Hirochika Imoto

Effective suppression of hippocampal seizures in rats by direct hippocampal cooling with a Peltier chip

OBJECT The use of focal brain cooling to eliminate epileptic discharges (EDs) has attracted increasing attention in the scientific community. In this study, the inhibitory effect of selective hippocampal cooling on experimental hippocampal seizures was investigated using a newly devised cooling system with a thermoelectric (Peltier) chip. METHODS A copper needle coated with silicone and attached to the Peltier chip was used for the cooling device. The experiments were performed first in a phantom model with thermography and second in adult male Sprague-Dawley rats in a state of halothane anesthesia. The cooling needle, a thermocouple, and a needle electrode for electroencephalography recording were inserted into the right hippocampus. Kainic acid (KA) was injected into the right hippocampus to provoke the EDs. The animals were divided into hippocampal cooling (10 rats) and noncooling (control, 10 rats) groups. RESULTS In the phantom study, the cooling effects (9 degrees C) occurred in the spherical areas around the needle tip. In the rats the temperature of the cooled hippocampus decreased below 20 degrees C within a 1.6-mm radius and below 25 degrees C within a 2.4-mm radius from the cooling center. The temperature at the needle tip decreased below 20 degrees C within 1 minute and was maintained at the same level until the end of the cooling process. The amplitude of the EDs was suppressed to 68.1 +/- 4.8% of the precooling value and remained low thereafter. No histological damage due to cooling was observed in the rat hippocampus. CONCLUSIONS Selective hippocampal cooling effectively suppresses the KA-induced hippocampal EDs. Direct hippocampal cooling with a permanently implantable system is potentially useful as a minimally invasive therapy for temporal lobe epilepsy and therefore could be an alternative to the temporal lobectomy.

The influence of focal brain cooling on neurophysiopathology: validation for clinical application

OBJECT Focal brain cooling has been recognized to have a suppressive effect on epileptiform discharges or a protective effect on brain tissue. However, the precise influence of brain cooling on normal brain function and histology has not yet been thoroughly investigated. The aim of this study was to investigate the neurophysiopathological consequences of focal cooling and to detect the threshold temperature that causes irreversible histological change and motor dysfunction. METHODS The experiments were performed in adult male Sprague-Dawley rats (weighing 250-350 g) after induction of halothane anesthesia. A thermoelectric chip (6 x 6 x 2 mm) was used as a cooling device and was placed on the surface of the sensorimotor cortex after a 10 x 8-mm craniotomy. A thermocouple was placed between the chip and the brain surface. Focal cooling of the cortex was performed at the temperatures of 20, 15, 10, 5, 0, and -5 degrees C for 1 hour (5 rats in each group). Thereafter, the cranial window was repaired. Motor function was evaluated using the beam-walking scale (BWS) every day for 7 days. The rats were killed 7 days after the operation for histological examination with H & E, Klüver-Barrera, glial fibrillary acidic protein, and terminal deoxynucleotidyl transferasemediated deoxyuridine triphosphate nick-end labeling stainings. The authors also euthanized some rats 24 hours after cooling and obtained brain sections by the same methods. RESULTS The BWS score was decreased on the day after cooling only in the -5 degrees C group (p < 0.05), whereas the score did not change in the other temperature groups. Histologically, the appearance of cryoinjury such as necrosis, apoptosis, loss of neurons, and marked proliferation of astrocytes at the periphery of the lesion was observed only in the -5 degrees C group, while no apparent changes were observed in the other temperature groups. CONCLUSIONS The present study confirmed that the focal cooling of the cortex for 1 hour above the temperature of 0 degrees C did not induce any irreversible histological change or motor dysfunction. These results suggest that focal brain cooling above 0 degrees C has the potential to be a minimally invasive and valuable modality for the treatment of severe brain injury or to assist in the examination of brain function.

An implantable, focal brain cooling device suppresses nociceptive pain in rats.

