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Groups of patients with idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy or Steele-Richardson-Olszewski syndrome, matched for overall clinical disability, were compared using three computerised cognitive tests previously shown to be sensitive to frontal lobe dysfunction. On a test of planning based on the Tower of London task, all three groups were impaired, but in different ways. The groups with palsy and Parkinson's disease were slower in the measure of initial thinking time, whereas the group with multiple system atrophy was only slower in a measure of thinking time subsequent to the first move, resembling patients with frontal lobe damage. On a test of spatial working memory, each group showed deficits relative to their matched control groups, but the three groups differed in their strategy for dealing with this task. On a test of attentional set shifting, each group was again impaired, mainly at the extradimensional shifting stage, but the group with Steele-Richardson-Olszewski syndrome exhibited the greatest deficit. The results are compared with previous findings in patients with Alzheimer's disease or frontal lobe damage. It is concluded that these basal ganglia disorders share a distinctive pattern of cognitive deficits on tests of frontal lobe dysfunction, but there are differences in the exact nature of the impairments, in comparison not only with frontal lobe damage but also with one another.

Twenty index patients with hereditary essential tremor and their kindreds were studied to define the phenotype of this condition. Ninety-three first degree and 38 more distant relatives were examined; 53 definite and 18 possible secondary cases were identified. The age of tremor onset was bimodally distributed with a median at approximately 15 years. Segregation analysis indicated autosomal dominant inheritance and penetrance was virtually complete by the age of 65 years. There were no examples of the disease skipping a generation. Men and women were affected in equal proportions. About 50% of cases were alcohol responsive. In the majority of families alcohol responsiveness was either consistently present or did not occur, but in 20% of kindreds definite heterogeneity of responsiveness was encountered within each family. The typical phenotype was a mild symmetrical postural tremor of the upper limbs. Tremor of the legs, head, facial muscles, voice, jaw and tongue occurred but never in isolation and rest, task specific (e.g. primary writing tremor) and primary orthostatic tremors were not found. Head tremor was invariably mild and 75% was of a 'no-no' type. Dystonia (e.g. torticollis and writer's cramp) were not encountered, a finding which strongly suggests that many previous studies of 'essential tremor' were contaminated by cases of idiopathic or hereditary torsion dystonia. No association with Parkinson's disease was found but classical migraine occurred in approximately 26% of cases and co-segregated with tremor. The severity of arm tremor (assessed using a clinical rating scale and by scoring tremor in Archimedes spirals) and disability increased with advancing age and increasing tremor duration, but there was no correlation between age at tremor onset and either tremor severity or disability. Men and women were affected with equal severity. The sex of the affected parent had no influence on the severity of tremor or the degree of disability experienced by an affected child. Disability commenced in the second decade and progressively increased. All the index patients and 59% of the definite secondary cases had tremor induced disabilities. Eighty-five percent of index patients and 38% of secondary cases also reported some degree of social handicap. Twenty-five percent of index patients and 12% of secondary cases had been compelled to change jobs or retire. Biological fitness was normal.

The basal ganglia play a role in controlling movement. The motor circuits within the striato-pallidal complex are thought to facilitate desired movement and inhibit unwanted movement through their influence via thalamus, mainly on precentral motor cortical regions. Lesions in the motor thalamus, or in the globus pallidus, therefore might be expected to impair voluntary movement. But stereotaxic lesions in patients with Parkinson's disease directed at the motor thalamus verified at autopsy, and lesions in the globus pallidus, which improve rigidity and tremor, apparently do not worsen parkinsonian hypokinesia and bradykinesia; nor do they regularly cause dyskinesias. Reasons for this discrepancy are reviewed. It is concluded that the motor circuits of the basal ganglia are part of a distributed motor system which can operate, albeit imperfectly, in the absence of striato-pallido-thalamo-cortical feedback. There may, however, be subtle defects in motor performance after thalamic and pallidal lesions which have escaped attention. Further consideration leads to two hypotheses concerning normal basal ganglia motor function. First, it seems most likely that it is a pause in firing of medial pallidal and substantia nigra reticulata neurons that, by disinhibition of thalamic targets, permits movements generated by cortical motor areas. An increase in firing of medial pallidal neurons, which so far has been the major focus of attention, may be more concerned with inhibition of unwanted movement. Secondly, we suggest that the basal ganglia play a particular role in motor control. A change in firing of medial pallidal neurons appears to occur too late to initiate a new movement. However, the motor circuit within the striato-pallidal system routinely receives a continuous delayed read-out of cortical motor activity and issues an output directed via thalamus mainly to premotor cortical regions. This may permit the routine automatic execution of sequences of movements generated in cortical motor areas. There is evidence that other regions of the striatum respond to significant external or internal cues as dictated by their cortical inputs, the significance being determined by memory, novelty, emotional and other contexts. We suggest that such events capture the attention of the non-motor striatum, which then interrupts the routine operation of the motor circuit, perhaps at the level of the medial pallidum and substantia nigra pars reticulata, to permit new cortical motor action.

Fourteen patients with focal or segmental involuntary movements affecting the ears, back, shoulder girdle, and upper extremity, as well as the abdomen and pelvic girdle, are presented. The unusual locations and appearance of these dyskinesias distinguishes them from recognized movement disorder syndromes. It is argued that the slow, sinuous, and semirhythmic character of the movements and the variable long-duration bursts of motor unit activity responsible for them most closely fit into the spectrum of dystonia. A history of pain in the affected region and/or peripheral trauma in some cases also suggests that peripheral factors may play a role in their pathogenesis.

The prognosis for patients who survive carbon monoxide (CO) poisoning is uncertain, particularly in those who develop persistent neurological complications after recovery from the initial coma. Thirty-one patients with the sequelae of CO poisoning, followed for a year, are described. Eight had a progressive course, and 23 had a delayed relapse after an initial recovery period of approximately 20 days (range, 1-36 days). Those with a progressive course developed a persistent akinetic-mute state, and four of the eight died. Those with the delayed relapsing course either developed a parkinsonian state with behavioral and cognitive impairment but could walk (nine cases), or progressed further to an akinetic-mute state, and were bed-bound (14 cases); the deterioration to either condition occurred rapidly over a few days to a week. Fourteen of the patients with the delayed relapses (61%) subsequently improved, but three (13%) died. Those with a progressive course without initial recovery were younger (mean age, 37.0 years) than those with a delayed relapsing course (55.2 years; p < 0.01). The mean duration of their initial coma (9.8 days) was longer than that in delayed relapsing cases (2.0 days; p < 0.01). The mean initial CO hemoglobin level was not different in the two groups. Brain computed tomography (CT) scans were obtained at the onset of sequelae in both groups. Ten patients had a normal CT scan, 13 had white matter low-density lesions, and four had globus pallidus low-density lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

A family with autosomal dominant inheritance of an early-onset and rapidly progressive parkinsonian syndrome and associated severe depression is reported. Three members had parkinsonism with depression, 3 had parkinsonism alone, and 2 suffered depression only. Pathological brain examination in 2 members with parkinsonism and depression revealed distinctive changes, with devastation of the substantia nigra, scarce Lewy bodies, and gliosis of the caudate nucleus and globus pallidus. The clinical and pathological findings were similar to those in four previously described families with autosomal dominant parkinsonism, depression, and alveolar hypoventilation.

