Multimodal mapping of regional brain vulnerability to focal cortical dysplasia.

Focal cortical dysplasia (FCD) type II is a highly epileptogenic developmental malformation and a common cause of surgically treated drug-resistant epilepsy. While clinical observations suggest frequent occurrence in the frontal lobe, mechanisms for such propensity remain unexplored. Here, we hypothesized that cortex-wide spatial associations of FCD distribution with cortical cytoarchitecture, gene expression and organizational axes may offer complementary insights into processes that predispose given cortical regions to harbour FCD. We mapped the cortex-wide MRI distribution of FCDs in 337 patients collected from 13 sites worldwide. We then determined its associations with (i) cytoarchitectural features using histological atlases by Von Economo and Koskinas and BigBrain; (ii) whole-brain gene expression and spatiotemporal dynamics from prenatal to adulthood stages using the Allen Human Brain Atlas and PsychENCODE BrainSpan; and (iii) macroscale developmental axes of cortical organization. FCD lesions were preferentially located in the prefrontal and fronto-limbic cortices typified by low neuron density, large soma and thick grey matter. Transcriptomic associations with FCD distribution uncovered a prenatal component related to neuroglial proliferation and differentiation, likely accounting for the dysplastic makeup, and a postnatal component related to synaptogenesis and circuit organization, possibly contributing to circuit-level hyperexcitability. FCD distribution showed a strong association with the anterior region of the antero-posterior axis derived from heritability analysis of interregional structural covariance of cortical thickness, but not with structural and functional hierarchical axes. Reliability of all results was confirmed through resampling techniques. Multimodal associations with cytoarchitecture, gene expression and axes of cortical organization indicate that prenatal neurogenesis and postnatal synaptogenesis may be key points of developmental vulnerability of the frontal lobe to FCD. Concordant with a causal role of atypical neuroglial proliferation and growth, our results indicate that FCD-vulnerable cortices display properties indicative of earlier termination of neurogenesis and initiation of cell growth. They also suggest a potential contribution of aberrant postnatal synaptogenesis and circuit development to FCD epileptogenicity.

Impact of epilepsy surgery on quality of life: Systematic review and meta-analysis.

Improved quality of life (QoL) is an important outcome goal following epilepsy surgery. This study aims to quantify change in QoL for adults with drug-resistant epilepsy (DRE) who undergo epilepsy surgery, and to explore clinicodemographic factors associated with these changes. We conducted a systematic review and meta-analysis using Medline, Embase, and Cochrane Central Register of Controlled Trials. All studies reporting pre- and post-epilepsy surgery QoL scores in adults with DRE via validated instruments were included. Meta-analysis assessed the postsurgery change in QoL. Meta-regression assessed the effect of postoperative seizure outcomes on postoperative QoL as well as change in pre- and postoperative QoL scores. A total of 3774 titles and abstracts were reviewed, and ultimately 16 studies, comprising 1182 unique patients, were included. Quality of Life in Epilepsy Inventory-31 item (QOLIE-31) meta-analysis included six studies, and QOLIE-89 meta-analysis included four studies. Postoperative change in raw score was 20.5 for QOLIE-31 (95% confidence interval [CI] = 10.9-30.1, I2 = 95.5) and 12.1 for QOLIE-89 (95% CI = 8.0-16.1, I2 = 55.0%). This corresponds to clinically meaningful QOL improvements. Meta-regression demonstrated a higher postoperative QOLIE-31 score as well as change in pre- and postoperative QOLIE-31 score among studies of cohorts with higher proportions of patients with favorable seizure outcomes. At an individual study level, preoperative absence of mood disorders, better preoperative cognition, fewer trials of antiseizure medications before surgery, high levels of conscientiousness and openness to experience at the baseline, engagement in paid employment before and after surgery, and not being on antidepressants following surgery were associated with improved postoperative QoL. This study demonstrates the potential for epilepsy surgery to provide clinically meaningful improvements in QoL, as well as identifies clinicodemographic factors associated with this outcome. Limitations include substantial heterogeneity between individual studies and high risk of bias.

