Eiichi Okumura

Optogenetically Induced Seizure and the Longitudinal Hippocampal Network Dynamics

Epileptic seizure is a paroxysmal and self-limited phenomenon characterized by abnormal hypersynchrony of a large population of neurons. However, our current understanding of seizure dynamics is still limited. Here we propose a novel in vivo model of seizure-like afterdischarges using optogenetics, and report on investigation of directional network dynamics during seizure along the septo-temporal (ST) axis of hippocampus. Repetitive pulse photostimulation was applied to the rodent hippocampus, in which channelrhodopsin-2 (ChR2) was expressed, under simultaneous recording of local field potentials (LFPs). Seizure-like afterdischarges were successfully induced after the stimulation in both W-TChR2V4 transgenic (ChR2V-TG) rats and in wild type rats transfected with adeno-associated virus (AAV) vectors carrying ChR2. Pulse frequency at 10 and 20 Hz, and a 0.05 duty ratio were optimal for afterdischarge induction. Immunohistochemical c-Fos staining after a single induced afterdischarge confirmed neuronal activation of the entire hippocampus. LFPs were recorded during seizure-like afterdischarges with a multi-contact array electrode inserted along the ST axis of hippocampus. Granger causality analysis of the LFPs showed a bidirectional but asymmetric increase in signal flow along the ST direction. State space presentation of the causality and coherence revealed three discrete states of the seizure-like afterdischarge phenomenon: 1) resting state; 2) afterdischarge initiation with moderate coherence and dominant septal-to-temporal causality; and 3) afterdischarge termination with increased coherence and dominant temporal-to-septal causality. A novel in vivo model of seizure-like afterdischarge was developed using optogenetics, which was advantageous in its reproducibility and artifact-free electrophysiological observations. Our results provide additional evidence for the potential role of hippocampal septo-temporal interactions in seizure dynamics in vivo. Bidirectional networks work hierarchically along the ST hippocampus in the genesis and termination of epileptic seizures.

Electro- and magneto-encephalographic spike source localization of small focal cortical dysplasia in the dorsal peri-rolandic region

OBJECTIVE Small focal cortical dysplasia (FCD) may be ambiguous or overlooked on magnetic resonance (MR) imaging. Source localization of EEG and magnetoencephalography (MEG) spikes was evaluated to confirm the diagnosis of small FCD. METHODS This study included 6 epilepsy patients with a single small lesion on MR imaging suggesting FCD within a single gyrus among 181 consecutive epilepsy patients admitted to our epilepsy monitoring unit over 27 months. Stereotypical interictal spikes were detected on simultaneous EEG and MEG recordings and the onset-related source of averaged spikes was estimated. RESULTS All 6 patients had unique clinical characteristics as follows: leg sensori-motor seizures in 5 patients and eye version in 1 patient; a small MR imaging lesion suggesting FCD in the dorsal peri-rolandic region, which had been overlooked until our evaluation; and both EEG and MEG dipoles were estimated adjacent to the MR imaging lesion. CONCLUSIONS Source localization of EEG and MEG spikes can confirm the diagnosis of FCD based on a single small MR imaging lesion, which was overlooked by previous examination of MR images. SIGNIFICANCE Examination of MR images should be based on spike source localization as well as seizure semiology to identify subtle MR imaging abnormalities.

Dysfunctional Cortical Connectivity During the Auditory Oddball Task in Patients with Schizophrenia

Background: We studied the imaginary coherence (IC) of gamma frequency oscillations between brain regions of male schizophrenia patients during an auditory oddball task using magnetoencephalography (MEG) and electroencephalography (EEG). Methods: Subjects were 10 right-handed male schizophrenia patients, evaluated by the positive and negative symptom scale (PANSS), and 10 healthy controls. Functional connectivity during the auditory oddball task was reconstructed in low (30-50 Hz) and high (50-100 Hz) gamma bands, and represented by imaginary coherence (IC) based on significant oscillatory power changes. We calculated correlations between PANSS scores and IC. Results: In the high gamma band, IC between left occipital and right prefrontal lobe areas during the time window 750-1000 ms from stimulus onset showed negative correlations with total negative scores, total positive scores, the sum of positive and negative scores in PANSS, conceptual disorganization, and social avoidance scores. In the low gamma band, IC between the same areas from 250-500 ms also showed a negative correlation with the conceptual disorganization score. In the same time window, IC between left occipital and right frontoparietal lobe areas in the low gamma band showed a positive correlation with hallucinatory behavior; IC between right temporal pole and left prefrontal lobe areas showed a positive correlation with delusion scores, although these ICs were decreased relative to controls. Conclusions: Functional disconnection of high and low gamma bands in auditory oddball task may play an important role in the auditory processing in schizophrenia patients.

