The concept that “denervation” or “pharmacological disuse” supersensitivity develops in central neuronal systems subsequent to sustained attenuation of normal neurohumoral mechanisms is reviewed. Particular emphasis is placed on biochemical and electrophysiological parameters of supersensitivity in dopaminergic (striatal) neuronal systems. The possible applicability of theories invoking changes in receptor sensitivity to the phenomenon of narcotic tolerance and physical dependence and to psychoactive drug therapy is discussed.

The history of the control of epileptic disturbances by conditioning techniques is reviewed. The preliminary results of a three year trial of feedback techniques in 13 epileptic patients are presented.

Thirteen epileptic patients (age 2.5 → 39 mean, 15.1 years) with lateralized focal discharges in the EEG were given repeated trials of feedback, the focal discharges being used to trigger auditory and somatosensory stimuli. Dosages and serum levels of medication were unchanged throughout the experimental period. The number of epileptic spikes per 15 seconds was assessed by automatic trend analysis during 20 to 30 minute control, biofeedback and post-feedback epochs. Ongoing EEG activity was quantified by 8 channel frequency analysis over 10 second epochs. The patients made efforts to increase and decrease the number of spike discharges with and without feedback and the results of both triggered and random auditory, somatosensory, photic and combined stimulation were compared at various intervals over a period of up to three years. A marked reduction in the number of focal discharges was noted in eight (61.5%) patients during and immediately following the sessions.

Intermittent biofeedback sessions were not associated with a serial reduction in the number of focal EEG discharges. There was a reduction in the number of clinical epileptic disturbances in six patients (46%) and possible reasons for this improvement are discussed.

One patient suffered an increase in focal temporal lobe discharges during triggered and random auditory stimulation whereas there was a marked reduction in the number of discharges during minimal electrical stimulation of the contralateral arm. The need for careful assessment of each patient to determine appropriate feedback stimulation is stressed.

One aim of this research has been to assess the feasibility of using miniature units for continuous feedback of focal discharges in epileptic patients.

A double-blind, double-observer study was carried out in twenty-five patients with Parkinson’s disease. Alpha methyldopahydrazine in combination with L-dopa was compared to placebo with L-dopa. Combination therapy resulted in a reduction in L-dopa dosage to 1/3 of the amount required during the baseline. There were no side effects attributed directly to the alpha methyldopahydrazine. The overall incidence of side effects in the two groups was similar but the combination therapy significantly reduced the incidence of nausea and vomiting. The limiting factor in the combination therapy was the presence of L-dopa induced dyskinesias.

The ultrastructural responses of cerebral tissue following temporary periods (½, 1, 2, 3, or 4 hour) of right, middle cerebral artery, (MCA) occlusion were studied acutely after a 3 day or 7 day interval following the removal of the MCA clip. Cortical and basal ganglia tissues for each ischemic duration were compared at 3 post-occlusive periods (acute, 3 days, 7 days).

With the short periods of ischemic insult (½, 1, 2, 3, and 4 hour), the temporal and insular cortex contained no greater changes in the 7 day group than in the 3 day group.

The basal ganglia were more susceptible to MCA occlusion as indicated by more marked cytological changes and/or necrosis in all intervals of ischemia.

The effect of diazepam on presynaptic inhibition in man has been examined in 5 patients with complete spinal transections and 7 patients with incomplete lesions. The inhibition of the H reflex by vibration applied to the tendo Achilles was used to assess presynaptic inhibition of the la monosynaptic pathway. Diazepam increased this inhibition in the patients with incomplete lesions, but had no significant effect on the inhibition in the patients with complete spinal transections.

Evidently diazepam can enhance presynaptic inhibition in man. The effect, however, cannot be demonstrated in patients with longstanding complete spinal lesions possibly because of some alteration in the segmental presynaptic inhibitory mechanism in this group.

A computerized analysis of 128 patients admitted with acute head injury and who underwent angiography is shown. Patients were divided into groups according to: age, sex, type of accident, state of consciousness and presence of localizing signs on admission, types of cerebral lesions on angiography, and discharge condition.

There is a preponderance of young males in this series of patients, related mainly to MVA. A total of 71% of the patients had abnormal angiograms, but the incidence of normal and abnormal results did not correlate significantly with any of the chosen parameters.

The same parameters were also analysed to assess their value as a prognostic index for the patient. The conclusion was drawn that the angiogram per se has no significant value as a prognostic tool, and that state of consciousness on admission is the best single index for prognosis.

