Simeon M. Wong

Dynamic modulation of epileptic high frequency oscillations by the phase of slower cortical rhythms

Pathological high frequency oscillations (pHFOs) have been proposed to be robust markers of epileptic cortex. Oscillatory activity below this frequency range has been shown to be modulated by phase of lower frequency oscillations. Here, we tested the hypothesis that dynamic cross-frequency interactions involving pHFOs are concentrated within the epileptogenic cortex. Intracranial electroencephalographic recordings from 17 children with medically-intractable epilepsy secondary to focal cortical dysplasia were obtained. A time-resolved analysis was performed to determine topographic concentrations and dynamic changes in cross-frequency amplitude-to-phase coupling (CFC). CFC between pHFOs and the phase of theta and alpha rhythms was found to be significantly elevated in the seizure-onset zone compared to non-epileptic regions (p<0.01). Data simulations showed that elevated CFC could not be attributed to the presence of sharp transients or other signal properties. The phase of low frequency oscillations at which pHFO amplitudes were maximal was inconsistent at seizure initiation, yet consistently at the trough of the low frequency rhythm at seizure termination. Amplitudes of pHFOs were most significantly modulated by the phase of alpha-band oscillations (p<0.01). These results suggest that increased CFC between pHFO amplitude and alpha phase may constitute a marker of epileptogenic brain areas and may be relevant for understanding seizure dynamics.

Preictal surrender of post–spike slow waves to spike-related high-frequency oscillations (80–200 Hz) is associated with seizure initiation

Spike and slow waves consist of a “spike” including high‐frequency oscillations (HFOs), which are linked to epileptogenicity and a “post–spike slow wave (PSS)” related to inhibitory activity. The aim of this study was to elucidate the spatiotemporal relationship between spike‐related HFOs and PSS in patients with focal cortical dysplasia (FCD) type II.

Dynamic preictal relations in FCD type II: Potential for early seizure detection in focal epilepsy

In focal epilepsy, power imbalance between spike-related high frequency oscillations (HFOs) with 80-200 Hz and post-spike slow waves (PSS) in the spike and slow waves selectively occurs within the seizure onset zone (SOZ) before seizure onset. The aim of this study was to elucidate when this preictal power imbalance could occur in the SOZ. We analyzed intracranial EEG data from 6 patients with focal cortical dysplasia. During preictal 3-min period, which was divided into three intervals: 0-1 min, 1-2 min 2-3 min before seizure onset, we performed correlation (Spearmans coefficient) and simple linear regression analyses comparing power of spike-related HFOs and PSS. We analyzed 719 ± 57 (mean ± SD) spike and slow waves per patient, which were obtained from three seizures. In the SOZ, the positive correlation between spike-related HFO and PSS power was drastically reduced during preictal 3-min period, and the slope of regression line (ΔPSS power/ΔHFO power) decreased significantly during 0-1 min before seizure onset (p < 0.05, Steel-Dwass test). The present results indicate that the preictal dynamics of HFO and PSS power in the SOZ may have utility for early seizure detection.

Presurgical thalamocortical connectivity is associated with response to vagus nerve stimulation in children with intractable epilepsy

Although chronic vagus nerve stimulation (VNS) is an established treatment for medically-intractable childhood epilepsy, there is considerable heterogeneity in seizure response and little data are available to pre-operatively identify patients who may benefit from treatment. Since the therapeutic effect of VNS may be mediated by afferent projections to the thalamus, we tested the hypothesis that intrinsic thalamocortical connectivity is associated with seizure response following chronic VNS in children with epilepsy. Twenty-one children (ages 5–21 years) with medically-intractable epilepsy underwent resting-state fMRI prior to implantation of VNS. Ten received sedation, while 11 did not. Whole brain connectivity to thalamic regions of interest was performed. Multivariate generalized linear models were used to correlate resting-state data with seizure outcomes, while adjusting for age and sedation status. A supervised support vector machine (SVM) algorithm was used to classify response to chronic VNS on the basis of intrinsic connectivity. Of the 21 subjects, 11 (52%) had 50% or greater improvement in seizure control after VNS. Enhanced connectivity of the thalami to the anterior cingulate cortex (ACC) and left insula was associated with greater VNS efficacy. Within our test cohort, SVM correctly classified response to chronic VNS with 86% accuracy. In an external cohort of 8 children, the predictive model correctly classified the seizure response with 88% accuracy. We find that enhanced intrinsic connectivity within thalamocortical circuitry is associated with seizure response following VNS. These results encourage the study of intrinsic connectivity to inform neural network-based, personalized treatment decisions for children with intractable epilepsy.

