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    Topographic divergence of atypical cortical asymmetry and atrophy patterns in temporal lobe epilepsy
    Park, B-Y ; Lariviere, S ; Rodriguez-Cruces, R ; Royer, J ; Tavakol, S ; Wang, Y ; Caciagli, L ; Caligiuri, ME ; Gambardella, A ; Concha, L ; Keller, SS ; Cendes, F ; Alvim, MKM ; Yasuda, C ; Bonilha, L ; Gleichgerrcht, E ; Focke, NK ; Kreilkamp, BAK ; Domin, M ; von Podewils, F ; Langner, S ; Rummel, C ; Rebsamen, M ; Wiest, R ; Martin, P ; Kotikalapudi, R ; Bender, B ; O'Brien, TJ ; Law, M ; Sinclair, B ; Vivash, L ; Kwan, P ; Desmond, PM ; Malpas, CB ; Lui, E ; Alhusaini, S ; Doherty, CP ; Cavalleri, GL ; Delanty, N ; Kalviainen, R ; Jackson, GD ; Kowalczyk, M ; Mascalchi, M ; Semmelroch, M ; Thomas, RH ; Soltanian-Zadeh, H ; Davoodi-Bojd, E ; Zhang, J ; Lenge, M ; Guerrini, R ; Bartolini, E ; Hamandi, K ; Foley, S ; Weber, B ; Depondt, C ; Absil, J ; Carr, SJA ; Abela, E ; Richardson, MP ; Devinsky, O ; Severino, M ; Striano, P ; Parodi, C ; Tortora, D ; Hatton, SN ; Vos, SB ; Duncan, JS ; Galovic, M ; Whelan, CD ; Bargallo, N ; Pariente, J ; Conde-Blanco, E ; Vaudano, AE ; Tondelli, M ; Meletti, S ; Kong, X-Z ; Francks, C ; Fisher, SE ; Caldairou, B ; Ryten, M ; Labate, A ; Sisodiya, SM ; Thompson, PM ; McDonald, CR ; Bernasconi, A ; Bernasconi, N ; Bernhardt, BC (OXFORD UNIV PRESS, 2022-03-25)
    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.
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    Machine learning approaches for imaging-based prognostication of the outcome of surgery for mesial temporal lobe epilepsy
    Sinclair, B ; Cahill, V ; Seah, J ; Kitchen, A ; Vivash, LE ; Chen, Z ; Malpas, CB ; O'Shea, MF ; Desmond, PM ; Hicks, RJ ; Morokoff, AP ; King, JA ; Fabinyi, GC ; Kaye, AH ; Kwan, P ; Berkovic, SF ; Law, M ; O'Brien, TJ (WILEY, 2022-03-25)
    OBJECTIVES: Around 30% of patients undergoing surgical resection for drug-resistant mesial temporal lobe epilepsy (MTLE) do not obtain seizure freedom. Success of anterior temporal lobe resection (ATLR) critically depends on the careful selection of surgical candidates, aiming at optimizing seizure freedom while minimizing postoperative morbidity. Structural MRI and FDG-PET neuroimaging are routinely used in presurgical assessment and guide the decision to proceed to surgery. In this study, we evaluate the potential of machine learning techniques applied to standard presurgical MRI and PET imaging features to provide enhanced prognostic value relative to current practice. METHODS: Eighty two patients with drug resistant MTLE were scanned with FDG-PET pre-surgery and T1-weighted MRI pre- and postsurgery. From these images the following features of interest were derived: volume of temporal lobe (TL) hypometabolism, % of extratemporal hypometabolism, presence of contralateral TL hypometabolism, presence of hippocampal sclerosis, laterality of seizure onset volume of tissue resected and % of temporal lobe hypometabolism resected. These measures were used as predictor variables in logistic regression, support vector machines, random forests and artificial neural networks. RESULTS: In the study cohort, 24 of 82 (28.3%) who underwent an ATLR for drug-resistant MTLE did not achieve Engel Class I (i.e., free of disabling seizures) outcome at a minimum of 2 years of postoperative follow-up. We found that machine learning approaches were able to predict up to 73% of the 24 ATLR surgical patients who did not achieve a Class I outcome, at the expense of incorrect prediction for up to 31% of patients who did achieve a Class I outcome. Overall accuracies ranged from 70% to 80%, with an area under the receiver operating characteristic curve (AUC) of .75-.81. We additionally found that information regarding overall extent of both total and significantly hypometabolic tissue resected was crucial to predictive performance, with AUC dropping to .59-.62 using presurgical information alone. Incorporating the laterality of seizure onset and the choice of machine learning algorithm did not significantly change predictive performance. SIGNIFICANCE: Collectively, these results indicate that "acceptable" to "good" patient-specific prognostication for drug-resistant MTLE surgery is feasible with machine learning approaches utilizing commonly collected imaging modalities, but that information on the surgical resection region is critical for optimal prognostication.
