Perisylvian and Hippocampal Anomalies in Individuals With Pathogenic GRIN2A Variants.

Background and Objectives: Pathogenic variants in GRIN2A are associated with a spectrum of epilepsy-aphasia syndromes (EASs). Seizures as well as speech and language disorders occur frequently but vary widely in severity, both between individuals and across the life span. The link between this phenotypic spectrum and brain characteristics is unknown. Specifically, altered brain networks at the root of speech and language deficits remain to be identified. Patients with pathogenic variants in GRIN2A offer an opportunity to interrogate the impact of glutamate receptor dysfunction on brain development. Methods: We characterized brain anomalies in individuals with pathogenic GRIN2A variants and EASs, hypothesizing alterations in perisylvian speech-language regions and the striatum. We compared structural MRI data from 10 individuals (3 children and 7 adults, 3 female) with pathogenic GRIN2A variants with data from age-matched controls (N = 51 and N = 203 in a secondary analysis). We examined cortical thickness and volume in 4 a priori hypothesized speech and language regions (inferior frontal, precentral, supramarginal, and superior temporal) and across the whole brain. Subcortical structures (hippocampus, basal ganglia, thalamus) and the corpus callosum were also compared. Results: Individuals with pathogenic GRIN2A variants showed increased thickness and volume in the posterior part of Broca's area (inferior frontal gyrus, pars opercularis). For thickness, the effects were bilateral but more pronounced in the left (large effect size, η2 = 0.37) than the right (η2 = 0.12) hemisphere. Both volume and thickness were also higher in the bilateral superior temporal region while the supramarginal region showed increased thickness only. Whole-brain analyses confirmed left-sided thickness increases in Broca's area, with additional increases in the occipital and superior frontal cortices bilaterally. Hippocampal volume was reduced in the left hemisphere. There were no age-dependent effects or corpus callosum group differences. Discussion: Anomalies in perisylvian regions, with largest differences in Broca's area, suggest an altered development of classical speech-language networks in GRIN2A-related EAS. Left hippocampal reduction suggests a role for this structure in early speech and language development and is consistent with GRIN2A gene expression in that region. Overall, elucidating the neural correlates of EAS provides insights into the impact of GRIN2A dysfunction, opening avenues for targeted intervention in developmental syndromes with compromised speech-language development.

A WORLDWIDE ENIGMA STUDY ON EPILEPSY-RELATED GRAY AND WHITE MATTER COMPROMISE ACROSS THE ADULT LIFESPAN.

Objectives: Temporal lobe epilepsy (TLE) is commonly associated with mesiotemporal pathology and widespread alterations of grey and white matter structures. Evidence supports a progressive condition although the temporal evolution of TLE is poorly defined. This ENIGMA-Epilepsy study utilized multimodal magnetic resonance imaging (MRI) data to investigate structural alterations in TLE patients across the adult lifespan. We charted both grey and white matter changes and explored the covariance of age-related alterations in both compartments. Methods: We studied 769 TLE patients and 885 healthy controls across an age range of 17-73 years, from multiple international sites. To assess potentially non-linear lifespan changes in TLE, we harmonized data and combined median split assessments with cross-sectional sliding window analyses of grey and white matter age-related changes. Covariance analyses examined the coupling of grey and white matter lifespan curves. Results: In TLE, age was associated with a robust grey matter thickness/volume decline across a broad cortico-subcortical territory, extending beyond the mesiotemporal disease epicentre. White matter changes were also widespread across multiple tracts with peak effects in temporo-limbic fibers. While changes spanned the adult time window, changes accelerated in cortical thickness, subcortical volume, and fractional anisotropy (all decreased), and mean diffusivity (increased) after age 55 years. Covariance analyses revealed strong limbic associations between white matter tracts and subcortical structures with cortical regions. Conclusions: This study highlights the profound impact of TLE on lifespan changes in grey and white matter structures, with an acceleration of aging-related processes in later decades of life. Our findings motivate future longitudinal studies across the lifespan and emphasize the importance of prompt diagnosis as well as intervention in patients.

Cognitive and psychological dysfunction is present after a first seizure, prior to epilepsy diagnosis and treatment at a First Seizure Clinic.

