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Declarative memory encompasses episodic and semantic divisions. Episodic memory captures singular events with specific spatiotemporal relationships, whereas semantic memory houses context-independent knowledge. Behavioural and functional neuroimaging studies have revealed common and distinct neural substrates of both memory systems, implicating mesiotemporal lobe (MTL) regions such as the hippocampus and distributed neocortices. Here, we explored declarative memory system reorganization in patients with unilateral temporal lobe epilepsy (TLE) as a human disease model to test the impact of variable degrees of MTL pathology on memory function. Our cohort included 31 patients with TLE and 60 age- and sex-matched healthy controls, and all participants underwent episodic and semantic retrieval tasks during a multimodal MRI session. The functional MRI tasks were closely matched in terms of stimuli and trial design. Capitalizing on non-linear connectome gradient-mapping techniques, we derived task-based functional topographies during episodic and semantic memory states, in both the MTL and neocortical networks. Comparing neocortical and hippocampal functional gradients between TLE patients and healthy controls, we observed a marked topographic reorganization of both neocortical and MTL systems during episodic memory states. Neocortical alterations were characterized by reduced functional differentiation in TLE across lateral temporal and midline parietal cortices in both hemispheres. In the MTL, in contrast, patients presented with a more marked functional differentiation of posterior and anterior hippocampal segments ipsilateral to the seizure focus and pathological core, indicating perturbed intrahippocampal connectivity. Semantic memory reorganization was also found in bilateral lateral temporal and ipsilateral angular regions, whereas hippocampal functional topographies were unaffected. Furthermore, leveraging MRI proxies of MTL pathology, we observed alterations in hippocampal microstructure and morphology that were associated with TLE-related functional reorganization during episodic memory. Moreover, correlation analysis and statistical mediation models revealed that these functional alterations contributed to behavioural deficits in episodic memory, but again not in semantic memory in patients. Altogether, our findings suggest that semantic processes rely on distributed neocortical networks, whereas episodic processes are supported by a network involving both the hippocampus and the neocortex. Alterations of such networks can provide a compact signature of state-dependent reorganization in conditions associated with MTL damage, such as TLE., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

The hippocampus is a central modulator of the HPA-axis, impacting the regulation of stress on brain structure, function, and behavior. The current study assessed whether three different types of 3 months mental Training Modules geared towards nurturing (a) attention-based mindfulness, (b) socio-affective, or (c) socio-cognitive skills may impact hippocampal organization by reducing stress. We evaluated mental training-induced changes in hippocampal subfield volume and intrinsic functional connectivity, by combining longitudinal structural and resting-state fMRI connectivity analysis in 332 healthy adults. We related these changes to changes in diurnal and chronic cortisol levels. We observed increases in bilateral cornu ammonis volume (CA1-3) following the 3 months compassion-based module targeting socio-affective skills ( Affect module), as compared to socio-cognitive skills ( Perspective module) or a waitlist cohort with no training intervention. Structural changes were paralleled by relative increases in functional connectivity of CA1-3 when fostering socio-affective as compared to socio-cognitive skills. Furthermore, training-induced changes in CA1-3 structure and function consistently correlated with reductions in cortisol output. Notably, using a multivariate approach, we found that other subfields that did not show group-level changes also contributed to changes in cortisol levels. Overall, we provide a link between a socio-emotional behavioural intervention, changes in hippocampal subfield structure and function, and reductions in cortisol in healthy adults., Competing Interests: SV, VE, LP, RL, BC, AB, NB, BB, TS No competing interests declared, (© 2023, Valk, Engert et al.)

Background and Objectives: Temporal lobe epilepsy (TLE) is assumed to follow a steady course that is similar across patients. To date, phenotypic and temporal diversities of TLE evolution remain unknown. In this study, we aimed at simultaneously characterizing these sources of variability based on cross-sectional data., Methods: We studied consecutive patients with TLE referred for evaluation by neurologists to the Montreal Neurological Institute epilepsy clinic, who underwent in-patient video EEG monitoring and multimodal imaging at 3 Tesla, comprising 3D T1 and fluid-attenuated inversion recovery and 2D diffusion-weighted MRI. The cohort included patients with drug-resistant epilepsy and patients with drug-responsive epilepsy. The neuropsychological evaluation included Wechsler Adult Intelligence Scale-III and Leonard tapping task. The control group consisted of participants without TLE recruited through advertisement and who underwent the same MRI acquisition as patients. Based on surface-based analysis of key MRI markers of pathology (gray matter morphology and white matter microstructure), the Subtype and Stage Inference algorithm estimated subtypes and stages of brain pathology to which individual patients were assigned. The number of subtypes was determined by running the algorithm 100 times and estimating mean and SD of disease trajectories and the consistency of patients' assignments based on 1,000 bootstrap samples. Effect of normal aging was subtracted from patients. We examined associations with clinical and cognitive parameters and utility for individualized predictions., Results: We studied 82 patients with TLE (52 female, mean age 35 ± 10 years; 11 drug-responsive) and 41 control participants (23 male, mean age 32 ± 8 years). Among 57 operated, 43/37/20 had Engel-I outcome/hippocampal sclerosis/hippocampal isolated gliosis, respectively. We identified 3 trajectory subtypes: S1 (n = 35), led by ipsilateral hippocampal atrophy and gliosis, followed by white-matter damage; S2 (n = 27), characterized by bilateral neocortical atrophy, followed by ipsilateral hippocampal atrophy and gliosis; and S3 (n = 20), typified by bilateral limbic white-matter damage, followed by bilateral hippocampal gliosis. Patients showed high assignability to their subtypes and stages (>90% bootstrap agreement). S1 had the highest proportions of patients with early disease onset (effect size d = 0.27 vs S2, d = 0.73 vs S3), febrile convulsions (χ 2 = 3.70), drug resistance (χ 2 = 2.94), a positive MRI (χ 2 = 8.42), hippocampal sclerosis (χ 2 = 7.57), and Engel-I outcome (χ 2 = 1.51), p FDR < 0.05 across all comparisons. S2 and S3 exhibited the intermediate and lowest proportions, respectively. Verbal IQ and digit span were lower in S1 ( d = 0.65 and d = 0.50, p FDR < 0.05) and S2 ( d = 0.76 and d = 1.09, p FDR < 0.05), compared with S3. We observed progressive decline in sequential motor tapping in S1 and S3 ( T = -3.38 and T = -4.94, p FDR = 0.027), compared with S2 ( T = 2.14, p FDR = 0.035). S3 showed progressive decline in digit span ( T = -5.83, p = 0.021). Supervised classifiers trained on subtype and stage outperformed subtype-only and stage-only models predicting drug response in 73% ± 1.0% (vs 70% ± 1.4% and 63% ± 1.3%) and 76% ± 1.6% for Engel-I outcome (vs 71% ± 0.8% and 72% ± 1.1%), p FDR < 0.05 across all comparisons., Discussion: Cross-sectional MRI-derived models provide reliable prognostic markers of TLE disease evolution, which follows distinct trajectories, each associated with divergent patterns of hippocampal and whole-brain structural alterations, as well as cognitive and clinical profiles.

