The amygdala is a subcortical region in the mesiotemporal lobe that plays a key role in emotional and sensory functions. Conventional neuroimaging experiments treat this structure as a single, uniform entity, but there is ample histological evidence for subregional heterogeneity in microstructure and function. The current study characterized subregional structure-function coupling in the human amygdala, integrating post-mortem histology and in vivo MRI at ultra-high fields. Core to our work was a novel neuroinformatics approach that leveraged multiscale texture analysis as well as non-linear dimensionality reduction techniques to identify salient dimensions of microstructural variation in a 3D post-mortem histological reconstruction of the human amygdala. We observed two axes of subregional variation in this region, describing inferior-superior as well as mediolateral trends in microstructural differentiation that in part recapitulated established atlases of amygdala subnuclei. Translating our approach to in vivo MRI data acquired at 7 Tesla, we could demonstrate the generalizability of these spatial trends across 10 healthy adults. We then cross-referenced microstructural axes with functional blood-oxygen-level dependent (BOLD) signal analysis obtained during task-free conditions, and revealed a close association of structural axes with macroscale functional network embedding, notably the temporo-limbic, default mode, and sensory-motor networks. Our novel multiscale approach consolidates descriptions of amygdala anatomy and function obtained from histological and in vivo imaging techniques.

The brain is a physically embedded and heavily interconnected system that expresses neural rhythms across multiple time scales. While these dynamics result from the complex interplay of local and inter-regional factors, the relative contribution of such mechanisms across the cortex remains unclear. Our study explores geometric, microstructural, and connectome-level constraints on cortex-wide neural activity. We leverage intracranial electroencephalography recordings to derive a coordinate system of human cortical dynamics. Using multimodal neuroimaging, we could then demonstrate that these patterns are largely explainable by geometric properties indexed by inter-regional distance. However, dynamics in transmodal association regions are additionally explainable by incorporation of inter-regional microstructural similarity and connectivity information. Our findings are generally consistent when cross-referencing electroencephalography and imaging data from large-scale atlases and when using data obtained in the same individuals, suggesting subject-specificity and population-level generalizability. Together, our results suggest that the relative contribution of local and macroscale constraints on cortical dynamics varies systematically across the cortical sheet, specifically highlighting the role of transmodal networks in inter-regional cortical coordination. Royer and colleagues find a principal dimension of neural dynamic similarity dissociating unimodal and association cortices. Systematic variations in local and macroscale constraints across the cortex also followed this pattern.

AbstractExcitation‐inhibition (E/I) imbalance is theorized as a key mechanism in the pathophysiology of epilepsy, with ample research focusing on elucidating its cellular manifestations. However, few studies investigate E/I imbalance at the macroscale, whole‐brain level, and its microcircuit‐level mechanisms and clinical significance remain incompletely understood. Here, the Hurst exponent, an index of the E/I ratio, is computed from resting‐state fMRI time series, and microcircuit parameters are simulated using biophysical models. A broad decrease in the Hurst exponent is observed in pharmaco‐resistant temporal lobe epilepsy (TLE), suggesting more excitable network dynamics. Connectome decoders point to temporolimbic and frontocentral cortices as plausible network epicenters of E/I imbalance. Furthermore, computational simulations reveal that enhancing cortical excitability in TLE reflects atypical increases in recurrent connection strength of local neuronal ensembles. Mixed cross‐sectional and longitudinal analyses show stronger E/I ratio elevation in patients with longer disease duration, more frequent electroclinical seizures as well as interictal epileptic spikes, and worse cognitive functioning. Hurst exponent‐informed classifiers discriminate patients from healthy controls with high accuracy (72.4% [57.5%–82.5%]). Replicated in an independent dataset, this work provides in vivo evidence of a macroscale shift in E/I balance in TLE patients and points to progressive functional imbalances that relate to cognitive decline.