Later onset focal epilepsy with roots in childhood: Evidence from early learning difficulty and brain volumes in the Human Epilepsy Project.

OBJECTIVE: Visual assessment of magnetic resonance imaging (MRI) from the Human Epilepsy Project 1 (HEP1) found 18% of participants had atrophic brain changes relative to age without known etiology. Here, we identify the underlying factors related to brain volume differences in people with focal epilepsy enrolled in HEP1. METHODS: Enrollment data for participants with complete records and brain MRIs were analyzed, including 391 participants aged 12-60 years. HEP1 excluded developmental or cognitive delay with intelligence quotient <70, and participants reported any formal learning disability diagnoses, repeated grades, and remediation. Prediagnostic seizures were quantified by semiology, frequency, and duration. T1-weighted brain MRIs were analyzed using Sequence Adaptive Multimodal Segmentation (FreeSurfer v7.2), from which a brain tissue volume to intracranial volume ratio was derived and compared to clinically relevant participant characteristics. RESULTS: Brain tissue volume changes observable on visual analyses were quantified, and a brain tissue volume to intracranial volume ratio was derived to compare with clinically relevant variables. Learning difficulties were associated with decreased brain tissue volume to intracranial volume, with a ratio reduction of .005 for each learning difficulty reported (95% confidence interval [CI] = -.007 to -.002, p = .0003). Each 10-year increase in age at MRI was associated with a ratio reduction of .006 (95% CI = -.007 to -.005, p < .0001). For male participants, the ratio was .011 less than for female participants (95% CI = -.014 to -.007, p < .0001). There were no effects from seizures, employment, education, seizure semiology, or temporal lobe electroencephalographic abnormalities. SIGNIFICANCE: This study shows lower brain tissue volume to intracranial volume in people with newly treated focal epilepsy and learning difficulties, suggesting developmental factors are an important marker of brain pathology related to neuroanatomical changes in focal epilepsy. Like the general population, there were also independent associations between brain volume, age, and sex in the study population.

Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy.

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy.

Wearable OPM-MEG: A changing landscape for epilepsy.

Magnetoencephalography with optically pumped magnometers (OPM-MEG) is an emerging and novel, cost-effective wearable system that can simultaneously record neuronal activity with high temporal resolution ("when" neuronal activity occurs) and spatial resolution ("where" neuronal activity occurs). This paper will first outline recent methodological advances in OPM-MEG compared to conventional superconducting quantum interference device (SQUID)-MEG before discussing how OPM-MEG can become a valuable and noninvasive clinical support tool in epilepsy surgery evaluation. Although OPM-MEG and SQUID-MEG share similar data features, OPM-MEG is a wearable design that fits children and adults, and it is also robust to head motion within a magnetically shielded room. This means that OPM-MEG can potentially extend the application of MEG into the neurobiology of severe childhood epilepsies with intellectual disabilities (e.g., epileptic encephalopathies) without sedation. It is worth noting that most OPM-MEG sensors are heated, which may become an issue with large OPM sensor arrays (OPM-MEG currently has fewer sensors than SQUID-MEG). Future implementation of triaxial sensors may alleviate the need for large OPM sensor arrays. OPM-MEG designs allowing both awake and sleep recording are essential for potential long-term epilepsy monitoring.

The effect of epilepsy surgery on productivity: A systematic review and meta-analysis.

