OBJECTIVE:This study aimed to assess the effects of focal brain cooling (FBC) on human brain tissue through use of multiple sensing techniques by monitoring cerebrovascular activity and brain temperature. METHODS:Intraoperative brain activity monitoring using a multimodality probe capable of measuring brain temperature, electrocorticography (ECoG) and changes in cerebral hemoglobin concentration was performed in 13 patients with refractory epilepsy. Brain temperature and neurovascular activity were measured beneath and surrounding the FBC device. Data were categorized into three temperature ranges [low-temperature range (LTR, <18 °C), moderate-temperature range (MTR, 18 °C-28 °C), and high-temperature range (HTR, >28 °C)] for analysis. RESULTS:Changes in oxyhemoglobin (ΔO2Hb) and deoxyhemoglobin (ΔHHb) across the temperature ranges showed a U-shape and inverted U-shape pattern, respectively. ΔO2Hb decreased and ΔHHb increased in the MTR, reflecting enhanced neuronal activity and increased oxygen consumption. Conversely, ΔO2Hb increased and ΔHHb decreased in the LTR, indicating suppressed neuronal activity and reduced oxygen consumption. These findings highlight the temperature-dependent modulation of neurovascular activity by FBC, driven by distinct non-linear patterns. CONCLUSIONS:FBC selectively influenced brain electrical activity and hemoglobin concentration, highlighting its subtle effects on neurovascular dynamics. SIGNIFICANCE:These findings provide critical insights into optimizing cooling strategies for neurological disorders using multimodality probes and FBC devices.

The development of novel anti-seizure drugs targeting novel mechanisms is crucial, especially for patients with intractable epilepsy. Previous studies using focal onset seizure rodent models have demonstrated that Icilin and WS-3, agonists of the transient receptor potential melastatin 8 (TRPM8) channel, suppress drug-induce epileptiform discharges (EDs) and seizures (ESs). In contrast, TRPM8 deficiency exacerbates EDs and ESs. This study investigated the mechanism underlying the anti-seizure effects of the TRPM8 agonist, WS-3, using a focal onset seizure mouse model. Mice were injected with WS-3 either before or after administering the seizure inducer, penicillin G potassium. EDs, ESs, and glutamate levels were subsequently evaluated. In wild-type (WT) mice, WS-3 injected after the seizure inducer reduced glutamate levels and ED power by 44% and 60%, respectively, with a positive correlation between WS-3 efficacy and these parameters. WS-3 injection before seizure induction suppressed the increase in glutamate levels and the development of ED and ES, with positive correlations observed among the three parameters. Conversely, TRPM8-knockout mice showed no anti-seizure effects from WS-3. TRPM8 deficiency led to a further increase in the glutamate levels, ED power, and ES severity after the seizure inducer injection. Additionally, TRPM8-deficient mice experienced EDs with fewer glutamate exposures and shortened latency to ED development following seizure induction. These findings suggest that TRPM8 agonists suppress the development of EDs and ESs by reduction of extracellular glutamate levels, indicating that TRPM8 channels may represent a promising treatment option for epilepsy.

The development of targeted anti-epilepsy drugs is crucial, as 30 % of patients with epilepsy are resistant to current therapeutics. Transient receptor potential vanilloid 1 (TRPV1) channel antagonists have been demonstrated to suppress drug-induced epileptiform discharges (EDs) and seizures (ESs). Here, we investigated the correlation between the anti-epileptiform efficacy of AMG9810 and extracellular glutamate levels. The somatosensory cortices of male C57BL/6N mice were intracortically injected with penicillin G (PG: 200 IU, 1 μL/10 min), a seizure inducer that inhibits the GABAA receptor. The mice were intracortically injected with AMG9810 (3 μM, 1 μL/10 min) either before or after PG administration. EDs, ESs, and glutamate levels were subsequently evaluated. The results of each experiment were compared between the vehicle and AMG9810-injected groups. AMG9810 injected after PG reduced glutamate levels and ED power, and there was a positive correlation between AMG9810 efficacy and these parameters. Injecting AMG9810 before PG injection decreased the increase in glutamate levels and development of EDs and ESs, with positive correlations observed among the three parameters. These findings suggest that TRPV1 antagonists suppress the development of EDs and ESs by decreasing extracellular glutamate levels, indicating that TRPV1 channels may represent a promising treatment option for epilepsy.