OBJECTIVE: Neuropsychological comorbidities found in chronic epilepsy have also been reported earlier in the disease course. However, recurrent seizures, antiseizure medication (ASM), and adjustment to a chronic diagnosis remain potential confounds of this literature. It thus remains unclear whether these comorbidities are primary or secondary attributes of epilepsy. To capture individuals as close to disease onset as possible, we studied the cognitive and psychological functioning in adults after their first seizure, yet prior to epilepsy diagnosis and treatment. METHODS: Using a telehealth-based prospective design, we screened cognition, mood, and anxiety symptoms in adult patients referred to a First Seizure Clinic (FSC), who were over 18 years, English-speaking and not taking ASM. We screened cognition via telephone, and psychological symptoms via online questionnaires, all prior to the patients' diagnostic evaluation. Data were collected on 32 individuals subsequently diagnosed with epilepsy at the FSC, and 30 healthy controls from the community, who were matched to the epilepsy group for age, gender, and education. RESULTS: A multivariate analysis of variance revealed that the groups differed significantly on combined cognitive measures with a large effect size (F[1,56] = 5.75, p < 0.001, η2 = 0.45). Post-hoc analyses showed that performances on measures of verbal memory, working memory, and executive functions were significantly worse for the newly diagnosed epilepsy group than controls. The epilepsy group also exhibited higher rates of clinically significant depressive and anxiety symptoms. SIGNIFICANCE: Cognitive and psychological dysfunction is prevalent in people with epilepsy as early as the first seizure event, before the influence of diagnosis, ASM and recurrent seizures. Their neuropsychological profile parallels that seen in chronic epilepsy, showing that this dysfunction is already present at the very onset of the disease. The current study demonstrates the viability of telehealth neuropsychological screening for all new epilepsy cases. PLAIN LANGUAGE STATEMENT: The results of this study show, using telephone-based cognitive assessment and online questionnaires, that people with newly diagnosed epilepsy can experience problems with their thinking and memory skills, and low mood and anxiety, as early as after their first seizure. These issues are apparent at the very beginning of the disease, before an epilepsy diagnosis is made and before antiseizure medication is commenced, which suggests that they are due to the underlying brain disturbance, rather than the secondary effects of seizures, treatment, or lifestyle changes. Telehealth-screening of thinking skills and mental health for all new epilepsy cases is recommended to promote early management of such problems.

Work productivity, quality of life, and care needs: An unfolding epilepsy burden revealed in the Australian Epilepsy Project pilot study.

OBJECTIVE: Epilepsy is a common and serious neurological disorder. This cross-sectional analysis addresses the burden of epilepsy at different stages of the disease. METHODS: This pilot study is embedded within the Australian Epilepsy Project (AEP), aiming to provide epilepsy support through a national network of dedicated sites. For this analysis, adults aged 18-65 years with first unprovoked seizure (FUS), newly diagnosed epilepsy (NDE), or drug-resistant epilepsy (DRE) were recruited between February-August 2022. Baseline clinicodemographic data were collected from the participants who completed questionnaires to assess their quality of life (QOLIE-31, EQ-5D-5L), work productivity (Work Productivity and Activity Impairment [WPAI]), and care needs. Univariate analysis and multivariate regression was performed. RESULTS: 172 participants formed the study cohort (median age 34, interquartile range [IQR]: 26-45), comprising FUS (n = 44), NDE (n = 53), and DRE (n = 75). Mean QOLIE-31 score was 56 (standard deviation [SD] ± 18) and median EQ-5D-5L score was 0.77 (IQR: 0.56-0.92). QOLIE-31 but not EQ-5D-5L scores were significantly lower in the DRE group compared to FUS and NDE groups (p < 0.001). Overall, 64.5% of participants participated in paid work, with fewer DRE (52.0%) compared with FUS (76.7%) and NDE (72.5%) (p < 0.001). Compared to those not in paid employment, those in paid employment had significantly higher quality of life scores (p < 0.001). Almost 5.8% of participants required formal care (median 20 h/week, IQR: 12-55) and 17.7% required informal care (median 16 h/week, IQR: 7-101). SIGNIFICANCE: Epilepsy is associated with a large burden in terms of quality of life, productivity and care needs. PLAIN LANGUAGE SUMMARY: This is a pilot study from the Australian Epilepsy Project (AEP). It reports health economic data for adults of working age who live with epilepsy. It found that people with focal drug-resistant epilepsy had lower quality of life scores and were less likely to participate in paid employment compared to people with new diagnosis epilepsy. This study provides important local data regarding the burden of epilepsy and will help researchers in the future to measure the impact of the AEP on important personal and societal health economic outcomes.