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    Atlas of lesion locations and postsurgical seizure freedom in focal cortical dysplasia: A MELD study
    Wagstyl, K ; Whitaker, K ; Raznahan, A ; Seidlitz, J ; Vertes, PE ; Foldes, S ; Humphreys, Z ; Hu, W ; Mo, J ; Likeman, M ; Davies, S ; Lenge, M ; Cohen, NT ; Tang, Y ; Wang, S ; Ripart, M ; Chari, A ; Tisdall, M ; Bargallo, N ; Conde-Blanco, E ; Carlos Pariente, J ; Pascual-Diaz, S ; Delgado-Martinez, I ; Perez-Enriquez, C ; Lagorio, I ; Abela, E ; Mullatti, N ; O'Muircheartaigh, J ; Vecchiato, K ; Liu, Y ; Caligiuri, M ; Sinclair, B ; Vivash, L ; Willard, A ; Kandasamy, J ; McLellan, A ; Sokol, D ; Semmelroch, M ; Kloster, A ; Opheim, G ; Yasuda, C ; Zhang, K ; Hamandi, K ; Barba, C ; Guerrini, R ; Gaillard, WD ; You, X ; Wang, I ; Gonzalez-Ortiz, S ; Severino, M ; Striano, P ; Tortora, D ; Kalviainen, R ; Gambardella, A ; Labate, A ; Desmond, P ; Lui, E ; O'Brien, T ; Shetty, J ; Jackson, G ; Duncan, JS ; Winston, GP ; Pinborg, L ; Cendes, F ; Cross, JH ; Baldeweg, T ; Adler, S (WILEY, 2021-11-29)
    OBJECTIVE: Drug-resistant focal epilepsy is often caused by focal cortical dysplasias (FCDs). The distribution of these lesions across the cerebral cortex and the impact of lesion location on clinical presentation and surgical outcome are largely unknown. We created a neuroimaging cohort of patients with individually mapped FCDs to determine factors associated with lesion location and predictors of postsurgical outcome. METHODS: The MELD (Multi-centre Epilepsy Lesion Detection) project collated a retrospective cohort of 580 patients with epilepsy attributed to FCD from 20 epilepsy centers worldwide. Magnetic resonance imaging-based maps of individual FCDs with accompanying demographic, clinical, and surgical information were collected. We mapped the distribution of FCDs, examined for associations between clinical factors and lesion location, and developed a predictive model of postsurgical seizure freedom. RESULTS: FCDs were nonuniformly distributed, concentrating in the superior frontal sulcus, frontal pole, and temporal pole. Epilepsy onset was typically before the age of 10 years. Earlier epilepsy onset was associated with lesions in primary sensory areas, whereas later epilepsy onset was associated with lesions in association cortices. Lesions in temporal and occipital lobes tended to be larger than frontal lobe lesions. Seizure freedom rates varied with FCD location, from around 30% in visual, motor, and premotor areas to 75% in superior temporal and frontal gyri. The predictive model of postsurgical seizure freedom had a positive predictive value of 70% and negative predictive value of 61%. SIGNIFICANCE: FCD location is an important determinant of its size, the age at epilepsy onset, and the likelihood of seizure freedom postsurgery. Our atlas of lesion locations can be used to guide the radiological search for subtle lesions in individual patients. Our atlas of regional seizure freedom rates and associated predictive model can be used to estimate individual likelihoods of postsurgical seizure freedom. Data-driven atlases and predictive models are essential for evidence-based, precision medicine and risk counseling in epilepsy.