OBJECTIVES: An important but understudied benefit of resective epilepsy surgery is improvement in productivity; that is, people's ability to contribute to society through participation in the workforce and in unpaid roles such as carer duties. Here, we aimed to evaluate productivity in adults with drug-resistant epilepsy (DRE) pre- and post-resective epilepsy surgery, and to explore the factors that positively influence productivity outcomes. METHODS: We conducted a systematic review and meta-analysis using four electronic databases: Medline (Ovid), EMBASE (Ovid), EBM Reviews - Cochrane Central Register of Controlled Trials (CENTRAL), and Cochrane Library. All studies over the past 30 years reporting on pre- and post-resective epilepsy surgical outcomes in adults with DRE were eligible for inclusion. Meta-analysis was performed to assess the post-surgery change in employment outcomes. RESULTS: A total of 1005 titles and abstracts were reviewed. Seventeen studies, comprising 2056 unique patients, were suitable for the final quantitative synthesis and meta-analysis. Resective epilepsy surgery resulted in a 22% improvement in overall productivity (95% confidence interval [CI]: 1.07-1.40). The factors associated with increased post-surgery employment risk ratios were lower pre-surgical employment in the workforce (relative risk ratio [RRR] =0.34; 95% CI: 0.15-0.74), shorter follow-up duration (RRR = 0.95; 95% CI: 0.90-0.99), and lower mean age at time of surgery (RRR= 0.97; 95% CI: 0.94-0.99). The risk of bias of the included studies was assessed using Risk Of Bias In Non-randomised Studies - of Interventions and was low for most variables except "measurement of exposure." SIGNIFICANCE: There is clear evidence that resective surgery in eligible surgical DRE patients results in improved productivity. Future work may include implementing a standardized method for collecting and reporting productivity in epilepsy cohorts and focusing on ways to reprioritize health care resource allocation to allow suitable candidates to access surgery earlier. This will ultimately benefit individuals with DRE, their families, our communities, and the wider health care system.

Event-based modeling in temporal lobe epilepsy demonstrates progressive atrophy from cross-sectional data.

OBJECTIVE: Recent work has shown that people with common epilepsies have characteristic patterns of cortical thinning, and that these changes may be progressive over time. Leveraging a large multicenter cross-sectional cohort, we investigated whether regional morphometric changes occur in a sequential manner, and whether these changes in people with mesial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS) correlate with clinical features. METHODS: We extracted regional measures of cortical thickness, surface area, and subcortical brain volumes from T1-weighted (T1W) magnetic resonance imaging (MRI) scans collected by the ENIGMA-Epilepsy consortium, comprising 804 people with MTLE-HS and 1625 healthy controls from 25 centers. Features with a moderate case-control effect size (Cohen d ≥ .5) were used to train an event-based model (EBM), which estimates a sequence of disease-specific biomarker changes from cross-sectional data and assigns a biomarker-based fine-grained disease stage to individual patients. We tested for associations between EBM disease stage and duration of epilepsy, age at onset, and antiseizure medicine (ASM) resistance. RESULTS: In MTLE-HS, decrease in ipsilateral hippocampal volume along with increased asymmetry in hippocampal volume was followed by reduced thickness in neocortical regions, reduction in ipsilateral thalamus volume, and finally, increase in ipsilateral lateral ventricle volume. EBM stage was correlated with duration of illness (Spearman ρ = .293, p = 7.03 × 10-16 ), age at onset (ρ = -.18, p = 9.82 × 10-7 ), and ASM resistance (area under the curve = .59, p = .043, Mann-Whitney U test). However, associations were driven by cases assigned to EBM Stage 0, which represents MTLE-HS with mild or nondetectable abnormality on T1W MRI. SIGNIFICANCE: From cross-sectional MRI, we reconstructed a disease progression model that highlights a sequence of MRI changes that aligns with previous longitudinal studies. This model could be used to stage MTLE-HS subjects in other cohorts and help establish connections between imaging-based progression staging and clinical features.

Temporal complexity of fMRI is reproducible and correlates with higher order cognition.

