Visualization of the Spatiotemporal Propagation of Interictal Spikes in Temporal Lobe Epilepsy: A MEG Pilot Study.

Magnetoencephalography (MEG) is clinically used to localize interictal spikes in discrete brain areas of epilepsy patients through the equivalent current dipole (ECD) method, but does not account for the temporal dynamics of spike activity. Recent studies found that interictal spike propagation beyond the temporal lobe may be associated with worse postsurgical outcomes, but studies using whole-brain data such as in MEG remain limited. In this pilot study, we developed a tool that visualizes the spatiotemporal dynamics of interictal MEG spikes normalized to spike-free sleep activity to assess their onset and propagation patterns in patients with temporal lobe epilepsy (TLE). We extracted interictal source data containing focal epileptiform activity in awake and asleep states from seven patients whose MEG ECD clusters localized to the temporal lobe and normalized the data against spike-free sleep recordings. We calculated the normalized activity over time per cortical label, confirmed maximal activity at onset, and mapped the activity over a 10 ms interval onto each patient's brain using a custom-built Multi-Modal Visualization Tool. The onset of activity in all patients appeared near the clinically determined epileptogenic zone. By 10 ms, four of the patients had propagated source activity restricted to within the temporal lobe, and three had propagated source activity spread to extratemporal regions. Using this tool, we show that noninvasively identifying the onset and propagation of interictal spike activity in MEG can be achieved, which may help provide further insight into epileptic networks and guide surgical planning and interventions in patients with TLE.

Regional healthy brain activity, glioma occurrence and symptomatology.

It is unclear why exactly gliomas show preferential occurrence in certain brain areas. Increased spiking activity around gliomas leads to faster tumour growth in animal models, while higher non-invasively measured brain activity is related to shorter survival in patients. However, it is unknown how regional intrinsic brain activity, as measured in healthy controls, relates to glioma occurrence. We first investigated whether gliomas occur more frequently in regions with intrinsically higher brain activity. Second, we explored whether intrinsic cortical activity at individual patients' tumour locations relates to tumour and patient characteristics. Across three cross-sectional cohorts, 413 patients were included. Individual tumour masks were created. Intrinsic regional brain activity was assessed through resting-state magnetoencephalography acquired in healthy controls and source-localized to 210 cortical brain regions. Brain activity was operationalized as: (i) broadband power; and (ii) offset of the aperiodic component of the power spectrum, which both reflect neuronal spiking of the underlying neuronal population. We additionally assessed (iii) the slope of the aperiodic component of the power spectrum, which is thought to reflect the neuronal excitation/inhibition ratio. First, correlation coefficients were calculated between group-level regional glioma occurrence, as obtained by concatenating tumour masks across patients, and group-averaged regional intrinsic brain activity. Second, intrinsic brain activity at specific tumour locations was calculated by overlaying patients' individual tumour masks with regional intrinsic brain activity of the controls and was associated with tumour and patient characteristics. As proposed, glioma preferentially occurred in brain regions characterized by higher intrinsic brain activity in controls as reflected by higher offset. Second, intrinsic brain activity at patients' individual tumour locations differed according to glioma subtype and performance status: the most malignant isocitrate dehydrogenase-wild-type glioblastoma patients had the lowest excitation/inhibition ratio at their individual tumour locations as compared to isocitrate dehydrogenase-mutant, 1p/19q-codeleted glioma patients, while a lower excitation/inhibition ratio related to poorer Karnofsky Performance Status, particularly in codeleted glioma patients. In conclusion, gliomas more frequently occur in cortical brain regions with intrinsically higher activity levels, suggesting that more active regions are more vulnerable to glioma development. Moreover, indices of healthy, intrinsic excitation/inhibition ratio at patients' individual tumour locations may capture both tumour biology and patients' performance status. These findings contribute to our understanding of the complex and bidirectional relationship between normal brain functioning and glioma growth, which is at the core of the relatively new field of 'cancer neuroscience'.

Common functional connectivity alterations in focal epilepsies identified by machine learning.