1. In ten normal volunteers, a transcranial magnetic or electric stimulus that was subthreshold for evoking an EMG response in relaxed muscles was used to condition responses evoked by a later, suprathreshold magnetic or electric test shock. In most experiments the test stimulus was given to the lateral part of the motor strip in order to evoke EMG responses in the first dorsal interosseous muscle (FDI). 2. A magnetic conditioning stimulus over the hand area of cortex could suppress responses produced in the relaxed FDI by a suprathreshold magnetic test stimulus at interstimulus intervals of 1-6 ms. At interstimulus intervals of 10 and 15 ms, the test response was facilitated. 3. Using a focal magnetic stimulus we explored the effects of moving the conditioning stimulus to different scalp locations while maintaining the magnetic test coil at one site. If the conditioning coil was moved anterior or posterior to the motor strip there was less suppression of test responses in the FDI. In contrast, stimulation at the vertex could suppress FDI responses by an amount comparable to that seen with stimulation over the hand area. With the positions of the two coils reversed, conditioning stimuli over the hand area suppressed responses evoked in leg muscles by vertex test shocks. 4. The intensity of both conditioning and test shocks influenced the amount of suppression. Small test responses were more readily suppressed than large responses. The best suppression was seen with small conditioning stimuli (0.7-0.9 times motor threshold in relaxed muscle); increasing the intensity to motor threshold or above resulted in less suppression or even facilitation. 5. Two experiments suggested that the suppression was produced by an action on cortical, rather than spinal excitability. First, a magnetic conditioning stimulus over the hand area failed to produce any suppression of responses evoked in active hand muscles by a small (approximately 200 V, 50 microsecond time constant) anodal electric test shock. Second, a vertex conditioning shock had no effect on forearm flexor H reflexes even though responses in the same muscles produced by magnetic cortical test shocks were readily suppressed at appropriate interstimulus intervals. 6. Small anodal electric conditioning stimuli were much less effective in suppressing magnetic test responses than either magnetic or cathodal electric conditioning shocks.(ABSTRACT TRUNCATED AT 400 WORDS)

The response of postural wrist tremors to supramaximal median nerve stimulation was examined in patients with hereditary essential tremor (n = 10) and Parkinson's disease (n = 9), and in normal subjects mimicking wrist tremor (n = 8). The average frequency of on-going tremor was the same in all three groups. Supramaximal peripheral nerve shocks inhibited and then synchronised the rhythmic electromyographic (EMG) activity of all types of tremor. The duration of inhibition ranged from 90 to 210ms, varying inversely with the frequency of on-going tremor. There was no significant difference in mean duration of inhibition or in the timing of the first peak after stimulation on the average rectified EMG records between the three groups. The degree to which supramaximal peripheral nerve shocks could modulate the timing of rhythmic EMG bursts in the forearm flexor muscles was also quantified by deriving a resetting index. No significant difference in mean resetting index of the three groups was found. These results suggest that such studies cannot be used to differentiate between the common causes of postural wrist tremors.

The effect of chronic administration of trifluoperazine on the perioral movement profile of Wistar and Sprague-Dawley rats was examined. Perioral movements were characterised by visual observations, coupled with electromyographic recording from the masseter muscle. In drug-naive animals from both strains the spectrum of perioral behaviours was essentially identical, primarily consisting of purposeless chewing, accompanied by occasional bursts of facial tremor and teeth chattering, with occasional yawning. Each burst of facial tremor was accompanied by a transient increase in the rate of purposeless chewing. Wistar rats exhibited a higher level of spontaneous purposeless chewing compared to Sprague-Dawley rats. In both strains, chronic administration of trifluoperazine (5 mg/kg per day, PO) for 5 months induced an increase in perioral behaviour, which primarily consisted of enhanced purposeless chewing. In Wistar rats the drug-induced increase in purposeless chewing was accompanied by an increase in the incidence of yawning, with no change in the incidence of either facial tremor or teeth chattering. In contrast, Sprague-Dawley rats displayed a drug-induced increase in purposeless chewing, accompanied by an increase in the incidence of facial tremor and teeth chattering, but not yawning. In Wistar rats withdrawal of trifluoperazine diminished but did not reverse the drug-induced increase in purposeless chewing. Drug withdrawal also precipitated a transient increase in the incidence of facial tremor and teeth chattering, but had no effect on yawning. In Wistar rats, the level of purposeless chewing and the incidence of yawning remained elevated above control levels for at least 13 weeks after drug withdrawal. In contrast, in Sprague-Dawley rats drug induced changes in perioral behaviour were rapidly reversed following withdrawal of trifluoperazine. These results indicate that the contradictory effects of chronic neuroleptic treatment on perioral movement obtained in previous studies may not be due to the differences in the spontaneous perioral movement profile of individual rat strains. However, the persistence of perioral movements following drug withdrawal appears to be related to rat strain. This may partially explain the controversy over whether these movements represent a model of acute dystonia or tardive dyskinesia.

Three siblings presented with a progressive neurological disorder beginning in the third decade of life and characterised by palatal myoclonus, nystagmus, bulbar weakness and spastic tetraparesis. There was no evidence of intellectual deterioration or seizures. CT scan showed marked brainstem atrophy in two patients and basal ganglia calcification in one. MRI scan in one showed high signal in the brainstem and periventricular region and cerebral biopsy in this patient showed myelin loss and the presence of Rosenthal fibres. A similar disease affected the siblings' mother, maternal aunt and two of the aunt's daughters, suggesting an autosomal dominant mode of transmission of what appears to be a unique genetic disorder.

