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Declarative memory encompasses episodic and semantic divisions. Episodic memory captures singular events with specific spatiotemporal relationships, while 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 as well as 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, both in the MTL and in 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, on the other hand, 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, while hippocampal functional topographies were unaffected. Leveraging MRI proxies of MTL pathology, we furthermore 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, but again not semantic memory in patients. Altogether, our findings suggest that semantic processes rely on distributed neocortical networks, while episodic processes are supported by a network involving both the hippocampus and 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.)

Network neuroscience offers a unique framework to understand the organizational principles of the human brain. Despite recent progress, our understanding of how the brain is modulated by focal lesions remains incomplete. Resection of the temporal lobe is the most effective treatment to control seizures in pharmaco-resistant temporal lobe epilepsy (TLE), making this syndrome a powerful model to study lesional effects on network organization in young and middle-aged adults. Here, we assessed the downstream consequences of a focal lesion and its surgical resection on the brain's structural connectome, and explored how this reorganization relates to clinical variables at the individual patient level. We included adults with pharmaco-resistant TLE (n = 37) who underwent anterior temporal lobectomy between two imaging time points, as well as age- and sex-matched healthy controls who underwent comparable imaging (n = 31). Core to our analysis was the projection of high-dimensional structural connectome data-derived from diffusion MRI tractography from each subject-into lower-dimensional gradients. We then compared connectome gradients in patients relative to controls before surgery, tracked surgically-induced connectome reconfiguration from pre- to postoperative time points, and examined associations to patient-specific clinical and imaging phenotypes. Before surgery, individuals with TLE presented with marked connectome changes in bilateral temporo-parietal regions, reflecting an increased segregation of the ipsilateral anterior temporal lobe from the rest of the brain. Surgery-induced connectome reorganization was localized to this temporo-parietal subnetwork, but primarily involved postoperative integration of contralateral regions with the rest of the brain. Using a partial least-squares analysis, we uncovered a latent clinical imaging signature underlying this pre- to postoperative connectome reorganization, showing that patients who displayed postoperative integration in bilateral fronto-occipital cortices also had greater preoperative ipsilateral hippocampal atrophy, lower seizure frequency and secondarily generalized seizures. Our results bridge the effects of focal brain lesions and their surgical resections with large-scale network reorganization and interindividual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Temporal lobe epilepsy (TLE), one of the most common pharmaco-resistant epilepsies, is associated with pathology of paralimbic brain regions, particularly in the mesiotemporal lobe. Cognitive dysfunction in TLE is frequent, and particularly affects episodic memory. Crucially, these difficulties challenge the quality of life of patients, sometimes more than seizures, underscoring the need to assess neural processes of cognitive dysfunction in TLE to improve patient management. Our work harnessed a novel conceptual and analytical approach to assess spatial gradients of microstructural differentiation between cortical areas based on high-resolution MRI analysis. Gradients track region-to-region variations in intracortical lamination and myeloarchitecture, serving as a system-level measure of structural and functional reorganization. Comparing cortex-wide microstructural gradients between 21 patients and 35 healthy controls, we observed a reorganization of this gradient in TLE driven by reduced microstructural differentiation between paralimbic cortices and the remaining cortex with marked abnormalities in ipsilateral temporopolar and dorsolateral prefrontal regions. Findings were replicated in an independent cohort. Using an independent post-mortem dataset, we observed that in vivo findings reflected topographical variations in cortical cytoarchitecture. We indeed found that macroscale changes in microstructural differentiation in TLE reflected increased similarity of paralimbic and primary sensory/motor regions. Disease-related transcriptomics could furthermore show specificity of our findings to TLE over other common epilepsy syndromes. Finally, microstructural dedifferentiation was associated with cognitive network reorganization seen during an episodic memory functional MRI paradigm and correlated with interindividual differences in task accuracy. Collectively, our findings showing a pattern of reduced microarchitectural differentiation between paralimbic regions and the remaining cortex provide a structurally-grounded explanation for large-scale functional network reorganization and cognitive dysfunction characteristic of TLE., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Cognitive impairment is a common comorbidity of epilepsy and adversely impacts people with both frontal lobe (FLE) and temporal lobe (TLE) epilepsy. While its