It has been hypothesized that resting state networks (RSNs), extracted from resting state functional magnetic resonance imaging (rsfMRI), likely display unique temporal complexity fingerprints, quantified by their multiscale entropy patterns (McDonough and Nashiro, 2014). This is a hypothesis with a potential capacity for developing digital biomarkers of normal brain function, as well as pathological brain dysfunction. Nevertheless, a limitation of McDonough and Nashiro (2014) was that rsfMRI data from only 20 healthy individuals was used for the analysis. To validate this hypothesis in a larger cohort, we used rsfMRI datasets of 987 healthy young adults from the Human Connectome Project (HCP), aged 22-35, each with four 14.4-min rsfMRI recordings and parcellated into 379 brain regions. We quantified multiscale entropy of rsfMRI time series averaged at different cortical and sub-cortical regions. We performed effect-size analysis on the data in 8 RSNs. Given that the morphology of multiscale entropy is affected by the choice of its tolerance parameter (r) and embedding dimension (m), we repeated the analyses at multiple values of r and m including the values used in McDonough and Nashiro (2014). Our results reinforced high temporal complexity in the default mode and frontoparietal networks. Lowest temporal complexity was observed in the subcortical areas and limbic system. We investigated the effect of temporal resolution (determined by the repetition time TR) after downsampling of rsfMRI time series at two rates. At a low temporal resolution, we observed increased entropy and variance across datasets. Test-retest analysis showed that findings were likely reproducible across individuals over four rsfMRI runs, especially when the tolerance parameter r is equal to 0.5. The results confirmed that the relationship between functional brain connectivity strengths and rsfMRI temporal complexity changes over time scales. Finally, a non-random correlation was observed between temporal complexity of RSNs and fluid intelligence suggesting that complex dynamics of the human brain is an important attribute of high-level brain function.

Multilayer network switching rate predicts brain performance.

Large-scale brain dynamics are characterized by repeating spatiotemporal connectivity patterns that reflect a range of putative different brain states that underlie the dynamic repertoire of brain functions. The role of transition between brain networks is poorly understood, and whether switching between these states is important for behavior has been little studied. Our aim was to model switching between functional brain networks using multilayer network methods and test for associations between model parameters and behavioral measures. We calculated time-resolved fMRI connectivity in 1,003 healthy human adults from the Human Connectome Project. The time-resolved fMRI connectivity data were used to generate a spatiotemporal multilayer modularity model enabling us to quantify network switching, which we define as the rate at which each brain region transits between different networks. We found (i) an inverse relationship between network switching and connectivity dynamics, where the latter was defined in terms of time-resolved fMRI connections with variance in time that significantly exceeded phase-randomized surrogate data; (ii) brain connectivity was lower during intervals of network switching; (iii) brain areas with frequent network switching had greater temporal complexity; (iv) brain areas with high network switching were located in association cortices; and (v) using cross-validated elastic net regression, network switching predicted intersubject variation in working memory performance, planning/reasoning, and amount of sleep. Our findings shed light on the importance of brain dynamics predicting task performance and amount of sleep. The ability to switch between network configurations thus appears to be a fundamental feature of optimal brain function.

The ENIGMA-Epilepsy working group: Mapping disease from large data sets.

Epilepsy is a common and serious neurological disorder, with many different constituent conditions characterized by their electro clinical, imaging, and genetic features. MRI has been fundamental in advancing our understanding of brain processes in the epilepsies. Smaller-scale studies have identified many interesting imaging phenomena, with implications both for understanding pathophysiology and improving clinical care. Through the infrastructure and concepts now well-established by the ENIGMA Consortium, ENIGMA-Epilepsy was established to strengthen epilepsy neuroscience by greatly increasing sample sizes, leveraging ideas and methods established in other ENIGMA projects, and generating a body of collaborating scientists and clinicians to drive forward robust research. Here we review published, current, and future projects, that include structural MRI, diffusion tensor imaging (DTI), and resting state functional MRI (rsfMRI), and that employ advanced methods including structural covariance, and event-based modeling analysis. We explore age of onset- and duration-related features, as well as phenomena-specific work focusing on particular epilepsy syndromes or phenotypes, multimodal analyses focused on understanding the biology of disease progression, and deep learning approaches. We encourage groups who may be interested in participating to make contact to further grow and develop ENIGMA-Epilepsy.

Dynamic analysis of fMRI activation during epileptic spikes can help identify the seizure origin.