High frequency oscillations are less frequent but more specific to epileptogenicity during rapid eye movement sleep

OBJECTIVE We hypothesized that high frequency oscillations (HFOs) are differently suppressed during rapid eye movement sleep (REM) between epileptogenic and less epileptogenic cortices, and that the suppressive effect can serve as a specific marker of epileptogenicity. METHODS Intracranial electroencephalography (EEG) was recorded in 13 patients with drug-resistant epilepsy. HFOs between 80 and 200Hz were semi-automatically detected from total 15-min EEG epochs each for REM and slow wave sleep (SWS). z-Score of HFO occurrence rate was calculated from the baseline rate derived from non-epileptogenic cortex. Intracranial electrodes were labeled as REM dominant HFO (RdH) if REM z-score was greater than SWS z-score or as SWS dominant HFO (SdH) if SWS z-score was greater than REM z-score. Relationship of electrode location to the area of surgical resection was compared between RdH and SdH electrodes. RESULTS Out of 1070 electrodes, 101 were defined as RdH electrodes and 115 as SdH electrodes. RdH electrodes were associated with the area of resection in patients with postoperative seizure freedom (P<0.001), but not in patients without seizure freedom. CONCLUSIONS HFOs near the epileptogenic zone are less suppressed during REM. SIGNIFICANCE The less suppressive effect of REM may provide a specific marker of epileptogenicity.

Changes in Event-Related Desynchronization and Synchronization during the Auditory Oddball Task in Schizophrenia Patients

Objective: We studied differences in the spatiotemporal dynamics of cortical oscillation across brain regions of patients with schizophrenia and normal subjects during the auditory oddball task using magnetoencephalography (MEG) and electroencephalography (EEG). Methods: Ten right-handed male schizophrenia patients were studied. We used a newly developed adaptive spatial filtering algorithm optimized for robust source time-frequency reconstruction of MEG and EEG data, and obtained consecutive images in functional maps of event-related desynchronization (ERD) and synchronization (ERS) in theta, lower alpha (8–10 Hz), upper alpha (10–13 Hz), and beta bands. Results: Beta ERD power at 750–1000 ms in patients was significantly increased in large right upper temporal and parietal regions and small upper portions of bilateral dorsal frontal and dorsal-medial parietal regions. Theta ERS power in schizophrenic patients during the oddball task was significantly increased in the left temporal pole at 250–500 ms, and was significantly increased in dorsal, medial frontal, and anterior portions of the anterior cingulate cortex in both hemispheres, and the left portion of lateral temporal regions at 500–750 ms, compared to the control group (family-wise error correction p<0.05). Lower alpha ERS power was significantly decreased in the right occipital region at 500–750 ms and in the right midline parietal and bilateral occipital regions at 750–1000 ms. Upper alpha ERS power was significantly decreased in right midline parietal and left occipital regions at 750–1000 ms. Conclusions: ERD/ERS changes were noted in the left temporal pole and midline frontal and anterior cingulate cortex in theta ERS, occipital lobe in alpha ERS, and right temporal-frontal-parietal, midline frontal, and anterior cingulate cortex in beta ERD. These findings may reflect disturbances in interaction among active large neuronal groups and their communication with each other that may be related to abnormal cognitive and psychopathological function. Significance: Study of ERD and ERS by time-frequency analyses using MEG is useful to clarify data processing dysfunction in schizophrenia.

The Brain’s Response to the Human Voice Depends on the Incidence of Autistic Traits in the General Population

Optimal brain sensitivity to the fundamental frequency (F0) contour changes in the human voice is important for understanding a speaker’s intonation, and consequently, the speaker’s attitude. However, whether sensitivity in the brain’s response to a human voice F0 contour change varies with an interaction between an individual’s traits (i.e., autistic traits) and a human voice element (i.e., presence or absence of communicative action such as calling) has not been investigated. In the present study, we investigated the neural processes involved in the perception of F0 contour changes in the Japanese monosyllables “ne” and “nu.” “Ne” is an interjection that means “hi” or “hey” in English; pronunciation of “ne” with a high falling F0 contour is used when the speaker wants to attract a listener’s attention (i.e., social intonation). Meanwhile, the Japanese concrete noun “nu” has no communicative meaning. We applied an adaptive spatial filtering method to the neuromagnetic time course recorded by whole-head magnetoencephalography (MEG) and estimated the spatiotemporal frequency dynamics of event-related cerebral oscillatory changes in beta band during the oddball paradigm. During the perception of the F0 contour change when “ne” was presented, there was event-related de-synchronization (ERD) in the right temporal lobe. In contrast, during the perception of the F0 contour change when “nu” was presented, ERD occurred in the left temporal lobe and in the bilateral occipital lobes. ERD that occurred during the social stimulus “ne” in the right hemisphere was significantly correlated with a greater number of autistic traits measured according to the Autism Spectrum Quotient (AQ), suggesting that the differences in human voice processing are associated with higher autistic traits, even in non-clinical subjects.

