triggering volitional movements, even when the movements are controlled from the contralateral hemisphere. Apparent subcortical hemineglect due to delay in initiation of motion can be distinguished from unilateral cortical neglect. Cortical neglect is usually transient and prolonged exposure to the stimulus does not elicit a response, whereas apparent subcortical neglect appears irreversible (lasting up to 18 months) and prolonged exposure to the stimulus eventually produces a response. In animals with such selective unilateral hypokinesia (long delay in initiation of movements triggered from one side, but normal triggering of the same m o v e m e n t from the opposite hemisphere), difficulty with initiating movements can be studied separately from other deficits in motor performance. Thus, the hemiparkinsonian m o n k e y provides an experimental animal model of the hypokinesia vividly described by Parkinson 2° and long considered by many to be the key abnormality in Parkinson's disease 9.
REFERENCES
10 Evarts, E.V., Traivainen, H. and Calne, D.B., Reaction time in Parkinson's disease, Brain, 104 (1981) 167-186. ll Feeney, D.M. and Wier, C.S., Sensory neglect after lesions of substantia nigra or lateral hypothalamus: differential severity and recovery of function, Brain Research, 178 (1983) 329-346. 12 Healton, E.B., Navarro, C., Bressman, S. and Brust, J.C., Subcortical neglect, Neurology, 32 (1982) 776-778. 13 Heilman, K.M., Bowers, D., Watson, R.T. and Greer, M., Reaction times in Parkinson disease, Arch. Neurol. (Chic), 33 (1976) 139-140. 14 Heilman, K.M., Watson, R.T. and Valenstein, E., In K.M. Heilman and E. Valenstein (Eds.), Clinical Neuropsychology, 2nd edn., Oxford University Press, New York, 1985, pp. 243-293. 15 Hier, D.B., Davis, K.R., Richardson, Jr., E.P. and Mohr, J.P., Hypertensive putaminal hemorrhage, Ann. Neurol., 1 (1977) 152-159. 16 Hoyman, L., Weese, G.D. and Frommer, G.P., Tactile discrimination performance deficits following neglect-producing unilateral lateral hypothalamic lesions in the rat, Physiol. Behav., 22 (1979) 139-147. 17 Langston, J.W., Ballard, P., Tetrud, J.W. and Irwin, I., Chronic parkinsonism in humans due to a product of meperidine-analog synthesis, Science, 219 (1983) 979-980. 18 Langston, J.W., Forno, L.S., Robert, C.S. and Irwin, I., Selective nigral toxicity after systematic administration of 1methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) in the squirrel monkey, Brain Research, 292 (1984) 390-394. 19 Ljungberg, T. and Ungerstedt, U., Sensory inattention produced by 6-hydroxydopamine-induced degeneration of ascending dopamine neurons in the brain, Exp. Neurol., 53 (1976) 585-600. 20 Parkinson, J., An Essay on the Shaking Palsy, Whittingham and Rowland, London, 1817. 21 Porrino, L.H., Ho, V., Palombo, E., Kennedy, C., Hogan, N., Cogan, D.G., Bankiewicz, K.S., Kopin, I.J. and Sokoloff, L.,
1 Bankiewicz, K.S., Oldfield, E.H., Chiueh, C.C., Doppman, J.L., Jacobowitz, D.M. and Kopin, I.J., Hemiparkinsonism in monkeys after unilateral internal carotid artery infusion of 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP), Life Sci., 39 (1986) 7-16. 2 Bankiewicz, K.S., Oldfield, E.H., Schuette, W.H. and Kopin, I.J., Apparent unilateral hemineglect in MPTP-induced hemiparkinsonian monkeys, Neurology, 37 (Suppl. 1) (1987) 340. 3 Bankiewicz, K.S., Zuddas, A., Wiesse, V., Plunkett, R.J. and Kopin, I.J., Dopamine and tyrosine hydroxylase levels in cortex and neostriatum in MPTP-hemiparkinsonian monkeys, Neuroscience, in press. 4 Barber, J., Tomer, R., Sroka, H. and Myslobodsky, M.S., Does unilateral dopamine deficit contribute to depression?, Psychiatry Res., 15 (1985) 17-24. 5 Burns, R.S., Chiuech, C.C., Markey, S., Ebert, M.H., Jacobowitz, D.M. and Kopin, I.J., A primate model of Parkinson's disease: selective destruction of substantia nigra pars compacta dopaminergic neurons by N-methyi-4-phenyi-l,2,3,6-tetrahydropyridine, Proc. Natl. Acad. Sci. U.S.A., 80 (1983) 45464550. 6 Carli, M., Evenden, J.L. and Robbins, T.W., Depletion of unilateral striatal dopamine impairs initiation of contralateral actions and not sensory attention, Nature, 313 (1985) 679-824. 7 Damasio, A.R., Damasio, H. and Chui, H.C., Neglect following damage to frontal lobe or basal ganglia, Neuropsychologia, 18 (1980) 123-132. 8 Davies, G.C., Williams, A.C., Markey, S.P., Ebert, M.N., Caine, E.D., Reichert, C.M. and Kopin, I.J., Chronic parkinsonism due to intravenous injection of meperidine analogues, Psychiatry Res., 1 (1979) 249-254. 9 Denny-Brown, D., Handbook of Clinical Neurology, Vol. 6, Elsevier, Amsterdam, 1968, pp. 133-211.