OBJECTIVE: We use the dynamic electroencephalography-functional magnetic resonance imaging (EEG-fMRI) method to incorporate variability in the amplitude and field of the interictal epileptic discharges (IEDs) into the fMRI analysis. We ask whether IED variability analysis can (a) identify additional activated brain regions during the course of IEDs, not seen in standard analysis; and (b) demonstrate the origin and spread of epileptic activity. We explore whether these functional changes recapitulate the structural connections and propagation of epileptic activity during seizures. METHODS: Seventeen patients with focal epilepsy and at least 30 IEDs of a single type during simultaneous EEG-fMRI were studied. IED variability and EEG source imaging (ESI) analysis extracted time-varying dynamic changes. General linear modeling (GLM) generated static functional maps. Dynamic maps were compared to static functional maps. The dynamic sequence from IED variability was compared to the ESI results. In a subset of patients, we investigated structural connections between active brain regions using diffusion-based fiber tractography. RESULTS: IED variability distinguished the origin of epileptic activity from its propagation in 15 of 17 (88%) patients. This included two cases where no result was obtained from the standard GLM analysis. In both of these cases, IED variability revealed activation in line with the presumed epileptic focus. Two cases showed no result from either method. Both had very high spike rates associated with dysplasia in the postcentral gyrus. In all 15 cases with dynamic activation, the observed dynamics were concordant with ESI. Fiber tractography identified specific white matter pathways between brain regions that were active at IED onset and propagation. SIGNIFICANCE: Dynamic techniques involving IED variability can provide additional power for EEG-fMRI analysis, compared to standard analysis, revealing additional biologically plausible information in cases with no result from the standard analysis and gives insight into the origin and spread of IEDs.

Clinical benefit of presurgical EEG-fMRI in difficult-to-localize focal epilepsy: A single-institution retrospective review.

OBJECTIVE: The aim of this report is to present our clinical experience of electroencephalography-functional magnetic resonance imaging (EEG-fMRI) in localizing the epileptogenic focus, and to evaluate the clinical impact and challenges associated with the use of EEG-fMRI in pharmacoresistant focal epilepsy. METHODS: We identified EEG-fMRI studies (n = 118) in people with focal epilepsy performed at our center from 2003 to 2018. Participants were referred from our Comprehensive Epilepsy Program in an exploratory research effort to address often difficult clinical questions, due to complex and difficult-to-localize epilepsy. We assessed the success of each study, the clinical utility of the result, and when surgery was performed, the postoperative outcome. RESULTS: Overall, 50% of EEG-fMRI studies were successful, meaning that data were of good quality and interictal epileptiform discharges were recorded. With an altered recruitment strategy since 2012 with increased inclusion of patients who were inpatients for video-EEG monitoring, we found that this patients in this selected group were more likely to have epileptic discharges detected during EEG-fMRI (96% of inpatients vs 29% of outpatients, P<.0001). To date, 48% (57 of 118) of patients have undergone epilepsy surgery. In 10 cases (17% of the 59 successful studies) the EEG-fMRI result had a "critical impact" on the surgical decision. These patients were difficult to localize because of subtle abnormalities, apparently normal MRI, or extensive structural abnormalities. All 10 had a good seizure outcome at 1 year after surgery (mean follow-up 6.5 years). SIGNIFICANCE: EEG-fMRI results can assist identification of the epileptogenic focus in otherwise difficult-to-localize cases of pharmacoresistant focal epilepsy. Surgery determined largely by localization from the EEG-fMRI result can lead to good seizure outcomes. A limitation of this study is its retrospective design with nonconsecutive recruitment. Prospective clinical trials with well-defined inclusion criteria are needed to determine the overall benefit of EEG-fMRI for preoperative localization and postoperative outcome in focal epilepsy.

Music training is neuroprotective for verbal cognition in focal epilepsy.