Groups of patients with idiopathic Parkinson's disease (PD), either medicated or unmedicated, were compared with matched groups of normal controls on a computerised battery of tests designed to investigate spatial working memory, visuospatial recognition memory and learning. The medicated PD patients were subdivided into those with mild and severe clinical disability on the basis of Hoehn and Yahr ratings, thus making three groups of PD patients in all. In a test of spatial recognition memory, a significant impairment was only evident in those PD patients who were medicated and had severe clinical symptoms (Hoehn and Yahr stage III–IV). In contrast, none of the three patient groups were impaired in a complementary test of visual pattern recognition memory. Whilst all three patient groups performed well in a test of simultaneous visual matching to sample, medicated patients (MED PD) with severe clinical symptoms were significantly impaired when a short (0–12 sec) delay was introduced. In a test of paired associates learning requiring both visual pattern and visuospatial memory, deficits in learning and memory were only evident in the severely impaired MED PD group. In contrast, in a test of spatial working memory known to be sensitive to frontal lobe damage, significant impairments were found in both groups of medicated PD patients and particularly in those patients with more severe clinical symptoms. Taken together, the results suggest that there are multiple memory impairments in PD which may differentially depend on the clinical severity of the disease.

We have tested the hypothesis that dysfunction of the vestibular control of posture is a principal cause of parkinsonian instability by measuring the body sway response induced by galvanic vestibular stimulation (0.5 mA for 2 s) in a group of patients with Parkinson's disease (n = 15). Responses were compared with those obtained from a group of age-matched control subjects (n = 10). Subjects were stimulated (randomized polarity) whilst standing with feet together, eyes closed and maintaining one of five head yaw angles. The motion of the body and the ground reaction forces were measured in three dimensions. There was no significant difference between patients and controls in the speed or direction of the induced body sway response. When the patients were subdivided into two groups according to a clinical assessment of postural deficit, the more disabled group was found to respond with significantly greater body speed than either the control group or the mildly affected patient group. However, the baseline speed of spontaneous body sway was also greater in these patients and it was found that response speed was linearly related to baseline body sway even for the control group. There were no significant differences between any of these groups in the latency to onset, latency to peak or peak amplitude of the initial horizontal ground reaction force response to the stimulus. We conclude that vestibular dysfunction does not explain the postural deficits of patients who are mildly or moderately affected by Parkinson's disease.

There is increasing evidence that defective function of the mitochondrial enzyme NADH CoQ reductase (complex I) is involved not only in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity, but also in idiopathic Parkinson's disease (PD). Complex I deficiency has been identified in PD substantia nigra and appears to be disease-specific and selective for the substantia nigra within the central nervous system. We describe a method for preparation of an enriched mitochondrial fraction from 60 mL blood. Using this technique, we analyzed respiratory chain function in 25 patients with PD and 15 matched control subjects. We confirm a previous report of a specific complex I deficiency in PD platelet mitochondria. Although there was a statistically significant decrease in complex I activity in the PD group compared with the control group (p = 0.005), the defect was mild (16%); it was not possible to distinguish PD from control values on an individual basis. This deficiency is not detectable in platelet whole-cell homogenates, presumably reflecting the relative insensitivity of this preparation and the limited decrease in complex I activity in PD. The presence of a mild complex I defect in platelets together with a more severe defect in substantia nigra suggests either that the pharmacological characteristics shared by these two tissues render them susceptible to a particular toxin or toxins, or that the defect is widely distributed and other biochemical events enhance the deficiency in substantia nigra.(ABSTRACT TRUNCATED AT 250 WORDS)

We reviewed the efficacy and adverse effects of repeated botulinum toxin injections into hyperactive neck muscles of 107 successive patients with spasmodic torticollis. They received 510 injection treatments over a median period of 15 months (range 3–42 months). One patient failed to benefit at all, but 101 (95%) patients reported considerable (moderate or excellent) benefit from at least one treatment. On a global subjective response rating, 93% of 429 treatments resulted in some improvement and 76% in moderate or excellent improvement. Pain reduction followed 89% of 190 treatments with moderate or excellent reduction after 66%. Median duration of benefit was 9 weeks. All torticollis types responded equally well and injections into two (or more) involved neck muscles were more effective than injection into a single muscle. The most frequent adverse effect was dysphagia, occurring after 44% of all treatments, but this was severe after only 2%. Antibodies to botulinum toxin were detected in the serum of three out of the five patients in whom loss of treatment efficacy occurred. We conclude that botulinum toxin treatment is the most effective available therapy for spasmodic torticollis and practical advice is provided for anyone wishing to set up the technique.

Debrisoquine (DBQ) metabolism was studied in 80 Parkinson's disease (PD) patients, 26 of whom had young onset Parkinson's disease (YOPD), and in 143 controls. There was no significant difference between the proportion of poor metabolisers of DBQ among YOPD patients compared either to other parkinsonians, or to controls. Nor was there a significant correlation between the age of disease onset and DBQ metabolic ratio (MR). The results do not support the suggestion that impairment of DBQ metabolism (and hence cytochrome P450) is a primary defect in YOPD. However, in comparison with controls, MR values were modestly but significantly higher in PD patients, even in those not treated with drugs known to affect DBQ metabolism.

Dissociations between different aspects of learning and memory in patients with amnesic syndromes and various neurodegenerative diseases has led to a fundamental revision of the taxonomy of human memory, and a greater understanding of its neurobiological basis. It has been suggested that, while lesions to temporal and diencephalic structures leave procedural learning intact, neurological disorders involving the striatum lead to deficits in this aspect of learning. However, as comparative evidence has accumulated on a variety of procedural tasks, it has become clear that different neurological diseases lead to varying patterns of impaired and intact performance. This has led to a revision of the concept of a unified procedural system in favour of parallel, independent systems, only some of which involve the striatum. There is a danger, however, that the effort to fit the patterns of functional association and dissociation into a neuroanatomical framework may be premature, It is suggested that the ...

Parkinson's disease leads to a breakdown in the execution of highly practised, skilled movements such as walking and handwriting. The improved execution of skilled movements with practice can be understood as a process of schema learning, the determining of the relevant parameters of the specific movement. The ability of patients with Parkinson's disease and age matched normal control subjects to improve their performance, with practice, on a skilled motor task, doing up buttons, was assessed. The task was assessed on its own and with simultaneous foot tapping. Both groups showed an initial improvement in the task on its own and deterioration in performance when buttoning with foot tapping. The amount of interference, however, decreased with practice, particularly in the patients with a 2 Hz tapping rate. The results suggest that patients with Parkinson's disease are capable of schema learning but require more practice than control subjects to achieve comparable levels of performance. This may be a reflection of the fundamental motor dysfunction of the disease rather than a specific learning deficit.

