Takashi Tsubokawa

Chronic motor cortex stimulation for the treatment of central pain.

Twelve patients with deafferentation pain secondary to central nervous system lesions were subjected to chronic motor cortex stimulation. The motor cortex was mapped as carefully as possible and the electrode was placed in the region where muscle twitch of painful area can be observed with the lowest threshold. 5 of the 12 patients reported complete absence of previous pain with intermittent stimulation at 1 year following the initiation of this therapy. Improvements in hemiparesis was also observed in most of these patients. The pain of these patients was typically barbiturate-sensitive and morphine-resistant. Another 3 patients had some degree of residual pain but considerable reduction of pain was still obtained by stimulation. Thus, 8 of the 12 patients (67%) had continued effect of this therapy after 1 year. In 3 patients, revisions of the electrode placement were needed because stimulation became incapable of inducing muscle twitch even with higher stimulation intensity. The effect of stimulation on pain and capability of producing muscle twitch disappeared simultaneously in these cases and the effect reappeared after the revisions, indicating that appropriate stimulation of the motor cortex is definitely necessary for obtaining satisfactory pain control in these patients. None of the patients subjected to this therapy developed neither observable nor electroencephalographic seizure activity.

Treatment of Thalamic Pain by Chronic Motor Cortex Stimulation

All forms of therapy, including chronic stimulation of the thalamic relay nucleus, can provide satisfactory pain control in only 20%‐30% of cases of thalamic pain syndrome. In order to develop a more effective treatment for fhalamic pain syndrome, we investigated the effects of stimulation of various brain regions on the burst hyperactivity of thalamic neurons recorded in cats after deafferentiation of the spinothalamic pathway. Complete, long‐ term inhibition of the burst hyperactivity was induced by stimulation of the motor cortex, Based on this experimental finding, we treated seven cases of thalamic pain syndrome by chronic motor cortex stimulation employing epidural plate electrodes. Excellent or good pain control was obtained in all cases without any complications or side effects. During the stimulation, an increase in regional blood flow of the cerebral cortex and thalamus, a marked rise in temperature of the painful skin regions, and improved movements of the painful limbs were observed. These results suggest that thalamic pain syndrome can be most effectively treated by chronic motor cortex stimulation.

Calcium-dependent glutamate release concomitant with massive potassium flux during cerebral ischemia in vivo

The changes in extracellular glutamate ([Glu]e) and potassium ([K+]e) in the rat hippocampus during cerebral ischemia were determined simultaneously by microdialysis in vivo. Biphasic increases in [Glu]e, i.e. an earlier rapid increase concomitant with an abrupt increase in [K+]e followed by a later slow increase, were observed. Dialysis with Ca(2+)-free perfusate containing Co2+ blocked the earlier rapid increase completely but the later slow increase only partially. These findings suggest that Ca(2+)-dependent exocytotic release from the presynaptic nerve terminals is involved predominantly in the earlier rapid increase in [Glu]d. The later slow increase in [Glu]d may be due in part to a breakdown of membrane function resulting from several causes, including a loss of the electrogenic component of the glutamate gradients across the plasma membrane, and a loss of function of the glutamate uptake system.

Corticospinal direct response in humans: identification of the motor cortex during intracranial surgery under general anaesthesia.

The corticospinal direct (D) response to stimulation of the motor cortex exposed for intracranial surgery was recorded in 20 cases from wire electrodes inserted into the spinal epidural space. The D response was obtained from stimulation of restricted areas of the cerebral cortex, that is, the hand, trunk and thigh areas of the motor cortex. The D response was resistant to anaesthesia and unaffected by muscle relaxants. Thus, recordings of the D response are useful for identifying the location of the motor cortex during intracranial surgery under general anaesthesia.

Pharmacological classification of central post-stroke pain : comparison with the results of chronic motor cortex stimulation therapy

Abstract In an attempt to clarify the neurochemical background of central post‐stroke pain and to undertake a pharmacological analysis, the basic pharmacological characteristics of this intractable pain syndrome were investigated by the morphine, thiamylal and ketamine tests. In addition, the correlation between the pharmacological characteristics and the effects of chronic motor cortex stimulation therapy was examined. The study employed 39 central post‐stroke pain patients who had intractable hemibody pain associated with dysesthesias, and radiologically demonstrated lesions in the thalamic area (thalamic pain, n=25) or suprathalamic area (suprathalamic pain, n=14). The pharmacological evaluations showed that definite pain reduction occurred in eight of the 39 cases (20.5%) by the morphine test, in 22 of the 39 cases (56.4%) by the thiamylal test, and in 11 of 23 cases (47.8%) by the ketamine test. Based on these pharmacological assessments, there was no obvious difference between thalamic and suprathalamic pain. A comparison of the long‐term follow‐up results of chronic motor cortex stimulation therapy revealed that thiamylal and ketamine‐sensitive and morphine‐resistant cases displayed long‐lasting pain reduction with chronic motor cortex stimulation therapy, whereas the remaining cases did not show good results. We conclude that pharmacological classification of central post‐stroke pain by the morphine, thiamylal and ketamine tests could be useful for predicting the effects of chronic motor cortex stimulation therapy. It has recently been suggested that excitatory amino acids may be involved in the development of central post‐stroke pain. However, the fact that only 23 of the present 39 cases (59.0%) of thalamic and suprathalamic pain were sensitive to the thiamylal or ketamine test reflects the complex pharmacological background and the difficulties associated with treating central post‐stroke pain.

