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In order to assess quantitatively the state of the disease or the effect of drugs in parkinsonian patients, it would be helpful to have at our disposal mathematical models that reflect in their parameter values the deficiencies associated with the disease. This paper proposes a class of such models that are easily obtained in practice and lend themselves to useful interpretations. A pursuit manual tracking experiment is used to derive these models for patients with Parkinson's disease undergoing drug therapy and for normal controls. The input (one-dimensional visual target) and operator's output (manual tracking) are analyzed using a time series approach aiming at obtaining an auto-regressive moving-average (ARMA) model that minimizes the mean square error between the actual and model response. This mathematical model takes the form of a difference equation expressing, in discrete time, the present output value as a linear combination of past output values and past and present input values. Our experimental results indicate that a difference equation (ARMA model) involving the two previous output values and the present and past input values fits best both patient and control data. A comparison between the mean estimated model parameters for patients and controls shows a statistically significant difference in two of these parameters. The first parameter, which is significantly increased in patients, relates the current response of the patient to the immediately preceding response which represents an increased 'damping' of the motor dynamics, reflecting the muscular rigidity associated with the disease (motor disorder). The other parameter, which is significantly decreased in patients, represents the relative degree to which the current response of the patient is influenced by the target position information at the previous point in time which points to a deficiency in sensing/processing of this information (possible a sensory disorder). Our results also showed a marked reduction in the mean-square error of a second trial of the experiment in normal subjects but failed to do so for the patients, possibly indicating learning deficiencies associated with the disease.

N-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a potent dopaminergic neurotoxin, was administered to cats systemically for 5 to 7 days. This treatment produced a behavioral syndrome characterized by akinesia, ataxia, bradykinesia, and feeding difficulties, lasting for several weeks. During this period of severe behavioral impairment, caudate and nucleus accumbens dopamine and norepinephrine concentrations were quite depleted. Behavioral recovery ensued over the next several weeks as did some recovery of striatal catecholamines. MPTP destroyed the majority of substantia nigra pars compacta neurons while affecting a much lesser number of locus ceruleus and ventral tegmental neurons. These results demonstrated for the first time that MPTP can cause long-lasting deficits in nigrostriatal functioning in the cat and may provide a means for studying the apparently selective neurotoxic effects of MPTP as well as for understanding the pathophysiology of Parkinson's disease.

Patterns of local cerebral glucose utilization were measured with positron emission tomography using the fluorine-18-labeled fluorodeoxyglucose (18FDG) method in 8 patients with Parkinson's disease, in 13 patients with Huntington's disease, in 15 subjects at risk for Huntington's disease, and in aged-matched normal control subjects. On the average, global cerebral metabolism in patients with Parkinson's disease was moderately reduced (20%), but the relative distribution of glucose utilization throughout the brain in these patients was normal. These results support the conclusion that alterations of the nigrostriatal pathway in Parkinson's disease have no major selective effect on the metabolism of particular cerebral regions. In Huntington's disease, however, there was a characteristic decrease in glucose utilization in the caudate nuclei and putamen, and this local hypometabolism appeared early and preceded bulk tissue loss. In patients with Huntington's disease, glucose utilization typically was normal throughout the rest of the brain, regardless of the severity of symptoms and despite the apparent shrinkage of brain tissue. The results also suggest the possibility that the caudate nuclei may be hypometabolic in some asymptomatic subjects who are potential carriers of the autosomal dominant gene for Huntington's disease.

Brain stem pause neurons play an important role in the regulation of rapid eye movements. However, the input sources that drive pause neurons are uncertain. In the present study, horizontal canal type II neurons in the medial vestibular nucleus were antidromically activated by electrical stimulation of the pause neuron region. Systematic microstimulation tracks within that region showed an antidromic activation pattern of low-threshold sites separated by high-threshold sites consistent with axonal branching of type II neurons in the pause neuron region. Spike-triggered averaging of single spontaneously firing type II vestibular neuronal discharges in the pause neuron region resulted in short-latency, positive field responses. These results supported the conclusion that horizontal canal type II neurons of the medial vestibular nucleus project to and inhibit pause neurons monosynaptically.

