Richard N. Johnson

Effects of valproate and ethosuximide on thalamocortical excitability.

Sodium valproate and ethosuximide are anticonvulsants employed in the treatment of petit mal epilepsy; both drugs are considered to be thalamically active. Valproate and ethosuximide both decreased the average evoked response following the second of two stimuli delivered to the ventrolateral thalamus at stimulus frequencies in the region of 3 Hz. Ethosuximide, but not valproate, enhanced the average evoked response at high stimulus frequencies an action shared with several convulsant treatments having different modes of action. The clinical effects of valproate and ethosuximide can be related to this differential modulation of thalamocortical excitability.

Effects of antiepileptic drugs on thalamocortical excitability

Comparative effects of anticonvulsant drugs on the thalamocortical system were analyzed quantitatively. Paired stimuli were delivered to the ventrolateral thalamus with evoked responses recorded from the ipsilateral sensorimotor cortex in the cat. Threshold and excitability profiles were developed with an on-line computer. Effects of phenytoin and diazepam were generally similar, with depression of excitability and slight elevation of thresholds. Ethosuximide produced a pronounced pair-interval dependent effect of unchanged or increased excitability and lowered threshold at shorter intervals, with depressed excitability and raised threshold at longer intervals. These data demonstrate a marked difference in effect of the petit mal and grand mal agents tested and suggest a basis for the effectiveness of ethosuximide in controlling 3-per-second repetitive activity.

A theoretical and experimental determination of vestibular dynamics in caloric stimulation

A biophysical model was established for predicting the temperature at the horizontal semicircular canal and the horizontal slowphase velocity (SPV) in response to water or air irrigations of various flow rates and time varying temperatures. This model considered the thermal characteristics and blood flows of the skin and temporal bone. Long-term caloric stimulation with air at 101/min was performed on 16 healthy subjects using step input and pseudo-random temperature variations. The results were in agreement with the predicted static and dynamic SPV responses. The model predictions were also correct in the case of water irrigations performed by other investigations with respect to SPV and the temperatures measured at the semicircular canal. An association of higher responses with lower response time as postulated by the model, was confirmed by the experimental results, and was thought to be due to vasomotor changes in the skin. The most important model parameters were the length of the heat transmission path, the effective heat conductivity of the skin, and the blood flow and heat conductivity of the temporal bone, in addition to the flow rates and thermodynamic properties of the irrigation. These parameters should thus be considered in further caloric stimulation studies for a better understanding of the large variability in vestibular responses.

The thalamocortical system as a neuronal machine: The interaction of ventrolateral nucleus with sensorimotor cortex in the cat

Summary The concept that the ventrolateral (VL) thalamic projections to sensorimotor cortex form a ‘self-modifying’ machine— i.e. , a machine whose response is due to both incoming information and information from its past history of use — has been substantiated by: (1) Developing a quantitative measure (specific output) of the cortical response evoked from pulse pairs delivered to VL. (2) Utilizing this measure to illustrate the differences which occur when nonsequential versus sequential testing is used. The dependence of specific output on both parameter changes put in by the experimenter and the existing conditions within the neuronal machine at the time of testing — i.e. , conditions set by past history — are illustrated. The adoption of a specific trajectory due to a selected sequence of stimuli further illustrates the adaptive nature of this system. Cerebellar influences have been investigated, in part, by ablating contralateral brachium conjunctivum and observing the changes which occur in machine performance. The principal influence of the cerebellum appears to be to impose stricter bounds on the modifying factors, on specific output amplitudes over sequential trajectories and on the dynamic cortical activity occurring during the first 10–25 msec after the delivery of a stimulus to VL.

Development of the Thalamocortical Augmenting Response in the Kitten

Summary: Study of the developing central nervous system can lead to better understanding of the mature central nervous system. The thalamocortical augmenting response is a complex neurophysiological response considered to be related to the occurrence of some forms of epileptic activity. Using a paradigm previously developed in adult cats, we assessed the development of the thalamocortical augmenting response in kittens and found that the relative proportion of thalamocortical activity occurring at high frequencies of thalamic stimulation increased with increasing age. Anticonvulsants effective against petit mal seizures also increase the relative proportion of thalamocortical activity following high frequencies of thalamic stimulation. Developmental changes in the thalamocortical augmenting response can be related to the age‐dependent decreases in the prevalence of petit mal seizures.