Objective: In drug-resistant temporal lobe epilepsy (TLE), it is not well-established in how far surgery should target morphological anomalies to achieve seizure freedom. Here, we assessed interactions between structural brain compromise and surgery to identify region-specific predictors of seizure outcome., Methods: We obtained pre- and post-operative 3D T1-weighted MRI in 55 TLE patients who underwent selective amygdalo-hippocampectomy (SAH) or anterior temporal lobectomy (ATL) and 40 age and sex-matched healthy subjects. We measured surface-based morphological alterations of the mesiotemporal lobe structures (hippocampus, amygdala, entorhinal and piriform cortices), the neocortex and the thalamus on both pre- and post-operative MRI. Using precise co-registration, in each patient we mapped the surgical cavity onto the MRI acquired before surgery, thereby quantifying the amount of pathological tissue resected; these features, together with the preoperative morphometric data, served as input to a supervised classification algorithm for postsurgical outcome prediction., Results: On pre-operative MRI, patients who became seizure-free (TLE-SF) presented with severe ipsilateral amygdalar and hippocampal atrophy, while not seizure-free patients (TLE-NSF) displayed amygdalar hypertrophy. Stratifying patients based on the surgical approach, post-operative MRI showed similar patterns of mesiotemporal and thalamic changes, but divergent neocortical thinning affecting the parieto-temporo-occipital regions following ATL and the frontal lobes after SAH. Irrespective of the surgical approach, hippocampal atrophy on pre-operative MRI and its extent of resection were the most predictive features of seizure-freedom in 89% of patients (selected 100% across validations)., Significance: Our study indicates a critical role of the extent of resection of MRI-derived hippocampal morphological anomalies on seizure outcome. Precise pre-operative quantification of the mesiotemporal lobe provides non-invasive prognostics for individualized surgery., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The hippocampus is an archicortical structure, consisting of subfields with unique circuits. Understanding its microstructure, as proxied by these subfields, can improve our mechanistic understanding of learning and memory and has clinical potential for several neurological disorders. One prominent issue is how to parcellate, register, or retrieve homologous points between two hippocampi with grossly different morphologies. Here, we present a surface-based registration method that solves this issue in a contrast-agnostic, topology-preserving manner. Specifically, the entire hippocampus is first analytically unfolded, and then samples are registered in 2D unfolded space based on thickness, curvature, and gyrification. We demonstrate this method in seven 3D histology samples and show superior alignment with respect to subfields using this method over more conventional registration approaches., Competing Interests: JD, NP, OK, NL, SM, MA, KA, AK, BB, AE No competing interests declared, (© 2023, DeKraker et al.)

The hippocampus is a uniquely infolded allocortical structure in the medial temporal lobe that consists of the microstructurally and functionally distinct subregions: subiculum, cornu ammonis, and dentate gyrus. The hippocampus is a remarkably plastic region that is implicated in learning and memory. At the same time it has been shown that hippocampal subregion volumes are heritable, and that genetic expression varies along a posterior to anterior axis. Here, we studied how a heritable, stable, hippocampal organisation may support its flexible function in healthy adults. Leveraging the twin set-up of the Human Connectome Project with multimodal neuroimaging, we observed that the functional connectivity between hippocampus and cortex was heritable and that microstructure of the hippocampus genetically correlated with cortical microstructure. Moreover, both functional and microstructural organisation could be consistently captured by anterior-to-posterior and medial-to-lateral axes across individuals. However, heritability of functional, relative to microstructural, organisation was found reduced, suggesting individual variation in functional organisation may be explained by experience-driven factors. Last, we demonstrate that structure and function couple along an inherited macroscale organisation, suggesting an interplay of stability and plasticity within the hippocampus. Our study provides new insights on the heritability of the hippocampal of the structure and function within the hippocampal organisation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2022. Published by Elsevier Inc.)

Objective: Although temporal lobe epilepsy (TLE) is recognized as a system-level disorder, little work has investigated pathoconnectomics from a dynamic perspective. By leveraging computational simulations that quantify patterns of information flow across the connectome, we tested the hypothesis that network communication is abnormal in this condition, studied the interplay between hippocampal- and network-level disease effects, and assessed associations with cognition., Methods: We simulated signal spreading via a linear threshold model that temporally evolves on a structural graph derived from diffusion-weighted magnetic resonance imaging (MRI), comparing a homogeneous group of 31 patients with histologically proven hippocampal sclerosis to 31 age- and sex-matched healthy controls. We evaluated the modulatory effects of structural alterations of the neocortex and hippocampus on network dynamics. Furthermore, multivariate statistics addressed the relationship with cognitive parameters., Results: We observed a slowing of in- and out-spreading times across multiple areas bilaterally, indexing delayed information flow, with the strongest effects in ipsilateral frontotemporal regions, thalamus, and hippocampus. Effects were markedly reduced when controlling for hippocampal volume but not cortical thickness, underscoring the central role of the hippocampus in whole-brain disease expression. Multivariate analysis associated slower spreading time in frontoparietal, limbic, default mode, and subcortical networks with impairment across tasks tapping into sensorimotor, executive, memory, and verbal abilities., Significance: Moving beyond descriptions of static topology toward the formulation of brain dynamics, our work provides novel insight into structurally mediated network dysfunction and demonstrates that altered whole-brain communication dynamics contribute to common cognitive difficulties in TLE., (© 2021 International League Against Epilepsy.)

Identifying a structural brain lesion on MRI has important implications in epilepsy and is the most important factor that correlates with seizure freedom after surgery in patients with drug-resistant focal onset epilepsy. However, at conventional magnetic field strengths (1.5 and 3T), only approximately 60%-85% of MRI examinations reveal such lesions. Over the last decade, studies have demonstrated the added value of 7T MRI in patients with and without known epileptogenic lesions from 1.5 and/or 3T. However, translation of 7T MRI to clinical practice is still challenging, particularly in centers new to 7T, and there is a need for practical recommendations on targeted use of 7T MRI in the clinical management of patients with epilepsy. The 7T Epilepsy Task Force-an international group representing 21 7T MRI centers with experience from scanning over 2,000 patients with epilepsy-would hereby like to share its experience with the neurology community regarding the appropriate clinical indications, patient selection and preparation, acquisition protocols and setup, technical challenges, and radiologic guidelines for 7T MRI in patients with epilepsy. This article mainly addresses structural imaging; in addition, it presents multiple nonstructural MRI techniques that benefit from 7T and hold promise as future directions in epilepsy. Answering to the increased availability of 7T MRI as an approved tool for diagnostic purposes, this article aims to provide guidance on clinical 7T MRI epilepsy management by giving recommendations on referral, suitable 7T MRI protocols, and image interpretation., (© 2020 American Academy of Neurology.)

Objective: To test the hypothesis that in periventricular nodular heterotopia (PVNH) structure and function of cortical areas overlying the heterotopic gray matter are preferentially affected., Methods: We studied a group of 40 patients with PVNH and normal-appearing cortex and compared their quantitative MRI markers of brain development, structure, and function to those of 43 age- and sex-matched healthy controls. Inspired by models of neocortical development suggesting that neuronal migration follows a curvilinear path to preserve topologic correspondence between the outer ventricular zone and the cortical surface, we computationally defined the overlying cortex using the Laplace equation and generated synthetic streamlines that link the ventricles, where nodules are located, and the neocortex., Results: We found multilobar cortical thickening encompassing prefrontal, latero-basal temporal, and temporoparietal cortices largely corresponding with the PVNH group-averaged map of the overlying cortex, the latter colocalized with areas of abnormal function, as defined by resting-state fMRI. Patients also presented hippocampal functional hyperconnectivity and malrotation, the latter positively correlating with neocortical maldevelopment indexed by increased folding complexity of the parahippocampus. In clusters of thickness and curvature findings, there were no significant differences between unilateral and bilateral PVNH; contrasting brain-wide metrics between cohorts was also unrevealing. There was no relationship between imaging markers and disease duration except for positive correlation with functional anomalies., Conclusion: Our quantitative image analysis demonstrates widespread structural and functional alterations in PVNH with differential interaction with the overlying cortex and the hippocampus. Right hemispheric predominance may be explained by an early insult, likely genetically determined, on brain morphogenesis., (© 2020 American Academy of Neurology.)