OBJECTIVE: This study was undertaken to identify shared functional network characteristics among focal epilepsies of different etiologies, to distinguish epilepsy patients from controls, and to lateralize seizure focus using functional connectivity (FC) measures derived from resting state functional magnetic resonance imaging (MRI). METHODS: Data were taken from 103 adult and 65 pediatric focal epilepsy patients (with or without lesion on MRI) and 109 controls across four epilepsy centers. We used three whole-brain FC measures: parcelwise connectivity matrix, mean FC, and degree of FC. We trained support vector machine models with fivefold cross-validation (1) to distinguish patients from controls and (2) to lateralize the hemisphere of seizure onset in patients. We reported the regions and connections with the highest importance from each model as the common FC differences between the compared groups. RESULTS: FC measures related to the default mode and limbic networks had higher importance relative to other networks for distinguishing epilepsy patients from controls. In lateralization models, regions related to somatosensory, visual, default mode, and basal ganglia showed higher importance. The epilepsy versus control classification model trained using a 400-parcel connectivity matrix achieved a median testing accuracy of 75.6% (median area under the curve [AUC] = .83) in repeated independent testing. Lateralization accuracy using the 400-parcel connectivity matrix reached a median accuracy of 64.0% (median AUC = .69). SIGNIFICANCE: Machine learning models revealed common FC alterations in a heterogeneous group of patients with focal epilepsies. The distribution of the most altered regions supports the hypothesis that shared functional alteration exists beyond the seizure onset zone and its epileptic network. We showed that FC measures can distinguish patients from controls, and further lateralize focal epilepsies. Future studies are needed to confirm these findings by using larger numbers of epilepsy patients.

Presurgical accuracy of dipole clustering in MRI-negative pediatric patients with epilepsy: Validation against intracranial EEG and resection.

OBJECTIVE: To assess the utility of interictal magnetic and electric source imaging (MSI and ESI) using dipole clustering in magnetic resonance imaging (MRI)-negative patients with drug resistant epilepsy (DRE). METHODS: We localized spikes in low-density (LD-EEG) and high-density (HD-EEG) electroencephalography as well as magnetoencephalography (MEG) recordings using dipoles from 11 pediatric patients. We computed each dipole's level of clustering and used it to discriminate between clustered and scattered dipoles. For each dipole, we computed the distance from seizure onset zone (SOZ) and irritative zone (IZ) defined by intracranial EEG. Finally, we assessed whether dipoles proximity to resection was predictive of outcome. RESULTS: LD-EEG had lower clusterness compared to HD-EEG and MEG (p < 0.05). For all modalities, clustered dipoles showed higher proximity to SOZ and IZ than scattered (p < 0.001). Resection percentage was higher in optimal vs. suboptimal outcome patients (p < 0.001); their proximity to resection was correlated to outcome (p < 0.001). No difference in resection percentage was seen for scattered dipoles between groups. CONCLUSION: MSI and ESI dipole clustering helps to localize the SOZ and IZ and facilitate the prognostic assessment of MRI-negative patients with DRE. SIGNIFICANCE: Assessing the MSI and ESI clustering allows recognizing epileptogenic areas whose removal is associated with optimal outcome.

Influence of epileptogenic region on brain structural changes in Rolandic epilepsy.

To investigate the influence of epileptogenic cortex (Rolandic areas) with executive functions in Rolandic epilepsy using structural covariance analysis of structural magnetic resonance imaging (MRI). Structural MRI data of drug-naive patients with Rolandic epilepsy (n = 70) and typically developing children as healthy controls (n = 83) were analyzed using voxel-based morphometry. Gray matter volumes in the patients were compared with those of healthy controls, and were further correlated with epilepsy duration and cognitive score of executive function, respectively. By applying Granger causal analysis to the sequenced morphometric data according to disease progression information, causal network of structural covariance was constructed to assess the causal influence of structural changes from Rolandic cortices to the regions engaging executive function in the patients. Compared with healthy controls, epilepsy patients showed increased gray matter volume in the Rolandic regions, and also the regions engaging in executive function. Covariance network analyses showed that along with disease progression, the Rolandic regions imposed positive causal influence on the regions engaging in executive function. In the patients with Rolandic epilepsy, epileptogenic regions have causal influence on the structural changes in the regions of executive function, implicating damaging effects of Rolandic epilepsy on human brain.

