Publications by authors named "Akio Ikeda"

216 Publications

A Biomarker for Benign Adult Familial Myoclonus Epilepsy: High-Frequency Activities in Giant Somatosensory Evoked Potentials.

Mov Disord 2021 May 28. Epub 2021 May 28.

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Background: Benign adult familial myoclonus epilepsy (BAFME) is one of the diseases that cause cortical myoclonus (CM) with giant somatosensory evoked potentials (SEPs). There are no useful diagnostic biomarkers differentiating BAFME from other CM diseases.

Objective: To establish reliable biomarkers including high-frequency oscillations (HFOs) with giant SEPs for the diagnosis of BAFME.

Methods: This retrospective case study included 49 consecutive CM patients (16 BAFME and 33 other CM patients) who exhibited giant P25 or N35 SEPs. SEPs were processed by a band-pass filter of 400-1000 Hz to analyze HFOs. Clinical and SEP findings were compared between (1) BAFME and other CM groups and (2) patients with presence and absence of P25-HFOs (HFOs superimposed on giant P25). The diagnostic power of each factor for BAFME was calculated.

Results: All 16 BAFME patients showed SEP P25-HFOs with significantly higher occurrence (P < 0.0001) compared with that of other CM groups. The presence of P25-HFOs significantly correlated with a BAFME diagnosis (P < 0.0001) and high SEP P25 and N35 amplitudes (P = 0.01 and P < 0.0001, respectively). BAFME was reliably diagnosed using P25-HFOs with high sensitivity (100%), specificity (87.9%), positive predictive value (80%), and negative predictive value (100%), demonstrating its superiority as a diagnostic factor compared to other factors.

Conclusions: P25-HFOs with giant SEPs is a potential biomarker for BAFME diagnosis. P25-HFOs may reflect cortical hyperexcitability partly due to paroxysmal depolarizing shifts in epileptic neuronal activities and higher degrees of rhythmic tremulousness than those in ordinary CM. © 2021 International Parkinson and Movement Disorder Society.
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http://dx.doi.org/10.1002/mds.28666DOI Listing
May 2021

The initial impact of the SARS-CoV-2 pandemic on epilepsy research.

Epilepsia Open 2021 06 26;6(2):255-265. Epub 2021 Feb 26.

ERN EpiCARE.

The COVID-19 pandemic has changed the face of many practices throughout the world. Through necessity to minimize spread and provide clinical care to those with severe disease, focus has been on limiting face-to-face contact. Research in many areas has been put on hold. We sought to determine the impact of the COVID-19 pandemic on epilepsy research from international basic science and clinical researchers. Responses to five questions were solicited through a convenience sample by direct email and through postings on the ILAE social media accounts and an ILAE online platform (utilizing Slack). Information was collected from 15 respondents in 11 countries by email or via Zoom interviews between May 19, 2020, and June 4, 2020. Several themes emerged including a move to virtual working, project delays with laboratory work halted and clinical work reduced, funding concerns, a worry about false data with regard to COVID research and concern about research time lost. However, a number of positive outcomes were highlighted, not least the efficiency of online working and other adaptations that could be sustained in the future.
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http://dx.doi.org/10.1002/epi4.12471DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013398PMC
June 2021

[Non-convulsive status epilepticus manifesting as ictal catatonia: a case report].

Rinsho Shinkeigaku 2021 May 20. Epub 2021 May 20.

Department of Neurology, Kyoto University Graduate School of Medicine.

A 66 year-old right-handed female was admitted to our hospital presenting with recurrent episodes of catatonic symptoms consisting of stupor, waxy flexibility, and catalepsy lasting about 5-20 minutes. A brain MRI showed no significant abnormalities. An scalp-electroencephalography (EEG) concurrent with the symptoms showed ictal EEG activities arising from the left fronto-central area, which evolved into the bilateral frontal and bilateral parietal areas together. An F-fluorodeoxy glucose positron emission tomography (F-FDG-PET) 4 days after improvement of the symptoms showed hypermetabolism in the bilateral frontal and parietal lobes. Her catatonic symptoms are assumed to be due to non-convulsive status epilepticus (NCSE), namely ictal catatonia. The introduction of several anti-epileptic drugs improved the symptoms and normalized the EEG and FDG-PET findings. NCSE must be considered as one of the underlying state of catatonic symptoms because the treatment plan for acute and chronic state is different from that of catatonic syndrome due to psychiatric disorders.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001560DOI Listing
May 2021

Frequency-Dependent Cortical Interactions during Semantic Processing: An Electrocorticogram Cross-spectrum Analysis Using a Semantic Space Model.

Cereb Cortex 2021 May 4. Epub 2021 May 4.

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, Sakyo, Kyoto 606-8507, Japan.

Convergent evidence has demonstrated that semantics are represented by the interaction between a multimodal semantic hub at the anterior temporal lobe (ATL) and other modality-specific association cortical areas. Electrocorticogram (ECoG) recording with high spatiotemporal resolutions is efficient in evaluating such cortical interactions; however, this has not been a focus of preceding studies. The present study evaluated cortical interactions during picture naming using a novel ECoG cross-spectrum analysis, which was formulated from a computational simulation of neuronal networks and combined with a vector space model of semantics. The results clarified three types of frequency-dependent cortical networks: 1) an earlier-period (0.2-0.8 s from stimulus onset) high-gamma-band (90-150 Hz) network with a hub at the posterior fusiform gyrus, 2) a later-period (0.4-1.0 s) beta-band (15-40 Hz) network with multiple hubs at the ventral ATL and posterior middle temporal gyrus, and 3) a pre-articulation theta-band (4-7 Hz) network distributed over widely located cortical regions. These results suggest that frequency-dependent cortical interactions can characterize the underlying processes of semantic cognition, and the beta-band network with a hub at the ventral ATL is especially associated with the formation of semantic representation.
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http://dx.doi.org/10.1093/cercor/bhab089DOI Listing
May 2021

Effects of a stable concentration of propofol on interictal high-frequency oscillations in drug-resistant epilepsy.