102 Columnar organization of metabolic activity in the striate cortex of hemiparkinsonian monkeys, Neurology, 37 3 (Suppl. 1) (1987) 340. 22 Schuette, W.H., Bankiewicz, K.S., Markowitz, A., Plowman, EA. and Kopin, I.J., A system for measuring the angular response of hemiparkinsonian monkeys to a food stimulus, Med. lnstrum., 21 (1987) 314-316. 23 Schultz, W., Studer, A., Jonsson, G., Sundstrom, E. and Mefford, I., Deficits in behavioral initiation and execution process in monkeys with 1-methyl-4-phenyl-l,2,3,6-tetrahy-
dropyridine-induced parkinsonism, Neurosci. Lett., 59 (1985) 225-232. 24 Watson, R.T., Miller, B.D. and Heilman, K.M., Nonsensory neglect, Ann. Neurol., 3 (1978) 505-508. 25 Villardita, C., Smirni, P. and Zappala, G., Visual neglect in Parkinson's disease, Arch. Neurol., 40 (1983) 737-739. 26 Valenstein, E., Watson, R.T., Van den Abell, T., Carter, R. and Heilman, K.M., Response time in monkeys with unilateral neglect, Arch. Neurol., 44 (5) (1987) 517-520.
Brain Research, 541 (1991) 98-102 Elsevier
BRES 16312
Apparent unilateral visual neglect in MPTP-hemiparkinsonian monkeys is due to delayed initiation of motion K.S. Bankiewicz 1, E.H. Oldfield 1, R.J. Plunkett 1, W.H. Schuette 1, D.G. Cogan 2, N. Hogan 2, A. Zuddas I and I.J. Kopin 1. 1Surgical Neurology Branch, NINDS and 2National Eye Institute, National Institutes of Health, Bethesda, MD 20892 (U.S.A.)
(Accepted 4 September 1990) Key words: MPTP; Monkey; Neglect; Parkinson's disease; Hypokinesia
Monkeys made hemiparkinsonian by infusion of a solution of MPTP into one carotid artery appeared to ignore food presented from the contralateral side. Initial observations suggested neglect of visual stimuli presented as fruit treats by automated delivery system in the half-field contralateral to MPTP treatment. Further studies in which fruit treats were left in the 'neglected' visual field indicated that this apparent neglect, unlike neglect attending cortical lesions, was rather a marked delay in initiating movements (unilateral hypokinesia). These observations may explain apparent subcortical neglect and are consistent with the known role of nigrostriatal dopaminergic neurones in movement regulation. This is a useful animal model in which difficulties in initiation of movement (hypokinesia), a cardinal symptom of Parkinson's disease, can be studied separately from other deficits in motor performance.
INTRODUCTION
alleviates all motor deficits and reverses the direction of turning I .