7T versus 3T MRI in the presurgical evaluation of patients with drug-resistant epilepsy.

BACKGROUND AND PURPOSE: MRI has a crucial role in presurgical evaluation of drug-resistant focal epilepsy patients. Whether and how much 7T MRI further improves presurgical diagnosis compared to standard of care 3T MRI remains to be established. We investigate the added value 7T MRI offers in surgical candidates with remaining clinical uncertainty after 3T MRI. METHODS: 7T brain MRI was obtained on sequential patients with drug-resistant focal epilepsy undergoing presurgical evaluation at a comprehensive epilepsy center, including patients with and without suspected lesions on standard 3T MRI. Clinical information and 3T images informed the interpretation of 7T images. Detection of a new lesion on 7T or better characterization of a suspected lesion was considered to add value to the presurgical workup. RESULTS: Interpretable 7T MRI was acquired in 19 patients. 7T MRI identified a lesion relevant to the seizures in three of eight patients (38%) without a lesion on 3T MRI; no lesion in 7/11 patients (64%) with at least one suspected lesion on 3T MRI, contributing to the final classification of all seven as nonlesional; and confirmed and better characterized the lesion suspected at 3T MR in the remaining 4/11 patients. CONCLUSIONS: 7T MRI detected new lesions in over a third of 3T MRI nonlesional patients, confirmed and better characterized a 3T suspected lesion in one third of patients, and helped exclude a 3T suspected lesion in the remainder. Our initial experience suggests that 7T MRI adds value to surgical planning by improving detection and characterization of suspected brain lesions in drug-resistant focal epilepsy patients.

Mapping Functional Connectivity of Epileptogenic Networks through Virtual Implantation.

Children with medically refractory epilepsy (MRE) require resective neurosurgery to achieve seizure freedom, whose success depends on accurate delineation of the epileptogenic zone (EZ). Functional connectivity (FC) can assess the extent of epileptic brain networks since intracranial EEG (icEEG) studies have shown its link to the EZ and predictive value for surgical outcome in these patients. Here, we propose a new noninvasive method based on magnetoencephalography (MEG) and high-density (HD-EEG) data that estimates FC metrics at the source level through an "implantation" of virtual sensors (VSs). We analyzed MEG, HD-EEG, and icEEG data from eight children with MRE who underwent surgery having good outcome and performed source localization (beamformer) on noninvasive data to build VSs at the icEEG electrode locations. We analyzed data with and without Interictal Epileptiform Discharges (IEDs) in different frequency bands, and computed the following FC matrices: Amplitude Envelope Correlation (AEC), Correlation (CORR), and Phase Locking Value (PLV). Each matrix was used to generate a graph using Minimum Spanning Tree (MST), and for each node (i.e., each sensor) we computed four centrality measures: betweenness, closeness, degree, and eigenvector. We tested the reliability of VSs measures with respect to icEEG (regarded as benchmark) via linear correlation, and compared FC values inside vs. outside resection. We observed higher FC inside than outside resection (p<0.05) for AEC [alpha (8-12 Hz), beta (12-30 Hz), and broadband (1-50 Hz)] on data with IEDs and AEC theta (4-8 Hz) on data without IEDs for icEEG, AEC broadband (1-50 Hz) on data without IEDs for MEG-VSs, as well as for all centrality measures of icEEG and MEG/HD-EEG-VSs. Additionally, icEEG and VSs metrics presented high correlation (0.6-0.9, p<0.05). Our data support the notion that the proposed method can potentially replicate the icEEG ability to map the epileptogenic network in children with MRE.Clinical Relevance - The estimation of FC with noninvasive techniques, such as MEG and HD-EEG, via VSs is a promising tool that would help the presurgical evaluation by delineating the EZ without waiting for a seizure to occur, and potentially improve the surgical outcome of patients with MRE undergoing surgery.

Synchronization patterns reveal neuronal coding of working memory content.