Background: Febrile seizures (FSs) are the most frequent type of seizures in infancy and childhood. Epileptiform discharges (EDs) on electroencephalogram at the time of first FS recurrence can increase the risk of epilepsy development. Therefore, inhibition of EDs is important. Recently, WS-3, a transient receptor potential melastatin 8 (TRPM8) agonist, reportedly suppressed penicillin G-induced cortical-focal EDs. However, the effects of TRPM8 agonists on FSs remain unknown. In this study, we aimed to clarify the effects of the TRPM8 agonist, and the absence of TRPM8 channels, on hyperthermia-induced FS by analyzing the fast ripple band. Methods: Hyperthermia (43°C for 30 min) induced by a heating pad caused FSs in postnatal day 7 wild-type (WT) and TRPM8 knockout (TRPM8KO) mice. FSs were defined as EDs occurring during behavioral seizures involving hindlimb clonus and loss of the righting reflex. Mice were injected with 1% dimethyl sulfoxide or 1 mM WS-3 20 min before the onset of hyperthermia, and electroencephalograms; movies; and rectal, brain and heating pad temperatures were recorded. Results: In wild-type mice, WS-3 reduced the fast ripple amplitude in the first FS without changing rectal and brain temperature thresholds. In contrast, the anti-FS effect induced by the TRPM8 agonist was not observed in TRPM8KO mice and, compared with wild-type mice, TRPM8 deficiency lowered the rectal and brain temperature thresholds for FSs, exacerbated the fast ripple amplitude, and prolonged the duration of the initial FS induced by hyperthermia. Conclusion: Our findings suggest that TRPM8 agonists can be used to treat hyperthermia-induced FSs.

Epilepsy is a relatively common condition, but more than 30% of patients have refractory epilepsy that is inadequately controlled by or is resistant to multiple drug treatments. Thus, new antiepileptic drugs based on newly identified mechanisms are required. A previous report revealed the suppressive effects of transient receptor potential melastatin 8 (TRPM8) activation on penicillin G-induced epileptiform discharges (EDs). However, it is unclear whether TRPM8 agonists suppress epileptic seizures or affect EDs or epileptic seizures in TRPM8 knockout (TRPM8KO) mice. We investigated the effects of TRPM8 agonist and lack of TRPM8 channels on EDs and epileptic seizures. Mice were injected with TRPM8 agonist 90 min after or 30 min before epilepsy-inducer injection, and electrocorticograms (ECoGs) were recorded under anesthesia, while behavior was monitored when awake. TRPM8 agonist suppressed EDs and epileptic seizures in wildtype (WT) mice, but not in TRPM8KO mice. In addition, TRPM8KO mice had a shorter firing latency of EDs, and EDs and epileptic seizures were deteriorated by the epilepsy inducer compared with those in WT mice, with the EDs being more easily propagated to the contralateral side. These findings suggest that TRPM8 activation in epileptic regions has anti-epileptic effects.

BACKGROUND Functional mapping in awake craniotomy has the potential risk of electrical stimulation-related seizure. The authors have developed a novel mapping technique using a brain-cooling device. The cooling probe is cylindrical in shape with a thermoelectric cooling plate (10 × 10 mm) at the bottom. A proportional integration and differentiation-controlled system adjusts the temperature accurately (Japan patent no. P5688666). The authors used it in two patients with glioblastoma. Broca’s area was identified by electrical stimulation, and then the cooling probe set at 5°C was attempted on it. OBSERVATIONS Electrocorticogram was suppressed, and the temperature dropped to 8°C in 50 sec. A positive aphasic reaction was reproduced on Broca’s area at a latency of 7 sec. A negative reaction appeared on the adjacent cortices despite the temperature decrease. The sensitivity and specificity were 60% and 100%, respectively. No seizures or other adverse events related to the cooling were recognized, and no histological damage to the cooled cortex was observed. LESSONS The cooling probe suppressed topographical brain function selectively and reversibly. Awake functional mapping based on thermal neuromodulation technology could substitute or compensate for the conventional electrical mapping.