Epileptic Disord 2021 Apr;23(2):299-312

Department of Neurosurgery, Kyoto University Graduate School of Medicine, 54, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan.

The aim of this study was to clarify the effect of a stable concentration of propofol on interictal high-frequency oscillations (HFOs), which may contribute to identifying the epileptogenic zone intraoperatively for resection surgery. Nine patients with drug-resistant focal epilepsy who underwent invasive pre-surgical evaluation with chronic subdural electrodes were recruited. Five-minute electrocorticograms during wakefulness, slow-wave sleep, and under a stable brain concentration of propofol were recorded with the same electrodes. In each patient, 1-10 pairs of electrodes were selected for both electrodes with EEG changes within 5 seconds from the ictal onset (ictal pattern for 5 seconds [IP5]) and those outside the area of IP5 with no interictal epileptiform discharges (non-epileptiform [nEPI]). The numbers of ripples (80-250 Hz) and fast ripples (>250 Hz) were measured semi-automatically using an established algorithm. Statistical testing was performed with a mixed effect model. Thirty-seven pairs of electrodes from nine patients were analysed for IP5 and 29 pairs from seven patients were analysed for nEPI. The numbers of HFOs differed between the areas (IP5 and nEPI) and among the conditions (wakefulness, slow-wave sleep, propofol anaesthesia) (all p <0.01). The HFO occurrence rates were significantly higher for IP5 than those for nEPI in all conditions (for both ripples and fast ripples in all conditions; p <0.01). The occurrence rates of HFOs for IP5 were significantly higher than those for nEPI under propofol anaesthesia. These are fundamental findings for intraoperative HFO analysis, however, the following limitations should be considered: physiological HFOs could not be completely differentiated from pathological HFOs; in order to apply an HFO detector, an appropriate cut-off threshold is needed; an artefact of the impulse response filter appears as an HFO; and the series was comprised of a small number of heterogeneous patients.
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http://dx.doi.org/10.1684/epd.2021.1264DOI Listing
April 2021

[Paradoxical effect of levetiracetam on seizure suppression: three cases showing U curve association between dose and effect].

Rinsho Shinkeigaku 2021 Apr 25;61(4):247-252. Epub 2021 Mar 25.

Department of Neurology, Kyoto University Graduate School of Medicine.

We experienced 3 adult patients with intractable focal epilepsy treated by levetiracetam (LEV) as polytherapy, who showed paradoxical effect (PE). Starting dose of LEV was small (62.5, 250 mg/day) and we gradually increased by less than 250 mg/day, every more than 2 weeks. Within 6 months after LEV was added, LEV of 750 to 1,000 mg/day brought reduction of seizure frequency. Serum concentration of LEV was 13.3 and 14.0 μg/ml. In order to obtain better seizure control, LEV was increased up to 1,000-2,500 mg/day (19.3-35.0 μg/ml) within one year, and they developed PE. They all showed increased habitual seizures, occurring in cluster. Once dose of LEV deceased down to what produced the maximum seizure suppression, all of the patients regained the better seizure control. It is most likely that at least in some patients like present 3 cases, PE of LEV may express U curve association between dose and effect and that it was only delineated by slow titration.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001553DOI Listing
April 2021

Cortico-cortical evoked potential by single-pulse electrical stimulation is a generally safe procedure.

Clin Neurophysiol 2021 May 3;132(5):1033-1040. Epub 2021 Feb 3.

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, Japan. Electronic address:

Objective: Cortico-cortical evoked potential (CCEP) by single-pulse electrical stimulation (SPES) is useful to investigate effective connectivity and cortical excitability. We aimed to clarify the safety of CCEPs.

Methods: We retrospectively analyzed 29 consecutive patients with intractable partial epilepsy undergoing chronic subdural grid implantation and CCEP recording. Repetitive SPES (1 Hz) was systematically applied to a pair of adjacent electrodes over almost all electrodes. We evaluated the incidences of afterdischarges (ADs) and clinical seizures.

Results: Out of 1283 electrode pairs, ADs and clinical seizures were observed in 12 and 5 pairs (0.94% and 0.39%, per electrode pair) in 7 and 3 patients (23.3% and 10.0%, per patient), respectively. Of the 18-82 pairs per patient, ADs and clinical seizures were induced in 0-4 and 0-3 pairs, respectively. Stimulating 4 SOZ (seizure onset zone) (2.5%) and 8 non-SOZ pairs (0.75%) resulted in ADs. We observed clinical seizures in stimulating 4 SOZ (2.5%) and 1 non-SOZ pair (0.09%). The incidence of clinical seizures varied significantly between SOZ and non-SOZ stimulations (p = 0.001), while the difference in AD incidence tended towards significance (p = 0.058).

Conclusion: Although caution should be taken in stimulating SOZ, CCEP is a safe procedure for presurgical evaluation.

Significance: CCEP is safe under the established protocol.
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http://dx.doi.org/10.1016/j.clinph.2020.12.022DOI Listing
May 2021

Role of Astrocytic Inwardly Rectifying Potassium (Kir) 4.1 Channels in Epileptogenesis.

Front Neurol 2020 23;11:626658. Epub 2020 Dec 23.