Neuronal oscillations are suggested to play an important role in auditory working memory (WM), but their contribution to content-specific representations has remained unclear. Here, we measure magnetoencephalography during a retro-cueing task with parametric ripple-sound stimuli, which are spectrotemporally similar to speech but resist non-auditory memory strategies. Using machine learning analyses, with rigorous between-subject cross-validation and non-parametric permutation testing, we show that memorized sound content is strongly represented in phase-synchronization patterns between subregions of auditory and frontoparietal cortices. These phase-synchronization patterns predict the memorized sound content steadily across the studied maintenance period. In addition to connectivity-based representations, there are indices of more local, "activity silent" representations in auditory cortices, where the decoding accuracy of WM content significantly increases after task-irrelevant "impulse stimuli." Our results demonstrate that synchronization patterns across auditory sensory and association areas orchestrate neuronal coding of auditory WM content. This connectivity-based coding scheme could also extend beyond the auditory domain.

Delayed brain development of Rolandic epilepsy profiled by deep learning-based neuroanatomic imaging.

OBJECTIVES: Although Rolandic epilepsy (RE) has been regarded as a brain developmental disorder, neuroimaging studies have not yet ascertained whether RE has brain developmental delay. This study employed deep learning-based neuroanatomic biomarker to measure the changed feature of "brain age" in RE. METHODS: The study constructed a 3D-CNN brain age prediction model through 1155 cases of typically developing children's morphometric brain MRI from open-source datasets and further applied to a local dataset of 167 RE patients and 107 typically developing children. The brain-predicted age difference was measured to quantitatively estimate brain age changes in RE and further investigated the relevancies with cognitive and clinical variables. RESULTS: The brain age estimation network model presented a good performance for brain age prediction in typically developing children. The children with RE showed a 0.45-year delay of brain age by contrast with typically developing children. Delayed brain age was associated with neuroanatomic changes in the Rolandic regions and also associated with cognitive dysfunction of attention. CONCLUSION: This study provided neuroimaging evidence to support the notion that RE has delayed brain development. KEY POINTS: • The children with Rolandic epilepsy showed imaging phenotypes of delayed brain development with increased GM volume and decreased WM volume in the Rolandic regions. • The children with Rolandic epilepsy had a 0.45-year delay of brain-predicted age by comparing with typically developing children, using 3D-CNN-based brain age prediction model. • The delayed brain age was associated with morphometric changes in the Rolandic regions and attentional deficit in Rolandic epilepsy.

Anti-seizure medication correlated changes of cortical morphology in childhood epilepsy with centrotemporal spikes.

To investigate the morphological changes of cerebral cortex correlating with anti-seizure medication in Childhood Epilepsy with Centrotemporal Spikes (CECTS), and their relationships with seizure control. This study included a total of 188 children, including 62 patients with CECTS taking anti-seizure drugs, 56 patients with drug-naive, and 70 healthy controls. A portion of cases were also followed-up for longitudinal analysis. Cortical morphological parameters were quantitatively measured by applying surface-based morphometry analysis to high-resolution three-dimension T1 weighted images. Among the three groups, the morphological indices were compared to quantify any cortical changes affected by seizures and medication. The relationships among anti-seizure medication, seizure controls and cortical morphometry were investigated using causal mediator analysis. The Rolandic cortex of the drug-naive patients showed abnormal cortical thickness by comparing with that of healthy controls, and thinning by comparing with that of patients with medication. The cortical thickness in the Rolandic regions was negatively correlated with duration of medication and duration of seizure-free. Longitudinal analysis further demonstrated that the thickness of Rolandic cortex thinned in post-medication state relative to the pre-medication state. Mediation analysis revealed that morphological alteration of the Rolandic cortex might act as a mediator in the path of anti-seizure medication on seizure control. Our findings highlighted that anti-seizure medication was associated with regression of abnormal increment of cortical thickness in the Rolandic regions in CECTS. The neuroanatomical alteration might be a mediating factor in the process of seizure control by anti-seizure medication.

Cortico-striato-thalamo-cerebellar networks of structural covariance underlying different epilepsy syndromes associated with generalized tonic-clonic seizures.