The superior temporal gyri were measured in 33 infants and in 33 adults. In the adults, most right superior temporal gyri were larger. This asymmetry was not found in infants, a difference which suggests greater growth of the right superior temporal gyri in the population from which our sample was taken. The asymmetry may be related to the functional asymmetry found by Penfield: some of his patients reported re-experiencing of past sensory experiences with electrical stimulation of the temporal lobe. This response was more frequently evoked from the right hemisphere.

Three elderly women with marked progressive voice tremor, without other neurological symptoms, and negative family histories were investigated.

All had a 4-5 Hz respiratory tremor in expiration and, to a lesser degree, in inspiration; and all had vocal tremulousness synchronous with their respiratory irregularity. Articulation of phonemes was normal. In two cases the neurological examination was otherwise normal; in the third case there was a minimal 7½ Hz tremor in the left thumb and index finger.

Simultaneous speech and vocal air pressure recordings, as well as cinematographic studies of the vocal apparatus and diaphragm were carried out.

It is suggested that these cases represent primarily an action tremor of respiration, that they belong in the spectrum of essential tremor, and hence may be amenable to treatment with propranolol.

The light and electron microscopic features of a pituitary adenoma composed of adrenocorticotrophic hormone (ACTH) and melanocyte stimulating hormone (MSH) cells with perivascular amyloid deposition is reported. Histochemical and fine structural data indicate that this material is APUDamyloid and is present in the extra-cellular perivascular spaces. It is suggested that the differences in fine structure and of distribution of the amyloid in pituitary adenomas is dependent upon the cell of origin.

A 63 year old female with the ataxic form of Creutzfeldt-Jakob disease (CJD) is presented. In addition to amyloid plaques which were not associated with Alzheimer’s neurofibrillary tangles, rare profiles similar to those reported in Scrapie were also seen. To our knowledge, these profiles have never been observed in CJD and their presence in this condition adds a further morphologic similarity between the human and animal forms of subacute spongiform “viral” encephalopathies.

It is certainly a mark of great wisdom to the organizer of this meeting to have chosen Charles Phillips as our Guest Lecturer for this meeting.

Whilst I am grateful for this opportunity of saying a few words of introduction, I am sure it can be said of Charles Phillips that very little introduction is necessary, since we meet him at the most important meetings in Neurophysiology around the world. Any meeting on the motor system, of course, is not complete without the participation of Dr. Phillips. However, some of the less old-timers than myself, and the students, might be interested in the beginnings of Dr. Phillips’ career in neurophysiology and to know that he was first a clinical neurologist beginning his medical studies in Oxford just before the war, where he came under the influence of Sir Charles Sherrington with Jack Eccles as his tutor.

It is a great pleasure to welcome all participants and members of the audience on behalf of the Organizing Committee of this Symposium. John Girvin, Bob Lee and I hope that joint considerations of basic and clinical problems in Neuroscience will become a regular feature from now on at this Annual Canadian Congress of Neurological Sciences, with participation by members of the Society for Neuroscience.

This prologue to a symposium of research studies on motor mechanisms is a general commentary by a clinical neurologist. The vast extent and intricacy of modern basic neurological scientific knowledge presents a rather bewildering challenge to reasonable clinical application. In some degree this is being handled by complex and diverse neurological subspecialization. It is recalled that many past advances in the knowledge of neurological disease were achieved by a series of alternating and supporting bedside and laboratory observations and studies.

The varied disorders of movement and muscle tone which signal disordered motor mechanisms will continue to demand explanation and will keep the human model in a leading research position. Clinical and laboratory research leading to part discoveries of mechanisms of disease is sometimes productive of dramatic new means of therapy. The story of Wilson’s disease is briefly reviewed in that context. Some recent studies on hypoxic myoclonus are described with the evidence of a serotonin defect and useful related therapy.

For several years our interest has been in a postural Parkinson-like tremor at 4-6/sec. which can be produced in the monkey by lesions of the central nervous system. We have also studied the effects of harmaline, a drug which evokes or intensifies the Parkinson-like tremor in lesioned animals and which also induces a fine, generalized tremor at 7-12/sec. in normal animals. The results obtained so far indicate that these two types of tremor are generated by two independent central mechanisms which do not require the integrity of peripheral feedback loops. The experimental Parkinson-like tremor is generated by a thalamo-cortical mechanism while the olivo-cerebellar system is responsible for the faster ”physiological“ tremor. Similar tremor mechanisms may be involved in some movement disorders in man.

