Tatsuji Tokiwa

Cooling of the epileptic focus suppresses seizures with minimal influence on neurologic functions.

Purpose:  Focal brain cooling is effective for suppression of epileptic seizures, but it is unclear if seizures can be suppressed without a substantial influence on normal neurologic function. To address the issue, a thermoelectrically driven cooling system was developed and applied in free‐moving rat models of focal seizure and epilepsy.

Neuroprotective effects of focal brain cooling on photochemically-induced cerebral infarction in rats: Analysis from a neurophysiological perspective

Although systemic hypothermia provides favorable outcomes in stroke patients, it has only been adopted in a limited number of patients because of fatal complications. To resolve these issues, focal brain cooling (FBC) has recently drawn attention as a less-invasive treatment for brain injuries. Therefore, we investigated whether FBC has a favorable effect on focal cerebral ischemia (FCI). Male-adult-Wistar rats were used. Under general anesthesia, a small burr hole was made and FCI was induced in the primary sensorimotor area (SI-MI) using photothrombosis. An additional craniotomy was made over the SI-MI and FBC was performed at a temperature of 15°C for 5h. Electrocorticograms (ECoG) were recorded on the border cortex of the ischemic focus. Thereafter, rats were sacrificed and the infarct area was measured. In another experiment, rats were allowed to recover for 5 days after cooling and neurobehavioral function was evaluated. FBC suppressed all ECoG frequency bands during and after cooling (p<0.05), except for the delta frequency band in the precooling versus rewarming periods. The injured areas in the cooling and non-cooling groups were 0.99±0.30 and 1.71±0.54 mm(2), respectively (p<0.03). The grip strength at 2 days after surgery was preserved in the cooling group (p<0.05). We report the novel finding that epileptiform discharges were suppressed in the ischemic border, the infarct area was reduced and neurobehaviour was preserved by FBC. These results indicate that FBC is neuroprotective in the ischemic brain and has demonstrated therapeutic potential for cerebral infarction.

Penicillin-induced epileptiform activity elevates focal brain temperature in anesthetized rats

To elucidate a relationship between changes in focal brain temperature and severity of abnormal brain activity, epileptiform discharges and behavioral seizures were induced by Penicillin G in anesthetized rats, and focal brain-temperature was measured. Penicillin G was injected into the right primary sensorimotor cortex (400IU/μl). After the injection, epileptiform discharges induced a temperature increase gradually by 0.65±0.24°C. Moreover, when behavioral seizures were induced by reducing the anesthesia level, the temperature was raised by 0.26±0.22°C. These results suggest that elevation of the focal brain temperature is associated with the severity of epileptic activity.

Development of a focal cerebral cooling system for the treatment of intractable epilepsy: An experimental study in cats and non-human primates

Focal brain cooling is under investigation in clinical trials of drug resistant epilepsy. This method has been studied intensively in rodents, but more evidence from large animal studies is required. To provide evidence that focal brain cooling is a safe and effective therapeutic intervention for intractable focal epilepsy, we investigated the placement of a newly-developed cooling device over the motor cortex of animals and investigated whether focal brain cooling can prevent and/or terminate focal neocortical seizures without having a significant impact on behavior. Two cats (n = 2) and a macaque monkey (n = 1) were chronically implanted with an epidural focal brain cooling device over the somatosensory and motor cortex, with adjacent EEG electrodes and a micro-injection tube. Penicillin G (PG) was delivered via the tube for induction of local seizures. Recordings were performed under awake but weakly restrained conditions. The cats and monkey exhibited spontaneous seizures with repetitive epileptiform discharges after administration of PG, and these discharges decreased at 15°C cooling. The results of this study suggest that epidural focal brain cooling is a safe and effective potential treatment modality for intractable focal epilepsy.

Epidural focal brain cooling abolishes neocortical seizures in cats and non-human primates

Focal brain cooling (FBC) is under investigation in preclinical trials of intractable epilepsy (IE), including status epilepticus (SE). This method has been studied in rodents as a possible treatment for epileptic disorders, but more evidence from large animal studies is required. To provide evidence that FBC is a safe and effective therapy for IE, we investigated if FBC using a titanium cooling plate can reduce or terminate focal neocortical seizures without having a significant impact on brain tissue. Two cats and two macaque monkeys were chronically implanted with an epidural FBC device over the somatosensory and motor cortex. Penicillin G was delivered via the intracranial cannula for induction of local seizures. Repetitive FBC was performed using a cooling device implanted for a medium-term period (FBC for 30min at least twice every week; 3 months total) in three of the four animals. The animals exhibited seizures with repetitive epileptiform discharges (EDs) after administration of penicillin G, and these discharges decreased at less than 20°C cooling with no adverse histological effects. The results of this study suggest that epidural FBC is a safe and effective potential treatment for IE and SE.