Objective: MRI studies of genetic generalized epilepsies have mainly described group-level changes between patients and healthy controls. To determine the endophenotypic potential of structural MRI in juvenile myoclonic epilepsy (JME), we examined MRI-based cortical morphologic markers in patients and their healthy siblings., Methods: In this prospective, cross-sectional study, we obtained 3T MRI in patients with JME, siblings, and controls. We mapped sulco-gyral complexity and surface area, morphologic markers of brain development, and cortical thickness. Furthermore, we calculated mean geodesic distance, a surrogate marker of cortico-cortical connectivity., Results: Compared to controls, patients and siblings showed increased folding complexity and surface area in prefrontal and cingulate cortices. In these regions, they also displayed abnormally increased geodesic distance, suggesting network isolation and decreased efficiency, with strongest effects for limbic, fronto-parietal, and dorsal-attention networks. In areas of findings overlap, we observed strong patient-sibling correlations. Conversely, neocortical thinning was present in patients only and related to disease duration. Patients showed subtle impairment in mental flexibility, a frontal lobe function test, as well as deficits in naming and design learning. Siblings' performance fell between patients and controls., Conclusion: MRI markers of brain development and connectivity are likely heritable and may thus serve as endophenotypes. The topography of morphologic anomalies and their abnormal structural network integration likely explains cognitive impairments in patients with JME and their siblings. By contrast, cortical atrophy likely represents a marker of disease., (Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objective: To study the intrinsic organization of the thalamocortical circuitry in patients with generalized epilepsy with tonic-clonic seizures (GTCS) via resting-state fMRI (rs-fMRI) connectome analysis and to evaluate its relation to drug response., Methods: In a prospectively followed-up sample of 41 patients and 27 healthy controls, we obtained rs-fMRI and structural MRI. After 1 year of follow-up, 27 patients were classified as seizure-free and 14 as drug-resistant. We examined connectivity within and between resting-state communities in cortical and thalamic subregions. In addition to comparing patients to controls, we examined associations with seizure control. We assessed reproducibility in an independent cohort of 21 patients., Results: Compared to controls, patients showed a more constrained network embedding of the thalamus, while frontocentral neocortical regions expressed increased functional diversity. Findings remained significant after regressing out thalamic volume and cortical thickness, suggesting independence from structural alterations. We observed more marked network imbalances in drug-resistant compared to seizure-free patients. Findings were similar in the reproducibility dataset., Conclusions: Our findings suggest a pathoconnectomic mechanism of generalized epilepsy centered on diverging changes in cortical and thalamic connectivity. More restricted thalamic connectivity could reflect the tendency to engage in recursive thalamocortical loops, which may contribute to hyperexcitability. Conversely, increased connectional diversity of frontocentral networks may relay abnormal activity to an extended bilateral territory. Network imbalances were observed shortly after diagnosis and related to future drug response, suggesting clinical utility., (© 2019 American Academy of Neurology.)

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., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

The majority of MRI studies in temporal lobe epilepsy (TLE) have utilized morphometry to map widespread cortical alterations. Morphological markers, such as cortical thickness or grey matter density, reflect combinations of biological events largely driven by overall cortical geometry rather than intracortical tissue properties. Because of its sensitivity to intracortical myelin, quantitative measurement of longitudinal relaxation time (qT 1 ) provides and an in vivo proxy for cortical microstructure. Here, we mapped the regional distribution of qT 1 in a consecutive cohort of 24 TLE patients and 20 healthy controls. Compared to controls, patients presented with a strictly ipsilateral distribution of qT 1 increases in temporopolar, parahippocampal and orbitofrontal cortices. Supervised statistical learning applied to qT 1 maps could lateralize the seizure focus in 92% of patients. Intracortical profiling of qT 1 along streamlines perpendicular to the cortical mantle revealed marked effects in upper levels that tapered off at the white matter interface. Findings remained robust after correction for cortical thickness and interface blurring, suggesting independence from previously reported morphological anomalies in this disorder. Mapping of qT 1 along hippocampal subfield surfaces revealed marked increases in anterior portions of the ipsilateral CA1-3 and DG that were also robust against correction for atrophy. Notably, in operated patients, qualitative histopathological analysis of myelin stains in resected hippocampal specimens confirmed disrupted internal architecture and fiber organization. Both hippocampal and neocortical qT 1 anomalies were more severe in patients with early disease onset. Finally, analysis of resting-state connectivity from regions of qT 1 increases revealed altered intrinsic functional network embedding in patients, particularly to prefrontal networks. Analysis of qT 1 suggests a preferential susceptibility of ipsilateral limbic cortices to microstructural damage, possibly related to disrupted myeloarchitecture. These alterations may reflect atypical neurodevelopment and affect the integrity of fronto-limbic functional networks., (Copyright © 2017 Elsevier Inc. All rights reserved.)

The hippocampus plays key roles in cognition and affect and serves as a model system for structure/function studies in animals. So far, its complex anatomy has challenged investigations targeting its substructural organization in humans. State-of-the-art MRI offers the resolution and versatility to identify hippocampal subfields, assess its microstructure, and study topographical principles of its connectivity in vivo. We developed an approach to unfold the human hippocampus and examine spatial variations of intrinsic functional connectivity in a large cohort of healthy adults. In addition to mapping common and unique connections across subfields, we identified two main axes of subregional connectivity transitions. An anterior/posterior gradient followed long-axis landmarks and metaanalytical findings from task-based functional MRI, while a medial/lateral gradient followed hippocampal infolding and correlated with proxies of cortical myelin. Findings were consistent in an independent sample and highly stable across resting-state scans. Our results provide robust evidence for long-axis specialization in the resting human hippocampus and suggest an intriguing interplay between connectivity and microstructure., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Objective: In drug-resistant temporal lobe epilepsy (TLE), relative to the large number of whole-brain morphological studies, neocortical T2 changes have not been systematically investigated. The aim of this study was to assess the anatomical principles that govern the distribution of neocortical T2-weighted fluid-attenuated inversion recovery (FLAIR) signal intensity and uncover its topographic principles., Methods: Using a surface-based sampling scheme, we mapped neocortical FLAIR intensity of 61 TLE patients relative to 38 healthy controls imaged at 3 T. To address topographic principles of the susceptibility to FLAIR signal changes in TLE, we assessed associations with normative data on tissue composition using 2 complementary approaches. First, we evaluated whether the degree of TLE-related FLAIR intensity changes differed across cytoarchitectonic classes as defined by Von Economo-Koskinas taxonomy. Second, as a proxy to map regions with similar intracortical composition, we carried out a FLAIR intensity covariance paradigm in controls by seeding systematically from all cortical regions, and identified those networks that were the best spatial predictors of the between-group FLAIR changes., Results: Increased intensities were observed in bilateral limbic and paralimbic cortices (hippocampus, parahippocampus, cingulate, temporopolar, insular, orbitofrontal). Effect sizes were highest in periallocortical limbic and insular classes as defined by the Von Economo-Koskinas cytoarchitectonic taxonomy. Furthermore, systematic FLAIR intensity covariance analysis in healthy controls revealed that similarity patterns characteristic of limbic cortices, most notably the hippocampus, served as sensitive predictors for the topography of FLAIR hypersignal in patients. FLAIR intensity findings were robust against correction for morphological confounds. Patients with a history of febrile convulsions showed more marked signal changes in parahippocampal and retrosplenial cortices, known to be strongly connected to the hippocampus., Significance: FLAIR intensity mapping and covariance analysis provide a model of TLE gray matter pathology based on shared vulnerability of periallocortical and limbic cortices., (Wiley Periodicals, Inc. © 2018 International League Against Epilepsy.)

Growing evidence highlights the importance of white matter in the pathogenesis of focal epilepsy. Ex vivo and post-mortem studies show pathological changes in epileptic patients in white matter myelination, axonal integrity, and cellular composition. Diffusion-weighted MRI and its analytical extensions, particularly diffusion tensor imaging (DTI), have been the most widely used technique to image the white matter in vivo for the last two decades, and have shown microstructural alterations in multiple tracts both in the vicinity and at distance from the epileptogenic focus. These techniques have also shown promising ability to predict cognitive status and response to pharmacological or surgical treatments. More recently, the hypothesis that focal epilepsy may be more adequately described as a system-level disorder has motivated a shift towards the study of macroscale brain connectivity. This review will cover emerging findings contributing to our understanding of white matter alterations in focal epilepsy, studied by means of histological and ultrastructural analyses, diffusion MRI, and large-scale network analysis. Focus is put on temporal lobe epilepsy and focal cortical dysplasia. This topic was addressed in a special interest group on neuroimaging at the 70th annual meeting of the American Epilepsy Society, held in Houston December 2-6, 2016., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: To characterize in vivo MRI signatures of focal cortical dysplasia (FCD) type IIA and type IIB through combined analysis of morphology, intensity, microstructure, and function., Methods: We carried out a multimodal 3T MRI profiling of 33 histologically proven FCD type IIA (9) and IIB (24) lesions. A multisurface approach operating on manual consensus labels systematically sampled intracortical and subcortical lesional features. Geodesic distance mapping quantified the same features in the lesion perimeter. Logistic regression assessed the relationship between MRI and histology, while supervised pattern learning was used for individualized subtype prediction., Results: FCD type IIB was characterized by abnormal morphology, intensity, diffusivity, and function across all surfaces, while type IIA lesions presented only with increased fluid-attenuated inversion recovery signal and reduced diffusion anisotropy close to the gray-white matter interface. Similar to lesional patterns, perilesional anomalies were more marked in type IIB extending up to 16 mm. Structural MRI markers correlated with categorical histologic characteristics. A profile-based classifier predicted FCD subtypes with equal sensitivity of 85%, while maintaining a high specificity of 94% against healthy and disease controls., Conclusions: Image processing applied to widely available MRI contrasts has the ability to dissociate FCD subtypes at a mesoscopic level. Integrating in vivo staging of pathologic traits with automated lesion detection is likely to provide an objective definition of lesional boundary and assist emerging approaches, such as minimally invasive thermal ablation, which do not supply tissue specimen., (© 2017 American Academy of Neurology.)