More than 30% of patients with epilepsy are refractory and have inadequate seizure control. Focal cortical cooling (FCC) suppresses epileptiform discharges (EDs) in patients with refractory focal cortical epilepsy. However, little is known about the mechanism by which FCC inhibits seizures at 15°C, and FCC treatment is highly invasive. Therefore, new antiepileptic drugs are needed that produce the same effects as FCC but with different mechanisms of action. To address this need, we focused on transient receptor potential melastatin 8 (TRPM8), an ion channel that detects cold, which is activated at 15°C. We examined whether TRPM8 activation suppresses penicillin G (PG)-induced EDs in anesthetized rats. Icilin, a TRPM8 and TRP Ankyrin 1 agonist, was administered after PG injection, and a focal electrocorticogram (ECoG) and cortical temperature were recorded for 4 h. We measured spike amplitude, duration, firing rate, and power density in each band to evaluate the effects of icilin. PG-induced EDs and increased delta, theta, alpha, and beta power spectra were observed in the ECoG. Icilin suppressed EDs while maintaining cortical temperature. In particular, 3.0-mM icilin significantly suppressed PG-induced spike amplitude, duration, and firing rate and improved the increased power density of each band in the EDs to the level of basal activity in the ECoG. These suppressive effects of 3.0-mM icilin on EDs were antagonized by administering N-(3-aminopropyl)-2-[(3-methylphenyl) methoxy]-N-(2-thienylmethyl)-benzamide hydrochloride (AMTB), a selective TRPM8 inhibitor. Our results suggest that TRPM8 activation in epileptic brain regions may be a new therapeutic approach for patients with epilepsy.

Local brain cooling of an epileptic focus at 15°C reduces the number of spikes on an electrocorticogram (ECoG), terminates seizures, and maintains neurological functions. In this study, we attempted to suppress generalized motor seizures (GMSs) by cooling a unilateral sensorimotor area. GMSs were induced in rats by intraperitoneal injection of bicuculline methiodide, an antagonist of gamma-aminobutyric acid. While monitoring the ECoG and behavior, the right sensorimotor cortex was cooled for 10 min using an implanted device. The number of spikes recorded from the cooled cortex significantly decreased to 71.2% and 62.5% compared with the control group at temperatures of 15 and 5°C (both P <0.01), respectively. The number of spikes recorded from the contralateral mirror cortex reduced to 61.7% and 62.7% (both P <0.05), respectively. The ECoG power also declined to 85% and 50% in the cooled cortex, and to 94% and 49% in the mirror cortex by the cooling at 15 and 5°C, respectively. The spikes regained in the middle of the cooling period at 15°C and in the late period at 5°C. Seizure-free durations during the 10-min periods of cooling at 15 and 5°C lasted for 4.1 ± 2.2 and 5.9 ± 1.1 min, respectively. Although temperature-dependent seizure alleviation was observed, the effect of local cortical cooling on GMSs was limited compared with the effect of local cooling of the epileptic focus on GSMs.

OBJECTIVE:Traditionally, angiographic vasospasm (aVS) has been thought to cause delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, successful treatment of aVS alone does not result in improved neurological outcome. Therefore, there may be other potential causes of poor neurological outcome, including spreading depolarization (SD). A recent study showed beneficial effects of cilostazol on DCI and neurological outcome. The present prospective clinical trial and experimental study focused on effects of cilostazol on SDs.METHODS:Fifty aSAH patients were treated with clip ligation and randomly assigned to a cilostazol (n = 23) or control group (n = 27). Effects of cilostazol on DCI, aVS, and SDs, measured with subdural electrodes, were examined. The effect of cilostazol on SD-induced perfusion deficits (spreading ischemia) was assessed in an aSAH-mimicking model.RESULTS:There was a trend for less DCI in the cilostazol group, but it did not reach our threshold for statistical significance (13.0% vs 40.0%, odds ratio = 0.266, 95% confidence interval [CI] = 0.059-1.192, p = 0.084). However, the total SD-induced depression duration per recording day (22.2 vs 30.2 minutes, β = -251.905, 95% CI = -488.458 to -15.356, p = 0.043) and the occurrence of isoelectric SDs (0 vs 4 patients, β = -0.916, 95% CI = -1.746 to -0.085, p = 0.037) were significantly lower in the cilostazol group. In rats, cilostazol significantly shortened SD-induced spreading ischemia compared to vehicle (Student t test, difference = 30.2, 95% CI = 5.3-55.1, p = 0.020).INTERPRETATION:Repair of the neurovascular response to SDs by cilostazol, as demonstrated in the aSAH-mimicking model, may be a promising therapy to control DCI. Ann Neurol 2018;84:873-885.