Department of Pharmacology, Osaka University of Pharmaceutical Sciences, Takatsuki, Japan.

Astrocytes regulate potassium and glutamate homeostasis via inwardly rectifying potassium (Kir) 4.1 channels in synapses, maintaining normal neural excitability. Numerous studies have shown that dysfunction of astrocytic Kir4.1 channels is involved in epileptogenesis in humans and animal models of epilepsy. Specifically, Kir4.1 channel inhibition by gene mutation or expressional down-regulation increases the extracellular levels of potassium ions and glutamate in synapses and causes hyperexcitation of neurons. Moreover, recent investigations demonstrated that inhibition of Kir4.1 channels facilitates the expression of brain-derived neurotrophic factor (BDNF), an important modulator of epileptogenesis, in astrocytes. In this review, we summarize the current understanding on the role of astrocytic Kir4.1 channels in epileptogenesis, with a focus on functional and expressional changes in Kir4.1 channels and their regulation of BDNF secretion. We also discuss the potential of Kir4.1 channels as a therapeutic target for the prevention of epilepsy.
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http://dx.doi.org/10.3389/fneur.2020.626658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786246PMC
December 2020

[A case of the successful treatment of severe myoclonus with Lance-Adams syndrome by add-on perampanel showing long term effects].

Rinsho Shinkeigaku 2021 Jan 15;61(1):18-23. Epub 2020 Dec 15.

Department of Neurology, Nissan Tamagawa Hospital.

Perampanel is an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist that has been marked as an antiepileptic drug for partial-onset and primary generalized tonic-clonic seizures. There have been some recent reports of perampanel being effective against cortical myoclonus by Lafora disease and Unverricht-Lundborg disease. We herein report a 49-year-old man who presented with myoclonus due to Lance-Adams syndrome (LAS) after cardiopulmonary arrest caused by a severe bronchial asthma attack. Perampanel was very effective against myoclonus induced by LAS even in the chronic state, over 10 years after the remote onset. Perampanel should be considered for the treatment of extremely refractory myoclonus due to LAS.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001477DOI Listing
January 2021

Prescription patterns of antiepileptic drugs for adult patients with newly diagnosed focal epilepsy from 2006 to 2017 in Japan.

Epilepsy Res 2021 Jan 18;169:106503. Epub 2020 Nov 18.

Department of Pharmacoepidemiology, Graduate School of Medicine and Public Health, Kyoto University, Kyoto, Japan. Electronic address:

Objective: This study aimed to examine prescription patterns of antiepileptic drugs (AEDs) for adult patients with newly diagnosed focal epilepsy in Japan and whether these patterns adhere to the 2010 Japanese Society of Neurology Guidelines of Epilepsy Treatment.

Methods: Data from the JMDC Claims Database were obtained for patients aged between 20 and 65 years with newly diagnosed focal epilepsy who were prescribed AEDs between 2006 and 2017. Available prescription information up to the patient's first year was recorded and longitudinal descriptive statistics, Cochran Armitage Trend (CAT) tests, and annual percentage change (APC) were used to analyze AED trends and overall guideline adherence. In addition, logistic regression analyses were used to compare these results across different health facilities.

Results: A total of 6024 adult patients with newly diagnosed focal epilepsy were enrolled. The prescription of new AEDs increased significantly (CAT, p < 0.001, APC = 28.74 %) up to 36.8 % of all prescriptions in 2017 when compared to 2006. Among new AEDs, prescriptions for levetiracetam increased most rapidly and were followed by lamotrigine. In contrast, prescriptions for older AEDs, especially valproate, decreased over this same time period. The average guideline adherence rate from 2010 to 2017 was 75.3 %, and was not significantly different over time (CAT, p = 0.55). Health facilities with either more than 500 beds or between 20-499 beds had higher odds of prescribing new AEDs and improved guideline adherence when compared to facilities with 0-19 beds.

Conclusion: Prescription patterns of AEDs for adult patients with newly diagnosed focal epilepsy exhibited a trend from older to new AED classes between 2006 and 2017, with consistent, high guideline adherence from 2010 to 2017. Health facilities with 0-19 beds were less likely to prescribe new AEDs and completely adhere to proposed guidelines.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106503DOI Listing
January 2021

[The Oscillatory Phenomena in Human Epileptic Seizure: From A Glial-Neuronal Function Perspective in the Brain].

Brain Nerve 2020 Nov;72(11):1207-1221

Department of Neurology, Kyoto University Graduate School of Medicine.

The brain is a kind of very large-scale integration circuit or its beyond that produces extremely various ranges of electroencephalogram. Epilepsy is a state caused by explosively hyperexcitable brain activities. Recently, it has been suggested that not only the hyperexcitability of neurons but also glial cells, which were previously thought to be silent or plain, play a crucial role in the acquisition of epileptogenicity. In this review article, we will comprehensively describe the utility of the analysis of brain activities from extremely low to high frequency oscillations. Our multi-institute study confirmed that ictal direct current shifts (ictal DC) precedes ictal high-frequency oscillations (ictal HFOs), being more prominent in neocortical epilepsy than in temporal lobe epilepsy. Moreover, we revealed that the complete resection of the core regions of ictal DC shifts significantly correlated with favorable outcomes after epileptic surgery. Taking our findings and previous knowledge into account, we will address the importance of not only neuronal but also glial functions towards the better understanding of pathogenesis of the so-called "chronic" state of epilepsy.
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http://dx.doi.org/10.11477/mf.1416201673DOI Listing
November 2020

[Convulsive syncope then convulsive seizure occurred in the long clinical course: a case report].

Rinsho Shinkeigaku 2020 Sep 8;60(9):627-630. Epub 2020 Aug 8.