The Palm-Sized Cryoprobe System Based on Refrigerant Expansion and Boiling and Its Application to an Animal Model of Epilepsy

Goal: The purpose of this study is to propose the palm-sized cryoprobe system based on a new concept and to suggest that the freezing technique could be used for treatment of epilepsy. Methods: We propose herein a cryoprobe system based on the boiling effect that uses a specific refrigerants with a boiling point higher than that of liquid nitrogen yet low enough to result in cell necrosis. To evaluate and verify the effectiveness of the proposed system, cooling characteristics are investigated in agar. In addition, the system is applied to a Wistar rat brain-model, in which the epileptic activities are induced in advance by a potent epileptogenic substance. Results: The design concept yielded the following benefits: 1) the selected refrigerant promotes sealing in the tank; 2) the tank can be made as compact as possible, limited only by the volume required for the refrigerant; 3) because the tank and probe units can be separated by a nonconducting, flexible, and high-pressure tube, the tank unit can be manipulated without disturbing the probe tip with mechanical vibrations and electrical noise. Although the agar experiments, we verified that the proposed system can uniquely and reproducibly create an ice ball. Moreover, in the rat experiments in vivo, it was confirmed that penicillin G-induced epileptic activities disappeared on freezing with the proposed system. Conclusions: The palm-sized system has desired characteristics and can apply for an animal model of epilepsy. Significance: Results of in vivo experiments suggest that cryosurgery may be an effective treatment for epilepsy.

Alterative treatment of intractable epilepsy with focal brain cooling - A review of our past studies -

Focal cooling of the brain has the potential to terminate epileptic discharges. Therefore, in the present report, we review our past studies and discuss the future perspectives of brain cooling as a potential therapy for intractable epilepsy. The experiments were performed on Sprague-Dawley rats under halothane anesthesia. After craniotomy, the cooling device (Peltier chip) was placed on the cortical surface or inserted in the hippocampus. Kainic acid was then injected into either the cortex or hippocampus to provoke epileptiform discharges (EDs). Cortical cooling was also applied in patients with intractable epilepsy. The EDs decreased during either cortical or hippocampal cooling (20–25 °C) in rats. The EDs diminished, and neurotransmitters, such as glutamate, were observed to decrease during cooling in epileptic patients. Both the effectiveness and safety of focal cooling for intractable epilepsy were demonstrated. Based on these data, developments of implantable focal cooling device have been promoted.

Multi-space Competitive DGA and its application to localization of multiple signal sources

In this paper, a new optimization method, which is effective for the problem that the optimum solution should be searched in several solution spaces, is proposed. The proposed method is an extension of distributed genetic algorithm (DGA), in which each sub-population searches a solution in different space. Based on the competition between sub-populations, population sizes are adequately changed. The proposed method is applied to signal source localization, in which the number of sources is unknown, and simulation results show the effectiveness of the method.

Detailed spectral profile analysis of electrocorticograms during freezing against penicillin-induced epileptiform discharges in the anesthetized rat

OBJECTIVES Cryosurgery is an alternative technique for minimally invasive treatment of lesions. We have recently examined cryosurgery for epilepsy in animal models, and found that penicillin G (PG)-induced epileptiform discharges (EDs) mostly vanished after freezing. However, EDs were provoked again after insufficient freezing. Inadequate freezing is not visually detectable during and just after freezing and is not predictable beforehand. To manage this problem, we examined whether intraoperative monitoring of electrocorticograms (ECoGs) can predict recurrence of EDs after cryosurgery. METHODS A palm-sized cryoprobe system was applied to focal seizures in a Wistar rat model in which EDs were induced in advance by intracerebral injection of PG. During stable induction of EDs, the cryoprobe was carefully inserted into the epileptic region and this region was immediately frozen. After the series of prefreezing, freezing, and postfreezing, rats in which PG-induced EDs relapsed within 3 h were defined as the ED-relapsed (EDR) group, and other rats were defined as the ED-vanished (EDV) group. Time-frequency analysis was conducted on the ECoGs in each group through each freezing series. RESULTS Relapse of PG-induced EDs on ECoG after the freezing series was associated with the remaining power of the delta band in the freezing period more strongly in the EDR group than in the EDV group. CONCLUSIONS Success or failure of the freezing procedure can be predicted by the specificity of the delta band of the ECoG obtained intraoperatively.

Minimally-invasive epileptogenic focus detection using the subdural electrodes manipulated by the shape-memory-alloy thin wire

We propose a subdural electrode array guided by a 0.3mm-diameter shape memory alloy guidewire for a minimally-invasive method of electrocorticogram recording. The measured electric characteristics showed that the proposed electrodes are compatible with the application of electrocorticogram recording. Somatosensory evoked potential was measured by the proposed method in the animal test in vivo. The results confirmed that the proposed electrode array is available for the electrocorticogram recording under a minimally invasive surgery.