Generalized tonic-clonic seizures (GTCS) are the severest and most remarkable clinical expressions of human epilepsy. Cortical, subcortical, and cerebellar structures, organized with different network patterns, underlying the pathophysiological substrates of genetic associated epilepsy with GTCS (GE-GTCS) and focal epilepsy associated with focal to bilateral tonic-clonic seizure (FE-FBTS). Structural covariance analysis can delineate the features of epilepsy network related with long-term effects from seizure. Morphometric MRI data of 111 patients with GE-GTCS, 111 patients with FE-FBTS and 111 healthy controls were studied. Cortico-striato-thalao-cerebellar networks of structural covariance within the gray matter were constructed using a Winner-take-all strategy with five cortical parcellations. Comparisons of structural covariance networks were conducted using permutation tests, and module effects of disease duration on networks were conducted using GLM model. Both patient groups showed increased connectivity of structural covariance relative to controls, mainly within the striatum and thalamus, and mostly correlated with the frontal, motor, and somatosensory cortices. Connectivity changes increased as a function of epilepsy durations. FE-FBTS showed more intensive and extensive gray matter changes with volumetric loss and connectivity increment than GE-GTCS. Our findings implicated cortico-striato-thalamo-cerebellar network changes at a large temporal scale in GTCS, with FE-FBTS showing more severe network disruption. The study contributed novel imaging evidence for understanding the different epilepsy syndromes associated with generalized seizures.

Persistent abnormalities in Rolandic thalamocortical white matter circuits in childhood epilepsy with centrotemporal spikes.

OBJECTIVE: Childhood epilepsy with centrotemporal spikes (CECTS) is a common, focal, transient, developmental epilepsy syndrome characterized by unilateral or bilateral, independent epileptiform spikes in the Rolandic regions of unknown etiology. Given that CECTS presents during a period of dramatic white matter maturation and thatspikes in CECTS are activated during non-rapid eye movement (REM) sleep, we hypothesized that children with CECTS would have aberrant development of white matter connectivity between the thalamus and the Rolandic cortex. We further tested whether Rolandic thalamocortical structural connectivity correlates with spike rate during non-REM sleep. METHODS: Twenty-three children with CECTS (age = 8-15 years) and 19 controls (age = 7-15 years) underwent 3-T structural and diffusion-weighted magnetic resonance imaging and 72-electrode electroencephalographic recordings. Thalamocortical structural connectivity to Rolandic and non-Rolandic cortices was quantified using probabilistic tractography. Developmental changes in connectivity were compared between groups using bootstrap analyses. Longitudinal analysis was performed in four subjects with 1-year follow-up data. Spike rate was quantified during non-REM sleep using manual and automated techniques and compared to Rolandic connectivity using regression analyses. RESULTS: Children with CECTS had aberrant development of thalamocortical connectivity to the Rolandic cortex compared to controls (P = .01), where the expected increase in connectivity with age was not observed in CECTS. There was no difference in the development of thalamocortical connectivity to non-Rolandic regions between CECTS subjects and controls (P = .19). Subjects with CECTS observed longitudinally had reductions in thalamocortical connectivity to the Rolandic cortex over time. No definite relationship was found between Rolandic connectivity and non-REM spike rate (P > .05). SIGNIFICANCE: These data provide evidence that abnormal maturation of thalamocortical white matter circuits to the Rolandic cortex is a feature of CECTS. Our data further suggest that the abnormalities in these tracts do not recover, but are increasingly dysmature over time, implicating a permanent but potentially compensatory process contributing to disease resolution.

Diet modulates brain network stability, a biomarker for brain aging, in young adults.

Epidemiological studies suggest that insulin resistance accelerates progression of age-based cognitive impairment, which neuroimaging has linked to brain glucose hypometabolism. As cellular inputs, ketones increase Gibbs free energy change for ATP by 27% compared to glucose. Here we test whether dietary changes are capable of modulating sustained functional communication between brain regions (network stability) by changing their predominant dietary fuel from glucose to ketones. We first established network stability as a biomarker for brain aging using two large-scale (n = 292, ages 20 to 85 y; n = 636, ages 18 to 88 y) 3 T functional MRI (fMRI) datasets. To determine whether diet can influence brain network stability, we additionally scanned 42 adults, age < 50 y, using ultrahigh-field (7 T) ultrafast (802 ms) fMRI optimized for single-participant-level detection sensitivity. One cohort was scanned under standard diet, overnight fasting, and ketogenic diet conditions. To isolate the impact of fuel type, an independent overnight fasted cohort was scanned before and after administration of a calorie-matched glucose and exogenous ketone ester (d-ß-hydroxybutyrate) bolus. Across the life span, brain network destabilization correlated with decreased brain activity and cognitive acuity. Effects emerged at 47 y, with the most rapid degeneration occurring at 60 y. Networks were destabilized by glucose and stabilized by ketones, irrespective of whether ketosis was achieved with a ketogenic diet or exogenous ketone ester. Together, our results suggest that brain network destabilization may reflect early signs of hypometabolism, associated with dementia. Dietary interventions resulting in ketone utilization increase available energy and thus may show potential in protecting the aging brain.