Drug-resistant temporal lobe epilepsy is increasingly recognized as a system-level disorder affecting the structure and function of large-scale grey matter networks. While diffusion magnetic resonance imaging studies have demonstrated deep fibre tract alterations, the superficial white matter immediately below the cortex has so far been neglected despite its proximity to neocortical regions and key role in maintaining cortico-cortical connectivity. Using multi-modal 3 T magnetic resonance imaging, we mapped the topography of superficial white matter diffusion alterations in 61 consecutive temporal lobe epilepsy patients relative to 38 healthy controls and studied the relationship to large-scale structural as well as functional networks. Our approach continuously sampled mean diffusivity and fractional anisotropy along surfaces running 2 mm below the cortex. Multivariate statistics mapped superficial white matter diffusion anomalies in patients relative to controls, while correlation and mediation analyses evaluated their relationship to structural (cortical thickness, mesiotemporal volumetry) and functional parameters (resting state functional magnetic resonance imaging amplitude) and clinical variables. Patients presented with overlapping anomalies in mean diffusivity and anisotropy, particularly in ipsilateral temporo-limbic regions. Diffusion anomalies did not relate to cortical thinning; conversely, they mediated large-scale functional amplitude decreases in patients relative to controls in default mode hub regions (i.e. anterior and posterior midline regions, lateral temporo-parietal cortices), and were themselves mediated by hippocampal atrophy. With respect to clinical variables, we observed more marked diffusion anomalies in patients with a history of febrile convulsions and those with longer disease duration. Similarly, more marked diffusion alterations were associated with seizure-free outcome. Bootstrap analyses indicated high reproducibility of our findings, suggesting generalizability. The temporo-limbic distribution of superficial white matter anomalies, together with the mediation-level findings, suggests that this so far neglected region serves a key link between the hippocampal atrophy and large-scale default mode network alterations in temporal lobe epilepsy., (© The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objectives: Our aim is to assess the subfield-specific histopathological correlates of hippocampal volume and intensity changes (T1, T2) as well as diff!usion MRI markers in TLE, and investigate the efficacy of quantitative MRI measures in predicting histopathology in vivo., Experimental Design: We correlated in vivo volumetry, T2 signal, quantitative T1 mapping, as well as diffusion MRI parameters with histological features of hippocampal sclerosis in a subfield-specific manner. We made use of on an advanced co-registration pipeline that provided a seamless integration of preoperative 3 T MRI with postoperative histopathological data, on which metrics of cell loss and gliosis were quantitatively assessed in CA1, CA2/3, and CA4/DG., Principal Observations: MRI volumes across all subfields were positively correlated with neuronal density and size. Higher T2 intensity related to increased GFAP fraction in CA1, while quantitative T1 and diffusion MRI parameters showed negative correlations with neuronal density in CA4 and DG. Multiple linear regression analysis revealed that in vivo multiparametric MRI can predict neuronal loss in all the analyzed subfields with up to 90% accuracy., Conclusion: Our results, based on an accurate co-registration pipeline and a subfield-specific analysis of MRI and histology, demonstrate the potential of MRI volumetry, diffusion, and quantitative T1 as accurate in vivo biomarkers of hippocampal pathology., (© 2015 Wiley Periodicals, Inc.)

Accurate tissue classification is a crucial prerequisite to MRI morphometry. Automated methods based on intensity histograms constructed from the entire volume are challenged by regional intensity variations due to local radiofrequency artifacts as well as disparities in tissue composition, laminar architecture and folding patterns. Current work proposes a novel anatomy-driven method in which parcels conforming cortical folding were regionally extracted from the brain. Each parcel is subsequently classified using nonparametric mean shift clustering. Evaluation was carried out on manually labeled images from two datasets acquired at 3.0 Tesla (n = 15) and 1.5 Tesla (n = 20). In both datasets, we observed high tissue classification accuracy of the proposed method (Dice index >97.6% at 3.0 Tesla, and >89.2% at 1.5 Tesla). Moreover, our method consistently outperformed state-of-the-art classification routines available in SPM8 and FSL-FAST, as well as a recently proposed local classifier that partitions the brain into cubes. Contour-based analyses localized more accurate white matter-gray matter (GM) interface classification of the proposed framework compared to the other algorithms, particularly in central and occipital cortices that generally display bright GM due to their highly degree of myelination. Excellent accuracy was maintained, even in the absence of correction for intensity inhomogeneity. The presented anatomy-driven local classification algorithm may significantly improve cortical boundary definition, with possible benefits for morphometric inference and biomarker discovery., (© 2015 Wiley Periodicals, Inc.)

Objective: In temporal lobe epilepsy (TLE), although hippocampal atrophy lateralizes the focus, the value of magnetic resonance imaging (MRI) to predict postsurgical outcome is rather modest. Prediction solely based on the hippocampus may be hampered by widespread mesiotemporal structural damage shown by advanced imaging. Increasingly complex and high-dimensional representation of MRI metrics motivates a shift to machine learning to establish objective, data-driven criteria for pathogenic processes and prognosis., Methods: We applied clustering to 114 consecutive unilateral TLE patients using 1.5T MRI profiles derived from surface morphology of hippocampus, amygdala, and entorhinal cortex. To evaluate the diagnostic validity of the classification, we assessed its yield to predict outcome in 79 surgically treated patients. Reproducibility of outcome prediction was assessed in an independent cohort of 27 patients evaluated on 3.0T MRI., Results: Four similarly sized classes partitioned our cohort; in all, alterations spanned over the 3 mesiotemporal structures. Compared to 46 controls, TLE-I showed marked bilateral atrophy; in TLE-II atrophy was ipsilateral; TLE-III showed mild bilateral atrophy; whereas TLE-IV showed hypertrophy. Classes differed with regard to histopathology and freedom from seizures. Classwise surface-based classifiers accurately predicted outcome in 92 ± 1% of patients, outperforming conventional volumetry. Predictors of relapse were distributed bilaterally across structures. Prediction accuracy was similarly high in the independent cohort (96%), supporting generalizability., Interpretation: We provide a novel description of individual variability across the TLE spectrum. Class membership was associated with distinct patterns of damage and outcome predictors that did not spatially overlap, emphasizing the ability of machine learning to disentangle the differential contribution of morphology to patient phenotypes, ultimately refining the prognosis of epilepsy surgery., (© 2014 American Neurological Association.)

