Yoichi Katayama

Non-invasive electrical and magnetic stimulation of the brain, spinal cord and roots: basic principles and procedures for routine clinical application. Report of an IFCN committee

P.M. Rossini (Chairman) (Rome, Baly), A.T. Barker (Sheffield, UK), A. Berardelli (Rome, Italy), M.D. Caramia (Rome, Italy), G. Caruso (Naples, Italy), R.Q. Cracco (Brooklyn, NY;, USA), M.R. Dimitrijevid (Houston, TX, USA), M. Hallett ( Bethesda, MD, USA), Y. Katayama (Tokyo, Japan), C.H. Liicking ( Freiburg, Germany), A.L. Maertens de Noordhout (Liege, Belgium), C.D. Marsden (London, UK), N.M.F. Murray (London, UK), J.C. Rothwell (London, UK), M. Swash (London, UK) and C. Tomberg (Brussels, Belgium)

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.

Dynamic changes in local cerebral glucose utilization following cerebral concussion in rats: evidence of a hyper- and subsequent hypometabolic state

Following cerebral concussion, in which there is no evidence of direct morphological damage, cells are exposed to an increase in extracellular potassium as well as an accumulation of calcium. This concussion-induced ionic flux most likely alters the cellular energy demands thereby modifying metabolic processes. To investigate the metabolic changes after cerebral concussion, local cerebral metabolic rates for glucose (lCMRglc) utilizing [14C]2-deoxy-D-glucose were studied in rats (n = 98; 250-300 g) immediately, 30 min, 6 h, 1, 2, 3, 5 and 10 days following a unilateral frontoparietal fluid percussion (F-P) injury (3.7-4.3 atm). Compared to sham controls, animals exhibited bilateral hypermetabolism immediately following brain injury. However, this effect was more pronounced in structures ipsilateral to the site of F-P and was especially marked for the cerebral cortex (46.6-30.1% higher than control) and hippocampus (90.1-84.4% higher than control). By 30 min post-trauma many ipsilateral regions still showed evidence of hypermetabolism, although their lCMRglc had subsided. Beginning as early as 6 h following injury many regions within the ipsilateral cortex and hippocampus went into a state of metabolic depression (16.4-33.7% of control) which lasted for as long as 5 days. These results indicate that, although not mechanically damaged from the insult, cells exposed to concussive injury dramatically alter their metabolic functioning. This period of post-concussive metabolic dysfunction may delineate a period of time, following injury, during which cells are functionally compromised.

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.

Diffuse prolonged depression of cerebral oxidative metabolism following concussive brain injury in the rat : a cytochrome oxidase histochemistry study

Utilizing a lateral fluid percussion injury as a model of cerebral concussion, rats were studied histochemically measuring the degree of cytochrome oxidase activity present within different structures at different times following injury. After concussion, the cerebral cortex ipsilateral to the site of injury exhibited a diffuse decrease in its level of chromotome oxidase (CO) activity beginning at as soon as one day and lasting for up to 10 days after the insult. The ipsilateral dorsal hippocampus also exhibited an injury-induced decrease in CO activity, however, it was not as severe as in the cortex. These results indicate that oxidative metabolism is depressed primarily within the cerebral cortex and hippocampus for several days following a cerebral concussion. We propose that this period of metabolic depression may delineate a period of time during which the injured brain is unable to function normally and thus would be vulnerable to a second insult.

Administration of Excitatory Amino Acid Antagonists via Microdialysis Attenuates the Increase in Glucose Utilization Seen following Concussive Brain Injury