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    Assessment of the DTI-ALPS Parameter Along the Perivascular Space in Older Adults at Risk of Dementia
    Steward, CE ; Venkatraman, VK ; Lui, E ; Malpas, CB ; Ellis, KA ; Cyarto, EV ; Vivash, L ; O'Brien, TJ ; Velakoulis, D ; Ames, D ; Masters, CL ; Lautenschlager, NT ; Bammer, R ; Desmond, PM (WILEY, 2021-02-08)
    BACKGROUND AND PURPOSE: Recently, there has been growing interest in the glymphatic system (the functional waste clearance pathway for the central nervous system and its role in flushing solutes (such as amyloid ß and tau), metabolic, and other cellular waste products in the brain. Herein, we investigate a recent potential biomarker for glymphatic activity (the diffusion tensor imaging along the perivascular space [DTI-ALPS] parameter) using diffusion MRI imaging in an elderly cohort comprising 10 cognitively normal, 10 mild cognitive impairment (MCI), and 16 Alzheimer's disease (AD). METHODS: All 36 participants imaged on a Siemens 3.0T Tim Trio. Single-SE diffusion weighted Echo-planar imaging scans were acquired as well as T1 magnetization prepared rapid gradient echo, T2 axial, and susceptibility weighted imaging. Three millimeter regions of interest were drawn in the projection and association fibers adjacent to the medullary veins at the level of the lateral ventricle. The DTI-ALPS parameter was calculated in these regions and correlated with cognitive status, Mini-Mental State Examination (MMSE), and ADASCog11 measures. RESULTS: Significant correlations were found between DTI-ALPS and MMSE and ADASCog11 in the right hemisphere adjusting for age, sex, and APoE ε4 status. Significant differences were also found in the right DTI-ALPS indices between cognitively normal and AD groups (P < .026) and MCI groups (P < .025) in a univariate general linear model corrected for age, sex, and APoE ε4. Significant differences in apparent diffusion coefficient between cognitively normal and AD groups were found in the right projection fibers (P = .028). CONCLUSION: Further work is needed to determine the utility of DTI-ALPS index in larger elderly cohorts and whether it measures glymphatic activity.
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    Artificial intelligence for classification of temporal lobe epilepsy with ROI-level MRI data: A worldwide ENIGMA-Epilepsy study
    Gleichgerrcht, E ; Munsell, BC ; Alhusaini, S ; Alvim, MKM ; Bargallo, N ; Bender, B ; Bernasconi, A ; Bernasconi, N ; Bernhardt, B ; Blackmon, K ; Caligiuri, ME ; Cendes, F ; Concha, L ; Desmond, PM ; Devinsky, O ; Doherty, CP ; Domin, M ; Duncan, JS ; Focke, NK ; Gambardella, A ; Gong, B ; Guerrini, R ; Hatton, SN ; Kalviainen, R ; Keller, SS ; Kochunov, P ; Kotikalapudi, R ; Kreilkamp, BAK ; Labate, A ; Langner, S ; Lariviere, S ; Lenge, M ; Lui, E ; Martin, P ; Mascalchi, M ; Meletti, S ; O'Brien, TJ ; Pardoe, HR ; Pariente, JC ; Rao, JX ; Richardson, MP ; Rodriguez-Cruces, R ; Ruber, T ; Sinclair, B ; Soltanian-Zadeh, H ; Stein, DJ ; Striano, P ; Taylor, PN ; Thomas, RH ; Vaudano, AE ; Vivash, L ; von Podewills, F ; Vos, SB ; Weber, B ; Yao, Y ; Yasuda, CL ; Zhang, J ; Thompson, PM ; Sisodiya, SM ; McDonald, CR ; Bonilha, L (ELSEVIER SCI LTD, 2021-07-30)
    Artificial intelligence has recently gained popularity across different medical fields to aid in the detection of diseases based on pathology samples or medical imaging findings. Brain magnetic resonance imaging (MRI) is a key assessment tool for patients with temporal lobe epilepsy (TLE). The role of machine learning and artificial intelligence to increase detection of brain abnormalities in TLE remains inconclusive. We used support vector machine (SV) and deep learning (DL) models based on region of interest (ROI-based) structural (n = 336) and diffusion (n = 863) brain MRI data from patients with TLE with ("lesional") and without ("non-lesional") radiographic features suggestive of underlying hippocampal sclerosis from the multinational (multi-center) ENIGMA-Epilepsy consortium. Our data showed that models to identify TLE performed better or similar (68-75%) compared to models to lateralize the side of TLE (56-73%, except structural-based) based on diffusion data with the opposite pattern seen for structural data (67-75% to diagnose vs. 83% to lateralize). In other aspects, structural and diffusion-based models showed similar classification accuracies. Our classification models for patients with hippocampal sclerosis were more accurate (68-76%) than models that stratified non-lesional patients (53-62%). Overall, SV and DL models performed similarly with several instances in which SV mildly outperformed DL. We discuss the relative performance of these models with ROI-level data and the implications for future applications of machine learning and artificial intelligence in epilepsy care.