Objective: To detect automatically focal cortical dysplasia (FCD) type II in patients with extratemporal epilepsy initially diagnosed as MRI-negative on routine inspection of 1.5 and 3.0T scans., Methods: We implemented an automated classifier relying on surface-based features of FCD morphology and intensity, taking advantage of their covariance. The method was tested on 19 patients (15 with histologically confirmed FCD) scanned at 3.0T, and cross-validated using a leave-one-out strategy. We assessed specificity in 24 healthy controls and 11 disease controls with temporal lobe epilepsy. Cross-dataset classification performance was evaluated in 20 healthy controls and 14 patients with histologically verified FCD examined at 1.5T., Results: Sensitivity was 74%, with 100% specificity (i.e., no lesions detected in healthy or disease controls). In 50% of cases, a single cluster colocalized with the FCD lesion, while in the remaining cases a median of 1 extralesional cluster was found. Applying the classifier (trained on 3.0T data) to the 1.5T dataset yielded comparable performance (sensitivity 71%, specificity 95%)., Conclusion: In patients initially diagnosed as MRI-negative, our fully automated multivariate approach offered a substantial gain in sensitivity over standard radiologic assessment. The proposed method showed generalizability across cohorts, scanners, and field strengths. Machine learning may assist presurgical decision-making by facilitating hypothesis formulation about the epileptogenic zone., Classification of Evidence: This study provides Class II evidence that automated machine learning of MRI patterns accurately identifies FCD among patients with extratemporal epilepsy initially diagnosed as MRI-negative., (© 2014 American Academy of Neurology.)

Objective: Evidence for disease progression in the mesiotemporal lobe is mainly derived from global volumetry of the hippocampus. In this study, we tracked progressive structural changes in the hippocampus, amygdala, and entorhinal cortex in drug-resistant temporal lobe epilepsy at a subregional level. Furthermore, we evaluated the relation between disease progression and surgical outcome., Methods: We combined cross-sectional modeling of disease duration in a large cohort of patients (n = 134) and longitudinal analysis in a subset that delayed surgery (n = 31). To track subregional pathology, we applied surface-shape analysis techniques on manual mesiotemporal labels., Results: Longitudinal and cross-sectional designs showed consistent patterns of progressive atrophy in hippocampal CA1, anterolateral entorhinal, and the amygdalar laterobasal group bilaterally. These regions also exhibited more marked age-related volume loss in patients compared with controls. We found a faster progression of hippocampal atrophy in patients with a seizure frequency ≥6 per month. High rates of contralateral entorhinal cortex atrophy predicted postsurgical seizure relapse., Conclusion: We observed progressive atrophy in hippocampal, amygdalar, and entorhinal subregions that frequently display neuronal loss on histology. The bilateral character of cumulative atrophy highlights the importance of early surgery. In patients who nevertheless delay this procedure, serial scanning may provide markers of surgical outcome.

In drug-resistant temporal lobe epilepsy (TLE), detecting hippocampal atrophy on MRI is crucial as it allows defining the surgical target. In addition to atrophy, about 40% of patients present with malrotation, a developmental anomaly characterized by atypical morphologies of the hippocampus and collateral sulcus. We have recently shown that both atrophy and malrotation impact negatively the performance of volume-based techniques. Here, we propose a novel hippocampal segmentation algorithm (SurfMulti) that integrates deformable parametric surfaces, vertex-wise modeling of locoregional texture and shape, and multiple templates in a unified framework. To account for inter-subject variability, including shape variants, we used a library derived from a large database of healthy (n=80) and diseased (n=288) hippocampi. To quantify malrotation, we generated 3D models from manual hippocampal labels and automatically extracted collateral sulci. The accuracy of SurfMulti was evaluated relative to manual labeling and segmentation obtained through a single atlas-based algorithm (FreeSurfer) and a volume-based multi-template approach (Vol-multi) using the Dice similarity index and surface-based shape mapping, for which we computed vertex-wise displacement vectors between automated and manual segmentations. We then correlated segmentation accuracy with malrotation features and atrophy. SurfMulti outperformed FreeSurfer and Vol-multi, and achieved a level of accuracy in TLE patients (Dice=86.9%) virtually identical to healthy controls (Dice=87.5%). Vertex-wise shape mapping showed that SurfMulti had an excellent overlap with manual labels, with sub-millimeter precision. Its performance was not influenced by atrophy or malrotation (|r|<0.20, p>0.2), while FreeSurfer (|r|>0.35, p<0.0001) and Vol-multi (|r|>0.28, p<0.05) were hampered by both anomalies. The magnitude of atrophy detected using SurfMulti was the closest to manual volumetry (Cohen's d: manual=1.71, t=7.6; SurfMulti=1.60, t=7.0; Vol-multi=1.38, t=6.1; FreeSurfer=0.91, t=3.9). The high performance of SurfMulti regardless of cohort, atrophy and shape variants identifies this algorithm as a robust segmentation tool for hippocampal volumetry., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Nearly one-third of patients with focal epilepsy experience disabling seizures that are refractory to pharmacotherapy. Drug-resistant focal epilepsy is, however, potentially curable by surgery. Although lesions associated with the epileptic focus can often be accurately detected by MRI, in many patients conventional imaging based on visual evaluation is unable to pinpoint the surgical target. Patients with so-called cryptogenic epilepsy represent one of the greatest clinical challenges in many tertiary epilepsy centers. In recent years, it has become increasingly clear that epilepsies that are considered cryptogenic are not necessarily nonlesional, the primary histopathological substrate being subtle cortical dysplasia. This Review considers the application of new advances in brain imaging, such as MRI morphometry, computational modeling and diffusion tensor imaging. By revealing dysplastic lesions that previously eluded visual assessments, quantitative structural MRI methods such as these have clearly demonstrated an increased diagnostic yield of epileptic lesions, and have provided successful surgical options to an increasing number of patients with 'cryptogenic' epilepsy.

Objective: Converging evidence suggests that abnormalities of brain development may play a role in the pathogenesis of temporal lobe epilepsy (TLE). As sulco-gyral patterns are thought to be a footprint of cortical development, we set out to quantitatively map folding complexity across the neocortex in TLE. Additionally, we tested whether there was a relationship between cortical complexity and features of hippocampal maldevelopment, commonly referred to as malrotation., Methods: To quantify folding complexity, we obtained whole-brain surface-based measures of absolute mean cortical curvature from MRI scans acquired in 43 drug-resistant patients with TLE with unilateral hippocampal atrophy, and 40 age- and sex-matched healthy controls. In patients, we correlated changes in cortical curvature with 3-dimensional measures of hippocampal positioning., Results: We found increased folding complexity in the temporolimbic cortices encompassing parahippocampal, temporopolar, insular, and fronto-opercular regions. Increased complexity was observed ipsilateral to the seizure focus in patients with left TLE (LTLE), whereas these changes were bilateral in patients with right TLE (RTLE). In both TLE groups, increased temporolimbic complexity was associated with increased hippocampal malrotation. We found tendencies for increased complexity in bilateral posterior temporal cortices in LTLE and contralateral parahippocampal cortices in RTLE to be predictive of unfavorable seizure outcome after surgery., Conclusion: The anatomic distribution of increased cortical complexity overlapping with limbic seizure networks in TLE and its association with hippocampal maldevelopment further imply that neurodevelopmental factors may play a role in the epileptogenic process of TLE.

The most frequent drug-resistant epilepsy is temporal lobe epilepsy (TLE) related to hippocampal atrophy. In addition, TLE is associated with atypical hippocampal morphologies. Automatic hippocampal segmentations have generally provided unsatisfactory results in this condition. We propose a novel segmentation method (SurfMulti) to statistically estimate locoregional texture and shape using a surface-based approach that guarantees shape-inherent point-wise correspondences. To account for inter-subject variability, including shape variants, we used a multi-template library derived from a large database of controls and patients. SurfMulti outperformed state-of-the-art volume-based single- and multi-template approaches, with performances comparable to controls (Dice index: 86.1 vs. 87.5%). Furthermore, the sensitivity of SurfMulti to detect atrophy was similar to that of manual volumetry. Given that the presence of hippocampal atrophy in TLE predicts a favorable seizure outcome after surgery, the proposed automated algorithm assures to be a robust surrogate tool in the presurgical evaluation for the time-demanding manual procedure.