Spatiotemporal Dynamics of High-Gamma Activities during a 3-Stimulus Visual Oddball Task

Although many studies have investigated the neural basis of top-down and bottom-up attention, it still requires refinement in both temporal and spatial terms. We used magnetoencephalography to investigate the spatiotemporal dynamics of high-gamma (52–100 Hz) activities during top-down and bottom-up visual attentional processes, aiming to extend the findings from functional magnetic resonance imaging and event-related potential studies. Fourteen participants performed a 3-stimulus visual oddball task, in which both infrequent non-target and target stimuli were presented. We identified high-gamma event-related synchronization in the left middle frontal gyrus, the left intraparietal sulcus, the left thalamus, and the visual areas in different time windows for the target and non-target conditions. We also found elevated imaginary coherence between the left intraparietal sulcus and the right middle frontal gyrus in the high-gamma band from 300 to 400 ms in the target condition, and between the left thalamus and the left middle frontal gyrus in theta band from 150 to 450 ms. In addition, the strength of high-gamma imaginary coherence between the left middle frontal gyrus and left intraparietal sulcus, between the left middle frontal gyrus and the right middle frontal gyrus, and the high-gamma power in the left thalamus predicted inter-subject variation in target detection response time. This source-level electrophysiological evidence enriches our understanding of bi-directional attention processes: stimulus-driven bottom-up attention orientation to a salient, but irrelevant stimulus; and top-down allocation of attentional resources to stimulus evaluation.

High-gamma activity in an attention network predicts individual differences in elderly adults' behavioral performance

The current study used a magnetoencephalogram to investigate the relationship between high-gamma (52-100 Hz) activity within an attention network and individual differences in behavioral performance among healthy elderly adults. We analyzed brain activity in 41 elderly subjects performing a 3-stimulus visual oddball task. In addition to the average amplitude of event-related fields in the left intraparietal sulcus (IPS), high-gamma power in the left middle frontal gyrus (MFG), the strength of high-gamma imaginary coherence between the right MFG and the left MFG, and those between the right MFG and the left thalamus predicted individual differences in reaction time. In addition, high-gamma power in the left MFG was correlated with task accuracy, whereas high-gamma power in the left thalamus and left IPS was correlated with individual processing speed. The direction of correlations indicated that higher high-gamma power or coherence in an attention network was associated with better task performance and, presumably, higher cognitive function. Thus, high-gamma activity in different regions of this attention network differentially contributed to attentional processing, and such activity could be a fundamental process associated with individual differences in cognitive aging.

Time-varying inter-hemispheric coherence during corpus callosotomy

OBJECTIVE Corpus callosotomy limits the bilateral synchrony of epileptic discharges. However, the instantaneous changes in bilateral synchrony during corpus callosotomy are unclear. The present study investigated how and when bilateral synchrony is suppressed in the anterior and then posterior steps of corpus callosotomy. METHODS Intra-operative scalp electroencephalography (EEG) was recorded simultaneously with surgical video for six patients who underwent total corpus callosotomy for medically intractable drop attacks. The time-varying EEG inter-hemispheric coherence was quantified by wavelet transform coherence and trend analysis. RESULTS The 4-13 Hz coherence decreased after corpus callosotomy in five patients. Significant decrease in coherence was observed only during the posterior step of callosal sectioning in three patients, but throughout both steps in two patients. CONCLUSIONS Decrease in inter-hemispheric coherence is not always correlated with the stages of callosal sectioning. Inter-hemispheric coherence is decreased during the final stage of corpus callosotomy and the effect is maximized after sectioning is completed. SIGNIFICANCE Various patterns of coherence decrease suggest individual variations in the participation of the corpus callosum in the genesis of bilateral synchrony. Time-varying inter-hemispheric EEG coherence is useful to monitor the physiological completeness of corpus callosotomy.

sLORETA-qm for interictal MEG epileptic spike analysis: Comparison of location and quantity with equivalent dipole estimation

OBJECTIVE To determine whether quantitative modification of a standardised low-resolution brain electromagnetic tomography (sLORETA-qm) could be used as a reliable tool for quantitative analysis of magnetoencephalography (MEG) for analysis of the interictal epileptic spike. To verify the performance of sLORETA-qm, magnetic source location and quantity were compared with the equivalent current dipole (ECD) method. METHODS A total of 50 sources from 10 patients with epilepsy were obtained. Analyses were performed after the MEG data were 3-70 Hz band-pass filtered. Time points for analysis were selected referring to waveform patterns and the isofield contour map. With the same spherical model, source estimation was conducted with two methods of analysis: ECD and sLORETA-qm. Distance from the centre of the spherical model and intensities were compared between the methods. RESULTS There were no significant differences between the methods in the distance from the spherical model (paired t-test, p=0.8761). Source intensities between the methods were strongly correlated (Spearmans Rho=0.9803, p<0.001). CONCLUSIONS sLORETA-qm was closely correlated with ECD concerning point source location and quantity in analysis of the interictal epileptic spike. SIGNIFICANCE sLORETA-qm is a reliable quantifiable method without arbitrariness for analysis of the interictal epileptic spike.