Severe motor deficits which resemble closely the signs of Parkinson's disease have occurred in young drug addicts after self administration of illicit narcotics containing 1-methyl-4-phenyl- 1,2,3,6-tetrahydropyridine (MPTP) 8'17. MPTP administered to non-human primates causes selective destruction of dopaminergic cells in the substantia nigra pars compacta and their projections to the striatum with consequent severe motor impairment characteristic of human parkinsonism 5'18. Because MPTP metabolism is rapid and its toxic metabolite does not penetrate easily from the brain into blood, we have been able, by infusing a solution of MPTP into one internal carotid artery, to produce in monkeys selective destruction of the ipsilateral nigrostriatal pathway 1. There is marked depletion of dopamine and its metabolites in the striatum on the treated side, but levels of dopamine in cortical areas are not significantly altered 3. This is attended by permanent (for at least 5 years) contralateral motor impairment; both upper and lower limbs show characteristic parkinsonian signs of bradykinesia, rigidity, cogwheeling and some tremor. Spontaneous motor activity is characterized by continuous and consistent circling towards the MPTP-treated side. Treatment with L-dopa/carbidopa or apomorphine
We noticed that these animals failed to respon to food (e.g. a piece of apple) offered from the side contralateral to the MPTP infusion. When food was presented from that side, the monkey did not reach for it until it came to or passed the midline. The lack of response was initially interpreted as hemianopia yet monkeys treated systemically with MPTP are not blind 21. Could the lack of response represent hemispatial neglect? Although visual neglect is usually associated with cortical lesions a4, its occurrence has been reported in humans with lesions involving the basal ganglia 7"~2"15 and in rats after unilateral 6-hydroxy-dopamine-induced damage of the ascending dopamine pathways 1Lx9. Mild visual neglect has also been described in association with Parkinson's Disease 4,25, particularly in patients with symptoms localized to the left (suggesting predominant right hemisphere involvement) and consistent with the concept that, in humans, the right hemisphere is dominant for attention ~4. These reports of sensory neglect associated with lesions involving dopaminergic systems encouraged us to examine in greater detail the lack of responses by the MPTP-hemiparkinsonian monkey. Our initial results in which food treats were kept in the visual field for short periods of time were consistent with
Correspondence: K. Bankiewicz, Surgical Neurology, NINDS, Bldg. 10/5D37, Bethesda, MD 20892, U.S.A.
99 unilateral visual neglect 2. In neglect there is complete failure to respond, regardless of the time of exposure to the stimulus. Further testing showed that the animals did respond to food held in the affected visual half-field, but there was a marked delay in the initiation of movements triggered from the dopamine-deficient hemisphere. It is likely that, as in patients with Parkinson's disease, there is a loss of ability to implement willed movements, but in these animals the deficit is limited to one side. The sensory-motor deficit observed in the MPTP-parkinsonian monkeys is unlike to be attributed to the loss of dopamine in the cortex, since levels of the amine were not significantly different on the two sides of various cortical brain areas 3. The neostriatum on the MPTPtreated side, however, was severely depleted of dopamine 1'3'17. The deficits, which were reversed by treatments with dopa, are probably a consequence of the striatal dopamine deficiency.
MATERIALS AND METHODS
Animals and M P T P administration Hemiparkinsonism was produced in 3 female Cynomologus and 5 male Rhesus monkeys (4.2-8.5 kg at the time of operation). The monkeys were housed in quarters with a 12-h light/dark cycle and were fed purina monkey chow twice daily but had free access to water. As previously described1'3, the monkeys received a single infusion of 60 ml saline solution containing 0.4 mg/kg of MPTP-HC! into either the left (2 Rhesus) or right (3 Rhesus, 3 Cynomologus) internal carotid artery. The behavioral studies were performed either about 18 months (3 Cynomologus) or 2-3 weeks (5 Rhesus) after MPTP administration.
Behavioral testing Animals were examined at various intervals for behavioral changes by direct observation, by videotaping, and with an apparatus 22 designed to record the visual angle on each side at which offered food was accepted. About one week before the experiments using this apparatus, the animals were anesthetized and a metal holder bolted to the back of the skull and embedded in acrylic plastic. After the animals were chair adapted they were seated in a primate chair with its head mechanically immobilized by fixing the holder to the chair frame. The head could be fixed so that the nose was directed forward or at a 45° angle to the right or left. Round food pellets or raisins were offered in the random fashion to the animal using a computer controlled revolving arm (18 cm radius with the center of revolution above the vertex of the animal's head) which delivered the food in an eye-level circular path moving at a rate of about 15° (15 cm) per second clockwise or counter-clockwise from the back of the animal. The angle in the visual field (nose direction = 0°) at which the food was taken was recorded by monitoring, with a solid state pressure transducer, the vacuum pressure in the delivery arm which was used to take up and hold the food offering. Eye movements were videotaped during the experiment. Studies were repeated after oral administration (imbedded in an orange) of 100 or 200 mg L-dopa in combination with 10 or 20 mg carbidopa. The medication was administered while the monkey was in its home cage. After 25-35 min, when the direction of turning during spontaneous activity had reversed, the animal was placed in the primate chair for retesting. Other studies were performed to examine the possible role of akinesia in the apparent visual half-field neglect. The animals were tested for their responses to food presented and held at eye level
Visual Field Angles at Which Food Offerings were Accepted by MPTP-Hemiparkinsonian Monkeys
hfom DOPA
After DOPA
MlrrP Into Left Carotid
MPTP Into Right Carotid
Fig. 1. Angles in visual field at which MPTP hemiparkinsonian monkeys grasp food. The animals were tested in a primate chair with head movements restricted so that the nose pointed forward (or at 45° to left or right). Food was offered to the animal from either side using a device with a revolving arm so that the exact position at which the food was removed could be determined (see text). Results show mean position in the visual field where food was removed (+ S.D.). Experiments were performed before and after treatment with L-dopa in animals which had received MPTP in the left or right carotid arteries.