Epileptic activity underlying idiopathic generalized epilepsy (IGE) is related to abnormal thalamo-cortical interactions. Our purpose was to map in vivo the organization of the thalamo-cortical network in IGE. We measured cortical thickness and thalamic volumes on MRI in 23 IGE patients with generalized tonic-clonic seizures only and 46 healthy controls. Significant correlations between thalamic volumes and cortical thickness were interpreted as thalamo-cortical network connections. In controls, thickness of frontal, limbic, and occipital regions was positively correlated with the thalamic volumes, corresponding to known anatomical connections from sacrificial tracer studies in primates and human in vivo DTI data. In patients, thalamo-cortical network correlations increased in fronto-central and parietal regions, but decreased in limbic areas. Group analysis revealed that, compared to controls, IGE patients had bilateral thalamic atrophy and widespread cortical thinning that was most prominent in fronto-central areas, with a prevalence of up to 40%. Duration of epilepsy affected negatively thalamic volumes and thickness of fronto-central and limbic cortices. These effects were significantly different from aging in controls. Patients with poorly controlled seizures showed an even faster progression in these neocortical regions. Fronto-centro-parietal atrophy in IGE is likely the effect of generalized seizure activity inducing thalamo-cortical network remodeling. On the other hand, limbic abnormalities may take place secondary to thalamic disconnection.

Analysis of surface-based displacement vectors using spherical harmonic description (SPHARM) localizes shape changes accurately. However, it does not allow differentiating volume variations from shifting and/or bending. We propose a new approach to quantify local volume changes by computing the surface-based Jacobian determinant. This measurement is computed on the displacement vector fields estimated by a heat equation interpolation on the displacement vectors produced by SPHARM. Data simulation showed that the surface-based Jacobian determinant enables accurate quantification of local volume changes without interference of shifting/bending. In patients with temporal lobe epilepsy and left hippocampal atrophy, SPHARM detected widespread inward deformation related to atrophy in the hippocampal head and body, and showed areas of mirrored inward/outward deformations mostly at the level of the hippocampal tail. In these areas, the surface-based Jacobian determinant showed atrophy. Our method facilitates the interpretation of SPHARM because it allows decomposing volume changes and shifting/bending. Furthermore, it provides a better delineation of the extent of hippocampal atrophy.

Focal cortical dysplasia (FCD), a malformation of cortical development, is an important cause of pharmacoresistant epilepsy. Small FCD lesions are difficult to distinguish from normal cortex and remain often overlooked on radiological MRI inspection. This paper presents a method to detect small FCD lesions on T1-MRI relying on surface-based features that model their textural and morphometric characteristics. The automatic detection was performed by a two step classification. First, a vertex-wise classifier based on a neural-network bagging trained on manual labels. Then, a cluster-wise classification designed to remove false positive clusters. The method was tested on 19 patients with small FCD. At the first classification step, 18/19 (95%) lesions were detected. The second classification step kept 13/19 (68%) lesions and decreased efficiently the amount of false positive. This new approach may assist the presurgical evaluation of patients with intractable epilepsy, especially those with unremarkable MRI findings.

Focal cortical dysplasia (FCD) is the most frequent malformation of cortical development in patients with medically intractable epilepsy. On MRI, FCD lesions are not easily differentiable from the normal cortex and defining their spatial extent is challenging. In this paper, we introduce a method to segment FCD lesions on T1-weighted MRI. It relies on two successive three-dimensional deformable models, whose evolutions are based on the level set framework. The first deformable model is driven by probability maps obtained from three MRI features: cortical thickness, relative intensity and gradient. These features correspond to the visual characteristics of FCD and allow discriminating lesions and normal tissues. In a second stage, the previous result is expanded towards the underlying and overlying cortical boundaries, throughout the whole cortical section. The method was quantitatively evaluated by comparison with manually traced labels in 18 patients with FCD. The automated segmentations achieved a strong agreement with the manuals labels, demonstrating the applicability of the method to assist the delineation of FCD lesions on MRI. This new approach may become a useful tool for the presurgical evaluation of patients with intractable epilepsy related to cortical dysplasia.

Purpose: On MRI, focal cortical dysplasia (FCD) is characterized by a combination of increased cortical thickness, hyperintense signal within the dysplastic lesion, and blurred transition between gray and white matter (GM-WM). The visual identification of these abnormal characteristics may be difficult, and it is unclear to what degree these features occur among different FCD lesions. Our purpose was to investigate the pattern of occurrence of abnormal MRI characteristics in FCD by using a set of computational models and to generate quantitative lesion profiling., Methods: A set of voxel-wise operators was applied to high-resolution 3D T1-weighted MRI in 23 patients with histologically proven FCD and 39 healthy controls, creating maps of GM thickness, maps of relative intensity highlighting areas with hyperintense signal, and maps of gradient magnitude modeling the GM-WM transition. All FCD lesions were segmented manually on the T1-weighted MRI., Results: FCD volumes ranged from 734 mm3 to 80,726 mm3 (mean, 8,629 mm3 +/- 16,238). The manually segmented FCD lesions were used to estimate features in the lesional area and to determine possible local variations of each feature by means of a histogram. In 78% of the patients, FCD lesions were characterized by simultaneous GM thickening, hyperintense signal, and blurring of the GM-WM transition. Moreover, in all patients, the FCD lesion had at least two of these three characteristics., Conclusions: The three features occurred regardless of the lesion volume, and they characterized not only large FCD lesions, but also subtle ones that had been overlooked by conventional radiologic inspection before surgery.

The purpose of this study was to evaluate systematically shape and positioning of the hippocampal formation (HF) in patients with partial epilepsy related to malformations of cortical development (MCD) and those with temporal lobe epilepsy (TLE). We studied 76 patients with MCD, including focal cortical dysplasia (n = 29; lesions located outside the temporal lobe in all), heterotopia (lesions outside of the temporal lobe, n = 14; lesions extending into the temporal lobe, n = 16), polymicrogyria (bilateral perisylvian, n = 14; unilateral perisylvian, n = 3) and 30 patients with TLE (hippocampal atrophy, n = 15; normal hippocampal volumes, n = 15). Shape and positioning of the HF were evaluated using a set of eight predefined morphological characteristics. In addition, the degree of hippocampal vertical orientation and medial positioning were assessed quantitatively. Patients were compared with 50 healthy controls. At least three criteria describing abnormal HF shape and positioning were found in 5/50 (10%) healthy controls, 37/76 (49%) MCD and 13/30 (43%) TLE patients. An association with all criteria was found in MCD and TLE, but not in healthy controls. In MCD there was no association between the side of HF shape abnormalities and the side of the cortical malformation or the EEG focus. Likewise, in TLE, HF abnormalities were not related to the side of the EEG focus. In both MCD and TLE patients who had hippocampal atrophy, no association was found between the side of HF shape abnormalities and the side of atrophy. Abnormal HF shape and positioning are found in a similar proportion in MCD and TLE. In TLE, they may be a marker of a more extensive disorder of brain development and may participate in the development of this condition.

Focal cortical dysplasia (FCD), a malformation of cortical development, is an important cause of medically intractable epilepsy. FCD lesions are difficult to distinguish from non-lesional cortex and their delineation on MRI is a challenging task. This paper presents a method to segment FCD lesions on T1-weighted MRI, based on a 3D deformable model, implemented using the level set framework. The deformable model is driven by three MRI features: cortical thickness, relative intensity and gradient. These features correspond to the visual characteristics of FCD and allow to differentiate lesions from normal tissues. The proposed method was tested on 18 patients with FCD and its performance was quantitatively evaluated by comparison with the manual tracings of two trained raters. The validation showed that the similarity between the level set segmentation and the manual labels is similar to the agreement between the two human raters. This new approach may become a useful tool for the presurgical evaluation of patients with intractable epilepsy.

The objective of this study was to assess temporal lobe white matter (WM) quantitatively using T2 relaxometry in patients with pharmacologically intractable temporal lobe epilepsy (TLE). T2 relaxometry was performed using a dual-echo sequence with 23 contiguous oblique coronal slices in 56 consecutive TLE patients and in 30 healthy subjects. Averages of six slices were chosen to calculate T2 relaxation time in the temporal lobe WM (WM-T2) and the hippocampus (Hippo-T2). Twenty-seven patients had unilateral hippocampal atrophy (HA), and twenty-nine patients had normal hippocampal volumes (NV) on volumetric MRI. Mean WM-T2 was increased ipsilateral to the seizure focus in TLE patients with HA and those with NV (P < 0.001). Contralateral mean WM-T2 was increased in left and right TLE with HA (P < 0.001) and in right TLE with NV (P = 0.001). There was a positive correlation between WM-T2 and Hippo-T2. Individual analysis showed a prolongation of WM-T2 in about 70% of TLE patients with HA and NV. In half of the patients, WM-T2 increase was bilateral and symmetric. However, in 33% of patients with NV and bilateral symmetric increase in Hippo-T2, WM-T2 provided a correct lateralization of the seizure focus. Regardless of the pattern of T2 abnormalities, that is, bilateral symmetric or ipsilateral, the majority of patients with HA became seizure-free after surgery, while those with NV did not have a favorable outcome. In patients with NV, WM-T2 measurement may provide additional lateralizing information compared to Hippo-T2.