Scalp ripples as prognostic biomarkers of epileptogenicity in pediatric surgery.

OBJECTIVE: To assess the ability of high-density Electroencephalography (HD-EEG) and magnetoencephalography (MEG) to localize interictal ripples, distinguish between ripples co-occurring with spikes (ripples-on-spike) and independent from spikes (ripples-alone), and evaluate their localizing value as biomarkers of epileptogenicity in children with medically refractory epilepsy. METHODS: We retrospectively studied 20 children who underwent epilepsy surgery. We identified ripples on HD-EEG and MEG data, localized their generators, and compared them with intracranial EEG (icEEG) ripples. When ripples and spikes co-occurred, we performed source imaging distinctly on the data above 80 Hz (to localize ripples) and below 70 Hz (to localize spikes). We assessed whether missed resection of ripple sources predicted poor outcome, separately for ripples-on-spikes and ripples-alone. Similarly, predictive value of spikes was calculated. RESULTS: We observed scalp ripples in 16 patients (10 good outcome). Ripple sources were highly concordant to the icEEG ripples (HD-EEG concordance: 79%; MEG: 83%). When ripples and spikes co-occurred, their sources were spatially distinct in 83-84% of the cases. Removing the sources of ripples-on-spikes predicted good outcome with 90% accuracy for HD-EEG (P = 0.008) and 86% for MEG (P = 0.044). Conversely, removing ripples-alone did not predict outcome. Resection of spike sources (generated at the same time as ripples) predicted good outcome for HD-EEG (P = 0.036; accuracy = 87%), while did not reach significance for MEG (P = 0.1; accuracy = 80%). INTERPRETATION: HD-EEG and MEG localize interictal ripples with high precision in children with refractory epilepsy. Scalp ripples-on-spikes are prognostic, noninvasive biomarkers of epileptogenicity, since removing their cortical generators predicts good outcome. Conversely, scalp ripples-alone are most likely generated by non-epileptogenic areas.

Contralateral Preoperative Resting-State Functional MRI Network Integration Is Associated with Surgical Outcome in Temporal Lobe Epilepsy.

Background Although most patients with medically refractory temporal lobe epilepsy (TLE) experience seizure freedom after anterior temporal lobectomy, approximately 40% may continue to have seizures. Functional network integration, as measured with preoperative resting-state functional MRI, may help stratify patients who are more likely to experience postoperative seizure freedom. Purpose To relate preoperative resting-state functional MRI and surgical outcome in patients with medically refractory TLE. Materials and Methods Data from patients with medically intractable TLE were retrospectively analyzed. Patients underwent preoperative resting-state functional MRI between March 2010 and April 2013 and subsequent unilateral anterior temporal lobectomy. Postoperative seizure-free status was categorized using the Engel Epilepsy Surgery Outcome Scale. Global and regional resting-state functional MRI network properties on preoperative functional MRI scans related to integration were calculated and statistically compared between patients who experienced complete postoperative seizure freedom (Engel class IA) and all others (Engel class IB to class IV) using t tests and multiple logistic regression. Results Forty patients (mean age, 34 years ± 15 [standard deviation]; 21 female) were evaluated. Preoperative global network integration was different (P = .01) between patients who experienced seizure freedom after surgery and all other patients, with 9% lower leaf fraction and 10% lower tree hierarchy in patients with ongoing seizures. Preoperative regional network integration in the contralateral temporoinsular region was different (P = .04) between patients in these two groups. Specifically, the group-level leaf proportion was 59% lower in the entorhinal cortex, 73% lower in the inferior temporal gyrus, 43% lower in the temporal pole, and 69% lower in the insula in patients with ongoing seizures after surgery. When using multivariate regression, contralateral temporoinsular leaf proportion (P = .002) and epilepsy duration (P = .04) were predictive of postoperative seizure freedom, while age (P > .70) and age at seizure onset (P > .50) were not. Conclusion Lower network integration globally and involving the contralateral temporoinsular cortex on preoperative resting-state functional MRI scans is associated with ongoing postoperative seizures in patients with temporal lobe epilepsy. © RSNA, 2020.

