Evoked metabolic responses in the limbic-striate system produced by stimulation of anterior thalamic nucleus in man.

Six human subjects (5 male, 1 female, age 23.7 + 5.7 years) with incapacitating partial seizure disorders intractable to medical therapy have been treated by ongoing pulsed electrical stimulation of anterior nucleus of the thalamus. Four of the six patients have demonstrated statistically significant clinical control of the seizure disorder. One patient (D.L.) has been seizure-free for the last two years. In two of these six patients, it was possible to study not only electrophysiological activity of the brain, but also regional cerebral glucose metabolism by the (18F) 2-fluoro-2-deoxy-D-glucose method, blood cortisol levels, and blood levels of valproic acid, diphenylhydantoin, and carbamazepine. Significant changes were seen during periods of stimulation compared with control periods without stimulation. These results imply that stimulation of the principal thalamic relay nucleus of the limbic system causes clinical, behavioral, cerebral metabolic, electroencephalographic, endocrinologic, and pharmacokinetic responses.

Chronic cerebellar stimulation (CCS) and deep brain stimulation (DBS) in involuntary movement disorders.

Motor disorders of disinhibition may be modified by prosthetic mobilization of CNS inhibitory mechanisms by chronic electrical stimulation of the cerebellar cortex (CCS) and by deep brain stimulation of the thalamus and internal capsule (DBS). Reduction in spasticity, abnormal movements, intractable epilepsy and aggressive behavior has been reported after CCS, although negative results in human and animal studies have been published. No adverse neurologic, psychologic or intellectual effects of stimulation have occurred after 7 years of CCS, although subclinical histological changes may occur in the cerebellar cortex under the electrodes. CCS has been shown to produce physiological changes in evoked potentials, motoneurone excitability, epileptic discharges in the EEG and quantitative changes in movement. Surface and deep thalamic recordings have shown reduced amplitudes of somatosensory responses after CCS. Over the last 2 years we have employed chronic deep brain stimulation (DBS) in 49 patients with clinically useful results in half the patients. The technique allows reversible modification of movement disorders, and the technique can be used on the second side after a previous thalamectomy. Physiological testing, direct thalamic recordings and quantitative analysis of movement have allowed assessment of optimal rate and voltage of stimulation. For some intractable movement disorders DBS has effected significant therapeutic results when all other therapeutic techniques have failed.

Twenty-five years of experience with physiological neurosurgery.

Twenty-five years of experience with physiological neurosurgery for the treatment of movement disorders leads the author to conclude that such syndromes are caused by disordered mechanisms of sensory communication within the brain. The physiological and therapeutic effects of ablation of the posterior portions of the ventrolateral nucleus of the thalamus, the stimulation of the anterior or rostral cerebellar cortex, and deep brain stimulation of some thalamic nuclei are due to the decrease of pathological disinhibition of motor mechanisms. Further advances in the reversal of chronic neurological symptoms by the alleviation of pathological sensory disinhibition are anticipated.

Correlation of clinical and physiological effects of cerebellar stimulation.

The value of clinical assessment of patients undergoing chronic cerebellar stimulation (CCS) is limited by lack of objective measures but neurophysiological tests can be used to "biocalibrate" the stimulator and may be used to predict effects of CCS. Eighty-seven patients undergoing CCS have been assessed clinically and neurophysiologically over the last 4 years. Somatosensory evoked responses were significantly ( p less than 0.05) reduced in amplitude in 35 patients, cortical somatosensory evoked responses in 44 patients and one or both responses were reduced in 55 patients. There were no clinical or physiological changes in 16 patients. Evoked responses showed significant changes in only 3 patients who did not show clinical improvement. The mean voltage settings were 5.2 volts and most patients were stimulated at 200 herz. These results indicate that significant changes in those somatosensory evoked potentials are a good indication of clinical benefits from CCS but clinical improvement may occur in the absence of any acute effect on evoked responses.

Reversibility of chronic neurologic deficits. Some effects of electrical stimulation of the thalamus and internal capsule in man.

Stimulation of the thalamus and internal capsule with Medtronic deep brain stimulation electrodes produced improvement in pain, hemiparesis, dystonia, torticollis, tremor. speech impairment and epilepsy. Stimulation at voltages above or below clinically effective levels (e.g., 6 V, 0.3 ms, 74 Hz) resulted in a loss of clinical efficacy. Somatosensory evoked responses (short and long latency) and depth electrode recordings were helpful in localisation and 'biocalibration' of electrical stimulation.

Clinical, physiological and philosophical implications of innovative brain surgery in humans.

Abnormal states of motor behaviour can be reversed by interruption of facilitating mechanisms and augmentation of inhibitory mechanisms. Similarly, psychological and emotional behaviours which were abnormal due to disinhibition, such as screaming, repetitive speech and aggressive violent behaviour, have been favourably affected from a clinical and sociological standpoint. The mechanisms of the facilitatory and inhibitory systems which modulate motor behaviour also modify psychological and emotional behaviour. The findings of our studies in experimental neurosurgery may help to provide new insights into mechanisms of mental capacity and behaviour.

Use of chronic cerebellar stimulation for disorders of disinhibition.