Department of Neurology, Ijinkai Takeda General Hospital.

A 17-year-old woman presented with transient consciousness impairment attack and convulsion after bathing and prolonged standing since age 12. EEG showed WHAM ( wake, high amplitude, anterior, male) type of phantom spikes that usually carry the high risk of epilepsy at age 13. At age 17, EEG wise generalized spike and wave complex was recorded once, and head-up tilt test was positive. She was carefully observed without antiepileptic drugs since convulsive syncope due to neurally mediated syncope was most likely. During the follow-up period, she had eventually unprovoked generalized tonic-clonic seizures (convulsive seizure) twice and thus she was started with antiepileptic drug with success. Although both convulsive syncope and convulsive seizure differ in nature and effects on quality of life, in this patient, the latter occurred later and both occurs together. It is important to distinguish them by means of the degree of convulsion and EEG finding.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001451DOI Listing
September 2020

Engagement of cortico-cortical and cortico-subcortical networks in a patient with epileptic spasms: An integrated neurophysiological study.

Clin Neurophysiol 2020 09 29;131(9):2255-2264. Epub 2020 May 29.

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, 54, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Electronic address:

Objective: We aimed to delineate the engagement of cortico-cortical and cortico-subcortical networks in the generation of epileptic spasms (ES) using integrated neurophysiological techniques.

Methods: Seventeen-year-old male patient with intractable ES underwent chronic subdural electrode implantation for presurgical evaluation. Networks were evaluated in ictal periods using high-frequency oscillation (HFO) analysis and in interictal periods using magnetoencephalography (MEG) and simultaneous electroencephalography, and functional magnetic resonance imaging (EEG-fMRI). Cortico-cortical evoked potentials (CCEPs) were recorded to trace connections among the networks.

Results: Ictal HFO revealed a network comprising multilobar cortical regions (frontal, parietal, and temporal), but sparing the positive motor area. Interictally, MEG and EEG-fMRI revealed spike-and-wave-related activation in these cortical regions. Analysis of CCEPs provided evidence of connectivity within the cortico-cortical network. Additionally, EEG-fMRI results indicate the involvement of subcortical structures, such as bilateral thalamus (predominantly right) and midbrain.

Conclusions: In this case study, integrated neurophysiological techniques provided converging evidence for the involvement of a cortico-cortical network (sparing the positive motor area) and a cortico-subcortical network in the generation of ES in the patient.

Significance: Cortico-cortical and cortico-subcortical pathways, with the exception of the direct descending corticospinal pathway from the positive motor area, may play important roles in the generation of ES.
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http://dx.doi.org/10.1016/j.clinph.2020.04.167DOI Listing
September 2020

A taxonomy of seizure dynamotypes.

Elife 2020 07 21;9. Epub 2020 Jul 21.

Department of Biomedical Engineering, BioInterfaces Institute, University of Michigan, Ann Arbor, United States.

Seizures are a disruption of normal brain activity present across a vast range of species and conditions. We introduce an organizing principle that leads to the first objective Taxonomy of Seizure Dynamics (TSD) based on bifurcation theory. The 'dynamotype' of a seizure is the dynamic composition that defines its observable characteristics, including how it starts, evolves and ends. Analyzing over 2000 focal-onset seizures from multiple centers, we find evidence of all 16 dynamotypes predicted in TSD. We demonstrate that patients' dynamotypes evolve during their lifetime and display complex but systematic variations including hierarchy (certain types are more common), non-bijectivity (a patient may display multiple types) and pairing preference (multiple types may occur during one seizure). TSD provides a way to stratify patients in complement to present clinical classifications, a language to describe the most critical features of seizure dynamics, and a framework to guide future research focused on dynamical properties.
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http://dx.doi.org/10.7554/eLife.55632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375810PMC
July 2020

Comparison of Phase Synchronization Measures for Identifying Stimulus-Induced Functional Connectivity in Human Magnetoencephalographic and Simulated Data.

Front Neurosci 2020 19;14:648. Epub 2020 Jun 19.

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Phase synchronization measures are widely used for investigating inter-regional functional connectivity (FC) of brain oscillations, but which phase synchronization measure should be chosen for a given experiment remains unclear. Using neuromagnetic brain signals recorded from healthy participants during somatosensory stimuli, we compared the performance of four phase synchronization measures, imaginary part of phase-locking value, imaginary part of coherency (ImCoh), phase lag index and weighted phase lag index (wPLI), for detecting stimulus-induced FCs between the contralateral primary and ipsilateral secondary somatosensory cortices. The analyses revealed that ImCoh exhibited the best performance for detecting stimulus-induced FCs, followed by the wPLI. We found that amplitude weighting, which is related to computing both ImCoh and wPLI, effectively attenuated the influence of noise contamination. A simulation study modeling noise-contaminated periodograms replicated these findings. The present results suggest that the amplitude-dependent measures, ImCoh followed by wPLI, may have the advantage in detecting stimulus-induced FCs.
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http://dx.doi.org/10.3389/fnins.2020.00648DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318889PMC
June 2020

[Scalp-recorded cortical spreading depolarizations (CSDs) of EEG with time constant of 2 seconds in a patient with acute traumatic brain injury].

Rinsho Shinkeigaku 2020 Jul 13;60(7):473-478. Epub 2020 Jun 13.

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine.