We reviewed 49 patients in whom a diagnosis of Huntington's disease (HD) seemed possible on clinical grounds, but who gave no history of definitely affected relatives. In 32 with the typical clinical features of HD (progressive chorea and dementia, postural instability, abnormal initiation of saccadic eye movements), the diagnosis was confirmed in 7 patients who had had autopsies, affected relatives were found in 5 others, and HD remained probable in a further 13 who were reexamined. In the 17 with a less typical clinical picture, a diagnosis of HD appeared most likely in 2; other causes for chorea such as cerebrovascular disease, neuroacanthocytosis, recrudescence of Sydenham's chorea, and drug-induced tardive dyskinesia could be invoked in the remainder. We conclude that the likelihood of HD in a patient with the typical clinical features of this disorder but no history of affected relatives is at least 75%, which for practical purposes implies a risk to their children hardly less than in familial HD. The most plausible explanations for seemingly sporadic patients with HD are nonpaternity and mild, late-onset disease that is overlooked by other family members.

1. Reflexes were elicited in the first dorsal interosseous muscle of seven normal subjects by electrical stimulation of the digital nerves of the index finger at 3 times perceptual threshold while subjects maintained a constant voluntary contraction of the muscle. The average response in the surface-rectified electromyogram (EMG) consisted of an early inhibitory (I1) component followed by a later excitation (E2). 2. Low intensity anodal electrical or magnetic scalp stimuli were given over the motor cortex in order to elicit muscle responses within the period of the I1 and E2 reflex components. 3. Compared with control responses elicited in the absence of digital nerve stimulation, responses to electrical cortex stimulation were suppressed in the I1 period and facilitated during the E2 period of the reflex. In contrast, responses evoked by magnetic stimulation were suppressed during I1 and also for the first 10 ms or so of the E2 response. Magnetically evoked responses were facilitated during the later part of the E2 reflex. 4. Similar effects were seen when the probability of firing of single motor units was studied. 5. In three subjects, small taps were given to the abducted index finger in order to stretch the first dorsal interosseous muscle and evoke reflexes which were of comparable size to the E2 reflex evoked by digital nerve stimulation. In contrast to the experiments in which digital nerve stimuli were given, responses evoked by magnetic stimulation over motor cortex were facilitated at all times during the course of the reflex evoked when the muscle was stretched. 6. We conclude that single electrical stimuli applied to the digital nerves can reduce for a short period the excitability of motor cortex to magnetic stimulation. This occurs at a time when the same stimulus is evoking an excitatory (E2) reflex in the average surface-rectified EMG.

Equilibrium striatal: cerebellar 11C-raclopride (RAC) uptake ratios reflect the density of striatal dopamine D2 binding sites. Using positron emission tomographic scanning we have measured striatal RAC uptake in 6 untreated patients with Parkinson's disease (PD), 5 chronically treated patients with PD and a fluctuating response to L-dopa, 10 patients with striatonigral degeneration (SND), and 9 patients with progressive supranuclear palsy (PSP). Regional cerebral blood flow was determined also, with C15O2. Mean strital: cerebellar RAC uptake was not significantly different from normal in untreated patients with PD, though 2 of these 6 patients showed significantly increased putamen tracer binding. Mean caudate and putamen: cerebellar RAC uptake ratios of the group with PD and fluctuating response to L-dopa were significantly reduced by 30% and 18%, respectively. The patients with SND had lesser, but significant, 10% and 11% decreases in mean caudate and putamen: cerebellar RAC uptake ratios, respectively, whereas patients with PSP showed 24% and 9% reductions in caudate and putamen: cerebellar RAC binding. Striatal and frontal blood flow were significantly reduced in patients with PSP, but not in patients with PD or SND. In conclusion, striatal D2 binding potential is normal or raised in untreated patients with PD, but reduced in patients with PD and a fluctuating response to L-dopa. Patients with SND and PSP show a decrease in striatal RAC binding, but to a lesser extent than patients with PD and a fluctuating response to treatment. Failure of patients with SND and PSP to respond well to L-dopa cannot therefore be due to losss of striatal D2 sites alone, but must reflect loss of other basal ganglia connections.

The startle response to an unexpected auditory stimulus was studied in eight patients with a clinical diagnosis of the Steele-Richardson-Olszewski syndrome (SRO), 11 patients with idiopathic Parkinson's disease (PD) and 12 normal subjects. The patients with PD were studied 'on' at the time of maximal effect of their treatment; five of these patients were also studied in their 'off' state without treatment. The auditory startle response was absent in three patients with SRO: in the remaining five the latency to onset of earliest electromyography activity (EMG) of the auditory startle response was delayed and few muscles (orbicularis oculi, sternocleidomastoid and rectus abdominis) were recruited in the response. In PD the auditory startle response was similar to that recorded in normal subjects, both in terms of the pattern of muscles recruited and the amplitude of the EMG responses, but the latency of responses in orbicularis oculi and sternocleidomastoid muscles were significantly delayed. This result was not influenced by treatment with L-dopa. In patients with SRO the finding of an abnormal startle response is consistent with loss of neurons in the lower pontine reticular formation. This region is intimately involved in the startle response in animal studies. In patients with PD the late auditory startle response might be related to withdrawal of facilitatory input to brainstem centres and reticulospinal pathways from basal ganglia. The similarity of the responses in patients when 'on' and 'off' suggests these pathways are not under potent dopaminergic control.