Immediately following concussive brain injury, cells exhibit an increase of energy demand represented by the activation of glucose utilization. We have proposed that this trauma-induced hypermetabolism reflects the effort of cells to restore normal ionic balance disrupted by massive ionic fluxes through transmitter-gated ion channels. In the present study, changes in local CMRglc following fluid-percussion concussive injury were determined using [14C]2-deoxy-d-glucose autoradiography, and the effects of in situ administration (via microdialysis) of excitatory amino acid (EAA) antagonists [kynurenic acid (KYN), 2-amino-5-phosphonovaleric acid (APV; 100 μM, 1 mM, and 10 mM), and 6-cyano-7-nitroquinoxaline-2,3-dine (CNQX; 300 μM, 1 mM, and 10 mM] on glucose utilization were investigated. Animals that did not receive dialysis showed a remarkable increase (up to 181% of normal control) in cortical glucose utilization following injury. In contrast, this high demand for glucose was reduced in areas infiltrated with KYN, APV, and CNQX. These results indicate that EAA-activated ion channels are involved in the posttraumatic increase in glucose utilization, reflecting the energy demand of cells required to drive pumping mechanisms against an ionic perturbation seen immediately following the concussive injury. The effects of KYN, APV, and CNQX suggest that although all subtypes of the glutamate receptor appear to be involved in this phenomenon, N-methyl-d-aspartate-activated channels may play a major role.

Lactate accumulation following concussive brain injury: the role of ionic fluxes induced by excitatory amino acids

During the first few minutes following traumatic brain injury, cells are exposed to an indiscriminate release of glutamate from nerve terminals resulting in a massive ionic flux (e.g., K+ efflux) via stimulation of excitatory amino acid (EAA)-coupled ion channels. The present study was undertaken to elucidate the causal relationship between these ionic shifts and lactate accumulation in the injured brain, by examining the effects of ouabain (an inhibitor of Na+/K+-ATPase), Ba2+ (an inhibitor or non-energy-dependent glial K+ uptake) and kynurenic acid (KYN; a broad-spectrum EAA antagonist) on lactate accumulation. Two microdialysis probes were placed bilaterally in the rat parietal cortex. One was perfused with a test drug (1.0 mM ouabain, 2.0 mM Ba2+ or 10 mM KYN) and the other with Ringers solution (control) for 30 min prior to injury. Following a 2.2-2.7 atm fluid-percussion injury, lactate levels in the dialysate increased (up to 116.6% above baseline) for the first 16 min and returned to baseline levels within 20 min after injury. This lactate accumulation was attenuated by preinjury administration of ouabain and KYN and was prolonged by Ba2+ administration. These findings indicate that lactate accumulations following concussive brain injury is a result of increased glycolysis which supports ion-pumping mechanisms, thereby, restoring the ionic balance which was disrupted by stimulation of EAA-coupled ion channels.

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.

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.

Promoter hypermethylation of the DNA repair gene O6-methylguanine-DNA methyltransferase is an independent predictor of shortened progression free survival in patients with low-grade diffuse astrocytomas

The O6‐methylguanine‐DNA methyltransferase (MGMT) plays a major role in repairing DNA damage from alkylating agents. In several human neoplasms including low‐grade diffuse astrocytomas, promoter hypermethylation of MGMT has been shown to correlate with an increased frequency of p53 mutation. In the present study, we analyzed MGMT promoter methylation by the methylation‐specific PCR in 49 newly diagnosed WHO grade II astrocytomas and evaluated its clinical usefulness. MGMT promoter methylation was found in 21 (43%) of the 49 tumors. A tight correlation existed between MGMT methylation and p53 protein accumulation (P=0.0424). The presence of MGMT methylation was significantly associated with a shorter progression free survival (PFS) on both univariate analysis (P=0.0014) and multivariate analysis (P=0.0081). It was a more powerful determinant of the PFS than age, sex, performance status, proliferative activity, or p53 expression, and was independent of the extent of surgery. In terms of the overall survival, MGMT methylation demonstrated a prognostic utility in the univariate analysis but not in the multivariate analysis. The present findings indicate that aberrant methylation of the MGMT promoter independently augurs for an unfavorable clinical course in patients with low‐grade diffuse astrocytomas. Since the presence of MGMT methylation is expected to predict an increased sensitivity to alkylating chemotherapeutic agents, earlier chemotherapy could serve to improve an unfavorable natural history in tumors with MGMT methylation.