neural substrates have been investigated extensively in TLE, functional imaging studies in FLE are scarce. In this study, we profiled the neural processes underlying cognitive impairment in FLE and directly compared FLE and TLE to establish commonalities and differences. We investigated 172 adult participants (56 with FLE, 64 with TLE and 52 controls) using neuropsychological tests and four functional MRI tasks probing expressive language (verbal fluency, verb generation) and working memory (verbal and visuo-spatial). Patient groups were comparable in disease duration and anti-seizure medication load. We devised a multiscale approach to map brain activation and deactivation during cognition and track reorganization in FLE and TLE. Voxel-based analyses were complemented with profiling of task effects across established motifs of functional brain organization: (i) canonical resting-state functional systems; and (ii) the principal functional connectivity gradient, which encodes a continuous transition of regional connectivity profiles, anchoring lower-level sensory and transmodal brain areas at the opposite ends of a spectrum. We show that cognitive impairment in FLE is associated with reduced activation across attentional and executive systems, as well as reduced deactivation of the default mode system, indicative of a large-scale disorganization of task-related recruitment. The imaging signatures of dysfunction in FLE are broadly similar to those in TLE, but some patterns are syndrome-specific: altered default-mode deactivation is more prominent in FLE, while impaired recruitment of posterior language areas during a task with semantic demands is more marked in TLE. Functional abnormalities in FLE and TLE appear overall modulated by disease load. On balance, our study elucidates neural processes underlying language and working memory impairment in FLE, identifies shared and syndrome-specific alterations in the two most common focal epilepsies and sheds light on system behaviour that may be amenable to future remediation strategies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Temporal lobe epilepsy, a common drug-resistant epilepsy in adults, is primarily a limbic network disorder associated with predominant unilateral hippocampal pathology. Structural MRI has provided an in vivo window into whole-brain grey matter structural alterations in temporal lobe epilepsy relative to controls, by either mapping (i) atypical inter-hemispheric asymmetry; or (ii) regional atrophy. However, similarities and differences of both atypical asymmetry and regional atrophy measures have not been systematically investigated. Here, we addressed this gap using the multisite ENIGMA-Epilepsy dataset comprising MRI brain morphological measures in 732 temporal lobe epilepsy patients and 1418 healthy controls. We compared spatial distributions of grey matter asymmetry and atrophy in temporal lobe epilepsy, contextualized their topographies relative to spatial gradients in cortical microstructure and functional connectivity calculated using 207 healthy controls obtained from Human Connectome Project and an independent dataset containing 23 temporal lobe epilepsy patients and 53 healthy controls and examined clinical associations using machine learning. We identified a marked divergence in the spatial distribution of atypical inter-hemispheric asymmetry and regional atrophy mapping. The former revealed a temporo-limbic disease signature while the latter showed diffuse and bilateral patterns. Our findings were robust across individual sites and patients. Cortical atrophy was significantly correlated with disease duration and age at seizure onset, while degrees of asymmetry did not show a significant relationship to these clinical variables. Our findings highlight that the mapping of atypical inter-hemispheric asymmetry and regional atrophy tap into two complementary aspects of temporal lobe epilepsy-related pathology, with the former revealing primary substrates in ipsilateral limbic circuits and the latter capturing bilateral disease effects. These findings refine our notion of the neuropathology of temporal lobe epilepsy and may inform future discovery and validation of complementary MRI biomarkers in temporal lobe epilepsy., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

In drug-resistant temporal lobe epilepsy, precise predictions of drug response, surgical outcome and cognitive dysfunction at an individual level remain challenging. A possible explanation may lie in the dominant 'one-size-fits-all' group-level analytical approaches that does not allow parsing interindividual variations along the disease spectrum. Conversely, analysing inter-patient heterogeneity is increasingly recognized as a step towards person-centred care. Here, we used unsupervised machine learning to estimate latent relations (or disease factors) from 3 T multimodal MRI features [cortical thickness, hippocampal volume, fluid-attenuated inversion recovery (FLAIR), T1/FLAIR, diffusion parameters] representing whole-brain patterns of structural pathology in 82 patients with temporal lobe epilepsy. We assessed the specificity of our approach against age- and sex-matched healthy individuals and a cohort of frontal lobe epilepsy patients with histologically verified focal cortical dysplasia. We identified four latent disease factors variably co-expressed within each patient and characterized by ipsilateral hippocampal microstructural alterations, loss of myelin and atrophy (Factor 1), bilateral paralimbic and hippocampal gliosis (Factor 2), bilateral neocortical atrophy (Factor 3) and bilateral white matter microstructural