We examine the evidence for free radical involvement and oxidative stress in the pathological process underlying Parkinson's disease, from postmortem brain tissue. The concept of free radical involvement is supported by enhanced basal lipid peroxidation in substantia nigra in patients with Parkinson's disease, demonstrated by increased levels of malondialdehyde and lipid hydroperoxides. The activity of many of the protective mechanisms against oxidative stress does not seem to be significantly altered in the nigra in Parkinson's disease. Thus, activities of catalase and glutathione peroxidase are more or less unchanged, as are concentrations of vitamin C and vitamin E. The activity of mitochondrial superoxide dismutase and the levels of the antioxidant ion zinc are, however, increased, which may reflect oxidative stress in substantia nigra. Levels of reduced glutathione are decreased in nigra in Parkinson's disease; this decrease does not occur in other brain areas or in other neurodegenerative illnesses affecting this brain region (i.e., multiple system atrophy, progressive supranuclear palsy). Altered glutathione metabolism may prevent inactivation of hydrogen peroxide and enhance formation of toxic hydroxyl radicals. In brain material from patients with incidental Lewy body disease (presymptomatic Parkinson's disease), there is no evidence for alterations in iron metabolism and no significant change in mitochondrial complex I function. The levels of reduced glutathione in substantia nigra, however, are reduced to the same extent as in advanced Parkinson's disease. These data suggest that changes in glutathione function are an early component of the pathological process of Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS)

In six patients with Parkinson's disease exhibiting severe "on-off" phenomena, a 200-mg intravenous bolus of either L-DOPA or of its methyl ester were equally effective in reversing motor deficits, although the duration of action of the methyl ester was shorter. There were no marked differences in pharmacokinetic parameters for L-DOPA plasma levels after administration of L-DOPA and the methyl ester. In three patients, optimal infusion rates for the maintenance of mobility were established for L-DOPA and L-DOPA methyl ester. Both drugs were able to maintain patients "on" throughout a 12-h infusion period. However, on average the optimal infusion rate of L-DOPA methyl ester was 2.7 times greater than that for L-DOPA. There was no marked difference in the plasma levels of L-DOPA achieved, but 3-O-methyl DOPA levels increased more after infusion of L-DOPA methyl ester than after infusion of L-DOPA itself. The half-life of elimination and volume of distribution of L-DOPA formed from the methyl ester were markedly increased compared with values obtained after either an intravenous bolus of methyl ester or after an intravenous infusion of L-DOPA itself. An intravenous bolus of L-DOPA methyl ester produces an equivalent magnitude of clinical response to the same dose of L-DOPA. However, higher optimal infusion rates of methyl ester than L-DOPA are required to produce continuous effect. The pharmacokinetic handling of L-DOPA methyl ester given by intravenous infusion may differ from that of L-DOPA when given by the same route.

The clinical and physiological features of six new patients with primary orthostatic tremor are described. We suggest that use of the term primary orthostatic tremor be confined to the clinical syndrome in which unsteadiness when standing is the predominant complaint and accompanied by characteristic electrophysiological findings of a rapid (frequency around 16 Hz), regular leg tremor which is not influenced by peripheral feedback, is synchronous between homologous leg muscles, and in certain postures of the upper limbs, between muscles of the arm and leg. The fast frequency of muscle activity in primary orthostatic tremor of the legs causes unsteadiness when standing (presumably due to partially fused muscle contraction) but only a fine ripple of muscle activity is visible. In contrast, the slower frequency of other leg tremors, for example essential tremor, results in obvious leg movement which is evident in many leg postures, is variable over time and can be reset by a peripheral nerve stimulus. Essential tremor and orthostatic tremor do not respond to the same therapies, suggesting differences in the pharmacological profiles of the two conditions. Accordingly, there are clinical, physiological and pharmacological differences between primary orthostatic and essential tremor. Whether these factors are sufficient to regard these tremors as separate conditions is discussed.

Groups of patients with idiopathic Parkinson's disease, either medicated or unmedicated, were compared with matched groups of normal controls on a computerized battery previously shown to be sensitive to frontal lobe dysfunction, including tests of planning, spatial working memory and attentional set-shifting. In a series of problems based on the 'Tower of London' test, medicated patients with Parkinson's disease were shown to be impaired in the amount of time spent thinking about (planning) the solution to each problem. Additionally, an impairment in terms of the accuracy of the solution produced on this test was only evident in those patients with more severe clinical symptoms and was accompanied by deficits in an associated test of spatial short-term memory. Medicated patients with both mild and severe clinical symptoms were also impaired on a related test of spatial working memory. In contrast, a group of patients who were unmedicated and 'early in the course' of the disease were unimpaired in all three of these tests. However, all three Parkinson's disease groups were impaired in the test of attentional set-shifting ability, although unimpaired in a test of pattern recognition which is insensitive to frontal lobe damage. These data are compared with those previously published from a group of young neurosurgical patients with localized excisions of the frontal lobes and are discussed in terms of the specific nature of the cognitive deficit at different stages of Parkinson's disease.

The sex ratio, age at onset, and ictal features of nine patients with nocturnal paroxysmal dystonia were compared with those of eight patients with daytime frontal lobe seizures and eight patients with nocturnal motor attacks of known epileptic origin. All patients underwent video electroencephalography telemetry. There were no clinical features that would allow distinction between the groups and no single phenomenon was uniquely seen in nocturnal paroxysmal dystonia. This study provides no evidence that nocturnal paroxysmal dystonia is a separate diagnostic entity.

The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with idiopathic Parkinson's disease has provided new understanding into the possible mechanisms that may underlie this neurodegenerative disorder. The biochemical defect is identical to that induced in humans, primates and mice exposed to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. We have studied mitochondrial respiratory chain function in various brain regions, in skeletal muscle and in blood platelets from patients with idiopathic Parkinson's disease and from matched controls. We provide evidence suggesting that the complex I deficiency in Parkinson's disease is limited to the brain and that this defect is specific for the substantia nigra. The tissue specificity of the complex I deficiency in Parkinson's disease and its localization to the substantia nigra support the proposition that complex I deficiency may be directly involved in the cause of dopaminergic cell death in Parkinson's disease. An understanding of the molecular basis of this biochemical defect will provide valuable insight into the cause of Parkinson's disease. Our findings of normal mitochondrial function in platelet homogenates suggests that this tissue cannot be used to develop a 'diagnostic test' for Parkinson's disease.

A mosaic pattern of striatal pathology is described in a male who developed severe generalised dystonia from the age of 10 years, and died at the age of 18 years. There was no family history of dystonia, and extensive investigations during his life failed to identify a cause for the dystonia. The caudate nucleus and putamen showed a network of cell loss and gliosis surrounding islands of preserved striatum. Dorsal parts showed confluent gliosis, and ventral parts were spared. The pattern suggested a correlation with patch-matrix organisation, but there was no correlation with the distribution of calbindin immunoreactive cells, which are present in the matrix of the classical striosome-matrix organisation. The pathological findings were unlike those in status marmoratus, perinatal hypoxia-ischaemia, Huntington's disease, and neuroacanthocytosis, but similar to those reported in a 44-year-old man with predominantly cranial dystonia.