Anatomic and electrophysiologic evidence suggests there is a vestibular input to eye movement-related pause neurons in the midline of the pontine reticular formation of the cat. The present investigation sought to explore the functional significance of this vestibular drive by examining pause neuron response to horizontal rotational stimulation as cats were anesthetized with halothane or went into natural light sleep. Anesthesia unmasks the vestibular input to pause neurons in that during anesthesia, pause neurons continue to fire but their firing rate is modulated by vestibular stimulation. The particular response patterns of pause neurons to anesthesia are not uniform. We suggest that the results observed could be explained if pause neurons received input from both vestibular nuclei, either directly or possibly via the prepositus hypoglossi.

Four subjects considered resistant to motion sickness were tested in KC-135 parabolic flight to examine ocular torsion at hypo- and hypergravity. Three of these showed no significant torsion at zero G in either the upright position or when tilted 30 degrees to right or left. At 1.8 G in the tilted positions they showed greater ocular counterrolling than at 1 G. None of these three subjects became motion sick. The fourth subject showed eye torsion toward his left in all positions at zero G. This leftward bias could also be seen at 1.8 G when tilted left ear down, the side that induces rightward counterrolling. There he had less eye torsion than at 1 G. This subject became motion sick. All subjects had normal counterrolling in ground-based testing. These results support the hypothesis that asymmetry of the utricular system may be well compensated in the normal 1 G environment, but unmasked in unaccustomed gravitational situations, suggesting a possible predictive test for space adaptation syndrome.

Light and electron microscopic observation 3--4 days after microinjection of Herpes simplex virus (HSV) into the left neostriatum of rat demonstrated the following results. (1) Virus labeled nerve cells were found in the ipsilateral substantia nigra; a large number of infected neurons were in the zona compacta and some were in the zona reticulata. No virus infection was evident in the contralateral side. (2) Virus labeled neurons were found in the cortex, a greater number ipsilaterally than contralaterally, and in the dorsal raphé nuclei. Cortical microinjection of HSV led to infection of some cortical cells but no neostriatal cells. We conclude, therefore, that spread of the virus to the cortex, the substantia nigra and the dorsal raphé following neostriatal injection was by retrograde axonal transport. (3) The left neostriatum, where HSV was injected, showed a surprisingly small number of virus infected neurons. The infected neurons were mostly the large neurons; the majority of medium sized neurons were well preserved. There was massive degeneration of nerve terminals throughout the neuropil. Most of these degenerating nerve terminals are considered to be afferent fibers.

The morphology of horizontal canal second-order type I neurons was investigated by intracellular staining with horseradish peroxidase (HRP) and three-dimensional reconstruction of the cell bodies and axons. Axons penetrated in and around the abducens nucleus were identified as originating from type I neurons by their characteristic firing pattern to horizontal rotation and by their monosynaptic response to stimulation of the ipsilateral vestibular nerve. A total of 47 type I neurons were stained. The cell bodies were located in the rostral portion of the medial vestibular nucleus (MVN) and were large or medium sized and had rather elongated shapes and rich dendritic arborizations. The neurons were divided into two groups: those which projected to the contralateral side of the brain stem (type Ic neurons) and those which projected to the ipsilateral side of the brainstem (type Ii neurons). All stem axons of type Ic neurons crossed the midline and bifurcated into rostral and caudal branches in the contralateral medial longitudinal fasciculus (MLF). Two or three collaterals arising close to this bifurcation distributed terminals in a relatively wide area in the contralateral abducens nucleus. Some of these collaterals projected further to the contralateral MVN and thus are vestibular commissural axons. Some of the rostral and caudal stem axons had collaterals which projected to the contralateral nucleus prepositus hypoglossi (PH), nucleus raphe pontis, or medullary reticular formation. There were at least six classes of type Ii neurons, most of which distributed to a relatively limited region in the ipsilateral abducens nucleus and they were categorized according to their future projections into the following categories: A) no further collaterals beyond the abducens nucleus; B) collaterals in the abducens nucleus and a branch descending and terminating in ipsilateral PH; C) projected to the abducens nucleus, PH, and an area rostral to the abducens nucleus; D) projected to the abducens nucleus and to ipsilateral reticular formation rostral and caudal to the abducens nucleus; E) collaterals in the abducens nucleus and a thick caudal stem axon entering and descending in ipsilateral MLF; F) a thick caudal stem axon entering and descending in ipsilateral MLF and no collaterals to the abducens nucleus. Some type Ii neurons also had recurrent collaterals which projected back to the ipsilateral MVN; these may inhibit type II neurons during ipsilateral rotation.