Dysmature superficial white matter microstructure in developmental focal epilepsy.

Benign epilepsy with centrotemporal spikes is a common childhood epilepsy syndrome that predominantly affects boys, characterized by self-limited focal seizures arising from the perirolandic cortex and fine motor abnormalities. Concurrent with the age-specific presentation of this syndrome, the brain undergoes a developmentally choreographed sequence of white matter microstructural changes, including maturation of association u-fibres abutting the cortex. These short fibres mediate local cortico-cortical communication and provide an age-sensitive structural substrate that could support a focal disease process. To test this hypothesis, we evaluated the microstructural properties of superficial white matter in regions corresponding to u-fibres underlying the perirolandic seizure onset zone in children with this epilepsy syndrome compared with healthy controls. To verify the spatial specificity of these features, we characterized global superficial and deep white matter properties. We further evaluated the characteristics of the perirolandic white matter in relation to performance on a fine motor task, gender and abnormalities observed on EEG. Children with benign epilepsy with centrotemporal spikes (n = 20) and healthy controls (n = 14) underwent multimodal testing with high-resolution MRI including diffusion tensor imaging sequences, sleep EEG recordings and fine motor assessment. We compared white matter microstructural characteristics (axial, radial and mean diffusivity, and fractional anisotropy) between groups in each region. We found distinct abnormalities corresponding to the perirolandic u-fibre region, with increased axial, radial and mean diffusivity and fractional anisotropy values in children with epilepsy (P = 0.039, P = 0.035, P = 0.042 and P = 0.017, respectively). Increased fractional anisotropy in this region, consistent with decreased integrity of crossing sensorimotor u-fibres, correlated with inferior fine motor performance (P = 0.029). There were gender-specific differences in white matter microstructure in the perirolandic region; males and females with epilepsy and healthy males had higher diffusion and fractional anisotropy values than healthy females (P ≤ 0.035 for all measures), suggesting that typical patterns of white matter development disproportionately predispose boys to this developmental epilepsy syndrome. Perirolandic white matter microstructure showed no relationship to epilepsy duration, duration seizure free, or epileptiform burden. There were no group differences in diffusivity or fractional anisotropy in superficial white matter outside of the perirolandic region. Children with epilepsy had increased radial diffusivity (P = 0.022) and decreased fractional anisotropy (P = 0.027) in deep white matter, consistent with a global delay in white matter maturation. These data provide evidence that atypical maturation of white matter microstructure is a basic feature in benign epilepsy with centrotemporal spikes and may contribute to the epilepsy, male predisposition and clinical comorbidities observed in this disorder.

Neuroepigenetic signatures of age and sex in the living human brain.

Age- and sex-related alterations in gene transcription have been demonstrated, however the underlying mechanisms are unresolved. Neuroepigenetic pathways regulate gene transcription in the brain. Here, we measure in vivo expression of the epigenetic enzymes, histone deacetylases (HDACs), across healthy human aging and between sexes using [11C]Martinostat positron emission tomography (PET) neuroimaging (n = 41). Relative HDAC expression increases with age in cerebral white matter, and correlates with age-associated disruptions in white matter microstructure. A post mortem study confirmed that HDAC1 and HDAC2 paralogs are elevated in white matter tissue from elderly donors. There are also sex-specific in vivo HDAC expression differences in brain regions associated with emotion and memory, including the amygdala and hippocampus. Hippocampus and white matter HDAC expression negatively correlates with emotion regulation skills (n = 23). Age and sex are associated with HDAC expression in vivo, which could drive age- and sex-related transcriptional changes and impact human behavior.