Exploring individual fixel-based white matter abnormalities in epilepsy.

Diffusion MRI has provided insight into the widespread structural connectivity changes that characterize epilepsies. Although syndrome-specific white matter abnormalities have been demonstrated, studies to date have predominantly relied on statistical comparisons between patient and control groups. For diffusion MRI techniques to be of clinical value, they should be able to detect white matter microstructural changes in individual patients. In this study, we apply an individualized approach to a technique known as fixel-based analysis, to examine fibre-tract-specific abnormalities in individuals with epilepsy. We explore the potential clinical value of this individualized fixel-based approach in epilepsy patients with differing syndromic diagnoses. Diffusion MRI data from 90 neurologically healthy control participants and 10 patients with epilepsy (temporal lobe epilepsy, progressive myoclonus epilepsy, and Dravet Syndrome, malformations of cortical development) were included in this study. Measures of fibre density and cross-section were extracted for all participants across brain white matter fixels, and mean values were computed within select tracts-of-interest. Scanner harmonized and normalized data were then used to compute Z-scores for individual patients with epilepsy. White matter abnormalities were observed in distinct patterns in individual patients with epilepsy, both at the tract and fixel level. For patients with specific epilepsy syndromes, the detected white matter abnormalities were in line with expected syndrome-specific clinical phenotypes. In patients with lesional epilepsies (e.g. hippocampal sclerosis, periventricular nodular heterotopia, and bottom-of-sulcus dysplasia), white matter abnormalities were spatially concordant with lesion location. This proof-of-principle study demonstrates the clinical potential of translating advanced diffusion MRI methodology to individual-patient-level use in epilepsy. This technique could be useful both in aiding diagnosis of specific epilepsy syndromes, and in localizing structural abnormalities, and is readily amenable to other neurological disorders. We have included code and data for this study so that individualized white matter changes can be explored robustly in larger cohorts in future work.

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.

Systematic Review of Cost-Effectiveness Analysis for Surgical and Neurostimulation Treatments for Drug-Resistant Epilepsy in Adults.

BACKGROUND AND OBJECTIVES: Surgical and neurostimulator treatments are effective for reducing seizure burden in selected individuals living with drug-resistant epilepsy (DRE). We aimed to determine the presence and key model determinants for cost-effectiveness of these interventions, compared with medical management alone, to assist with decisions about resource allocation. METHODS: A systematic literature search was conducted on June 1, 2022, using MEDLINE, EMBASE, the NHS Economic Evaluation Database, and the Cost-Effectiveness Analysis database. Included studies were economic evaluations in adult DRE cohorts, comparing surgical and neurostimulator treatments (vagus nerve stimulation [VNS], responsive neurostimulation [RNS], and deep brain stimulation [DBS]) vs medical management alone and reporting cost-benefit analysis, cost-utility, or cost-effectiveness. Exclusion criteria were studies with pediatric cohorts and those published in a language other than English. Three independent reviewers screened, extracted, and assessed data against the Consolidated Health Economic Evaluation Reporting Standards checklist, and a fourth reviewer adjudicated discrepancies. RESULTS: Ten studies met inclusion criteria. Seven studies evaluated epilepsy surgery, and 3 evaluated neurostimulation treatments. All relevant studies established that epilepsy surgery is a cost-effective intervention compared with medical management alone, for quality-adjusted life-years and seizure freedom at 2 and 5 years. All relevant studies found neurostimulator treatments to be potentially cost-effective. The incremental cost-effectiveness ratio (ICER), with lower ICER indicating greater cost-effectiveness, was reported for 9 studies and varied between GBP £3,013 and US $61,333. Cost adaptation revealed ICERs from US $170 to US $121,726. Key model determinants included, but were not limited to, improved surgical outcomes and quality of life, reduced surgical and presurgical evaluation costs, higher rates of surgical eligibility after referral and evaluation, epilepsy subtype, less expensive neurostimulator devices with improved longevity, and cost analysis strategy used in the analysis. DISCUSSION: There is consistent evidence that epilepsy surgery is a cost-effective treatment of eligible candidates with DRE. Limited evidence suggests that VNS, RNS, and DBS may be cost-effective therapies for DRE, although more health economic evaluations alongside prospective clinical trials are needed to validate these findings. STUDY REGISTRATION INFORMATION: PROSPERO CRD42021278436.