Dynamic changes of interictal post-spike slow waves toward seizure onset in focal cortical dysplasia type II

OBJECTIVE A post-spike slow wave (PSS) as part of a spike and slow wave is presumably related to inhibition of epileptic activity. In this study, we evaluated dynamic changes of PSS power toward seizure onset in patients with focal cortical dysplasia (FCD) type II. METHODS We collected data from 10 pediatric patients with FCD type II, who underwent invasive monitoring with subdural grids. The PSS were averaged based on spike-triggering in 30s epochs during both interictal and preictal periods. We quantitatively measured and compared PSS power and distribution between interictal and preictal periods, both within and outside the seizure onset zone (SOZ). RESULTS PSS power was significantly higher in all areas during preictal period compared with interictal period. During preictal period, PSS power within SOZ was significantly higher than outside SOZ. From interictal to preictal period, the number of electrodes with high power PSS significantly increased within SOZ and decreased outside SOZ. CONCLUSIONS Toward seizure onset, PSS power increased in all areas, predominantly within SOZ, and became confined into SOZ in a subset of FCD type II patients. SIGNIFICANCE Preictal PSS power increase and confinement into SOZ accompany transition to seizures.

Presurgical hyperconnectivity of the ablation volume is associated with seizure-freedom after magnetic resonance-guided laser interstitial thermal therapy

PURPOSE Magnetic Resonance-guided Laser Interstitial Thermal Therapy (MRgLITT) is an emerging minimally-invasive alternative to resective surgery for medically-intractable epilepsy. The precise lesioning effect produced by MRgLITT supplies opportunities to glean insights into epileptogenic regions and their interactions with functional brain networks. In this exploratory analysis, we sought to characterize associations between MRgLITT ablation zones and large-scale brain networks that portended seizure outcome using resting-state fMRI. METHODS Presurgical fMRI and intraoperatively volumetric structural imaging were obtained, from which the ablation volume was segmented. The network properties of the ablation volume within the brains large-scale brain networks were characterized using graph theory and compared between children who were and were not rendered seizure-free. RESULTS Of the seventeen included children, five achieved seizure freedom following MRgLITT. Greater functional connectivity of the ablation volume to canonical resting-state networks was associated with seizure-freedom (p < 0.05, FDR-corrected). The ablated volume in children who subsequently became seizure-free following MRgLITT had significantly greater strength, and eigenvector centrality within the large-scale brain network. CONCLUSIONS These findings provide novel insights into the interaction between epileptogenic cortex and large-scale brain networks. The association between ablation volume and resting-state networks may supply novel avenues for presurgical planning and patient stratification.

Post-traumatic stress disorder and chronic hyperconnectivity in emotional processing

Post-traumatic stress disorder (PTSD) is associated with heightened responses to threatening stimuli, particularly aggression-related emotional facial expressions. The stability over time of this neurophysiological ‘hyperactive’ threat response has not been determined. We studied implicit emotional face processing in soldiers with and without PTSD at two time-points (roughly 2 years apart) using magnetoencephalography to determine the response of oscillations and synchrony to happy and angry faces, and the reliability of this marker for PTSD over time. At the initial time-point we had 20 soldiers with and 25 without PTSD; 35 returned for follow-up testing 2 years later, and included 13 with and 22 without PTSD. A mixed-effects analysis was used. There were no significant differences (albeit a slight reduction) in the severity of PTSD between the two time-points. MEG contrasts of the neurophysiological networks involved in the processing of angry vs. happy faces showed that the PTSD group had elevated oscillatory connectivity for angry faces. Maladaptive hypersynchrony in PTSD for threatening faces was seen in subcortical regions, including the thalamus, as well as the ventromedial prefrontal cortex, cingulum gyri, inferior temporal and parietal regions. These results are generally consistent with prior studies and our own, and we demonstrate that this hyperconnectivity was stable over a two year period, in line with essentially stable symptomatology. Together, these results are consistent with the theory that hypervigilance in PTSD is driven by bottom-up, rapid processing of threat-related stimuli that engage a widespread network working in synchrony.