Functional specialization of brain areas and subregions, as well as their integration into large-scale networks, are key principles in neuroscience. Consolidating both local and global perspectives on cortical organization, however, remains challenging. Here, we present an approach to integrate inter- and intra-areal similarities of microstructure, structural connectivity, and functional interactions. Using high-field in-vivo 7 tesla (7 T) Magnetic Resonance Imaging (MRI) data and a probabilistic post-mortem atlas of cortical cytoarchitecture, we derive multimodal gradients that capture cortex-wide organization. Inter-areal similarities follow a canonical sensory-fugal gradient, linking cortical integration with functional diversity across tasks. However, intra-areal heterogeneity does not follow this pattern, with greater variability in association cortices. Findings are replicated in an independent 7 T dataset and a 100-subject 3 tesla (3 T) cohort. These results highlight a robust coupling between local arealization and global cortical motifs, advancing our understanding of how specialization and integration shape human brain function.

BACKGROUND AND OBJECTIVES:Neuroimaging studies in patients with temporal lobe epilepsy (TLE) show widespread brain network alterations beyond the mesiotemporal lobe. Despite the critical role of the cerebrovascular system in maintaining whole-brain structure and function, changes in cerebral blood flow (CBF) remain incompletely understood in the disease. Here, we studied whole-brain perfusion and vascular network alterations in TLE and assessed its associations with gray and white matter compromises and various clinical variables. METHODS:We included individuals with and without pharmaco-resistant TLE who underwent multimodal 3T MRI, including arterial spin labelling, structural, and diffusion-weighted imaging. Using surface-based MRI mapping, we generated individualized cortico-subcortical profiles of perfusion, morphology, and microstructure. Linear models compared regional CBF in patients with controls and related alterations to morphological and microstructural metrics. We further probed interregional vascular networks in TLE, using graph theoretical CBF covariance analysis. The effects of disease duration were explored to better understand the progressive changes in perfusion. We assessed the utility of perfusion in separating patients with TLE from controls using supervised machine learning. RESULTS:Compared with control participants (n = 38; mean ± SD age 34.8 ± 9.3 years; 20 females), patients with TLE (n = 24; mean ± SD age 35.8 ± 10.6 years; 12 females) showed widespread CBF reductions predominantly in fronto-temporal regions (Cohen d -0.69, 95% CI -1.21 to -0.16), consistent in a subgroup of patients who remained seizure-free after surgical resection of the seizure focus. Parallel structural profiling and network-based models showed that cerebral hypoperfusion may be partially constrained by gray and white matter changes (8.11% reduction in Cohen d) and topologically segregated from whole-brain perfusion networks (area under the curve -0.17, p < 0.05). Negative effects of progressive disease duration further targeted regional CBF profiles in patients (r = -0.54, 95% CI -0.77 to -0.16). Perfusion-derived classifiers discriminated patients from controls with high accuracy (71% [70%-82%]). Findings were robust when controlling for several methodological confounds. DISCUSSION:Our multimodal findings provide insights into vascular contributions to TLE pathophysiology affecting and extending beyond mesiotemporal structures and highlight their clinical potential in epilepsy diagnosis. As our work was cross-sectional and based on a single site, it motivates future longitudinal studies to confirm progressive effects, ideally in a multicentric setting.

ObjectiveTemporal lobe epilepsy (TLE) is typically associated with pathology of the hippocampus, a key structure involved in relational memory, including episodic, semantic, and spatial memory processes. While it is widely accepted that TLE-associated hippocampal alterations underlie memory deficits, it remains unclear whether impairments relate to a specific cognitive domain or multiple ones.MethodsWe administered a recently validated task paradigm to evaluate episodic, semantic, and spatial memory in 24 pharmacoresistant TLE patients and 50 age- and sex-matched healthy controls. We carried out two-way analyses of variance to identify memory deficits in individuals with TLE relative to controls across different relational memory domains, and used partial least squares correlation to identify factors contributing to variations in relational memory performance across both cohorts.ResultsCompared to controls, TLE patients showed marked impairments in episodic and spatial memory, with mixed findings in semantic memory. Even when additionally controlling for age, sex, and overall cognitive function, between-group differences persisted along episodic and spatial domains. Moreover, age, diagnostic group, and hippocampal volume were all associated with relational memory behavioral phenotypes.SignificanceOur behavioral findings show graded deficits across relational memory domains in people with TLE, which provides further insights into the complex pattern of cognitive impairment in the condition.