An 82-year-old female suffered from head trauma, and developed acute consciousness disturbance 6 days after the event. Head CT showed the acute subdural hematoma in the left temporooccipital area and the patient underwent emergency hematoma evacuation and decompression. However, her consciousness disturbance became worse after surgery. Intermittent large negative infraslow shifts (lasting longer than 40 seconds) were recorded in the right posterior quadrant by scalp EEG with TC of 2 sec, that was defined as cortical spreading depolarizations (CSDs). Clinically consciousness disturbance sustained poor until 1 month after surgery in spite of treatment by anti-epileptic drugs. CSDs were observed on the right side where head injury most likely occurred. It may explain the sustained consciousness disturbance associated with significant prolonged ischemia. Once scalp EEG could record CSDs in this particular patient, the degree and its prognosis of traumatic head injury were estimated.
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http://dx.doi.org/10.5692/clinicalneurol.60.cn-001421DOI Listing
July 2020

Electrical cortical stimulations modulate spike and post-spike slow-related high-frequency activities in human epileptic foci.

Clin Neurophysiol 2020 08 11;131(8):1741-1754. Epub 2020 May 11.

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address:

Objective: Using interictal epileptiform discharges (IEDs), consisting of spikes and post-spike slow waves (PSSs), and IED-related high-frequency activities (HFAs), we elucidated inhibitory effects of electrical cortical stimulation (ECS) on human epileptic foci.

Methods: We recruited 8 patients with intractable focal epilepsy, and 50-Hz ECS was applied to the seizure-onset zone (SOZ) and non-SOZ. Before (5-min) and after (20-min) ECS, we evaluated the number of IED, the amplitudes of spikes and PSSs, spike-related HFA power, and PSS-related low gamma (30-50 Hz) activities.

Results: SOZ stimulation significantly decreased the number of IEDs and amplitude of spikes. Spike-related HFA power values in fast ripple (200-300 Hz) and ripple (80-150 Hz) bands were significantly suppressed only by SOZ stimulation in 4 and 3 patients, respectively. Among 4 patients with discrete PSSs, the amplitude ratio of spike/PSS decreased and the PSS-related low gamma activity power increased significantly in 2 patients and marginally in 1 patient.

Conclusions: ECS potentially modulates cortical excitability by reducing excitation and increasing inhibition, and monitoring IED-related HFAs may help achieve the optimal effects of ECS.

Significance: IED and IED-related HFAs are dynamic, potential surrogate markers for epileptic excitability during the interictal period.
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http://dx.doi.org/10.1016/j.clinph.2020.03.042DOI Listing
August 2020

[Ictal EEG pattern of transient epileptic amnesia in acute phase of non-herpetic limbic encephalitis].

Rinsho Shinkeigaku 2020 Jun 19;60(6):446-451. Epub 2020 May 19.

Department of Neurology, Japan Community Health care Organization, Hoshigaoka Medical Centre.

A 60-year-old, right-handed woman was admitted to our hospital for amnesia as the only neurological abnormal findings following the autonomic symptoms and transient episodes of loss of awareness. EEG during the amnesia showed rhythmic alpha activity arising from the left mid-temporal region. Although this ictal activity showed evolution in the frequency and amplitude, the location was limited in the bilateral temporal areas. After the EEG evaluation, her amnesia was resolved immediately, suggesting that her presentation was transient epileptic amnesia (TEA). Meanwhile, given the clinical course and MRI findings (high intensity in the bilateral mesial temporal areas, more on the left), she was diagnosed with non-herpetic limbic encephalitis and treated with steroid and anti-epileptic drugs, leading to the positive outcome. The ictal EEG findings during TEA as the one of the presentation in acute phase of non-herpetic limbic encephalitis may contribute to further investigation of underlying mechanism of TEA.
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http://dx.doi.org/10.5692/clinicalneurol.60.cn-001414DOI Listing
June 2020

Anti-PDHA1 antibody is detected in a subset of patients with schizophrenia.

Sci Rep 2020 05 13;10(1):7906. Epub 2020 May 13.

Department of Rheumatology and Clinical Immunology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Autoantibodies have been implicated in schizophrenia aetiology. Here, novel autoantibodies were isolated from patients with schizophrenia. Autoantibody candidates were searched using two-dimensional gel electrophoresis and western blotting with rat brain proteins as antigens and two sera pools (25 schizophrenia patients versus 25 controls) as antibodies. Immunoreactive antigens were identified by mass spectrometry. Antibody prevalence were evaluated by western blotting using human recombinant proteins. Furthermore, brain magnetic resonance imaging data (regional brain volumes and diffusion tensor imaging measures) were compared. Two proteins of the mitochondrial respiration pathway were identified as candidate antigens. Three patients with schizophrenia, but no controls, expressed antibodies targeting one of the candidate antigens, i.e., pyruvate dehydrogenase E1 component subunit alpha, somatic form, mitochondrial (PDHA1, EC 1.2.4.1), which is related to mitochondrial energy production. Anti-PDHA1 antibody-positive patients (n = 3) had increased volumes in the left occipital fusiform gyrus compared to both controls (n = 23, p = 0.017) and antibody-negative patients (n = 16, p = 0.009), as well as in the left cuneus compared to antibody-negative patients (n = 16, p = 0.018). This is the first report of an anti-PDHA1 antibody in patients with schizophrenia. Compatible with recent findings of mitochondrial dysfunction in schizophrenia, this antibody may be involved in the pathogenesis of a specific subgroup of schizophrenia.
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http://dx.doi.org/10.1038/s41598-020-63776-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7220915PMC
May 2020

[A case of refractory generalized atonic seizure and hemifacial spasm with the possible causative pontocerebellar lesion].

Rinsho Shinkeigaku 2020 May 18;60(5):362-366. Epub 2020 Apr 18.

Department of Neurology, Kyoto University Graduate School of Medicine.