Focal cortical dysplasia (FCD), a malformation of cortical development, is a frequent cause of pharmacologically intractable epilepsy. FCD is characterized on Tl-weighted MRI by cortical thickening, blurring of the gray-matter/white-matter interface, and gray-level hyperintensity. We have previously used computational models of these characteristics to enhance visual lesion detection. In the present study we seek to improve our methods by combining these models with features derived from texture analysis of MRI, which allows measurement of image properties not readily accessible by visual analysis. These computational models and texture features were used to develop a two-stage Bayesian classifier to perform automated FCD lesion detection. Eighteen patients with histologically confirmed FCD and 14 normal controls were studied. On the MRI volumes of the 18 patients, 20 FCD lesions were manually labeled by an expert observer. Three-dimensional maps of the computational models and texture features were constructed for all subjects. A Bayesian classifier was trained on the computational models to classify voxels as cerebrospinal fluid, gray-matter, white-matter, transitional, or lesional. Voxels classified as lesional were subsequently reclassified based on the texture features. This process produced a 3D lesion map, which was compared to the manual lesion labels. The automated classifier identified 17/20 manually labeled lesions. No lesions were identified in controls. Thus, combining models of the T1-weighted MRI characteristics of FCD with texture analysis enabled successful construction of a classifier. This computer-based, automated method may be useful in the presurgical evaluation of patients with severe epilepsy related to FCD.

Purpose: We previously showed a reduction in the volume of the entorhinal cortex (EC) ipsilateral to the seizure focus in patients with intractable temporal lobe epilepsy (TLE). The purpose of this study was to examine the specificity of EC atrophy in epilepsy., Methods: We performed volumetric measurement of the EC on high-resolution magnetic resonance imaging (MRI) in patients with TLE (n = 70), extratemporal lobe epilepsy (ETE; n = 18), and idiopathic generalized epilepsy (IGE; n = 20). EC volumes of epilepsy patients were compared with those of 48 age- and sex-matched normal controls. Within the TLE group, 63 patients were selected prospectively with hippocampal atrophy ipsilateral to the seizure focus. The remaining seven patients were chosen retrospectively based on normal volumetric MRI of the hippocampus and amygdale, as well as normal histopathologic examination of the resected tissue., Results: Compared with normal controls, EC volume was smaller ipsilateral but not contralateral to the seizure focus in patients with TLE (p < 0.001). No difference in the EC volumes ipsilateral and contralateral to the seizure focus was seen in patients with ETE and IGE compared with normal controls. The individual analysis showed that the EC was atrophic in 73% of TLE patients with hippocampal atrophy. Three of the seven TLE patients with normal volumetric MRI of the hippocampus and amygdala and normal histopathologic examination had EC atrophy ipsilateral to the seizure focus. In no patient with ETE or IGE was the EC found to be atrophic., Conclusions: EC atrophy ipsilateral to the seizure focus appears to be specific to mesial temporal lobe structural damage associated with TLE.

Objective: To examine the specificity of thalamic atrophy in epilepsy., Methods: Thalamic volume measurements were carried out using high-resolution MRI in 40 patients with pharmacologically intractable temporal lobe epilepsy (TLE), 16 patients with extratemporal lobe epilepsy (ETE), and 17 with idiopathic generalized epilepsy (IGE). Thalamic volumes of patients were compared with those of 21 neurologically normal control subjects. Volumes were correlated with duration of epilepsy. The effect of prolonged febrile seizures and generalized seizures on thalamic volumes was examined., Results: Compared with normal control subjects, patients with TLE had a reduction in thalamic volume ipsilateral to the seizure focus. Thalamic volumes in patients with ETE and IGE were not significantly different from those of normal control subjects. In TLE patients, thalamic volumes ipsilateral to the seizure focus were negatively correlated with duration of epilepsy. Patients with a history of prolonged febrile seizures had more severe thalamic atrophy ipsilateral to the seizure focus than those without febrile seizures., Conclusions: Thalamic atrophy ipsilateral to the seizure focus is found in TLE but not in other forms of focal epilepsy or IGE. In TLE, thalamic atrophy is correlated with duration of disease. Patients with a history of prolonged febrile seizures had smaller thalamic volumes ipsilateral to the seizure focus than those without.

In many patients, focal cortical dysplasia (FCD) is characterized by minor structural changes that may go unrecognized by standard radiological analysis. We previously demonstrated that visual analysis of a composite map based on three simple models of MRI features of FCD increased the sensitivity of FCD lesion detection, compared to visual analysis of conventional MRI. Here we report on the use of improved methods for characterizing FCD which improve contrast in the composite maps: a Laplacian-based metric for measuring cortical thickness, a convolutional kernel to model blurring of the GM-WM interface, and an operator to measure hyperintense T1 signal. To validate these methods, we processed the MRIs of 14 FCD patients with our original set of image processing operators and an improved set of image processing operators. Comparison of the composite maps associated with the two sets of operators revealed that contrast between lesional tissue and nonlesional cortex was significantly increased in the composite maps associated with the set of improved operators. Increasing this contrast is an important step toward the goal of automated FCD lesion detection.

In many patients, focal cortical dysplasia (FCD) is characterized by minor structural changes that may go unrecognized by standard radiological analysis. To increase the sensitivity of magnetic resonance imaging (MRI) for the detection of subtle lesions of FCD, we developed voxel-based image postprocessing methods, including first-order texture analysis and morphological processing modeled on known MRI features of FCD. We selected 16 patients with histologically proven FCD. Image processing features were calculated over a neighborhood for each voxel in the three-dimensional T1-weighted MRI. Three feature maps were generated: (1) gray matter thickness map to model cortical thickening, (2) gradient map to model blurring of the gray matter-white matter junction, and (3) relative intensity map to model the hyperintense signal within the lesion. Two observers detected lesions on conventional MRI in 8/16 and on ratio maps in 14/16 patients. Sensitivity was 87.5% (14/16) for the ratio maps compared to 50% (8/16) for MRI (p < 0.003). Specificity was 95% (19/20) for ratio maps and 100% (20/20) for MRIs. Cohen's kappa was 0.53 for MRIs, indicating moderate agreement, and 0.83 for ratio maps, indicating strong agreement beyond chance between the 2 observers. The image-processing methods developed in this study improve visual detection of FCD, even in cases where no lesion is obvious on MRI. These techniques could increase the number of patients with partial epilepsy who could benefit from surgery.

In unselected patients with intractable temporal lobe epilepsy (TLE), approximately 15% do not have detectable hippocampal atrophy on MRI. The purpose of this study was to evaluate whether T2 relaxometry can identify hippocampal pathology and lateralize the epileptic focus in patients with intractable TLE, who do not demonstrate hippocampal atrophy on volumetric MRI (MRIV). We selected 14 patients with unilateral TLE who had unilateral atrophy and 11 patients with unilateral TLE who had no evidence of atrophy on MRIV. Images were acquired on a 1.5 T MR scan using a dual echo sequence with 23 contiguous oblique coronal slices in all patients and in 14 healthy subjects. Fitting a single exponential decay equation to the imaging data generated T2 maps. Averages of six slices containing the head, body, and tail of the hippocampus were used to calculate hippocampal T2 relaxation times (HT2). The epileptic focus was defined by history, video-EEG, and surgical response. All TLE patients with hippocampal atrophy and 9/11 (82%) patients with normal MRI had abnormally high HT2 ipsilateral to the epileptic focus. Bilateral abnormal HT2 were found in 6/14 (43%) of patients with unilateral hippocampal atrophy and 2/11 (18%) of patients with normal MRI. However, this increase was always greater ipsilateral to the epileptic focus. Qualitative hippocampal pathology showed gliosis and neuronal loss in 10/14 operated patients with hippocampal atrophy on MRIV and in 5/7 operated patients with normal MRI. In conclusion, hippocampal T2 mapping provides evidence of hippocampal damage in the majority of patients with intractable TLE who have no evidence of atrophy on MRI and can correctly lateralize the epileptic focus in most patients., (Copyright 2000 Academic Press.)