about 30° to the right or left of the center of the visual field. A videotape recording was used to determine the time required until a motor response (gaze direction or onset of arm motion) was initiated and to measure the interval between the initiation of the movements involved in the grasp of the food and its delivery to the mouth. Eye movements were videotaped during each experimental session and only these trials were considered in which monkeys were fixed on the object in front of them.
RESULTS
Behavioral changes The apparent lack of response by the hemiparkinsonian monkeys to food presented in the visual half-field contralateral to the MPTP-infused side was confirmed when the animals were examined in the automated device which recorded the angle at which food offerings were accepted. When animals which had received MPTP into the right internal carotid artery were tested, food presented from the left side was not taken until it was at or near the midline (4 + 20 ° to the right of the nose direction), whereas when presented from the right side, the food treats were grasped at 42 + 18° to the right of the direction of the nose (Fig. 1). Regardless of the direction from which the treat was presented, it was obtained using the right arm (ipsilateral to the MPTP infusion). The difference in the responses could not be attributed to the use of only the right arm, since similar results were obtained w h e n the h e a d was held with the
100 TABLE I Response times and movement intervals in MPTP-hemiparkinsonian and control monkeys
The time between the presentation of food and the first indication of a motor response seen on a videotape was taken as response time. The interval between this time and that for the food to be grabbed and brough to the mouth was determined from the videotape recording and recorded as movement intervals. The number of trials in three hemiparkinsonian monkeys before and after L-dopa on the 'parkinsonian side' (contralateral) and in one normal animal is indicated in parentheses.
MPTP-treated side (13) Contralateral (15) After DOPA (6) Normal monkey (8)
Response time (s)
Movement interval (s)
0.73 + 0.37 12.3 + 8.3 0.37 + 0.16 0.44 + 0.07
1.7 + 0.6 1.8 + 1.0 0.88 + 0.18 0.86 + 0.05
nose directed 45 ° to the right or to the left of the frontal plane. Similarly, in animals which had received MPTP into the left carotid artery, food presented from the right side was not taken until it passed about 23 + 21 ° to the left of the midline, but when presented from the left it was taken at 44 + 14° to that side (Fig. 1). There were no differences in the performance of monkeys treated 2 weeks or 18 months prior to testing. Effects o f L-dopa treatment After treatment with dopa-carbidopa the deficits in response were largely reversed (Fig. 1). In animals treated with MPTP on the right, food pellets were taken at 19 + 12° to the left of the midfine when presented from the left, representing an improvement of 23 °. A somewhat greater improvement in angle of response (from -23 to 24 °) was found after treatment of the left-side MPTP-treated animals (Fig. 1). Generally, the arm ipsilaterai to MPTP treatment continued to be favored for grasping the food, although after dopa treatment motor functions in the arm contralateral to MPTP-treated side returned to normal. In monkeys that preferred use of 'parkinsonian' arm after L-dopa treatment this arm was restrained and the tests were done with the same arm as prior to dopa administration. Reaction and m o v e m e n t time When food was presented and held in place on the side contralateral to the MPTP infusion, there was a marked delay (6-32 s) in the initiation of the responses compared to presentation on the opposite side (Table I). Once movement was initiated there was no difference between stimulus sides in the time required (movement interval) to grasp the food treat and to deliver it to the mouth (Table I). This might be expected, since the same arm,
ipsilateral to the MPTP-treated side, was used to obtain the food treat. The animals appeared to be unable to use the arm contralateral to M P T P treatment for grasping the food even when the ipsilateral arm was restrained for up to 1 min. The mean m o v e m e n t intervals in the hemiparkinsonian monkeys were greater than in the normal animals, but variations were large and the differences from normal or after dopa treatment were not significant. After treatment with dopa-carbidopa the responses were as rapid as recorded in the normal monkey. The mean response times to treats presented ipsilaterai to the MPTP-treated side were slightly prolonged (0.73 + 0.16 vs 0.44 + 0.07 s in the normal