The patient was a 35-year-old woman. At the age of 1, she had undergone resection and radiation therapy for neoplastic lesions in the pons. She had a history of gelastic seizures when she was in elementary school, and brief lapses of the neck and truncal muscular tone and convulsions on the left face occurred at the age of 23. After a generalized sharp wave in the ictal electroencephalogram and electromyogram recording, left orbicularis oris muscle contraction was observed followed by sudden cervical extensor atonia. Seizure propagation was noted in the cerebral cortex, left facial nerve nucleus, and brainstem reticular formation. In a simultaneous electroencephalography with functional MRI, the blood oxygen level-dependent effect related to generalized sharp waves was observed in the vicinity of brainstem lesions in addition to a decrease in bilateral frontal and parietal lobes signals, as detected in generalized seizures. These findings suggest that the lesion could be a part of the epilepsy network. Although most epileptic seizures are derived from the cerebral cortex, it is important to note that brainstem lesions are involved in seizures in the patient presented in this study.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001368DOI Listing
May 2020

Connectivity Gradient in the Human Left Inferior Frontal Gyrus: Intraoperative Cortico-Cortical Evoked Potential Study.

Cereb Cortex 2020 06;30(8):4633-4650

Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.

In the dual-stream model of language processing, the exact connectivity of the ventral stream to the anterior temporal lobe remains elusive. To investigate the connectivity between the inferior frontal gyrus (IFG) and the lateral part of the temporal and parietal lobes, we integrated spatiotemporal profiles of cortico-cortical evoked potentials (CCEPs) recorded intraoperatively in 14 patients who had undergone surgical resection for a brain tumor or epileptic focus. Four-dimensional visualization of the combined CCEP data showed that the pars opercularis (Broca's area) is connected to the posterior temporal cortices and the supramarginal gyrus, whereas the pars orbitalis is connected to the anterior lateral temporal cortices and angular gyrus. Quantitative topographical analysis of CCEP connectivity confirmed an anterior-posterior gradient of connectivity from IFG stimulus sites to the temporal response sites. Reciprocality analysis indicated that the anterior part of the IFG is bidirectionally connected to the temporal or parietal area. This study shows that each IFG subdivision has different connectivity to the temporal lobe with an anterior-posterior gradient and supports the classical connectivity concept of Dejerine; that is, the frontal lobe is connected to the temporal lobe through the arcuate fasciculus and also a double fan-shaped structure anchored at the limen insulae.
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http://dx.doi.org/10.1093/cercor/bhaa065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325718PMC
June 2020

Intraoperative Electrophysiologic Mapping of Medial Frontal Motor Areas and Functional Outcomes.

World Neurosurg 2020 06 4;138:e389-e404. Epub 2020 Mar 4.

Department of Neurosurgery, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.

Objective: To propose a method for intraoperative mapping and monitoring of the medial frontal motor areas (MFMA).

Methods: We estimated the location of the MFMA using the corticocortical evoked potential (CCEP) provoked by electric stimuli to the primary motor area (M1) of the upper limb. We localized or defined the MFMA by recording the motor evoked potentials (MEPs) provoked by electric stimuli to the medial frontal cortex around the estimated area. We monitored the patients' motor function during awake craniotomy and sequentially recorded the MEPs of the upper and/or lower limbs. This method was applied to 8 patients.

Results: Four patients who had part of the areas identified as the MFMA removed showed transient hemiparesis postoperatively (supplementary motor area [SMA] syndrome). The MEP from the M1 was preserved in the 4 patients. The resection of the identified MFMA might have caused their SMA syndrome. The CCEP showed a strong connection between the M1 and the SMA of the upper limb. Our method did not provoke any seizures.

Conclusions: This is a safe and sensitive method for intraoperative mapping and monitoring of the MFMA by combining electrophysiologic monitoring and awake craniotomy. It is clinically useful for mapping the MFMA and can prevent permanent motor deficits.
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http://dx.doi.org/10.1016/j.wneu.2020.02.129DOI Listing
June 2020

Scalp EEG Could Record Both Ictal Direct Current Shift and High-Frequency Oscillation Together Even With a Time Constant of 2 Seconds.

J Clin Neurophysiol 2020 Mar;37(2):191-194

Department of Epilepsy, Movement Disorders, and Physiology, Kyoto University Graduate School of Medicine, Kyoto, Japan; and.

Herein, the authors report for the first time, scalp-recorded (1) focal ictal direct current (DC) shifts (active DC shifts; that precede conventional pattern) from the chronic focus of focal epilepsy and (2) ictal high-frequency oscillation after ictal DC shifts (passive DC shifts; that follow both conventional and high-frequency oscillation ictal patterns) from the acute focus of acute symptomatic seizures (Szs) in a 77-year-old man. Sixteen episodes of clinical Szs were recorded by scalp EEG with a 2-seconds time constant. Among the 16 recorded episodes of Sz, four EEG Sz patterns originated from the left posterior temporal area (chronic focus), and all patterns (100%) exhibited active DC shifts preceding the conventional pattern by 12 seconds. Twelve EEG Sz patterns originated from the right parietal area (acute focus), and the high-frequency oscillations (five Szs) (41.6%) and DC shifts (six Szs) (50%) occurred first, followed by the conventional pattern 8 seconds later. Because both the active and the passive DC shifts were recorded with a time constant of 2 seconds, which was smaller than that reported previously for ictal DC shifts (e.g., time constant of 10 seconds), clinically useful ictal DC shifts could be routinely inspected with a time constant of 2 seconds.
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http://dx.doi.org/10.1097/WNP.0000000000000670DOI Listing
March 2020

Visualizing prolonged hyperperfusion in post-stroke epilepsy using postictal subtraction SPECT.