Previously we have shown that cell death in the substantia nigra (SN) in Parkinson's disease (PD) is associated with an increase in iron content but a decrease in the level of the iron-binding protein ferritin. Alterations in other metal ion levels were also observed; copper levels were reduced, whereas zinc levels were increased. The importance of these changes in iron, ferritin, and other metal ions in the pathophysiology of PD depends on whether they are specific to the illness. We measured levels of iron, copper, zinc, manganese, and ferritin in postmortem tissue from patients with progressive supranuclear palsy (PSP) and multiple system atrophy (MSA) (which shows pathology in the SN and striatum) and Huntington's disease (HD) (which shows pathological changes in the striatum, compared with control subjects). Total iron levels were elevated in areas of the basal ganglia showing pathological changes in these disorders. In particular, total iron content was increased in SN in PD, PSP, and MSA, but not in HD. Total iron levels in the striatum (caudate nucleus and/or putamen) were increased in PSP, MSA, and HD, but not in PD. There were no consistent alterations in manganese levels in the basal ganglia in any of the diseases studied. Copper levels were decreased in the SN in PD and in the cerebellum in PSP, and were elevated in the putamen and possibly the SN in HD. Zinc levels were only increased in PD in the SN, the caudate nucleus, and the putamen.(ABSTRACT TRUNCATED AT 250 WORDS)

Dyskinesias associated with dopaminergic treatment in idiopathic Parkinson's disease (PD) can be indistinguishable from those arising spontaneously in other conditions involving degeneration of, or damage to, the basal ganglia. However, those due to levodopa treatment of PD disappear on cessation of therapy. We report a patient with a clinical diagnosis of PD who, on levodopa treatment, developed hemiballism and chorea that were originally thought to be drug induced. However, the dyskinesias persisted despite stopping levodopa. Postmortem analysis showed a multisystem degeneration.

There is increasing evidence for a defect of mitochondrial respiratory chain function in Parkinson's disease. Specific NADH CoQ1 reductase (complex I) deficiency has been identified in the substantia nigra. Available evidence suggests that this defect is confined to the substantia nigra and is not present elsewhere in the parkinsonian brain. The absence of a detectable mitochondrial abnormality in the substantia nigra of patients with multiple system atrophy also suggests that the complex I deficiency in Parkinson's disease is not simply due to an artifact of neuronal degeneration. Evidence for abnormal mitochondrial function in skeletal muscle is conflicting; two studies showed multiple respiratory chain defects and one study was unable to demonstrate any deficiency. A severe deficiency of complex I activity has been found in platelet mitochondria from parkinsonian patients. This finding has not as yet been confirmed. Platelet homogenates do not show the complex I deficiency, however, suggesting that such a preparation may be too insensitive to detect the defect. The role of complex I deficiency in the events that culminate in dopaminergic cell death in Parkinson's disease remains unresolved. It is likely that if this mitochondrial defect is confirmed, it will be related to a number of other factors, including environmental agents, oxidative stress, and genetic predisposition. Copyright © 1992 The American Neurological Association

Successful treatment of torticollis with electromyographic (EMG) biofeedback has been reported in a number of single case and single group studies. The present investigation represents the first controlled outcome study. Twelve torticollis patients were randomly assigned to EMG biofeedback or relaxation training and graded neck exercises (RGP). The procedure involved three sessions of baseline assessment, 15 sessions of EMG BF or RGP, 6 sessions of EMG BF or RGP plus home-management, 6 sessions of home-management alone, and follow-up 3 months after the end of treatment. A variety of outcome measures were used including physiological (EMG from the two sternocleidomastoid muscles, skin conductance level), behavioral (angle of head deviation, range of movement of the head), and self-report (depression, functional disability, body concept), therapist and "significant other" reports and independent observer assessment of videos. In both groups, neck muscle activity was reduced from pre- to posttreatment. This reduction was greater in the EMG biofeedback group. There was evidence of feedback-specific neck muscle relaxation in the EMG biofeedback group. Therefore, the outcome was not due to nonspecific factors and could be attributed to feedback-specific effects. Changes in skin conductance level showed that neck muscle relaxation was not simply mediated by a general reduction of "arousal." Significant improvements of extent of head deviation, and range of movement of the head, as well as reductions of depression were present, which were not different in the two groups. At the end of treatment, no patient was asymptomatic. Any therapeutic benefit was generally maintained at follow-up. The results and the procedural simplicity of RGP make the issue of cost-efficacy of EMG biofeedback a pertinent one. Further controlled outcome studies of EMG biofeedback treatment of torticollis with larger samples are required.

The effect of voluntary contraction on the discharge of single motor units following electrical and magnetic stimulation of the motor cortex was examined using the post-stimulus time histogram (PSTH) technique. The latencies of responses in single motor units of the first dorsal interosseous muscle to cortical stimulation were 2-4 msec shorter when the muscle was contracting than when at rest in 9 of 10 units studied. These latency differences are comparable with those recorded by surface electromyography for compound muscle action potentials following cortical stimulation in relaxed and active muscles. The new findings are that the intensity of cortical stimulation required to discharge a resting motor unit to produce a single PSTH peak produced multiple PSTH peaks when the same unit was contracting. The timing of the PSTH peak of relaxed motor unit discharge corresponded to one of the later PSTH peaks (usually the second) when the motor unit was voluntarily activated. These findings are in keeping with our previous suggestions that the longer latency of responses in relaxed muscles is due to the time taken for temporal summation of multiple descending corticospinal volleys at the cortico-motoneurone synapse. Facilitation produced by voluntary contraction occurs at least in part at the level of the spinal cord by lowering motoneurone threshold to enable discharge on the initial descending volley. The higher threshold of relaxed muscles is related to the higher intensities of stimulation needed to recruit multiple descending volleys and discharge resting motoneurones.