alterations (Factor 4). Bootstrap analysis and parameter variations supported high stability and robustness of these factors. Moreover, they were not expressed in healthy controls and only negligibly in disease controls, supporting specificity. Supervised classifiers trained on latent disease factors could predict patient-specific drug response in 76 ± 3% and postsurgical seizure outcome in 88 ± 2%, outperforming classifiers that did not operate on latent factor information. Latent factor models predicted inter-patient variability in cognitive dysfunction (verbal IQ: r = 0.40 ± 0.03; memory: r = 0.35 ± 0.03; sequential motor tapping: r = 0.36 ± 0.04), again outperforming baseline learners. Data-driven analysis of disease factors provides a novel appraisal of the continuum of interindividual variability, which is probably determined by multiple interacting pathological processes. Incorporating interindividual variability is likely to improve clinical prognostics., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Episodic memory is the ability to remember events from our past accurately. The process of pattern separation is hypothesized to underpin this ability and is defined as the capacity to orthogonalize memory traces, to maximize the features that make them unique. Contemporary cognitive neuroscience suggests that pattern separation entails complex interactions between the hippocampus and neocortex, where specific hippocampal subregions shape neural reinstatement in the neocortex. To test this hypothesis, the current work studied both healthy controls and patients with temporal lobe epilepsy who presented with hippocampal structural anomalies. We measured neural activity in all participants using functional MRI while they retrieved memorized items or lure items, which shared features with the target. Behaviourally, patients with temporal lobe epilepsy were less able to exclude lures than controls and showed a reduction in pattern separation. To assess the hypothesized relationship between neural patterns in the hippocampus and neocortex, we identified the topographic gradients of intrinsic connectivity along neocortical and hippocampal subfield surfaces and determined the topographic profile of the neural activity accompanying pattern separation. In healthy controls, pattern separation followed a graded topography of neural activity, both along the hippocampal long axis (and peaked in anterior segments that are more heavily engaged in transmodal processing) and along the neocortical hierarchy running from unimodal to transmodal regions (peaking in transmodal default mode regions). In patients with temporal lobe epilepsy, however, this concordance between task-based functional activations and topographic gradients was markedly reduced. Furthermore, person-specific measures of concordance between task-related activity and connectivity gradients in patients and controls were related to inter-individual differences in behavioural measures of pattern separation and episodic memory, highlighting the functional relevance of the observed topographic motifs. Our work is consistent with an emerging understanding that successful discrimination between memories with similar features entails a shift in the locus of neural activity away from sensory systems, a pattern that is mirrored along the hippocampal long axis and with respect to neocortical hierarchies. More broadly, our study establishes topographic profiling using intrinsic connectivity gradients, capturing the functional underpinnings of episodic memory processes in a manner that is sensitive to their reorganization in pathology., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neuroimaging studies have consistently shown distributed brain anomalies in epilepsy syndromes associated with a focal structural lesion, particularly mesiotemporal sclerosis. Conversely, a system-level approach to focal cortical dysplasia has been rarely considered, likely due to methodological difficulties in addressing variable location and topography. Given the known heterogeneity in focal cortical dysplasia histopathology, we hypothesized that lesional connectivity consists of subtypes with distinct structural signatures. Furthermore, in light of mounting evidence for focal anomalies impacting whole-brain systems, we postulated that patterns of focal cortical dysplasia connectivity may exert differential downstream effects on global network topology. We studied a cohort of patients with histologically verified focal cortical dysplasia type II (n = 27), and age- and sex-matched healthy controls (n = 34). We subdivided each lesion into similarly sized parcels and computed their connectivity to large-scale canonical functional networks (or communities). We then dichotomized connectivity profiles of lesional parcels into those belonging to the same functional community as the focal cortical dysplasia (intra-community) and those adhering to other communities (inter-community). Applying hierarchical clustering to community-reconfigured connectome profiles identified three lesional classes with distinct patterns of functional connectivity: decreased intra- and inter-community connectivity, a selective decrease in intra-community connectivity, and increased intra- as well as inter-community connectivity. Hypo-connectivity classes were mainly composed of focal cortical dysplasia type IIB, while the hyperconnected lesions were type IIA. With respect to whole-brain networks, patients with hypoconnected focal cortical dysplasia and marked structural damage showed only mild imbalances, while those with hyperconnected subtle lesions had more pronounced