White matter abnormalities characterize the acute stage of sports-related mild traumatic brain injury.

Sports-related concussion, a form of mild traumatic brain injury, is characterized by transient disturbances of brain function. There is increasing evidence that functional brain changes may be driven by subtle abnormalities in white matter microstructure, and diffusion MRI has been instrumental in demonstrating these white matter abnormalities in vivo. However, the reported location and direction of the observed white matter changes in mild traumatic brain injury are variable, likely attributable to the inherent limitations of the white matter models used. This cross-sectional study applies an advanced and robust technique known as fixel-based analysis to investigate fibre tract-specific abnormalities in professional Australian Football League players with a recent mild traumatic brain injury. We used the fixel-based analysis framework to identify common abnormalities found in specific fibre tracts in participants with an acute injury (≤12 days after injury; n = 14). We then assessed whether similar changes exist in subacute injury (>12 days and <3 months after injury; n = 15). The control group was 29 neurologically healthy control participants. We assessed microstructural differences in fibre density and fibre bundle morphology and performed whole-brain fixel-based analysis to compare groups. Subsequent tract-of-interest analyses were performed within five selected white matter tracts to investigate the relationship between the observed tract-specific abnormalities and days since injury and the relationship between these tract-specific changes with cognitive abnormalities. Our whole-brain analyses revealed significant increases in fibre density and bundle cross-section in the acute mild traumatic brain injury group when compared with controls. The acute mild traumatic brain injury group showed even more extensive differences when compared with the subacute injury group than with controls. The fibre structures affected in acute concussion included the corpus callosum, left prefrontal and left parahippocampal white matter. The fibre density and cross-sectional increases were independent of time since injury in the acute injury group, and were not associated with cognitive deficits. Overall, this study demonstrates that acute mild traumatic brain injury is characterized by specific white matter abnormalities, which are compatible with tract-specific cytotoxic oedema. These potential oedematous changes were absent in our subacute mild traumatic brain injury participants, suggesting that they may normalize within 12 days after injury, although subtle abnormalities may persist in the subacute stage. Future longitudinal studies are needed to elucidate individualized recovery after brain injury.

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.

Structural network alterations in focal and generalized epilepsy assessed in a worldwide ENIGMA study follow axes of epilepsy risk gene expression.

Epilepsy is associated with genetic risk factors and cortico-subcortical network alterations, but associations between neurobiological mechanisms and macroscale connectomics remain unclear. This multisite ENIGMA-Epilepsy study examined whole-brain structural covariance networks in patients with epilepsy and related findings to postmortem epilepsy risk gene expression patterns. Brain network analysis included 578 adults with temporal lobe epilepsy (TLE), 288 adults with idiopathic generalized epilepsy (IGE), and 1328 healthy controls from 18 centres worldwide. Graph theoretical analysis of structural covariance networks revealed increased clustering and path length in orbitofrontal and temporal regions in TLE, suggesting a shift towards network regularization. Conversely, people with IGE showed decreased clustering and path length in fronto-temporo-parietal cortices, indicating a random network configuration. Syndrome-specific topological alterations reflected expression patterns of risk genes for hippocampal sclerosis in TLE and for generalized epilepsy in IGE. These imaging-transcriptomic signatures could potentially guide diagnosis or tailor therapeutic approaches to specific epilepsy syndromes.

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.

Seizure Duration and Spread Dynamics in MRI-Defined Subtypes of Temporal Lobe Epilepsy.