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    7T Magnetic Resonance Imaging Quantification of Brain Glutamate in Acute Ischaemic Stroke
    Nicolo, J-P ; Moffat, B ; Wright, DK ; Sinclair, B ; Neal, A ; Lui, E ; Desmond, P ; Glarin, R ; Davis, KA ; Reddy, R ; Yan, B ; O'Brien, TJ ; Kwan, P (Korean Stroke Society, 2021-05-01)
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    Study protocol for a phase II randomised, double-blind, placebo-controlled trial of perampanel as an antiepileptogenic treatment following acute stroke
    Nicolo, J-P ; Chen, Z ; Moffat, B ; Wright, DK ; Sinclair, B ; Glarin, R ; Neal, A ; Thijs, V ; Seneviratne, U ; Yan, B ; Cloud, G ; O'Brien, TJ ; Kwan, P (BMJ PUBLISHING GROUP, 2021-05-01)
    INTRODUCTION: Stroke is a common cause of epilepsy that may be mediated via glutamate dysregulation. There is currently no evidence to support the use of antiseizure medications as primary prevention against poststroke epilepsy. Perampanel has a unique antiglutamatergic mechanism of action and may have antiepileptogenic properties. This study aims to evaluate the efficacy and safety of perampanel as an antiepileptogenic treatment in patients at high risk of poststroke epilepsy. METHODS AND ANALYSIS: Up to 328 patients with cortical ischaemic stroke or lobar haemorrhage will be enrolled, and receive their first treatment within 7 days of stroke onset. Patients will be randomised (1:1) to receive perampanel (titrated to 6 mg daily over 4 weeks) or matching placebo, stratified by stroke subtype (ischaemic or haemorrhagic). Treatment will be continued for 12 weeks after titration. 7T MRI will be performed at baseline for quantification of cerebral glutamate by magnetic resonance spectroscopy and glutamate chemical exchange saturation transfer imaging. Blood will be collected for measurement of plasma glutamate levels. Participants will be followed up for 52 weeks after randomisation.The primary study outcome will be the proportion of participants in each group free of late (more than 7 days after stroke onset) poststroke seizures by the end of the 12-month study period, analysed by Fisher's exact test. Secondary outcomes will include time to first seizure, time to treatment withdrawal and 3-month modified Rankin Scale score. Quality of life, cognitive function, mood and adverse events will be assessed by standardised questionnaires. Exploratory outcomes will include correlation between cerebral and plasma glutamate concentration and stroke and seizure outcomes. ETHICS AND DISSEMINATION: This study was approved by the Alfred Health Human Research Ethics Committee (HREC No 44366, Reference 287/18). TRIAL REGISTRATION NUMBER: ACTRN12618001984280; Pre-results.