Focal epilepsy is a unilateral brain network disorder, providing an ideal neuropathological model with which to study the effects of focal neural disruption on a range of cognitive processes. While language and memory functions have been extensively investigated in focal epilepsy, music cognition has received less attention, particularly in patients with music training or expertise. This represents a critical gap in the literature. A better understanding of the effects of epilepsy on music cognition may provide greater insight into the mechanisms behind disease- and training-related neuroplasticity, which may have implications for clinical practice. In this cross-sectional study, we comprehensively profiled music and non-music cognition in 107 participants; musicians with focal epilepsy (n = 35), non-musicians with focal epilepsy (n = 39), and healthy control musicians and non-musicians (n = 33). Parametric group comparisons revealed a specific impairment in verbal cognition in non-musicians with epilepsy but not musicians with epilepsy, compared to healthy musicians and non-musicians (P = 0.029). This suggests a possible neuroprotective effect of music training against the cognitive sequelae of focal epilepsy, and implicates potential training-related cognitive transfer that may be underpinned by enhancement of auditory processes primarily supported by temporo-frontal networks. Furthermore, our results showed that musicians with an earlier age of onset of music training performed better on a composite score of melodic learning and memory compared to non-musicians (P = 0.037), while late-onset musicians did not differ from non-musicians. For most composite scores of music cognition, although no significant group differences were observed, a similar trend was apparent. We discuss these key findings in the context of a proposed model of three interacting dimensions (disease status, music expertise, and cognitive domain), and their implications for clinical practice, music education, and music neuroscience research.

Enlarged hippocampal fissure in psychosis of epilepsy.

Psychosis of epilepsy (POE) can be a devastating condition, and its neurobiological basis remains unclear. In a previous study, we identified reduced posterior hippocampal volumes in patients with POE. The hippocampus can be further subdivided into anatomically and functionally distinct subfields that, along with the hippocampal fissure, have been shown to be selectively affected in other psychotic disorders and are not captured by gross measures of hippocampal volume. Therefore, in this study, we compared the volume of selected hippocampal subfields and the hippocampal fissure in 31 patients with POE with 31 patients with epilepsy without psychosis. Cortical reconstruction, volumetric segmentation, and calculation of hippocampal subfields and the hippocampal fissure were performed using FreeSurfer. The group with POE had larger hippocampal fissures bilaterally compared with controls with epilepsy, which was significant on the right. There were no significant differences in the volumes of the hippocampal subfields between the two groups. Our findings suggest abnormal development of the hippocampus in POE. They support and expand the neurodevelopmental model of psychosis, which holds that early life stressors lead to abnormal neurodevelopmental processes, which underpin the onset of psychosis in later life. In line with this model, the findings of the present study suggest that enlarged hippocampal fissures may be a biomarker of abnormal neurodevelopment and risk for psychosis in patients with epilepsy.

Bilateral volume reduction in posterior hippocampus in psychosis of epilepsy.

OBJECTIVE: Psychosis of epilepsy (POE) occurs more frequently in temporal lobe epilepsy, raising the question as to whether abnormalities of the hippocampus are aetiologically important. Despite decades of investigation, it is unclear whether hippocampal volume is reduced in POE, perhaps due to small sample sizes and methodological limitations of past research. METHODS: In this study, we examined the volume of the total hippocampus, and the hippocampal head, body and tail, in a large cohort of patients with POE and patients with epilepsy without psychosis (EC). One hundred adults participated: 50 with POE and 50 EC. Total and subregional hippocampal volumes were manually traced and compared between (1) POE and EC; (2) POE with temporal lobe epilepsy, extratemporal lobe epilepsy and generalised epilepsy; and (3) patients with POE with postictal psychosis (PIP) and interictal psychosis (IP). RESULTS: Compared with EC the POE group had smaller total left hippocampus volume (13.5% decrease, p<0.001), and smaller left hippocampal body (13.3% decrease, p=0.002), and left (41.5% decrease, p<0.001) and right (36.4% decrease, p<0.001) hippocampal tail volumes. Hippocampal head volumes did not differ between groups. CONCLUSION: Posterior hippocampal volumes are bilaterally reduced in POE. Volume loss was observed on a posteroanterior gradient, with severe decreases in the tail and moderate volume decreases in the body, with no difference in the hippocampal head. Posterior hippocampal atrophy is evident to a similar degree in PIP and IP. Our findings converge with those reported for the paradigmatic psychotic disorder, schizophrenia, and suggest that posterior hippocampal atrophy may serve as a biomarker of the risk for psychosis, including in patients with epilepsy.