BACKGROUND AND OBJECTIVES: MRI and PET imaging enables subgroups of temporal lobe epilepsy (TLE) to be defined on the basis of structural pathology. Few studies have examined the variation in electroclinical seizure spread patterns based on imaging findings. We performed a retrospective cohort study to investigate the electroclinical differences among 3 specific groups of TLE: MRI-negative PET-positive TLE (MRI-negative TLE), temporal lobe lesion TLE (lesional TLE), and unilateral hippocampal sclerosis TLE (HS-TLE). METHODS: Patients with an electroclinical diagnosis of TLE who had video-scalp EEG recordings of seizures were identified from the retrospective database of the Austin Comprehensive Epilepsy Program between 2005 and 2019. The cohort was further selected into the 3 defined groups based on imaging findings, using MRI and FDG-PET. Timings of clinical and electrographic seizure progression were measured, considering the onset, ipsilateral lobar spread, contralateral spread, and termination. Durations were compared between groups using linear mixed models with inclusion of demographic and clinical covariates. RESULTS: A total of 105 patients (137 seizures) were included, comprising 36 with MRI-negative TLE (54 seizures), 36 with lesional TLE (18 lateral vs 16 mesial lesions; 44 seizures), and 33 with HS-TLE (39 seizures). Seizure duration was similar between MRI-negative TLE and lesional TLE (mean 75.9 vs 71.7 seconds; p = 0.91). Further dividing lesional TLE into medial vs lateral temporal revealed no timing difference. However, the HS-TLE group had longer total seizure duration (114 seconds) compared with both MRI-negative TLE (p < 0.001) and lesional TLE (p < 0.001). Progression of electrographic spread also reflected this pattern, with involvement of extratemporal regions and then the contralateral hemisphere each taking significantly longer in HS-TLE. DISCUSSION: MRI-negative TLE appears electrographically similar to lesional TLE, whether mesial or lateral, in the duration of seizures and the timing of electrographic spread. Both appear electrographically different from HS-TLE, where propagation is slower, suggesting engagement of different epileptogenic networks or seizure suppression mechanisms. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that the electroclinical features of seizures in HS-TLE are different than MRI-negative TLE and lesional TLE.

The Spatial Learning Task of Lhermitte and Signoret (1972): Normative Data in Adults Aged 18-45.

Objective: The Spatial Learning Task of Lhermitte and Signoret is an object-location arbitrary associative learning task. The task was originally developed to evaluate adults with severe amnesia. It is currently used in populations where the memory system either is not yet fully developed or where it has been compromised (e.g. epilepsy, traumatic brain injury, electroconvulsive therapy, cerebrovascular disease and dementia). Normative data have been published for paediatric cohorts and for older adults, however no data exist for the intervening adult years. Method: Here, we address this gap, collecting normative data from 101 adults aged 18-45. Results: Our data indicate that performance on the Spatial Learning Task is not influenced by age, gender, level of education or overall IQ. Less than 10% of the variance in learning scores is associated with variability in verbal memory. Ninety percent of participants achieved perfect scores on two successive trials (T2Cr) within five or fewer trials on the Spatial Learning Task. A T2Cr score of 6 is suggestive of impairment and a T2Cr score of 7 or more is statistically abnormal. Conclusion: These data expand the clinical utility of the Spatial Learning Task in the adult population. Future work should examine performance in lower IQ cohorts, including intellectual disability, and explore sensitivity to disease factors such as laterality of mesial temporal lobe damage.

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.

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.

Bilateral Structural Network Abnormalities in Epilepsy Associated With Bottom-of-Sulcus Dysplasia.

BACKGROUND AND OBJECTIVES: To identify white matter fiber tracts that exhibit structural abnormality in patients with bottom-of-sulcus dysplasia (BOSD) and investigate their association with seizure activity. METHODS: Whole-brain fixel-based analysis of diffusion MRI data was performed to identify white matter fiber tracts with significant reductions in fiber density and cross-section in patients with BOSD (n = 20) when compared to healthy control participants (n = 40). Results from whole-brain analysis were used to investigate the association of fiber tract abnormality with seizure frequency and epilepsy duration. RESULTS: Despite the focal nature of the dysplasia, patients with BOSD showed widespread abnormality in white matter fiber tracts, including the bilateral corticospinal, corticothalamic, and cerebellothalamic tracts, superior longitudinal fasciculi, corpus callosum (body), and the forceps major. This pattern of bilateral connectivity reduction was not related to the laterality of the lesion. Exploratory post hoc analyses showed that high seizure frequency was associated with greater reduction in fiber density at the forceps major, bilateral corticospinal, and cerebellothalamic tracts. DISCUSSION: We demonstrate evidence of a bilaterally distributed, specific white matter network that is vulnerable to disruption in BOSD. The degree of tract abnormality is partly related to seizure activity, but additional contributors such as the genetic background and effects of treatment or environment have not been excluded.