Deep-brain stimulation in a persistent vegetative state: Follow-up results and criteria for selection of candidates

Eight cases of a persistent vegetative state caused by brain damage were treated by chronic deep-brain stimulation (stimulation target: the mesencephalic reticular formation and/or non-specific thalamic nucleus) over a period of more than 6 months. Three of the patients are currently able to communicate and to express their demands by voice and one other patient has recovered very close to this state. These four cases showed changeable spectrograms with desynchronization on continuous EEG recording and all components of the BSR and SER could be recorded except for prolonged latency of both N20 (SER) and the V wave (BSR) 2 months after the initial coma. Following chronic deep-brain stimulation, EEG and behavioural arousal responses were observed with increased r-CBF, r-CMRO2 and r-CMRGL in the whole brain tissue. After 3-6 months of chronic deep brain stimulation, the prolonged coma scale rose in four of the eight cases and three cases emerged from the persistent vegetative state. Transmitter substances and their metabolites were also found to be increased in the CSF after chronic deep-brain stimulation. Based on these findings, chronic deep-brain stimulation represents a useful kind of treatment that can lead to emergence from a persistent vegetative state, if the candidate is selected by electrophysiological studies 2 months after the initial insult and if the stimulation is applied for more than 6-8 months using a high-safety chronic deep-brain stimulating instrument.

Chronic Motor Cortex Stimulation for Central Deafferentation Pain: Experience with Bulbar Pain Secondary to Wallenberg Syndrome

Six patients with bulbar pain caused by lateral medullary infarct were treated by stimulation therapy. Dysesthesia on the opposite side of the body was subjected to stimulation therapy in these patients. Of the subjects, 4 underwent thalamic stimulation and 3 were treated by motor cortex stimulation; the effects of both thalamic and motor cortex stimulation were investigated in 1 patient. No satisfactory pain control was obtained by thalamic stimulation in any of the patients in this series. In contrast, 2 of the 3 patients treated by motor cortex stimulation reported satisfactory pain control. The pain inhibition usually occurred at intensities below the threshold for the production of muscle contraction (pulse duration, 0.1-0.5 ms; intensity, 3-8 V). This finding was consistent with our previous observations made in a series of patients with thalamic pain, indicating that motor cortex stimulation is significantly more useful than thalamic stimulation for controlling deafferentation pain secondary to central nervous system lesions. We discuss the possibility that better control of deafferentation pain may be provided by stimulation at a level more rostral to the site of deafferentation.

Role of excitatory amino acid-mediated ionic fluxes in traumatic brain injury

One major event taking place at the moment of traumatic brain injury in neuronal cells is the occurrence of massive ionic fluxes across the plasma membrane, which can be referred to as traumatic depolarization (TD). Unlike spreading depression, TD can occur over wide brain areas simultaneously. Furthermore, recovery from TD often takes far longer than recovery from ionic perturbation elicited by the passage of a single wave of spreading depression. Neuronal cell damage caused by ischemic brain injury is also initiated by massive ionic fluxes, termed anoxic depolarization. The occurrence of similar ionic events in these two forms of brain injury may account for the genesis of diffuse ischemia‐like damage without actual episodes of hypoxia or ischemia in traumatic brain injury. We review the data indicating that excitatory amino acids (EAA) may play a vital role in producing TD, and that such EAA‐mediated ionic perturbation is responsible for a number of posttraumatic events including subcellular metabolic dysfunction and cellular responses such as microglial activation and astrocytic transformation. TD may represent one of the most important mechanisms of diffuse neuronal cell dysfunction and damage associated with traumatic brain injury.

Somatosensory evoked potentials from the thalamic sensory relay nucleus (VPL) in humans : correlations with short latency somatosensory evoked potentials recorded at the scalp

Somatosensory evoked potentials (SEPs) were recorded in humans from an electrode array which was implanted so that at least two electrodes were placed within the nucleus ventralis posterolateralis (VPL) of the thalamus and/or the medial lemniscus (ML) of the midbrain for therapeutic purposes. Several brief positive deflections (e.g., P11, P13, P14, P15, P16) followed by a slow negative component were recorded from the VPL. The sources of these components were differentiated on the basis of their latency, spatial gradient, and correlation with the sensory experience induced by the stimulation of each recording site. The results indicated that SEPs recorded from the VPL included activity volume-conducted from below the ML (P11), activity in ML fibers running through and terminating within the VPL (P13 and P14), activity in thalamocortical radiations originating in and running through the VPL (P15, P16 and following positive components) and postsynaptic local activity (the negative component). The sources of the scalp-recorded SEPs were also analyzed on the basis of the timing and spatial gradients of these components. The results suggested that the scalp P11 was a potential volume-conducted from below the ML, the scalp P13 and P14 were potentials reflecting the activity of ML fibers, the small notches on the ascending slope on N16 may potentially reflect the activity of thalamocortical radiations, and N16 may reflect the sum of local postsynaptic activity occurring in broad areas of the brain-stem and thalamus.

Assessment of brainstem damage by the auditory brainstem response in acute severe head injury.

In 64 cases suffering from severe head injury (Glasgow coma scale: less than seven- the auditory brainstem responses (FARs) recorded at the vertex, which are thought to be volumet conducted far-field potentials reflecting the sequential electrical activities of the auditory afferen) system in the brainstem, were recorded in the neurosurgical intensive care room immediately after admission. The alterations in the responses were compared with the types of primary injury, neurological signs., CT findings and outcome following treatment. Based on the results obtained, it is concluded that the FAR is a useful indicator for predicting the effects of treatment on brainstem damage in patients with severe head injury, and that it provides more reliable information about the function of the brainstem than the neurological signs or CT findings. Moreover, it also offers a diagnostic method for primary brainstem injury. Three cases or primary brainstem injury without lesions in the supratentorial region were diagnosed by means of combined CT and FAR recording.