The thalamocortical motor system and stability: Observation of a possible regulatory mechanism

Abstract1.A simplified model of the thalamocortical motor system (VL-MC) is proposed, containing as principal components, an integrator and a regulator. The integrator generates ramp functions, with the slope of the ramp determined by sensory (peripheral) input. The duration of the ramp function is controlled by the regulator. The regulator is assumed to be a higher order control system whose overall goal is to prevent the VL-MC system from shifting to an unstable (e.g. epileptiform) mode of operation.2.The VL-MC system has been investigated in cats utilizing 3 anesthetic agents; pentobarbital, chloralose and ketamine. The experimental results, when explained within the constraints of the model, were as follows: a) In the pentobarbital cases, ramp slopes were truncated by a negative slope of approximately equivalent magnitude. The ramp truncation mechanism (regulator) operates to limit the maximum amplitude of the ramp, resulting in a compensatory reduction in ramp duration for steeper ramp slopes. No cortical epileptiform activity was observed. b) In the chloralose cases, at a level of anesthesia where active nociceptive reflex action was present, steeper ramp slopes were observed which were not truncated by a negative slope of equivalent magnitude. Epileptiform spike activity was observed on motor cortex. The ramp truncation or regulatory mechanism appears to be significantly reduced in capacity, when chloralose is used as an anesthetic agent, as compared to pentobarbital. c) In the ketamine cases, the ramp generation mechanism appears to be completely disabled. No epileptiform activity was observed.3.It is suggested that a regulatory mechanism exists as a functional part of the thalamocortical motor system of the cat and that this regulatory mechanism plays a key role in preventing the system from shifting to an unstable mode, characterized by epileptiform cortical activity.4.A simplified model of the system has been implemented on an analog computer and suggests one possible design for the regulatory mechanism in terms of the variables measured and the parameters controlled.

Modulation of the thalamocortical motor system by sensory information.

Abstract A linear approximation of the input-output relationship between ventrolateral (VL) nucleus and sensorimotor cortex (MC) in the cat has been employed. The slope of the transfer function has been termed the central rate sensitivity (R). It has been shown that the system parameter R can be controlled by the time interval between a central thalamic stimulus and a peripheral stimulus, either auditory, visual or somesthetic. The response profile of the system, plotting central rate sensitivity (R) as a function of the peripheral-central time difference (X) indicates that the VL-MC system can perform as a null detector, with minimum R values occurring in the vicinity of peripheral-central signal correspondence. The system shows considerable hysteresis in the region of X= 0 with the value for R(X= 0) determined by the direction of approach toward X= 0, where the term direction implies a lead or lag relationship between the peripheral and central stimulus.

An elementary description of thalamocortical system dynamics in the cat

Summary A limited range linear approximation for the input-output relationship of the ventrolateral thalamic (VL)-motorsensory cortical (MC) system has been utilized. The slope of the transfer function has been termed central rate sensitivity (R) and considered as the major parameter of interest. The changes in central dynamics which occur between nonsequential and sequential (1/sec) testing have been illustrated, with particular emphasis on the hysteresis or delay effects between shifts in thalamic stimulus parameters and the resulting cortical response. Peripheral control of central dynamics has been demonstrated by varying the time relationship between peripheral and central stimuli and observing the dependence of central rate sensitivity (R) on the peripheral-central time difference (X). Minimum R values were shown to occur at the point of peripheral-central signal coincidence (X= 0). The dependence of R on the sequence of X has been shown, with specific X sequences capable of forcing the neuronal machine to high R values and subsequent breakaway from the linear mode. The variations which occur in central rate sensitivity (R) following the placement of a freeze lesion in the contralateral cortex, homologous to the recording site, have been shown. The disruptive influence of the developing freeze lesion on the functional relationship between R and the peripheral-central time difference (X) has been demonstrated, with the lesion apparently being capable of completely reversing the situation of minimum R at X= 0 to near maximal R at X= 0. This reversal from a negative feedback situation to one of positive feedback may provide a mechanism for signal precipitation of system runaway with resultant epileptiform cortical discharge.

Observations on the Effect of Morphine on Thalamocortical Excitability in the Cat

Summary: The acute effects of morphine on the thalamocortical augmenting response in the cat were evaluated. The thalamocortical augmenting response was elicited by delivering pairs of pulses to the ventrolateral thalamus and recording from ipsilateral sensorimotor cortex. A biphasic, dose‐related, naloxone‐attenuable effect on the augmenting response elicited by pulse pairs was observed. Although the clinical significance of those morphine‐induced changes is currently uncertain, they can be correlated with the convulsant and anticonvulsant effects of different doses of morphine.

Cerebellar Stimulation: Regional Effects on a Thalamocortical System

Summary: Regional effects of electrical stimulation of the cerebellar surface were quantitatively analyzed. Computer controlled stimulus sequences were delivered to ventrolateral thalamus and evoked responses recorded from ip‐silateral sensorimotor cortex in the cat. Threshold and excitability profiles were produced with an on‐line computer, and their modification by cerebellar stimulation was determined. The results of electrical stimulation of the cerebellar surface were: (1) depressed excitability from paramedian lobule and lobulus simplex; (2) uniquely elevated thresholds from paramedian lobule; and (3) a profound and long‐lasting depression of excitability following termination of lobulus simplex stimulation. In comparison with our anticonvulsant drug studies, these data suggest that cerebellar surface stimulation has a far greater capacity to control excitability and threshold responsiveness of thalamocortical systems. Cerebellar electrode placement and temporal pattern of stimulation appear to be important factors in the production of antiepileptic effects.