Although the classic idea of controlling pain through focal brain cooling is intriguing, the mechanism of this effect still remains to be elucidated. A thermoelectronic cooling system was developed and chronically implanted on the ipsilateral sensorimotor cortex of rats. Significant suppression of nociceptive pain was observed in limbs contralateral to the cooling cortex in hot plate tests and thermal withdrawal tests (p<0.05), with a minimal influence on neurological functions. This study identified, for the first time, the specific site and temperatures for the suppression of nociceptive pain, thus showing the potential feasibility of thermal neuromodulation therapy for pain.

Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban.

As limited amounts of data are available regarding thrombolytic therapy for patients taking novel oral anticoagulants, thrombolytic therapy is not recommended in such cases. Here, we report an acute stroke patient taking rivaroxaban who received intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA). An 80-year-old man with a history of nonvalvular atrial fibrillation, who had been receiving 10 mg of rivaroxaban showed abrupt onset of aphasia and right hemiparesis. National Institutes of Health Stroke Scale score was 10. Onset of neurologic deficits occurred 4 hours after the last dose of rivaroxaban. Clinical data on admission were as follows: blood pressure, 170/90 mm Hg; prothrombin time (PT), 22.6 seconds (control, 12.9 seconds); international normalized ratio, 2.03; activated partial thromboplastin time, 46 seconds (normal, 23-32 seconds); and creatinine level, 1.11 mg/dL. Magnetic resonance angiography revealed occlusion of the superior trunk of the left middle cerebral artery. Intravenous infusion of .6 mg/kg of rt-PA (total dose, 36 mg) was performed 6 hours after the last rivaroxaban administration with informed consent. The neurologic deficit improved during infusion of rt-PA. Repeat brain computed tomography showed left frontal cortical infarction without hemorrhagic changes. In the case of rivaroxaban, it is difficult to accurately determine the drug activity. As the anticoagulant activity of rivaroxaban can be estimated from its pharmacokinetics and PT, it is clinically important to obtain accurate information about the timing of medication and blood sampling.

Intra-operative monitoring of lower extremity motor-evoked potentials by direct cortical stimulation.

OBJECTIVE Motor-evoked potentials (MEPs) are commonly recorded from upper-extremity muscles, whereas lower-extremity MEP (LE-MEP) monitoring has not been adequately established. The goal of the study was to develop a MEP monitoring method using direct cortical stimulation (DCS) for predicting motor deficits of lower extremities. METHODS Intra-operative LE-MEP monitoring was performed in 22 patients. After craniotomy, a subdural electrode was placed on the cortex so that the optimal contact was positioned 2 cm lateral from the midline on the motor cortex. The electrodes for stimulation consisted of a cathode at Fpz and an anode at the optimal contact site on the motor cortex. After stimulation was performed with short trains of five stimuli, LE-MEPs were recorded from the lower-limb muscles. RESULTS LE-MEPs were consistently recorded in all patients. Disappearance or amplitude reduction of MEP waveforms was observed in five patients, but the MEP waveforms had recovered and remained at the control level by dural closure, and no permanent motor deficit was observed in any patient. CONCLUSIONS We accomplished LE-MEP recording during supratentorial surgery using monopolar DCS with a subdural electrode placed on the convex side of the motor cortex. SIGNIFICANCE A useful method of intra-operative LE-MEP recording was described.

Changes in glutamate concentration, glucose metabolism, and cerebral blood flow during focal brain cooling of the epileptogenic cortex in humans.

Recently, focal brain cooling (FBC) was proposed as a method for treating refractory epilepsy. However, the precise influence of cooling on the molecular basis of epilepsy has not been elucidated. Thus the aim of this study was to assess the effect of FBC on glutamate (Glu) concentration, cerebral blood flow (CBF), and glucose metabolism in patients with intractable epilepsy.

Effects of intrathecal baclofen therapy on motor and cognitive functions in a rat model of cerebral palsy.