Seven subjects 18 to 66 years old underwent 360 degrees rotation at a constant velocity of 3 degrees/sec, in 27 trials beginning randomly right ear down or left ear down. A camera on the rotating chair photographed both eyes every 10 degrees. Dual projectors measured counterrolling, the image from one projector being aligned and rotated until it was superimposed on the image from the other. Right and left eyes were measured independently. The group reached maximum counterrolling at about 70 degrees and 270 degrees in rotations to the right, with values of about -6 degrees and 4 degrees respectively. Rotations to the left reached maximum at 50 degrees and 270 degrees with about 4.5 degrees and -5.25 degrees respectively. Individual subjects showed ranges of counterrolling varying from 4.03 degrees to 17.44 degrees, mean 11.30 degrees. More counterrolling was observed when subjects were tilted to right than to left. The downward eye counterrolled more than the upward. Amount of counterrolling was inversely correlated with age.

Vestibular brain stem neurons responsive to angular acceleration in the plane of the horizontal canal were examined in cats 30 to 52 days after contralateral labyrinthectomy and compared with similar units in cats with intact labyrinths and in other cats immediately after transection of the contralateral eighth nerve. In the compensated state, the mean spontaneous firing rate of type I neurons was 24 spikes/s, in contrast to the mean of 45/s observed immediately after contralateral labyrinthectomy. In intact cats, mean firing rate was 19 spikes/s. Sensitivity, as measured in spikes/s/deg/s2, was significantly lower immediately after labyrinthectomy than in intact controls and remained so in compensated cats. On the other hand, time constants and the ratio of adapting:nonadapting units was unchanged. Ablation of the midline cerebellum including vermis and fastigial nuclei did not materially affect these results. We concluded that (i) the main defects in static posture and nystagmus in the uncompensated state were due to the striking difference in resting firing rates between the ipsi- and contralateral vestibular nuclei; (ii) compensation in the static posture was the result of a tendency to equalize the resting firing rates in the two vestibular nuclei; and (iii) recovery in the dynamic, head-turning situation was due to partial recovery of sensitivity on the ipsilateral side, bringing it to the relatively constant, unchanging depressed sensitivity on the contralateral side.

Fifteen undemented patients with Parkinson's disease (PD) and 15 age-matched controls were given a battery of tests to assess sensorimotor integration in the arms. PD patients made more errors (p less than 0.01) than controls, particularly in tests of proprioception. Age was not related to errors. Compared with controls, two-point discrimination thresholds were significantly higher (p less than 0.02) on the index finger of PD patients, but not on the forearm. Results confirm the sensorimotor deficits found earlier in an orofacial study, and imply that PD involves a generalized dysfunction of sensorimotor integration and proprioception, probably a result of impaired basal ganglia function in processing and integrating sensory input to organize and guide movement.

The conduction velocity and other physiological characteristics of the first order horizontal canal afferents were studied in 24 anesthesized cats. From their spontaneous discharge patterns, neurons were classified into three groups: regular, intermediate and irregular; The irregular units tended to have a low resting rate, high sensitivity to angular acceleration, frequently exhibited adaptation during prolonged acceleration, and showed a short latency from the time of electric stimulation of the labyrinth to recording the action potential near Scarpa's ganglion. The regular units tended to have a high resting discharge rate, low sensitivity, were mostly non-adapting, and showed longer latency to electric stimulation. The intermediate neurons had a mixed character of regular and irregular units. Based on the very short conduction times (mean 0.34 msec) and the work of Moxon (1971), we conclude the locus of activation of electrical stimulation is neural rather than the receptor cells. Since the latency is due predominantly to conduction in the first order axon, and since there is a direct linear relation between conduction velocity and fiber diameter in the medullated nerve fibers, it is possible to speculate that the regular cells have thin fibers which innervate the slope of the crista, the irregular neurons have thick fibers which innervate the summit of the crista, and the intermediate units have medium caliber fibers which innervate both the slope and summit of the crista ampullaris.