Neuroimaging and connectomics of drug-resistant epilepsy at multiple scales: From focal lesions to macroscale networks.

Epilepsy is among the most common chronic neurologic disorders, with 30%-40% of patients having seizures despite antiepileptic drug treatment. The advent of brain imaging and network analyses has greatly improved the understanding of this condition. In particular, developments in magnetic resonance imaging (MRI) have provided measures for the noninvasive characterization and detection of lesions causing epilepsy. MRI techniques can probe structural and functional connectivity, and network analyses have shaped our understanding of whole-brain anomalies associated with focal epilepsies. This review considers the progress made by neuroimaging and connectomics in the study of drug-resistant epilepsies due to focal substrates, particularly temporal lobe epilepsy related to mesiotemporal sclerosis and extratemporal lobe epilepsies associated with malformations of cortical development. In these disorders, there is evidence of widespread disturbances of structural and functional connectivity that may contribute to the clinical and cognitive prognosis of individual patients. It is hoped that studying the interplay between macroscale network anomalies and lesional profiles will improve our understanding of focal epilepsies and assist treatment choices.

Recommendations for the use of structural magnetic resonance imaging in the care of patients with epilepsy: A consensus report from the International League Against Epilepsy Neuroimaging Task Force.

Structural magnetic resonance imaging (MRI) is of fundamental importance to the diagnosis and treatment of epilepsy, particularly when surgery is being considered. Despite previous recommendations and guidelines, practices for the use of MRI are variable worldwide and may not harness the full potential of recent technological advances for the benefit of people with epilepsy. The International League Against Epilepsy Diagnostic Methods Commission has thus charged the 2013-2017 Neuroimaging Task Force to develop a set of recommendations addressing the following questions: (1) Who should have an MRI? (2) What are the minimum requirements for an MRI epilepsy protocol? (3) How should magnetic resonance (MR) images be evaluated? (4) How to optimize lesion detection? These recommendations target clinicians in established epilepsy centers and neurologists in general/district hospitals. They endorse routine structural imaging in new onset generalized and focal epilepsy alike and describe the range of situations when detailed assessment is indicated. The Neuroimaging Task Force identified a set of sequences, with three-dimensional acquisitions at its core, the harmonized neuroimaging of epilepsy structural sequences-HARNESS-MRI protocol. As these sequences are available on most MR scanners, the HARNESS-MRI protocol is generalizable, regardless of the clinical setting and country. The Neuroimaging Task Force also endorses the use of computer-aided image postprocessing methods to provide an objective account of an individual's brain anatomy and pathology. By discussing the breadth and depth of scope of MRI, this report emphasizes the unique role of this noninvasive investigation in the care of people with epilepsy.

Genetic absence epilepsy: Effective connectivity from piriform cortex to mediodorsal thalamus.

OBJECTIVE: The objective of the study was to quantify effective connectivity from the piriform cortex to mediodorsal thalamus, in Genetic Absence Epilepsy Rats from Strasbourg (GAERS). METHODS: Local field potentials (LFPs) were recorded using microelectrode arrays implanted in the mediodorsal thalamus and piriform cortex, in three urethane anesthetized GAERS and three control rats. Screw electrodes were placed in the primary motor cortex to identify epileptiform discharges. We used transfer entropy to measure effective connectivity from piriform cortex to mediodorsal thalamus prior to and during generalized epileptiform discharges. RESULTS: We observed increased theta band effective connectivity from piriform cortex to mediodorsal thalamus, prior to and during epileptiform discharges in GAERS compared with controls. Increased effective connectivity was also observed in beta and gamma bands from the piriform cortex to mediodorsal thalamus, but only during epileptiform discharges. CONCLUSIONS: This preliminary study suggests that increased effective theta connectivity from the piriform cortex to the mediodorsal thalamus may be a feature of the 'epileptic network' associated with genetic absence epilepsy. Our findings indicate an underlying predisposition of this direct pathway to propagate epileptiform discharges in genetic absence epilepsy.