OBJECT Cerebral palsy (CP) arises in the early stages of brain development and manifests as spastic paresis that is often associated with cognitive dysfunction. Available CP treatments are aimed at the management of spasticity and include botulinum toxin administration, selective dorsal rhizotomy, and intrathecal baclofen (ITB). In this study, the authors investigated whether the management of spasticity with ITB therapy affected motor function and whether the release of spasticity was associated with an improvement in intellectual function. METHODS Newborn Sprague-Dawley rats were divided into the following groups: control, CP model, and CP model with ITB therapy. For the CP model, postnatal Day 7 (P7) rats were exposed to hypoxic conditions (8% O(2)) for 150 minutes after ligation of the right common carotid artery. In the groups receiving ITB therapy, a spinal catheter was connected to an osmotic pump filled with baclofen and placed in the spinal subarachnoid space on P21 in the early group and on P35 in the late group. A daily dose of 12 μg of baclofen was continuously administered until P49, resulting in 28 days of therapy in the early group and 14 days in the late group. Changes in spasticity in the CP and CP with ITB treatment groups were confirmed by assessing the motor evoked potential in the plantar muscle. RESULTS In the CP group, the time required to complete a beam-walking test on P49 was significantly longer than that in the control and ITB treatment groups (4.15 ± 0.60 vs 2.10 ± 0.18 and 2.22 ± 0.22 seconds, respectively). Results of the beam-walking test are expressed as the mean ± SD. Radial arm maze performance on P49 indicated that spatial reference memory had significantly deteriorated in the CP group compared with controls (2.33 ± 0.87 vs 0.86 ± 0.90 points); moreover, working memory was also negatively affected by CP (0.78 ± 1.09 vs 0.14 ± 0.38 points). Results of the memory tests are expressed as the mean ± SE. These memory functions did not recover after ITB treatment. CONCLUSIONS Management of spasticity with ITB therapy improved the walking ability in the rat CP model. Intrathecal baclofen therapy-which reduces harmful sensory and motor stimulations caused by spasticity to more optimal levels-contributed to motor function recovery; however, it had no effect on intellectual recovery as assessed by memory performance in the rat CP model.

Epileptiform discharges and neuronal plasticity in the acute peri-infarct cortex of rats

Abstract While the peri-infarct cortex is thought to be responsible for functional recovery, the site is also a strong candidate for post-stroke seizures. Since it is crucial to identify the conditions when the site is changed with such beneficial or detrimental results, the peri-infarct changes were investigated before and just after inducing a focal infarct on rat cortex. The receptive fields in the peri-infarct cortex began to increase a few hours after the infarct, and reached a statistical significance at 6 hours (Dunnett post hoc tests; p<0·05). In temporal association with these changes, EEG in the peri-infarct cortex showed epileptiform activities containing large-amplitude spike-and-wave discharges. The gross amplitude, peak-to-peak amplitude and burst frequency showed statistically significant increases within 4 hours, in comparison to those of the controls (Dunnett post hoc tests; p<0·05). FFT power spectrum analyses showed a distinct increase in ∼25 Hz frequency bands in the post-stroke groups. The homogeneous area of the contralateral hemisphere in the infarct group, in contrast, did not show such plastic or excitability changes. This study demonstrated, for the first time, that the peri-infarct cortex acquires the characteristics of potential epileptogenesis and functional recovery within hours of a stroke.

Effects of focal brain cooling on extracellular concentrations of neurotransmitters in patients with epilepsy

Brain hypothermia controls epileptic discharge and reduces extracellular concentrations of glutamate (Glu), an excitatory neurotransmitter. We aimed to determine the effects of focal brain cooling (FBC) on levels of γ‐aminobutyric acid (GABA), which is a major inhibitory neurotransmitter. The relationship between Glu or GABA concentrations and the severity of epileptic symptoms was also analyzed.

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.