monkey) (Table I). DISCUSSION Neglect assumed to result from inattention to sensory stimuli on one side of the body can be also attributed to unilateral akinesia. Watson et al. 24 trained monkeys to respond to leg tactile stimuli with movements of the contralateral arm. After a unilateral frontal arcuate lesion the monkeys appeared to show contralateral neglect, but they responded normally to tactile stimulation of the neglected side while failing to respond when stimulated on the side ipsilateral to the lesion. However, the response time for these tasks were increased on both sides 26. These results were attributed to defective volitional motor responses to a perceived stimulus. Similarly, in rats trained to respond to unilateral stimulation, apparent neglect was seen after unilateral lesions of the lateral hypothalamus 16 or after unilateral dopamine depletion of the caudate induced by 6-hydroxydopamine infusion 6. In MPTP-hemiparkinsonian monkeys, visual stimuli presented in the visual half-field ipsilateral to MPTP treatment elicited immediate responses, whereas the same motor responses, performed with equally rapid movements, were markedly delayed in onset when the stimuli were presented in the visual half-field contralateral to the dopamine-deficient striatum. The food, which appeared to be ignored when passing across the visual half-field contralateral to MPTP treatment, evoked an immediate response when it passed the midline (Fig. 1) into the opposite visual half-field. The motor deficit in these MPTP-hemiparkinsonian monkeys cannot be attributed to hemianopia. When the food stimulus was held in place in the affected visual half-field the animals did respond, but only after a mean interval of 12.3 s (Table I). A motor response controlled by the untreated hemisphere could be triggered by a visual image projected to either hemisphere, but only after a long delay when the stimulus was projected to the contralateral MPTP-treated side. When the desired object reached a point in the visual field where it was projected to the
101 intact hemisphere, an appropriate motor response was initiated immediately. MPTP-induced selective destruction of the nigrostriatal dopaminergic system in monkeys has provided a remarkably faithful model of Parkinson's disease. The striking decrease in dopamine content of the caudate nucleus on the MPTP-treated side was not attended by significant asymmetry in the dopamine contents of the cerebral cortex 3. Although there is some depletion of dopamine in the prefrontal cortex, it is bilateral and it appears unlikely that any MPTP-induced functional deficits can be attributed to depletion of dopamine in the cerebral cortex 3. Monkeys with MPTP-induced parkinsonism have increased reaction times due predominantly to delayed activation of muscle 23 and many parkinsonian patients have abnormally long reaction times independent of slow performance of movements 1°'13. However, the prolongation of such reaction times, which are the intervals between awaited stimuli and predetermined responses, are less than 0.5 s. This is more than an order of magnitude less than the delays in volitional responses seen in our hemiparkinsonian monkeys or which characterize the disabling hypokinesia in severe Parkinson's disease. Although patients with parkinsonian akinesia are
aware of their difficulty in effecting willed actions, it is not possible in animals to determine the level of awareness of this m o t o r deficit. It is evident, however, that in the MPTP-hemiparkinsonian monkey, the side of the brain with a dopamine deficient striatum has difficulty in triggering volitional movements, even when the movements are controlled from the contralateral hemisphere. Apparent subcortical hemineglect due to delay in initiation of motion can be distinguished from unilateral cortical neglect. Cortical neglect is usually transient and prolonged exposure to the stimulus does not elicit a response, whereas apparent subcortical neglect appears irreversible (lasting up to 18 months) and prolonged exposure to the stimulus eventually produces a response. In animals with such selective unilateral hypokinesia (long delay in initiation of movements triggered from one side, but normal triggering of the same m o v e m e n t from the opposite hemisphere), difficulty with initiating movements can be studied separately from other deficits in motor performance. Thus, the hemiparkinsonian m o n k e y provides an experimental animal model of the hypokinesia vividly described by Parkinson 2° and long considered by many to be the key abnormality in Parkinson's disease 9.
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