Phase-Amplitude Coupling within the Anterior Thalamic Nuclei during Seizures

Cross-frequency phase-amplitude coupling (cfPAC) subserves an integral role in the hierarchical organization of interregional neuronal communication and is also expressed by epileptogenic cortex during seizures. Here, we sought to characterize patterns of cfPAC expression in the anterior thalamic nuclei during seizures by studying extra-operative recordings in patients implanted with deep brain stimulation electrodes for intractable epilepsy. Nine seizures from two patients were analyzed in the peri-ictal period. CfPAC was calculated using the modulation index and interregional functional connectivity was indexed using the phase-locking value. Statistical analysis was performed within subjects on the basis of nonparametric permutation and corrected with Gaussian field theory. Five of the nine analyzed seizures demonstrated significant cfPAC. Significant cfPAC occurred during the pre-ictal and ictal periods in three seizures, as well as the postictal windows in four seizures. The preferred phase at which cfPAC occurred differed 1) in space, between the thalami of the epileptogenic and nonepileptogenic hemispheres; and 2) in time, at seizure termination. The anterior thalamic nucleus of the epileptogenic hemisphere also exhibited altered interregional phase-locking synchrony concurrent with the expression of cfPAC. By analyzing extraoperative recordings from the anterior thalamic nuclei, we show that cfPAC associated with altered interregional phase synchrony is lateralized to the thalamus of the epileptogenic hemisphere during seizures. Electrophysiological differences in cfPAC, including preferred phase of oscillatory interactions may be further investigated as putative targets for individualized neuromodulation paradigms in patients with drug-resistant epilepsy. NEW & NOTEWORTHY The association between fast brain activity and slower oscillations is an integral mechanism for hierarchical neuronal communication, which is also manifested in epileptogenic cortex. Our data suggest that the same phenomenon occurs in the anterior thalamic nuclei during seizures. Further, the preferred phase of modulation shows differences in space, between the epileptogenic and nonepileptogenic hemispheres and time, as seizures terminate. Our data encourage the study of cross-frequency coupling for targeted, individualized closed-loop stimulation paradigms.

Default Mode Network Oscillatory Coupling Is Increased Following Concussion

Concussion is a common form of mild traumatic brain injury. Despite the descriptor “mild,” a single injury can leave long-lasting and sustained alterations to brain function, including changes to localized activity and large-scale interregional communication. Cognitive complaints are thought to arise from such functional deficits. We investigated the impact of injury on neurophysiological and functionally specialized resting networks, known as intrinsic connectivity networks (ICNs), using magnetoencephalography. We assessed neurophysiological connectivity in 40 males, 20 with concussion and 20 without. Regions-of-interest that comprise nodes of ICNs were defined, and their time courses derived using a beamformer approach. Pairwise fluctuations and covariations in band-limited amplitude envelopes were computed reflecting measures of functional connectivity. Intra-network connectivity was compared between groups using permutation testing and correlated with symptoms. We observed increased resting spectral connectivity in the default mode network (DMN) and motor networks (MOTs) in our concussion group when compared with controls, across alpha through gamma ranges. Moreover, these differences were not explained by power spectrum density within the ICNs. Furthermore, this increased coupling was significantly associated with symptoms in the DMN and MOTs—but once accounting for comorbidities (including, depression, anxiety, and ADHD) only the DMN continued to be associated with symptoms. The DMN plays a critical role in shifting between cognitive tasks. These data suggest even a single concussion can perturb the intrinsic coupling of this functionally specialized network in the brain, and may explain persistent and wide-ranging symptomatology.

Increased Functional Connectivity During Emotional Face Processing in Children With Autism Spectrum Disorder

Individuals with autism spectrum disorder (ASD) demonstrate poor social functioning, which may be related to atypical emotional face processing. Altered functional connectivity among brain regions, particularly involving limbic structures may be implicated. The current magnetoencephalography (MEG) study investigated whole-brain functional connectivity of eight a priori identified brain regions during the implicit presentation of happy and angry faces in 20 7 to 10-year-old children with ASD and 22 typically developing controls. Findings revealed a network of increased alpha-band phase synchronization during the first 400 ms of happy face processing in children with ASD compared to controls. This network of increased alpha-band phase synchronization involved the left fusiform gyrus, right insula, and frontal regions critical for emotional face processing. In addition, greater connectivity strength of the left fusiform gyrus (maximal 85 to 208 ms) and right insula (maximal 73 to 270 ms) following happy face presentation in children with ASD compared to typically developing controls was found. These findings reflect altered neuronal communication in children with ASD only to happy faces during implicit emotional face processing.