Vagus Nerve Stimulation (VNS) is treatment of refractory epilepsy; however, its physiological mechanism has not been fully understood. The effectiveness of VNS for each patient cannot be predicted preoperatively. Thus, the mechanism of VNS needs to be investigated in order to avoid ineffective operations. Because an epileptic seizure is caused by the spread of excessive discharge from neurons in the cerebrum, analyzing effects of VNS on electroencephalogram (EEG) would be useful for VNS mechanism investigation. In the present work, the EEG data of epileptic patients with VNS were analyzed by using Granger Causality (GC) and the graph theory. Since GC is an index which expresses the intensity of a causal relation between two time series, it may illustrate information interactions between EEG channels. In addition, a directed graph constructed from those GC values would express neural connection. The analysis was carried out with the EEG data of two patients with frontal lobe epilepsy receiving the VNS therapy. The result supported the existing hypothesis indicating the bilateral asymmetry of the VNS effect on the brain, and furthermore, it suggested that VNS would increase neural connection between the frontal lobe and other brain regions, and that should control epileptic seizures by keeping patients awake.

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.

Summary Objective 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. Methods Patients with intractable epilepsy underwent FBC at lesionectomized (n = 11) or hippocampectomized (n = 8) regions at 15°C for 30 min using custom‐made cooling devices. Concentrations of Glu (n = 18) and GABA (n = 12) were measured in extracellular fluid obtained through microdialysis using high‐performance liquid chromatography (HPLC). The reduction rate of neurotransmitter levels and its relationship with electrocorticography ( EC oG) signal changes in response to FBC were measured. Results We found no relationship between the concentrations of Glu or GABA and seizure severity. There was a significant decrease in the concentration of Glu to 66.3% of control levels during the cooling period (p = 0.001). This rate of reduction correlated with EC oG power (r 2 = 0.68). Cortical and hippocampal GABA levels significantly (p = 0.02) and nonsignificantly decreased to 47.7% and 32.4% of control levels, respectively. However, the rate of this reduction did not correlate with EC oG (r 2 = 0.11). Significance Although the decrease in hippocampal GABA levels was not significant due to wide variations in its concentration, the levels of cortical GABA and Glu were decreased following FBC . FBC suppresses epileptic discharge and the release of both excitatory and inhibitory neurotransmitters. The reduction in Glu levels further contributes to the reduction in epileptic discharge. However, the reduction in the levels of GABA has no impact on EC oG.

BACKGROUND:The aims of this study were to reveal the strategies and pitfalls of motor-evoked potential (MEP) monitoring methods during supratentorial aneurysm surgery, and to discuss the drawbacks and advantages of each method by reviewing our experiences.METHODS:Intraoperative MEP monitoring was performed in 250 patients. Results from 4 monitoring techniques using combinations of 2 stimulation sites and 2 recording sites were analyzed retrospectively.RESULTS:MEP was recorded successfully in 243 patients (97.2%). Direct cortical stimulation (DCS)-spinal recorded MEP (sMEP) was used in 134 patients, DCS-muscle recorded MEP (mMEP) in 97, transcranial electrical stimulation (TES)-mMEP in 11 and TES-sMEP in 1. TES-mMEP during closure of the skull was used in 21 patients. DCS-mMEP was able to detect waveforms from upper and/or lower limb muscles. Alternatively, DCS-sMEP (direct [D]-wave) could accurately estimate amplitude changes. A novel "early warning sign" indicating ischemia was found in 21 patients, which started with a transiently increased amplitude of D-wave and then decreased after proximal interruption of major arteries. False-negative findings in MEP monitoring in 2 patients were caused by a blood insufficiency in the lenticulostriate artery and by a TES-sMEP recording, respectively.CONCLUSIONS:The results of this study suggest that to perform accurate MEP monitoring, DCS-mMEP or DCS-sMEP recording should be used as the situation demands, with combined use of TES-mMEP recording during closure of the skull. DCS-sMEP is recommended for accurate analysis of waveforms. We also propose a novel "early warning sign" of blood insufficiency in the D-wave.