1. We have stimulated over the cerebellum of intact human subjects by applying single electrical stimuli through electrodes placed on the back of the head, approximately at the level of the inion. The intensity of stimulation used was below that required to produce direct EMG responses in pre-activated muscles of the hand. 2. In ten subjects the effect of the stimulus over the cerebellum was to reduce the size of the EMG response in first dorsal interosseous muscle evoked by a magnetic stimulus to the cerebral cortex. In all subjects the onset of the period of suppression occurred when the test magnetic cortical shock followed the conditioning cerebellar shock by 5 ms. The duration of the suppression lasted from 3 to 7 ms. 3. The amount of suppression was related to the intensity of stimulation over the cerebellum. At 15% below the threshold for direct motor activation there was no effect; increasing suppression was evident at 10, 5 and 0% below motor threshold. 4. With a conditioning-test interval of 5-6 ms the suppression was the same whether the target muscle was relaxed or active. With longer conditioning-test intervals (12 and 15 ms) the amount of suppression was greater in active than relaxed muscles. 5. The short-latency suppression was greatest when the stimulating anode was ipsilateral to the target muscle and contralateral to the stimulated sensorimotor cortex. The later period of suppression was insensitive to the polarity of stimulation. When the stimulating electrodes were moved 2 cm caudally or cranially the short latency suppression disappeared whereas the longer latency suppression was still observed with the electrodes in the lower position. 6. Different results were obtained when the test EMG response was produced by an electrical (rather than magnetic) stimulus over the sensorimotor cortex. The short latency effect was no longer visible whereas the longer latency effect was the same as when testing with a magnetic cortical stimulus. 7. We suggest that a single electrical stimulus across the base of the skull (particularly with the anode over one cerebellar hemisphere) produces a short latency (5-6 ms) disfacilitation of the contralateral motor cortex through activation of cerebellar structures. A later (12 and 15 ms), less specific suppression which is present when testing in active muscles is thought to be mediated by a different mechanism and probably produces its effect at the level of the spinal cord.

Generalised, multifocal or segmental idiopathic torsion dystonia (ITD), is caused by an autosomal dominant gene with reduced penetrance in about 85% of cases. Of 104 patients with these types of ITD, 17 (16.4%) gave a history which suggested that dystonic movements had been precipitated or exacerbated by trauma. Eight of these 17 patients had affected relatives. If precipitated, dystonia appeared first in the injured part of the body within days or up to 12 months after the trauma and later became more widespread. Peripheral injuries may influence basal ganglia function and provoke the onset of dystonic movements in individuals who are ITD gene carriers.

Rat brain mitochondria were incubated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its two metabolites (1-methyl-4-phenyl-2,3-dihydropyridium (MPDP+) and 1-methyl-4-phenylpyridinium (MPP+), and O2 uptake was assessed. MPP+ (500 and 1000 microM) inhibited state 3 and state 4 respiration with a reduction in the respiratory control ratio (RCR). In the presence of MPTP or MPDP+ (100-1000 microM) no inhibition of mitochondrial function occurred. Incubation with MPP+ (100-1000 microM) in combination with equimolar concentrations of MPDP+ or MPTP (100-1000 microM) did not increase the inhibition of mitochondrial function produced by MPP+ alone. Inhibition of mitochondrial function produced by MPP+ (500 microM) was not reduced by incorporation of superoxide dismutase (SOD) (50-1000 units/mL). However, the RCR in the presence of 500 microM MPP+ and 1000 units/mL SOD was not different from control values. SOD did not prevent the inhibition of state 3 and state 4 respiration produced by the combination of MPP+ and MPDP+. The results suggest that a redox reaction between MPP+ and MPDP+ to generate superoxide radicals does not contribute to the impairment of mitochondrial function produced by MPTP administration.

The syndrome of dopa‐responsive dystonia comprises a minority of patients with dystonia, yet it is of considerable diagnostic importance because patients respond dramatically to L‐dopa therapy. Benefits from this treatment are lasting, and the problems associated with long‐term L‐dopa therapy in patients with Parkinson's disease are generally absent. It has been suggested that this condition is due to a defect in the dopamine synthetic pathway, which is bypassed when patients are treated with L‐dopa. We have studied [18F]dopa uptake in 6 patients with classic doparesponsive dystonia (5 familial patients and 1 sporadic patient), aged 18 to 66 years. Data have been analyzed according to a graphic approach, calculating an influx constant for each region studied. We have also studied a seventh, clinically atypical, patient with juvenile dystonia‐parkinsonism. Similar data have been calculated for a group of 10 healthy control subjects and 10 patients with Parkinson's disease. The 6 patients with typical dopa‐responsive dystonia had a modest but significant reduction in the uptake of tracer into both caudate and putamen, which indicates a defect in the decarboxylation, vesicular uptake, and storage of [18F]dopa. This argues against the proposition that doparesponsive dystonia is due to an inherited defect of tyrosine hydroxylase alone. In the atypical patient, however, we found a greater reduction of [18F]dopa uptake into both caudate and putamen, comparable with that in patients with Parkinson's disease.

The effect of carbidopa (L-α-methyldopa hydrazine; 25 mg kg−1 i.p.) pretreatment on the pharmacokinetics and peripheral metabolism of orally and intra-aortically administered L-3,4-dihydroxy-phenylalanine (L-dopa; 50 mg kg−1) has been examined in rats. Following intra-aortic (i.a.) administration, plasma levels of the drug declined biexponentially. Pretreatment with carbidopa resulted in higher plasma concentrations after i.a. administration of L-dopa, but had no effect on the half-life (t1/2) for its distribution or elimination. Oral L-dopa gave peak plasma concentrations at 1.5 h and then a log-linear decline between 1.5 and 6 h. Pretreatment with carbidopa also produced higher plasma concentrations of L-dopa given orally, and the t1/2 for its elimination tended to be increased compared with values achieved after the drug alone. Pretreatment with carbidopa decreased volume of distribution and total plasma clearance and increased area under the curve (0-∞) after L-dopa i.a. and increased AUC0-∞ after L-dopa p.o. The fraction of the oral dose absorbed through the gut was not affected. Carbidopa pretreatment enhanced the accumulation of 3-O-methyldopa and decreased dopamine levels in plasma after both i.a. and oral administration of L-dopa. Higher plasma concentrations of 3,4-dihydroxyphenylacetic acid and homovanillic acid (HVA) were detected in the plasma after i.a. rather than oral administration of L-dopa and pretreatment with carbidopa greatly reduced these plasma concentrations. However, following oral L-dopa, only HVA levels were reduced by carbidopa pretreatment. The rat model displays similar peripheral pharmacokinetics and metabolism of L-dopa to those reported in human studies, and may be used for further investigations into the pharmacokinetic handling of the drug.

A genetic study of idiopathic focal dystonias was undertaken by examining 153 first-degree relatives of 40 index patients with torticollis (14 patients), other focal cranial dystonias (16 patients), and writer's cramp (10 patients). Nine relatives with dystonia were identified in 6 families; 8 of these had symptoms such as clumsiness or tremor, but none were aware of any dystonia. A further 4 relatives, now decreased, were affected by history. Overall, 25% of index patients had relatives with dystonia. The results of segregation analysis suggested the presence of an autosomal dominant gene or genes with reduced penetrance as a common cause for focal dystonia. Segregation ratios were not significantly different from those ratios observed in generalized or segmental dystonia in the United Kingdom, and it is possible that a single autosomal dominant gene mutation is responsible for inherited dystonia in the majority of patients irrespective of distribution or severity.