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    Seven-tesla quantitative magnetic resonance spectroscopy of glutamate, gamma-aminobutyric acid, and glutathione in the posterior cingulate cortex/precuneus in patients with epilepsy
    Gonen, OM ; Moffat, BA ; Desmond, PM ; Lui, E ; Kwan, P ; O'Brien, TJ (WILEY, 2020-10-28)
    OBJECTIVE: The posterior cingulate cortex (PCC)/precuneus is a key hub of the default mode network, whose function is known to be altered in epilepsy. Glutamate and γ-aminobutyric acid (GABA) are the main excitatory and inhibitory neurotransmitters in the central nervous system, respectively. Glutathione (GSH) is the most important free radical scavenging compound in the brain. Quantification of these molecules by magnetic resonance spectroscopy (MRS) up to 4 T is limited by overlapping resonances from other molecules. In this study, we used ultra-high-field (7 T) MRS to quantify their concentrations in patients with different epilepsy syndromes. METHODS: Nineteen patients with temporal lobe epilepsy (TLE) and 16 with idiopathic generalized epilepsy (IGE) underwent magnetic resonance imaging scans using a 7-T research scanner. Single-voxel (8 cm3 ) MRS, located in the PCC/precuneus, was acquired via stimulated echo acquisition mode. Their results were compared to 10 healthy volunteers. RESULTS: Mean concentrations of glutamate, GABA, and the glutamate/GABA ratio did not differ between the IGE, TLE, and healthy volunteer groups. The mean ± SD concentration of GSH was 1.9 ± 0.3 mmol·L-1 in healthy controls, 2.0 ± 0.2 mmol·L-1 in patients with TLE, and 2.2 ± 0.4 mmol·L-1 in patients with IGE. One-way analysis of variance with post hoc Tukey-Kramer test revealed a significant difference in the concentration of GSH between patients with IGE and controls (P = .03). Short-term seizure freedom in patients with epilepsy was predicted by an elevated concentration of glutamate in the PCC/precuneus (P = .01). In patients with TLE, the concentration of GABA declined with age (P = .03). SIGNIFICANCE: Patients with IGE have higher concentrations of GSH in the PCC/precuneus than healthy controls. There is no difference in the concentrations of glutamate and GABA, or their ratio, in the PCC/precuneus between patients with IGE, patients with TLE, and healthy controls. Measuring the concentration of glutamate in the PCC/precuneus may assist with predicting drug response.
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    Resting-state functional connectivity and quantitation of glutamate and GABA of the PCC/precuneus by magnetic resonance spectroscopy at 7T in healthy individuals
    Gonen, OM ; Moffat, BA ; Kwan, P ; O'Brien, TJ ; Desmond, PM ; Lui, E ; Stamatakis, EA (PUBLIC LIBRARY SCIENCE, 2020-12-29)
    The default mode network (DMN) is the main large-scale network of the resting brain and the PCC/precuneus is a major hub of this network. Glutamate and GABA (γ-amino butyric acid) are the main excitatory and inhibitory neurotransmitters in the CNS, respectively. We studied glutamate and GABA concentrations in the PCC/precuneus via magnetic resonance spectroscopy (MRS) at 7T in relation to age and correlated them with functional connectivity between this region and other DMN nodes in ten healthy right-handed volunteers ranging in age between 23-68 years. Mean functional connectivity of the PCC/precuneus to the other DMN nodes and the glutamate/GABA ratio significantly correlated with age (r = 0.802, p = 0.005 and r = 0.793, p = 0.006, respectively) but not with each other. Glutamate and GABA alone did not significantly correlate with age nor with functional connectivity within the DMN. The glutamate/GABA ratio and functional connectivity of the PCC/precuneus are, therefore, independent age-related biomarkers of the DMN and may be combined in a multimodal pipeline to study DMN alterations in various disease states.
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    Network-based atrophy modeling in the common epilepsies: A worldwide ENIGMA study
    Lariviere, S ; Rodriguez-Cruces, R ; Royer, J ; Caligiuri, ME ; Gambardella, A ; Concha, L ; Keller, SS ; Cendes, F ; Yasuda, C ; Bonilha, L ; Gleichgerrcht, E ; Focke, NK ; Domin, M ; von Podewills, F ; Langner, S ; Rummel, C ; Wiest, R ; Martin, P ; Kotikalapudi, R ; O'Brien, TJ ; Sinclair, B ; Vivash, L ; Desmond, PM ; Alhusaini, S ; Doherty, CP ; Cavalleri, GL ; Delanty, N ; Kalviainen, R ; Jackson, GD ; Kowalczyk, M ; Mascalchi, M ; Semmelroch, M ; Thomas, RH ; Soltanian-Zadeh, H ; Davoodi-Bojd, E ; Zhang, J ; Lenge, M ; Guerrini, R ; Bartolini, E ; Hamandi, K ; Foley, S ; Weber, B ; Depondt, C ; Absil, J ; Carr, SJA ; Abela, E ; Richardson, MP ; Devinsky, O ; Severino, M ; Striano, P ; Tortora, D ; Hatton, SN ; Vos, SB ; Duncan, JS ; Whelan, CD ; Thompson, PM ; Sisodiya, SM ; Bernasconi, A ; Labate, A ; McDonald, CR ; Bernasconi, N ; Bernhardt, BC (AMER ASSOC ADVANCEMENT SCIENCE, 2020-11-01)
    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.