topological alterations. Correcting for interictal epileptic discharges did not impact connectivity patterns. Multivariate structural equation analysis provided a mechanistic model of such complex, diverging interactions, whereby the focal cortical dysplasia structural makeup shapes its functional connectivity, which in turn modulates whole-brain network topology., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Progressive functional decline in the epilepsies is largely unexplained. We formed the ENIGMA-Epilepsy consortium to understand factors that influence brain measures in epilepsy, pooling data from 24 research centres in 14 countries across Europe, North and South America, Asia, and Australia. Structural brain measures were extracted from MRI brain scans across 2149 individuals with epilepsy, divided into four epilepsy subgroups including idiopathic generalized epilepsies (n =367), mesial temporal lobe epilepsies with hippocampal sclerosis (MTLE; left, n = 415; right, n = 339), and all other epilepsies in aggregate (n = 1026), and compared to 1727 matched healthy controls. We ranked brain structures in order of greatest differences between patients and controls, by meta-analysing effect sizes across 16 subcortical and 68 cortical brain regions. We also tested effects of duration of disease, age at onset, and age-by-diagnosis interactions on structural measures. We observed widespread patterns of altered subcortical volume and reduced cortical grey matter thickness. Compared to controls, all epilepsy groups showed lower volume in the right thalamus (Cohen's d = -0.24 to -0.73; P < 1.49 × 10-4), and lower thickness in the precentral gyri bilaterally (d = -0.34 to -0.52; P < 4.31 × 10-6). Both MTLE subgroups showed profound volume reduction in the ipsilateral hippocampus (d = -1.73 to -1.91, P < 1.4 × 10-19), and lower thickness in extrahippocampal cortical regions, including the precentral and paracentral gyri, compared to controls (d = -0.36 to -0.52; P < 1.49 × 10-4). Thickness differences of the ipsilateral temporopolar, parahippocampal, entorhinal, and fusiform gyri, contralateral pars triangularis, and bilateral precuneus, superior frontal and caudal middle frontal gyri were observed in left, but not right, MTLE (d = -0.29 to -0.54; P < 1.49 × 10-4). Contrastingly, thickness differences of the ipsilateral pars opercularis, and contralateral transverse temporal gyrus, were observed in right, but not left, MTLE (d = -0.27 to -0.51; P < 1.49 × 10-4). Lower subcortical volume and cortical thickness associated with a longer duration of epilepsy in the all-epilepsies, all-other-epilepsies, and right MTLE groups (beta, b < -0.0018; P < 1.49 × 10-4). In the largest neuroimaging study of epilepsy to date, we provide information on the common epilepsies that could not be realistically acquired in any other way. Our study provides a robust ranking of brain measures that can be further targeted for study in genetic and neuropathological studies. This worldwide initiative identifies patterns of shared grey matter reduction across epilepsy syndromes, and distinctive abnormalities between epilepsy syndromes, which inform our understanding of epilepsy as a network disorder, and indicate that certain epilepsy syndromes involve more widespread structural compromise than previously assumed., (© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Neuroimaging studies of malformations of cortical development have mainly focused on the characterization of the primary lesional substrate, while whole-brain investigations remain scarce. Our purpose was to assess large-scale brain organization in prevalent cortical malformations. Based on experimental evidence suggesting that distributed effects of focal insults are modulated by stages of brain development, we postulated differential patterns of network anomalies across subtypes of malformations. We studied a cohort of patients with focal cortical dysplasia type II (n = 63), subcortical nodular heterotopia (n = 44), and polymicrogyria (n = 34), and compared them to 82 age- and sex-matched controls. Graph theoretical analysis of structural covariance networks indicated a consistent rearrangement towards a regularized architecture characterized by increased path length and clustering, as well as disrupted rich-club topology, overall suggestive of inefficient global and excessive local connectivity. Notably, we observed a gradual shift in network reconfigurations across subgroups, with only subtle changes in focal cortical dysplasia type II, moderate effects in heterotopia and maximal effects in polymicrogyria. Analysis of resting state functional connectivity also revealed gradual network changes, with most marked rearrangement in polymicrogyria; contrary to findings in the structural domain, however, functional architecture was characterized by decreases in both local and global parameters. Diverging results in the structural and functional domain were supported by formal structure-function coupling analysis. Our findings support the concept that time of insult during corticogenesis impacts the severity of topological network reconfiguration. Specifically, late-stage malformations, typified by polymicrogyria, may selectively disrupt the formation of large-scale cortico-cortical networks and thus lead to a more profound impact on whole-brain organization than early stage disturbances of predominantly radial migration patterns observed in cortical dysplasia type II, which likely affect a relatively confined cortical territory., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

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.)