A patient with postanoxic encephalopathy, with both action- and stimulus-sensitive reflex myoclonus, is described. The action myoclonus was multifocal and cortical in origin. In contrast, reflex myoclonus elicited by somaesthetic and auditory stimulation was generalised. The earliest reflex electromyograph activity was recorded in the sternocleidomastoid; myoclonic activity then spread up the brainstem and down the spinal cord, suggesting that this reflex myoclonus had its origin in the caudal brainstem. Stimulus sensitivity was greatest in the limbs. The bulbospinal motor pathways involved in the generalised reflex myoclonus were rapidly conducting, and this characteristic distinguishes this form of brainstem reflex myoclonus from that described in hyperekplexia.

Neurons containing gamma-aminobutyric acid (GABA) are important outflow pathways from the striatum to the pallidal complex and substantia nigra. From these areas GABA-containing neurons pass to the thalamus and to various areas of the brainstem. Manipulation of GABA function in outflow zones in the rat can produce catalepsy, locomotor hyperactivity, stereotypy or circling behaviour, so mimicking the effect of altered dopamine function within basal ganglia. However, the behaviours produced by such manipulation do not form part of the animal's normal activities. Consequently manipulation of GABA action in the outflow zones of the basal ganglia may mimic extrapyramidal movement disorders more closely than the normal functions of these regions of the brain.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is thought to produce parkinsonism in humans and other primates through its inhibition of complex I. The recent discovery of mitochondrial complex I deficiency in the substantia nigra of patients with Parkinson's disease has provided a remarkable link between the idiopathic disease and the action of the neurotoxin MPTP. This article shows that complex I deficiency in Parkinson's disease is anatomically specific for the substantia nigra, and is not present in another neurodegenerative disorder involving the substantia nigra. Evidence is also provided to show that there is no correlation between L-3,4-dihydroxyphenylalanine therapy and complex I deficiency. These results suggest that complex I deficiency may be the underlying cause of dopaminergic cell death in Parkinson's disease.

1. In six subjects, H reflexes obtained in the flexor muscles in the forearm were inhibited by single motor threshold shocks to the radial nerve in the spiral groove. The first two phases of the inhibitory time course were studied: with intervals between the radial and median nerve shocks of -1 to +1 ms, and +5 to +30 ms. These two phases are thought to be due respectively to disynaptic inhibition between radial Ia afferents and flexor alpha-motoneurones, and to presynaptic inhibition of flexor Ia afferents. 2. Single or short trains (10 ms, 400 Hz) of cutaneous stimuli to the dorsal or palmar aspect of the proximal phalanx of the index finger or to the superficial radial nerve at the wrist, reduced the amount of presynaptic inhibition by 10-20%, but had no effect on the earlier disynaptic inhibition. Single stimuli to either side of the index finger or trains of stimuli to the ventral side, had no effect on the size of control H reflexes elicited alone. 3. Effects of cutaneous nerve shocks on presynaptic inhibition could be seen with stimuli as small as 1.5 x perceptual threshold. 4. Anaesthesia of the hand in one subject reversibly increased the amount of presynaptic inhibition and decreased the amount of disynaptic inhibition. 5. We conclude that, as in the cat, cutaneous input can modulate transmission in presynaptic inhibitory pathways in man.

• The rates of spontaneous remission and progression of dystonia to other sites were studied in 72 patients who first presented with adult-onset torticollis, and who were followed up for a mean of 7.7 years. Dystonia had progressed to sites other than the neck (mainly the face and upper limbs) in 23 patients (32%). The latter cases were not differentiated from those with isolated torticollis in terms of any of the demographic or clinical features studied, although they tended to have suffered from torticollis longer. Fifteen patients (20.8%) had experienced a spontaneous remission of their torticollis, which was sustained for a median period of 3 years in 9 cases (12.5%). Eighty-seven percent of the 15 remissions had occurred during the first 5 years of the illness. In the 9 cases with sustained remission, the duration of torticollis before spontaneous remission was significantly longer and remission had mostly occurred after 2 years of illness compared with the 6 who had relapsed. The 15 cases with spontaneous remission tended to have an earlier age of onset compared with those with no remission. Sixty-five percent of cases were correctly classified on the basis of age at onset, which emerged as the only salient variable in the discrimination of the 15 patients with spontaneous remission from the 57 without spontaneous remission. Age at onset, form of torticollis, gender, and direction of head deviation resulted in a correct classification rate of 70%, in the discrimination of the 9 cases with sustained remission from those with no remission. However, because of the high classification error rates in the above analyses (35% and 30%, respectively), these variables were not considered to constitute reliable prognostic indicators for future samples of torticollis sufferers.

Four adult marmosets were treated with increasing doses of 1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine (2'-methyl-MPTP) in the range 0.23-4.3 mg/kg i.p. to give a cumulative dose of 11.0-11.6 mg/kg over a 6-10 day period. After 4 days of treatment, and as the dosage was gradually increased, the animals exhibited mild motor deficits. These abnormalities slowly declined over the following 1-6 week period. In contrast, similar treatment of common marmosets with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1-4 mg/kg i.p.) for 3-5 days in a cumulative dose of 6.9-9.2 mg/kg produced gross impairment of motor function which persisted throughout the 5 weeks period of observation. Administration of 2'-methyl-MPTP for 6-10 days caused some decrease in dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), but not homovanillic acid (HVA) content in the caudate nucleus in animals 5-6 weeks after the start of treatment. There was a small decrease in [3H]dopamine uptake into putamen synaptosomes. This contrasted with the marked decreases in all these parameters observed after MPTP treatment of common marmosets. Histological examination of the substantia nigra from the four animals treated with 2'-methyl-MPTP did not show degeneration or loss of dopamine-containing cell bodies in the zona compacta. In contrast, MPTP caused severe destruction of these pigmented nigral neurones. In the common marmoset 2'-methyl-MPTP does not appear to show the same neurotoxic action as MPTP itself. This contrasts with findings in the mouse where 2'-methyl-MPTP is more toxic to dopamine-containing cells of substantia nigra than MPTP.