J Cereb Blood Flow Metab 2021 Jan 16;41(1):146-156. Epub 2020 Feb 16.

Department of Neurology, National Cerebral and Cardiovascular Center, Osaka, Japan.

Diagnosis of post-stroke epilepsy is often challenging because of a low incidence of epileptiform abnormalities on electroencephalography (EEG). Hence, this study evaluated whether postictal subtraction single-photon emission computed tomography (SPECT) could visualize epileptic activity and act as a diagnostic modality in post-stroke epilepsy. Fifty post-stroke epilepsy patients, who had undergone Tc-99m-ECD SPECT twice (postictal and interictal), were enrolled. The postictal hyperperfusion area was identified by subtraction (postictal-interictal) SPECT and classified into two distribution types: superficial or deep-seated. Laterality and distribution of postictal hyperperfusion on subtraction SPECT were compared with stroke lesions, seizure symptoms, and epileptiform EEG findings. Forty-three of the 50 patients (86%) had hyperperfusion on subtraction SPECT and 26 (52%) had epileptiform EEG findings. Subtraction SPECT showed prolonged postictal hyperperfusion despite the relatively long interval between seizure end and postictal SPECT (median: 19.1 h, range: 2.2-112.5 h). The laterality of the hyperperfusion area had a high concordance rate with the laterality of stroke lesions (97.7%), seizure symptoms (91.9%), and epileptiform EEG findings (100%). Scalp EEG identified epileptiform activity more frequently in superficial type of SPECT, but less frequently in deep-seated type (both,  = 0.03). Postictal SPECT can be complementary to scalp EEG in endorsing the diagnosis and location of post-stroke epilepsy.
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http://dx.doi.org/10.1177/0271678X20902742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747161PMC
January 2021

Active direct current (DC) shifts and "Red slow": two new concepts for seizure mechanisms and identification of the epileptogenic zone.

Neurosci Res 2020 Jul 8;156:95-101. Epub 2020 Feb 8.

Department of Neurology, Kyoto University Graduate School of Medicine, Japan.

An accurate identification of the epileptogenic zone is essential for patients with intractable epilepsy who are candidates to neurosurgery. EEG recordings can provide predictive biomarkers of the epileptogenic zone. Wide-band EEG makes it possible to record from infraslow (including DC shifts) to high frequency (HFO, over 300 Hz) oscillations for diagnostic purposes in patients with epilepsy. Although the presence of HFOs have been proposed to sign the epileptogenic zone, DC-like recordings demonstrate that DC shifts precede HFOs at seizure onset. This led to the proposal that "ictal active DC shifts" are causally related to seizure onset as opposed to "ictal passive DC shifts". Thus, active DC shifts may constitute predictive biomarkers of the epileptogenic zone in epilepsy. Since DC shift is commonly associated to a rise in extracellular potassium, potassium homeostasis regulated by Kir4.1 channels in astrocytes may play an key role at seizure onset. In addition, we hypothesize that, during the interictal period, the co-occurrence of slow events and interictal HFOs, so-called "Red slow", may also delineate an epileptogenic zone, even if a seizure would not be actually recorded.
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http://dx.doi.org/10.1016/j.neures.2020.01.014DOI Listing
July 2020

Mathematical structures for epilepsy: High-frequency oscillation and interictal epileptic slow (red slow).

Neurosci Res 2020 Jul 20;156:178-187. Epub 2019 Nov 20.

Department of Epilepsy, Movement Disorder and Physiology, Kyoto University, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.

In the present study, we attempted to characterize two characteristic features within the dynamic behavior of wideband electrocorticography data, which were recorded as the brain waves of epilepsy, comprising high-frequency oscillations (HFOs) and interictal epileptic slow (red slow). The results of power spectrum and nonlinear time series analysis indicate that, on one hand, HFOs at epileptic focus are characterized by one-dimensional dynamical systems in ictal onset time segments at an epileptic focus for two patients' datasets; on the other hand, an interictal epileptic slow is characterized by the residue of power spectrum. The results suggest that the degree of freedom of the brain dynamics during epileptic seizure with HFO degenerates to low-dimensional dynamics; hence, the interictal epileptic slow as the precursors of the seizure onset can be detected simply from interictal brain wave data for the dataset of one patient. Therefore, our results are essential to understand the brain dynamics in epilepsy.
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http://dx.doi.org/10.1016/j.neures.2019.11.008DOI Listing
July 2020

A score to map the lateral nonprimary motor area: Multispectrum intrinsic brain activity versus cortical stimulation.

Epilepsia 2019 11 15;60(11):2294-2305. Epub 2019 Oct 15.

Department of Epilepsy, Movement Disorders, and Physiology, Kyoto University Graduate School of Medicine, Kyoto, Japan.

Objective: Multispectrum electrocorticographic components are critical for mapping the nonprimary motor area (NPMA). The objective of this study was to derive and validate a reliable scoring system for electrocorticography-based NPMA mapping (NPMA score) to replace electrical cortical stimulation (ECS) during brain surgery.

Methods: We analyzed 14 consecutive epilepsy patients with subdural electrodes implanted in the frontal lobe at Kyoto University Hospital. The NPMA score was retrospectively derived from multivariate analysis in the derivation group (patients = 7, electrodes = 713, during 2010-2013) and validated in the validation group (patients = 7, electrodes = 772, during 2014-2017). We assessed the accuracy and reliability of the score relative to ECS in determining the NPMA and predicting postoperative functional outcomes.