Delayed cerebral ischemia (DCI) is a prominent complication after aneurysmal subarachnoid hemorrhage (aSAH). Although vasospasm of proximal cerebral arteries has been regarded as the main cause of DCI, vasospasm of distal arteries, microthrombosis, impaired autoregulation, cortical spreading depolarization (CSD), and spreading ischemia are thought to be involved in DCI after aSAH. Here, we describe a patient with aSAH in whom CSD and cerebrovascular autoregulation were evaluated using simultaneous electrocorticography and monitoring of the pressure reactivity index (PRx) after surgical clipping of a ruptured posterior communicating artery aneurysm. In this patient, a prolonged duration of CSD and elevation of PRx preceded delayed neurological deficit. Based on this observation, we propose a relationship between these factors and DCI. Assessment of cerebrovascular autoregulation may permit detection of the inverse hemodynamic response to cortical depolarization. Detection of DCI may be achieved through simultaneous monitoring of CSD and PRx in patients with aSAH.

BACKGROUND:Indications of clipping (Clip) or coil embolization (Coil) for unruptured cerebral aneurysms (uAN) was not elaborated because prediction of rupture and risk of treatment are difficult. This study aims to determine the risk-benefit analysis of treating uAN by a comprehensive and retrospective investigation of the adverse events and sequelae in patients treated by our Clip/Coil combined units.METHODS:Clip and Coil were performed in 141 and 80 patients, respectively; Clip for middle cerebral artery AN and Coil for paraclinoid or basilar apex AN. Worsening of modified Rankin scale or mini-mental state examination was defined as major morbidity. Minor morbidity or transient morbidity was defined as other neurologic deficits. Mortality and these morbidities were considered as serious adverse events. Convulsion or events outside the brain were defined as mild adverse events.RESULTS:Total mortality and major morbidity were low. Incidence of serious adverse events was not significantly different between the Clip and Coil (17 patients [12.1%] and 6 patients [7.5%]), but the number of total adverse events was significantly different (32 patients [22.7%] in Clip vs. 8 patients [10.0%] in Coil). Because mild morbidities were significantly more frequent in the Clip (20 patients [14.2%]) compared with the Coil (2 patients [2.5%]). Convulsion occurred in 11 (7.8%) patients in the Clip but none in the Coil.CONCLUSIONS:Our combined unit decreased the occurrence of mortality/major morbidity; however, minor adverse effects were common, especially in the Clip group because of many intrinsic problems of Clip itself. This result suggests further consideration for the treatment modality for uAN.

Neurosurgery has now reached a mature stage in Japan, and the baby-boomer generation who initially established Japanese neurosurgery is leaving the operating theater. Therefore, effective education to pass techniques, knowledge, and experience on to the next generation is becoming more and more important year by year. Specific questions in the field of education such as “What should be taught?” “How much should it be taught?” and “What teaching methods are best?” must be answered in order to design a framework for educating and assigning neurovascular surgeons, neuro-endovascular surgeons, and so-called “two-swords surgeons” (trained as both neurovascular and neuro-endovascular surgeons) to satisfy future requirements for neurosurgical care in Japan. Here we give an overview of these problems. Recently, surgical simulators based on physical virtual reality have been developed based on rapid advances in materials, technology, and IT knowledge, and laboratory training using such simulators has been widely accepted in medical education. However, many unsolved issues still remain in applying such laboratory training to the problems of actual neurosurgery. Surgical experience should be optimized for each trainee during residency, but the problems of individual needs have not yet been solved. For example, training may illustrate how to avoid serious bleeding from an aneurysm, but how to recover after this emergency by point aspiration, temporary clipping, or compression of the carotid artery at the neck portion is rather difficult to teach. Surgical manipulation during such a crisis by a clinical trainee sometimes results in a disaster even under direction of an experienced surgeon. Recently, awareness of patients’ rights has increased, so certification of surgeon’s skill has become an important issue. In this context, the clinical outcomes of the teaching hospital should be maintained to acceptable standards, and standardized education should be provided to each trainee. Further, overall and long-term views are essential for resolving these issues because of the large discrepancies in the population density in Japan of physicians from clinical specialties related to stroke, such as strokology, emergency medicine, neurology, rehabilitation, neurovascular surgery, and neuroendovascular surgery. The prefectural discrepancy ratio for neuroendovascular surgery is the largest at 21.5, but is 4-6 in most other specialties. Therefore, no rigid framework can be established to educate residents and to assign neurovascular surgeons, neuroendovascular surgeons, and two-swords surgeons. However, we must decide how to resolve these issues in the near future despite the many problems.

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.