One-Stage, Limited-Resection Epilepsy Surgery for Bottom-of-Sulcus Dysplasia.

OBJECTIVE: To determine whether 1-stage, limited corticectomy controls seizures in patients with MRI-positive, bottom-of-sulcus dysplasia (BOSD). METHODS: We reviewed clinical, neuroimaging, electrocorticography (ECoG), operative, and histopathology findings in consecutively operated patients with drug-resistant focal epilepsy and MRI-positive BOSD, all of whom underwent corticectomy guided by MRI and ECoG. RESULTS: Thirty-eight patients with a median age at surgery of 10.2 (interquartile range [IQR] 6.0-14.1) years were included. BOSDs involved eloquent cortex in 15 patients. Eighty-seven percent of patients had rhythmic spiking on preresection ECoG. Rhythmic spiking was present in 22 of 24 patients studied with combined depth and surface electrodes, being limited to the dysplastic sulcus in 7 and involving the dysplastic sulcus and gyral crown in 15. Sixty-eight percent of resections were limited to the dysplastic sulcus, leaving the gyral crown. Histopathology was focal cortical dysplasia (FCD) type IIb in 29 patients and FCDIIa in 9. Dysmorphic neurons were present in the bottom of the sulcus but not the top or the gyral crown in 17 of 22 patients. Six (16%) patients required reoperation for postoperative seizures and residual dysplasia; reoperation was not correlated with ECoG, neuroimaging, or histologic abnormalities in the gyral crown. At a median 6.3 (IQR 4.8-9.9) years of follow-up, 33 (87%) patients are seizure-free, 31 off antiseizure medication. CONCLUSION: BOSD can be safely and effectively resected with MRI and ECoG guidance, corticectomy potentially being limited to the dysplastic sulcus, without need for intracranial EEG monitoring and functional mapping. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that 1-stage, limited corticectomy for BOSD is safe and effective for control of seizures.

Artifact Reduction in Simultaneous EEG-fMRI: A Systematic Review of Methods and Contemporary Usage.

Simultaneous electroencephalography-functional MRI (EEG-fMRI) is a technique that combines temporal (largely from EEG) and spatial (largely from fMRI) indicators of brain dynamics. It is useful for understanding neuronal activity during many different event types, including spontaneous epileptic discharges, the activity of sleep stages, and activity evoked by external stimuli and decision-making tasks. However, EEG recorded during fMRI is subject to imaging, pulse, environment and motion artifact, causing noise many times greater than the neuronal signals of interest. Therefore, artifact removal methods are essential to ensure that artifacts are accurately removed, and EEG of interest is retained. This paper presents a systematic review of methods for artifact reduction in simultaneous EEG-fMRI from literature published since 1998, and an additional systematic review of EEG-fMRI studies published since 2016. The aim of the first review is to distill the literature into clear guidelines for use of simultaneous EEG-fMRI artifact reduction methods, and the aim of the second review is to determine the prevalence of artifact reduction method use in contemporary studies. We find that there are many published artifact reduction techniques available, including hardware, model based, and data-driven methods, but there are few studies published that adequately compare these methods. In contrast, recent EEG-fMRI studies show overwhelming use of just one or two artifact reduction methods based on literature published 15-20 years ago, with newer methods rarely gaining use outside the group that developed them. Surprisingly, almost 15% of EEG-fMRI studies published since 2016 fail to adequately describe the methods of artifact reduction utilized. We recommend minimum standards for reporting artifact reduction techniques in simultaneous EEG-fMRI studies and suggest that more needs to be done to make new artifact reduction techniques more accessible for the researchers and clinicians using simultaneous EEG-fMRI.

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.

Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study.

Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1021 adults with epilepsy compared to 1564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy colocalized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Negative effects of age on atrophy further revealed a strong influence of connectome architecture in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided deeper insights into the macroscale features that shape the pathophysiology of common epilepsies.