Six adult Macaca fascicularis monkeys were trained to perform an instrumentally conditioned, visually-guided forearm reaching task for fruit juice reinforcement. Once animals were overtrained on this task, they were given intravenous injections of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (0.15 to 0.33 mg/kg). Animals were tested daily for performance in the previously learned behavioural task and were assessed daily for abnormalities in motor functioning. Monkeys developed deficits in operant task performance characterized by termination of responses after an initial series of responses and long pauses between responses. Once an animal stopped responding to the task, responses could often be reinitiated if the experimenter guided the monkey through the task. This type of performance deficit was seen both before and without the appearance of distinct parkinsonian motor signs. Animals which developed motor signs had extensive ventral mesencephalic cell loss while an animal with performance deficits but without motor signs had cell loss restricted to the ventral substantia nigra pars compacta. The results demonstrate that operant performance deficits can be observed in MPTP-treated monkeys independent of the appearance of motor deficits.

Patterns of local cerebral glucose utilization were measured with positron emission CT using the 18F-fluorodeoxyglucose method in 13 patients with HD, 15 subjects at risk for HD, and control subjects. These data were compared with CT measures of cerebral atrophy, age, and duration and severity of symptoms. The results indicate that in HD there is a characteristic decrease in glucose utilization in the caudate and putamen and that this local hypometabolism appears early and precedes bulk tissue loss. In contrast to demented patients with Alzheimer's disease or Parkinson's disease, in these HD patients glucose utilization typically was normal throughout the rest of the brain, regardless of the severity of symptoms and despite apparent shrinkage of brain tissue. Our results indicate that the caudate is hypometabolic in some asymptomatic persons who are carriers of the autosomal-dominant gene for HD.

Four geographically diverse centers provided data on mortality in 359 patients with Parkinson's disease, the majority of whom began dopa treatment during the early experimental trials of 1968 to 1970. Patients were classified into three groups based on the duration of symptoms prior to starting dopa treatment: Group 1, 1 to 3 years; Group 2, 4 to 6 years; Group 3, 7 to 9 years. After 15 years of treatment and 3,689 person-years of observation, Group 1 had an observed-to-expected mortality ratio of 1.43; Group 2, 2.44; and Group 3, 2.95 (p less than 0.05). This result confirmed that increased duration of disease was associated with increased mortality risk. To examine the effect of the time of initiation of dopa treatment, duration of disease was held constant at 17 years for all three groups. Observed-to-expected mortality ratios were 1.43 for Group 1; 2.66 for Group 2; 2.63 for Group 3. This statistically significant advantage for Group 1 (p less than 0.0001) led to the conclusion that early treatment with dopa has a beneficial effect on life expectancy. After 17 years of disease, causes of death in Group 1 were less likely (p = 0.027) to be due to Parkinson's disease than was found in the other groups.

In a review of 61 patients with Parkinson's disease who were treated by cryothalamectomy, the technique of freezing a surgical target as compared with destroying it by alcohol or thermal heat was found effective and to a degree safer than other techniques. One patient died of unexpected cerebral hemorrhage. Of patients considered excellent candidates for the operation, 80 per cent had excellent and good results, while those considered good candidates showed 85 per cent excellent and good results. The results are more dependent on the selection of the patient as a candidate and the diffuseness of the pathophysiological circuits involved than on the technical factors of the cryogenic procedure.

Twenty-seven Parkinsonism patients and 31 controls, matched for age and verbal IQ, were tested on an objectively scored personality test (Minnesota Multiphasic Personality Inventory) at the beginning of the patients' levodopa therapy and three months later. Patients, but not the controls, were retested after 15 months of levodopa treatment. The patients, all of whom were intact intellectually, obtained MMPI scores indicating moderate depression before beginning levodopa treatment. There was no test evidence to indicate that levodopa significantly increased or decreased the amount of depression in the patients after three or 15 months of levodopa. The patient group, however, significantly increased their Index of Psychopathology (Ip) score after 15 months of levodopa but not after three months.

Electrical stimulation of the utricle in C-1 transected cats (whose labyrinths remained sensitive to natural stimulation) induced bilateral pupillary dilatation and bilateral 0.4 to 3.0 diopter lens change in an anti-accommodative direction. Both effects could still be induced two weeks after cutting the ipsilateral cervical sympathetic trunk. It is concluded that these effects take place by inhibiting the parasympathetic pathway originating in the Edinger-Westphal nucleus. The mediating pathways from the vestibular complex to the Edinger-Westphal nucleus pass through the brain stem in the region outside the medial longitudinal fasciculi.