Despite neuropathological and electrophysiological evidence for the involvement of parahippocampal structures in temporal lobe epilepsy (TLE), little attention has been paid to morphometric changes in these structures, and the relation of these changes to TLE. We performed high-resolution MRI volumetric analysis to examine in vivo the morphology of the parahippocampal region in 20 healthy subjects and 6 TLE patients with MRI evidence of unilateral hippocampal atrophy. In normal controls the standardized volume of the left entorhinal cortex (EC) was 1305 +/- 138 mm3 and that of the right EC was 1376 +/- 170 mm3; the left perirhinal cortex (PC) was 2900 +/- 554 mm3 and the right PC was 2771 +/- 486 mm3; the left posterior parahippocampal cortex (PPC) was 2499 +/- 583 mm3 and the right PPC was 2234 +/- 404 mm3. Using a 2 standard deviation cutoff from the mean of normal controls, we found ipsilateral to the seizure focus: (i) a reduction in the volume of the EC in all patients; (ii) a reduction of the PC in 2/6 (33%) patients; (iii) no reduction in the volume of the PPC in any patient. In 3/6 (50%) of patients, the EC was also abnormally small contralateral to the seizure focus. In patients with unilateral TLE, the EC is the most affected structure within the parahippocampal region. Whether this is due to a primary role of the EC in the genesis of TLE or is the consequence of its pivotal position in the reciprocal flow of information between the hippocampus and the neo- and limbic cortices remains to be explored.

Purpose: To elucidate the mechanisms of seizure origin in patients with celiac disease and bilateral occipital calcifications (CEBOC). Individuals with CEBOC frequently present with occipital lobe seizures, but additional lesions and additional attack patterns may occur., Methods: We studied two men and one woman who had CEBOC. Villous atrophy was revealed in the two patients who underwent duodenal biopsy. All had a comprehensive presurgical evaluation, including prolonged video-EEG recordings. Two had magnetic resonance imaging (MRI) with volumetric study of mesial temporal structures (MRIV). One patient had undergone stereotactic intracranial depth electrode studies (SEEG)., Results: All patients presented with intractable complex partial seizures. Two had partial simple seizures with visual aura. Neurologic examination was normal; one was of normal intelligence, and two were mildly retarded. Neuroimaging studies showed that each had bilateral occipital calcifications as well as epileptiform abnormalities over temporal lobes. In one, MRI showed an additional right frontal lesion, but SEEG demonstrated right occipital lobe seizure origin with anterior spread; this male patient later underwent a right occipital lobe resection. Another with a history of prolonged febrile convulsions had bilateral hippocampal and amygdalar atrophy demonstrated by MRIV., Conclusions: In one patient, SEEG confirmed that seizures originated in the occipital lobe. The presence of dual pathology was demonstrated in another, raising the possibility of both occipital and temporal seizure onset. The presence of extraoccipital lesions or of mesial temporal atrophy requires SEEG for clarification of seizure onset. In the absence of confounding factors and when laterality can be demonstrated, surgical treatment may be considered.

Objectives – To assess hippocampal volumes (HV) and signal changes on diffusion-weighted imaging (DWI) within 5 days of prolonged febrile seizures (PFS) and compare them with the PFS duration and EEG. Methods – We studied 12 children (mean age: 32 ± 21 months, range 10 months–5 years) within 5 days of a first episode of PFS (a seizure or series of seizures lasting for 30 min or longer, without return of consciousness between the seizures). The HV measurements were carried out using high-resolution magnetic resonance imaging and signal intensity abnormalities were evaluated visually on DWI. HV in patients were compared with those of 13 neurologically normal controls (mean age 31 ± 16 months, range 15 months–5 years). HV abnormalities correlated with PFS duration. HV and DWI abnormalities were compared with EEG abnormalities. Results – Seizure duration ranged from 40 to 95 min. In seven out of twelve patients, seizures were refractory and lasted for 60 min or longer despite intravenous infusion of diazepam. In the patients with PFS for 60 min or longer, HV were significantly larger than that of controls. In all patients, there was a positive correlation between HV and seizure duration. DWI showed hyperintensity in unilateral hippocampus in three patients with intractable seizures, ipsilateral thalamus in two, and cingulate in one. EEG showed abnormalities in temporal areas ipsilateral to the DWI abnormalities in these patients. Conclusions – Large HV and hippocampal hyperintensity on DWI were seen in patients with refractory PFS. Our results suggest that medically refractory PFS lasting for 60 min or longer may cause structural changes in limbic structures that could promote later epileptogenesis. [ABSTRACT FROM AUTHOR]

Abstract: High-resolution MRI of the brain has made it possible to identify focal cortical dysplasia (FCD) in an increasing number of patients. There is evidence for structural abnormalities extending beyond the visually identified FCD lesion. Voxel-based morphometry (VBM) has the potential of detecting both lesions and extra-lesional abnormalities because it performs a whole brain voxel-wise comparison. However, on T1-weighted MRI, FCD lesions are characterized by a wide spectrum of signal hyperintensity that may compromise the results of the segmentation step in VBM. Our purpose was to investigate gray matter (GM) changes in individual FCD patients using voxel-based morphometry (VBM). In addition, we sought to assess the performance of this technique for FCD detection with respect to lesion intensity using an operator designed to emphasize areas of hyperintense T1 signal. We studied 27 patients with known FCD and focal epilepsy and 39 healthy controls. We compared the GM map of each subject (controls and patients) with the average GM map of all controls and obtained a GM z-score map for each individual. The protocol being designed to achieve a maximal specificity, no differences in GM concentration were found in the control group. The z-score maps showed an increase in GM that coincided with the lesion in 21/27 (78%) patients. Five of the six remaining patients whose lesions were not detected by VBM presented with a strong lesion hyperintensity, and a significant part of their lesion was misclassified as white matter. In 16/27 (59%) patients, there were additional areas of GM increase distant from the primary lesion. Areas of GM decrease were found in 8/27 (30%) patients. In conclusion, individual voxel-based analysis was able to detect FCD in a majority of patients. Moreover, FCD was often associated with widespread GM changes extending beyond the visible lesion. In its current form, however, individual VBM may be unable to detect lesions characterized by strong signal intensity abnormalities. [Copyright &y& Elsevier]

Summary: Purpose: To analyze the results of surgical treatment of intractable epilepsy in patients with subcortical band heterotopia, or double cortex syndrome, a diffuse neuronal migration disorder. Methods: We studied eight patients (five women) with double cortex syndrome and intractable epilepsy. All had a comprehensive presurgical evaluation including prolonged video-EEG recordings and magnetic resonance imaging (MRI). Results: All patients had partial seizures, with secondary generalization in six of them. Neurologic examination was normal in all. Three were of normal intelligence, and five were mildly retarded. Six patients underwent invasive EEG recordings, three of them with subdural grids and three with stereotactic implanted depth electrodes (SEEG). Although EEG recordings showed multilobar epileptic abnormalities in most patients, regional or focal seizure onset was recorded in all. MRI showed bilateral subcortical band heterotopia, asymmetric in thickness in three. An additional area of cortical thickening in the left frontal lobe was found in one patient. Surgical procedures included multiple subpial transections in two patients, frontal lesionectomy in one, temporal lobectomy with amygdalohippocampectomy in five, and an additional anterior callosotomy in one. Five patients had no significant improvement, two had some improvement, and one was greatly improved. Conclusion: Our results do not support focal surgical removal of epileptogenic tissue in patients with double cortex syndrome, even in the presence of a relatively localized epileptogenic area. [ABSTRACT FROM AUTHOR]