A review of the clinical results from 200 patients and the neurophysiological results from 42 patients suggests that chronic cerebellar stimulation (c.c.s.) can improve cerebral palsy and reduce intractable seizures. The therapeutic effects of stimulation of the cerebellar surface may not be due to activation of Purkinje cells. There is evidence that stimulation of brainstem structures, particularly the reticular formation, may be associated with thalamic inhibition; such effects would explain the clinical results of c.c.s. as well as the reduction in amplitude of reflexes, evoked potentials, and paroxysmal discharges in the electroencephalogram. This hypothesis would explain the prolonged, rebound, paradoxical, and cumulative effects of c.c.s. No clinical disturbance or significant tissue damage has resulted from c.c.s. over 5 years. The technique is an example of the therapeutic manipulation of inhibitory and disinhibitory mechanisms in the central nervous system.

Time course of clinical and physiological effects of stimulation of the cerebellar surface in patients with spasticity.

A double-blind study of the short-term (12--48 hours) effects of cerebellar stimulation was performed on 11 selected patients with spasticity. Six of patients had a good clinical long-term response to chronic stimulation, four had a moderate response, and one had no response. Each patient received stimulation for two periods of 24 hours and was off stimulation for two periods of 24 hours. The periods were randomised over four consecutive days. Neither the patients nor the observer could distinguish between the days on stimulation and the days off stimulation. Simple tests of function of the upper limbs during stimulation, measurements of H responses, tonic vibration responses, vibration-induced suppression of H responses, stretch responses, and co-contraction, showed no differences between the four days. These results are contrasted with acute physiological changes seen in some patients during stimulation and also with the slow progressive improvement in clinical function that characterises the successful clinical response. It is suggested that lack of either acute or short-term changes in response to cerebellar stimulation does not predict the clinical outcome. If the strength of stimulation is changed, at least three days and preferably 10 days should be allowed for the effects to appear. The mechanisms responsible for the alleviation of spasticity are likely to be more complex than those mediating acute and reversible changes in reflex activity.

Effects of cerebellar stimulation on epilepsy, the EEG and cerebral palsy in man.

Eighteen of the first 29 patients with intractable epilepsy treated by chronic cerebellar stimulation (CCS) demonstrated a marked suppression of seizures. Sixty-eight of 100 patients with cerebral palsy showed clinical improvement after CCS. Electroencephalographic studies in three epileptic patients revealed a significant (P less than 0.001) reduction in number and duration of paroxysmal EEG discharges during epochs when the stimulator was on; prolonged effects were seen at stimulation rates of 200 c/sec and 10 c/sec (monophasic capacitively coupled stimuli). "Rebound" increases in numbers and durations of paroxysmal discharges occurred after cessation of CCS: immediate "rebounds" occurred within the next 5 min; such rebound effects were also seen in the frequency of clinical seizures. CCS at voltages well above threshold for the production of changes in H reflexes, late motor responses (V1 and V2), and evoked potentials resulted in increased "rebound" effects after cessation of stimulation and such effects were seen clinically and neurophysiologically in epileptic and cerebral palsy patients. Variability in the effects of CCS on seizures and the EEG may have been due to technical factors such as positions and impedances of electrodes, output of the stimulator, effects of anticonvulsant medication and patient differences; there was no clinical or physiological evidence of any undesirable neurological effect of CCS. In one patient, onset of CCS was frequently associated with cessation of polyspike and wave discharges; such results raise the possibility of triggering CCS from paroxysmal discharges in the EEG (contingency feedback) but rebound effects may complicate such therapy.

Safety and efficacy of chronic stimulation.

It is our conclusion that chronic cerebellar stimulation is both efficacious and safe as a therapeutic measure for selected neurological disease. Improvements in patient selection, with patients chosen who are not as incapacitated as those of our first group, showed make this even more apparent. In order to be certain that calibration of the present stimulating equipment is accurate, each such apparatus should be calibrated by the group treating the patient. We no make this a routine aspect of our follow-up re-examinations.

Tension reduction and alerting in man following chronic cerebellar stimulation for the relief of spasticity or intractable seizures.

Neurologically impaired patients on therapeutic regimens of chronic cerebellar stimulation for periods ranging from 4 to 29 months (mean = 12.8 months) commonly reported amelioration of tension and/or anxiety. Cerebral palsy patients emphasized tension reduction while seizure patients primarily reported increased alertness. Increased alertness and improvement in speech and mood were also noted by many patients. These changes correlated significantly with symptom reduction and functional improvement. Although the mechanisms of these changes are not yet clear, psychological and neurological explanatory hypotheses were presented.

Neurosurgical treatment of the dyskinesias.

I have attempted to review what I consider to be the principal conclusions of a 25 year study of the neurosurgical treatment of the dyskinesias. The concept that the pathological disinhibition which is responsible for the production of these syndromes can be modified by destructive lesions within the thalamus or by prosthetic mobilization of inhibitory mechanisms of the cerebellum is supported by the results presented in this report. Neurosurgical treatment of the dyskinesias is potentially a relatively safe and efficacious means of alleviating incapacitation of a large group of patients. However, meticulous attention to patient selection as well as adherence to the general principles of surgical technique which have been reviewed are essential if the full potential of these approaches is to be realized.

Safety and efficacy of chronic cerebellar stimulation.

It is our conclusion that CCS is both efficacious and safe as a therapeutic measure for neurologic disease. As indications become more concise and patients can be chosen who are not as incapacitated as those in our first group, this should become even more apparent. In order to be certain that calibration of the stimulating equipment is accurate each apparatus should be calibrated by the group treating the patient. We are now making this a routine aspect of our follow-up recheck examinations.