Multiunit cluster firing patterns of piriform cortex and mediodorsal thalamus in absence epilepsy.

OBJECTIVE: The objective of the study were to investigate patterns of multiunit cluster firing in the piriform cortex (PC) and mediodorsal thalamus (MDT) in a rat model of genetic generalized epilepsy (GGE) with absence seizures and to assess whether these regions contribute to the initiation or spread of generalized epileptiform discharges. METHODS: Multiunit clusters and their corresponding local field potentials (LFPs) were recorded from microelectrode arrays implanted in the PC and MDT in urethane anesthetized Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and nonepileptic control (NEC) rats. Peristimulus time histograms (PSTHs) and cross-correlograms were used to observe transient changes in both the rate of firing and synchrony over time. The phase locking of multiunit clusters to LFP signals (spike-LFP phase locking) was calculated for frequency bands associated with olfactory communication between the two brain regions. RESULTS: There were significant increases in both rate of firing and synchronous activity at the onset of generalized epileptiform discharges in both PC and MDT. Prior to and following these increases in synchronous activity, there were periods of suppression. Significant increases in spike-LFP phase locking were observed within the PC prior to the onset of epileptiform discharges across all spectral bands. There were also significant increases in spike-LFP phase locking within the theta band of the MDT prior to onset. Between the two brain regions, there was a significant decrease in spike-LFP phase locking -0.5 s prior to onset in the theta band which coincided with a significant elevation in spike-LFP phase locking in the gamma band. CONCLUSIONS: Both the PC and MDT are engaged in the absence epilepsy network. Early spike-LFP phase locking between these two brain regions suggests potential involvement in the initiation of seizure activity.

On the relationship between instantaneous phase synchrony and correlation-based sliding windows for time-resolved fMRI connectivity analysis.

Correlation-based sliding window analysis (CSWA) is the most commonly used method to estimate time-resolved functional MRI (fMRI) connectivity. However, instantaneous phase synchrony analysis (IPSA) is gaining popularity mainly because it offers single time-point resolution of time-resolved fMRI connectivity. We aim to provide a systematic comparison between these two approaches, on temporal, topological and anatomical levels. For this purpose, we used resting-state fMRI data from two separate cohorts with different temporal resolutions (45 healthy subjects from Human Connectome Project fMRI data with repetition time of 0.72 s and 25 healthy subjects from a separate validation fMRI dataset with a repetition time of 3 s). For time-resolved functional connectivity analysis, we calculated tapered CSWA over a wide range of different window lengths that were compared to IPSA. We found a strong association in connectivity dynamics between IPSA and CSWA when considering the absolute values of CSWA. The association between CSWA and IPSA was stronger for a window length of ∼20 s (shorter than filtered fMRI wavelength) than ∼100 s (longer than filtered fMRI wavelength), irrespective of the sampling rate of the underlying fMRI data. Narrow-band filtering of fMRI data (0.03-0.07 Hz) yielded a stronger relationship between IPSA and CSWA than wider-band (0.01-0.1 Hz). On a topological level, time-averaged IPSA and CSWA nodes were non-linearly correlated for both short (∼20 s) and long (∼100 s) windows, mainly because nodes with strong negative correlations (CSWA) displayed high phase synchrony (IPSA). IPSA and CSWA were anatomically similar in the default mode network, sensory cortex, insula and cerebellum. Our results suggest that IPSA and CSWA provide comparable characterizations of time-resolved fMRI connectivity for appropriately chosen window lengths. Although IPSA requires narrow-band fMRI filtering, it does not mandate a (semi-)arbitrary choice of window length and window overlap. A code for calculating IPSA is provided.