Results: Multivariate analysis in the derivation group led to an 8-point score for predicting ECS-based NPMA (1 point for anatomical localization of the electrode and 1 or 2 points for movement-related electrocorticographic components regardless of somatotopy in very slow cortical potential shifts [<0.5 Hz], 40-80-Hz band power increase, and 8-24-Hz band power decrease), which was validated in the validation group. The area under the receiver operating characteristic curve (AUC) was 0.89 in the derivation group. Good prediction (specificity = 94%, sensitivity = 100%) and discrimination (AUC = 0.87) were reproduced in the validation group. Overall, higher NPMA scores identified 2 patients with postoperative deficits after frontal lobe resection.

Significance: The NPMA score is reliable for NPMA mapping, potentially replacing ECS. It is a potential prognostic marker for postoperative functional deficits.
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http://dx.doi.org/10.1111/epi.16367DOI Listing
November 2019

[Clinical presentations of Ross syndrome have changed in their lateralities following the anteriotemporal lobectomy for refractory focal epilepsy].

Rinsho Shinkeigaku 2019 Oct 28;59(10):646-651. Epub 2019 Sep 28.

Department of Neurology, Kyoto University Graduate School of Medicine.

We describe a 60-year-old woman with medically refractory left mesial temporal lobe epilepsy accompanied by Ross syndrome. The patient had a partial triad of Ross syndrome with hypohydrosis only on her right side (contralateral to the epileptic seizure focus), Adie's tonic pupil on the right, and areflexia while her seizures used to be medically refractory. However, her hypohidrosis and Adie's tonic pupil have completely changed in terms of laterality following nearly complete seizure freedom resutling from left temporal lobectomy. This unique change in laterality in Ross syndrome is most likely caused by remote effects of the near-absent epileptic acitivity, and it also may contribute to understanding the pathophysiological mechanism of Ross syndrome.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001315DOI Listing
October 2019

Low-dose perampanel improves refractory cortical myoclonus by the dispersed and suppressed paroxysmal depolarization shifts in the sensorimotor cortex.

Clin Neurophysiol 2019 10 19;130(10):1804-1812. Epub 2019 Jul 19.

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University Graduate School of Medicine, Japan. Electronic address:

Objective: To elucidate the effects of perampanel (PER) on refractory cortical myoclonus for dose, etiology and somatosensory-evoked potential (SEP) findings.

Methods: We examined 18 epilepsy patients with seizure and cortical myoclonus. Based on data accumulated before and after PER treatment, correlations among clinical scores in myoclonus and activities of daily life (ADL); early cortical components of SEP; and PER blood concentration, were analyzed.

Results: PER (mean dose: 3.2 ± 2.1 mg/day) significantly improved seizures, myoclonus and ADL and significantly decreased the amplitude of and prolonged latency of giant SEP components. The degree of P25 and N33 prolongations (23.8 ± 1.6 to 24.7 ± 1.7 ms and 32.1 ± 4.0 to 33.7 ± 3.4 ms) were significantly correlated with improved ADL score (p = 0.019 and p = 0.025) and blood PER concentration (p = 0.011 and p = 0.025), respectively.

Conclusions: Low-dose PER markedly improved myoclonus and ADL in patients with refractory cortical myoclonus. Our results suggest that SEP, particularly P25 latency, can be used as a potential biomarker for assessing the objective effects of PER on intractable cortical myoclonus.

Significance: In this study, PER lessened the degree of synchronized discharges in the postsynaptic neurons in the primary motor cortex.
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http://dx.doi.org/10.1016/j.clinph.2019.07.006DOI Listing
October 2019

Human entorhinal cortex electrical stimulation evoked short-latency potentials in the broad neocortical regions: Evidence from cortico-cortical evoked potential recordings.

Brain Behav 2019 09 30;9(9):e01366. Epub 2019 Jul 30.

Department of Epilepsy, Movement Disorders and Physiology, Kyoto University, Kyoto, Japan.

Objective: We aimed at clarifying the clinical significance of the responses evoked by human entorhinal cortex (EC) electrical stimulation by means of cortico-cortical evoked potentials (CCEPs).

Methods: We enrolled nine patients with medically intractable medial temporal lobe epilepsy who underwent invasive presurgical evaluations with subdural or depth electrodes. Single-pulse electrical stimulation was delivered to the EC and fusiform gyrus (FG), and their evoked potentials were compared. The correlation between the evoked potentials and Wechsler Memory Scale-Revised (WMS-R) score was analyzed to investigate whether memory circuit was involved in the generation of the evoked potentials.

Results: In most electrodes placed on the neocortex, EC stimulation induced unique evoked potentials with positive polarity, termed as "widespread P1" (P1w). Compared with FG stimulation, P1w induced by EC stimulation were distinguished by their high occurrence rate, short peak latency (mean: 20.1 ms), small peak amplitude, and waveform uniformity among different recording sites. A stimulation of more posterior parts of the EC induced P1w with shorter latency and larger amplitude. P1w peak amplitude had a positive correlation (r = .69) with the visual memory score of the WMS-R. In one patient, with depth electrode implanted into the hippocampus, the giant evoked potentials were recorded in the electrodes of the anterior hippocampus and EC near the stimulus site.

Conclusions: The human EC electrical stimulation evoked the short-latency potentials in the broad neocortical regions. The origin of P1w remains unclear, although the limited evidence suggests that P1w is the far-field potential by the volume conduction of giant evoked potential from the EC itself and hippocampus. The significance of the present study is that those evoked potentials may be a potential biomarker of memory impairment in various neurological diseases, and we provided direct evidence for the functional subdivisions along the anterior-posterior axis in the human EC.
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http://dx.doi.org/10.1002/brb3.1366DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6749511PMC
September 2019