Scalp recorded spike ripples predict seizure risk in childhood epilepsy better than spikes.

In the past decade, brief bursts of fast oscillations in the ripple range have been identified in the scalp EEG as a promising non-invasive biomarker for epilepsy. However, investigation and clinical application of this biomarker have been limited because standard approaches to identify these brief, low amplitude events are difficult, time consuming, and subjective. Recent studies have demonstrated that ripples co-occurring with epileptiform discharges ('spike ripple events') are easier to detect than ripples alone and have greater pathological significance. Here, we used objective techniques to quantify spike ripples and test whether this biomarker predicts seizure risk in childhood epilepsy. We evaluated spike ripples in scalp EEG recordings from a prospective cohort of children with a self-limited epilepsy syndrome, benign epilepsy with centrotemporal spikes, and healthy control children. We compared the rate of spike ripples between children with epilepsy and healthy controls, and between children with epilepsy during periods of active disease (active, within 1 year of seizure) and after a period of sustained seizure-freedom (seizure-free, >1 year without seizure), using semi-automated and automated detection techniques. Spike ripple rate was higher in subjects with active epilepsy compared to healthy controls (P = 0.0018) or subjects with epilepsy who were seizure-free ON or OFF medication (P = 0.0018). Among epilepsy subjects with spike ripples, each month seizure-free decreased the odds of a spike ripple by a factor of 0.66 [95% confidence interval (0.47, 0.91), P = 0.021]. Comparing the diagnostic accuracy of the presence of at least one spike ripple versus a classic spike event to identify group, we found comparable sensitivity and negative predictive value, but greater specificity and positive predictive value of spike ripples compared to spikes (P = 0.016 and P = 0.006, respectively). We found qualitatively consistent results using a fully automated spike ripple detector, including comparison with an automated spike detector. We conclude that scalp spike ripple events identify disease and track with seizure risk in this epilepsy population, using both semi-automated and fully automated detection methods, and that this biomarker outperforms analysis of spikes alone in categorizing seizure risk. These data provide evidence that spike ripples are a specific non-invasive biomarker for seizure risk in benign epilepsy with centrotemporal spikes and support future work to evaluate the utility of this biomarker to guide medication trials and tapers in these children and predict seizure risk in other at-risk populations.

Beta oscillations in the sensorimotor cortex correlate with disease and remission in benign epilepsy with centrotemporal spikes.

INTRODUCTION: Benign epilepsy with centrotemporal spikes (BECTS) is a common form of childhood epilepsy with the majority of those afflicted remitting during their early teenage years. Seizures arise from the lower half of the sensorimotor cortex of the brain (e.g. seizure onset zone) and the abnormal epileptiform discharges observed increase during NREM sleep. To date no clinical factors reliably predict disease course, making determination of ongoing seizure risk a significant challenge. Prior work in BECTS have shown abnormalities in beta band (14.9-30 Hz) oscillations during movement and rest. Oscillations in this frequency band are modulated by state of consciousness and thought to reflect intrinsic inhibitory mechanisms. METHODS: We used high density EEG and source localization techniques to examine beta band activity in the seizure onset zone (sensorimotor cortex) in a prospective cohort of children with BECTS and healthy controls during sleep. We hypothesized that beta power in the sensorimotor cortex would be different between patients and healthy controls, and that beta abnormalities would improve with resolution of disease in this self-limited epilepsy syndrome. We further explored the specificity of our findings and correlation with clinical features. Statistical testing was performed using logistic and standard linear regression models. RESULTS: We found that beta band power in the seizure onset zone is different between healthy controls and BECTS patients. We also found that a longer duration of time spent seizure-free (corresponding to disease remission) correlates with lower beta power in the seizure onset zone. Exploratory spatial analysis suggests this effect is not restricted to the sensorimotor cortex. Exploratory frequency analysis suggests that this phenomenon is also observed in alpha and gamma range activity. We found no relationship between beta power and the presence or rate of epileptiform discharges in the sensorimotor cortex or a test of sensorimotor performance. CONCLUSION: These results provide evidence that cortical beta power in the seizure onset zone may provide a dynamic physiological biomarker of disease in BECTS.