Chronic recording is possible from nerve fibers which have grown through holes in an insulating medium (regeneration electrodes) or which are enclosed by an insulating sheath (cuff electrodes). Use of three electrodes in a balanced configuration permits good rejection of electromyographic (EMG) signals and other sources of electrical interference (fluorescent lights, 60 Hz signals from the mains, etc.). Equations are derived and tested for predicting the amplitude and form of the signals expected for a given cuff length and diameter. These equations can be used to design electrode units optimally for a given application. Finally, the use of transformers permits the neural signals to be carefully matched to the recording apparatus and further optimizes the neural signal-to-noise and signal-to-EMG ratios. Use of these methods in several physiological and clinical applications, as well as potential abuses, are discussed.

The pyramidal tract and particularly the direct corticomotoneuronal components (DCM) have become increasingly important in the higher primates. Minimal single pulse precentral stimulation in man evokes EMG discharges from the contralateral hand muscles with a latency of 18-21 milliseconds. The excitability changes produced by such cortical stimulation on the upper limb H-reflex has been observed to include a short duration early facilitation probably corresponding to the DCM input and a later, longer lasting facilitation mediated by the same and probably other corticofugal projections. Potentiation of the H-reflex in the upper limbs by means of postcentral excitation required much higher single pulse stimulus intensities and the changes in excitability produced on the spinal motoneurons could have been explained by physical extension of the stimulus current to the precentral region. Isometric contraction potentiated the H-reflex produced by combinations of precentral cortical and peripheral nerve stimulation but no direct evidence was found to support a possible transcortical basis for the V2 stretch reflex.

Postural or Parkinson-like tremor, which results from the impairment of mechanisms which are predominantly lateralized in the brain, is most likely related to the combined impairment of the dopaminergic nigrostriatal pathway and the corresponding rubro-olivo-cerebello-rubral loop (without excluding the possibility that other nervous mechanisms interconnected with these structures may represent an alternative disturbance). The integrity of the internal division of the pallidum and the ventrolateral area of the thalamus and their efferent fibers as well as the motor cortex and certain of its cortico-subcortico-spinal pathways (Figures 1 and 2) is apparently an essential feature for the elaboration of the rhythmic bursts associated with the appearance of postural tremor. The integrity of the spinal sensory roots and the rubro-tegmentospinal tract is not a prerequisite for the expression of postural tremor, a condition which seems essential for the production of rigidity. The latter facts suggest that the disturbances which subserve these two types of motor impairment, often concomitantly present in Parkinsonism, partially involve the impairment of different mechanisms although the loss of the DA fibers originating in the substantia nigra and ending in the neostriatum (Figure 1) appears to represent a disturbance common to both types of disorders.

Bradykinesia which may be associated with an impairment of catecholamine metabolism (and more especially the neostriatal DA mechanisms) on both sides of the brain may also result from bilateral lesions of the pallidum or of its outflow corresponding, in the main, to the pallidothalamic fibers ending in the ventrolateral thalamus. The latter types of lesion most likely exclude the influence of the monoaminergic, cholinergic and gabaminergic activities normally originating in the striopallidal system and influencing the activity transmitted to other CNS mechanisms. Severe akinesia, however, apparently depends on more profound and generalized disturbances of brain monoamine metabolism with or without the involvement of other ill-defined mechanisms. At any rate the impairment of the brain DA mechanisms (and especially those of the neostriatum) seems to represent a major feature in the production of the Parkinsonian type of akinesia. Further work is needed to establish the relative importance of the loss of catecholaminergic mechanisms other than those of the neostriatum in the production of akinesia.

Theories of function of the cerebellum and basal ganglia are examined in the light of recent experimental findings obtained with the local cooling method, and both are matched against clinical observations. Evidence is summarized for a programming and initiating role in monkeys’ elbow movements of the lateral, and to a lesser degree, intermediate, cerebellum. Cooling either nuclei affected movements, but neither seemed to be important for precentral cortical unit discharge accompanying compensation for suddenly applied load pulses. The globus pallidus seemed to be importantly involved in movement guidance in the absence of vision.

A primary control system for the arm position is formulated. The hypothesis that the cerebellum is a part of the system controller is checked by studying the nerve cells responses in the cerebellum, and motor cortex, to natural activation of muscular receptors. The results show that the cerebellum receives feedback information related to the speed of these receptors. The discussion concentrates on how the interruption of this feedback may result in excessive oscillations to instability. These observations are the base for evaluating how the cerebral lesions produce dismeasurements.