An investigation was made of both primary and “transfer” kindling as they occur in ipsilateral limbic sites. Primary kindling was found to involve progressive growth of afterdischarge (AD), propagation and convulsive behavior. It was noted that AD growth did not take place gradually but occurred in sudden, large increments. “Transfer” (a significant acceleration of secondary kindling) was found at every secondary limbic site. It was associated with the early appearance of full-blown AD's, super-normal propagation, and well-developed seizures. The post-transfer interference of primary site function previously reported by Goddard et al was also found, but it occurred in significant amounts only after transfer kindling of the amygdala. It is believed that the data offer some support for both of the hypothetical mechanisms of transfer which have been proposed.

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.

This patient presented as a subacute progressive cervical myelopathy and the differential diagnosis included cervical spondylotic myelopathy and intramedullary mass. Microscopically, vascular lesions plus a patchy myelomalacia indicated a vasculitis. However, there was no suggestion of a generalized vasculitis at autopsy and the only supporting laboratory study was a raised erythrocyte sedimentation rate. It would seem that a vasculitis similar to polyarteritis nodosa or other collagen disease may be confined to the spinal cord.

Rats were subjected to varying degrees of commissurotomy, followed by implantation of a bipolar electrode into each amygdala. After the kindling of six convulsions at one electrode (primary site), the procedure was applied to the contralateral amygdala (secondary site). Convulsions were observed to develop more rapidly, independent of the degree or kind of transection. After 6 secondary site convulsions, the primary site was re-tested and convulsion-triggering was blocked, except in animals with transection of the rostral portion of the corpus callosum (CC).

Collectively, the data indicate: (i) amygdala kindling develops a lasting trace which operates through the midbrain or brainstem; (ii) kindling from a second site utilizes this trace; (iii) a series of 6 convulsions produces negative after-effect which manifests itself at the convulsion level via the anterior CC; (iv) the anterior CC is important in determining the laterality of the forelimb clonus; and (v) the inter-amygdala propagation of after-discharge is blocked by the combined sectioning of the anterior CC and the anterior commissure.

Seizure development and transference phenomenon were investigated in hippocampal and amygdaloid kindled cats. The behavioral and electrographic findings during the kindling procedures showed that motor seizure development in hippocampal seizures occurred with the emergence of independent discharging in the amygdala, globus pallidus and contralateral hippocampus. Furthermore, secondary site convulsions developed upon the first stimulation of these structures in the hippocampal group but only after over a month of hippocampal stimulation in the amygdaloid group. It was, therefore, concluded that role of the amygdala and globus pallidus in hippocampal seizure development was more essential than that of hippocampal stimulation in amygdaloid seizure development. The common findings between the hippocampal and amygdaloid kindled animals were the systematic progression to seizures, the all-or-nothing nature of the electrical response and the relative permanency of the seizure susceptibility. Seizure susceptibility increased during slow wave sleep and decreased during REM sleep. These latter findings were examined with preliminary data of brain bioassays of catecholamines.

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.

A longitudinal study of the effects of sleep on amygdaloid kindling showed that kindling disrupted normal sleep patterns by reducing REM sleep and increasing awake time. Few interictal spike discharges were observed during the awake stage, while a marked increase in discharge was observed during the light and deep sleep stages. No discharges were observed during REM sleep. During the immediate post-stimulation period the nonstimulated amygdala showed a much higher rate of spike discharge. On the other hand, there was an increase in spike discharge in the stimulated amygdala during natural sleep without preceding amygdaloid stimulation. Amygdaloid stimulation at the generalized seizure threshold during each sleep stage resulted in a generalized convulsion.

The influence of subcortical electrical stimulation on kindled amygdaloid convulsions was investigated in a second experiment. Stimulation of the centre median and the caudate nucleus was without effect on kindled convulsions, while stimulation of the mesencephalic reticular formation at high frequency (300 Hz) reduced the latency of onset of kindled generalized convulsions. Stimulation of the nucleus ventralis lateralis of the thalamus at low frequency (10 Hz) prolonged the convulsion latency, and at high current levels blocked the induced convulsion. Stimulation in the central gray matter at low frequency (10 Hz) also blocked kindled amygdaloid convulsions.

This report presents studies which relate limbic epileptic excitability to behavioral measures of defensive suppression of predatory attack in cats. Correlated with heightened defensiveness to environmental stimuli among non-killer cats is a heightened amygdaloid epileptic excitability, as well as a heightened conduction of amygdaloid epileptic activity to thalamic and hypothalamic substrates of predatory response in the amygdala to the complex visual stimuli presented by rat prey. These neurosensory responses correlate well with measures of epileptic excitability. Brain and behavior measures appear related since enhancement of excitability in the amygdala and of projection of epileptic activity by repeated electrical stimulation of predatory attacks. Furthermore, the ventral hippocampus seems capable of antagonizing the behaviorally suppressive effects of heightened amygdaloid excitability perhaps at points of convergence of amygdaloid and hippocampal output.

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.

The purpose of the present investigations was to explore the generality of the kindling phenomenon and its applicability to clinical situations. Whether local brain stimulation, electroconvulsive shock (ECS), or metrazol the consequence of periodic administration of convulsive agents was found to be the same; in each case repeated application of the agent resulted in the gradual development and intensification of convulsive symptoms (kindling). Moreover, in each case the resulting intensification was not specific to the agent being used and seemed to increase the responsiveness to convulsive agents in general. In the present studies this interaction was seen in the form of an intensified alcohol withdrawal syndrome observed 18 days after cessation of a series of metrazol injections, amygdaloid stimulations, or ECS. Thus, it appears that one of the hazards of the convulsive therapies is that they may induce enduring changes in brain function which leave the patient in a state of increased susceptibility to a variety of potentially convulsive agents.

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.