Excitation-inhibition (E/I) imbalance is theorized as a key mechanism in the pathophysiology of epilepsy, with a mounting body of previous research focusing on elucidating its cellular manifestations. However, there are limited studies into E/I imbalance at macroscale and its microcircuit-level mechanisms and clinical associations. In our current work, we computed the Hurst exponent—a previously validated index of the E/I ratio—from resting-state fMRI time series, and simulated microcircuit parameters using biophysical computational models. We found a broad reduction in the Hurst exponent in pharmaco-resistant temporal lobe epilepsy (TLE), indicative of a shift towards more excitable network dynamics. Connectome decoders pointed to temporolimbic and frontocentral areas as plausible network epicenters of E/I imbalance. Computational simulations further revealed that enhancing cortical excitability in patients likely reflected atypical increases in recurrent connection strength of local neuronal ensembles. Moreover, mixed cross-sectional and longitudinal analyses revealed heightened E/I elevation in patients with longer disease duration, more frequent electroclinical seizures and inter-ictal epileptic spikes, and worse cognitive functioning. Replicated in an independent dataset, our work provides compelling in-vivo evidence of a macroscale shift in E/I balance in TLE patients that undergoes progressive changes and underpins cognitive impairments, potentially informing treatment strategies targeting E/I mechanisms.### Competing Interest StatementThe authors have declared no competing interest.

Temporal lobe epilepsy (TLE) is one of the most common pharmaco-resistant epilepsies in adults. While hippocampal pathology is the hallmark of this condition, emerging evidence indicates that brain alterations extend beyond the mesiotemporal epicenter and affect macroscale brain function and cognition. We studied macroscale functional reorganization in TLE, explored structural substrates, and examined cognitive associations. We investigated a multisite cohort of 95 patients with pharmaco-resistant TLE and 95 healthy controls using state-of-the-art multimodal 3T magnetic resonance imaging (MRI). We quantified macroscale functional topographic organization using connectome dimensionality reduction techniques and estimated directional functional flow using generative models of effective connectivity. We observed atypical functional topographies in patients with TLE relative to controls, manifesting as reduced functional differentiation between sensory/motor networks and transmodal systems such as the default mode network, with peak alterations in bilateral temporal and ventromedial prefrontal cortices. TLE-related topographic changes were consistent in all three included sites and reflected reductions in hierarchical flow patterns between cortical systems. Integration of parallel multimodal MRI data indicated that these findings were independent of TLE-related cortical grey matter atrophy, but mediated by microstructural alterations in the superficial white matter immediately beneath the cortex. The magnitude of functional perturbations was robustly associated with behavioral markers of memory function. Overall, this work provides converging evidence for macroscale functional imbalances, contributing microstructural alterations, and their associations with cognitive dysfunction in TLE.

A bstract O bjective Neuroimaging has been the prevailing method to study brain networks in temporal lobe epilepsy (TLE), showing widespread alterations beyond the mesiotemporal lobe. Despite the critical role of the cerebrovascular system in maintaining whole-brain structure and function, changes in cerebral blood flow (CBF) remain incompletely understood in the disease. M ethods We studied 24 individuals with pharmaco-resistant TLE and 38 healthy adults using multimodal 3T magnetic resonance imaging. We compared regional CBF changes in patients relative to controls and related our perfusion findings to morphological and microstructural metrics. We further probed inter-regional vascular networks in TLE, using graph theoretical CBF covariance analysis. Finally, we assessed the effects of disease duration to study progressive changes. R esults Compared to controls, individuals with TLE showed widespread CBF reductions, predominantly in fronto-temporal regions, with 83% of patients showing more marked decreases ipsilateral than contralateral to the seizure focus. Parallel structural profiling and network-based models showed that cerebral hypoperfusion may be partly constrained by grey and white matter changes and topologically segregated from whole-brain perfusion networks. Negative effects of progressive disease duration further targeted regional CBF profiles in patients. Findings were confirmed in a subgroup of patients who remained seizure-free after surgery. I nterpretation Our multimodal findings provide insights into vascular contributions to TLE pathophysiology and highlight their clinical potential in seizure lateralization.

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.

Objective Temporal lobe epilepsy (TLE) is the most common drug-resistant epilepsy in adults. Here, we aimed to profile local neural function in TLE in vivo , building on prior evidence that has identified widespread structural alterations. Using multimodal MRI, we mapped intrinsic neural timescales (INT) at rest, examined associations to TLE-related structural compromise, and evaluated the clinical utility of INT. Methods We studied 46 TLE patients and 44 healthy controls from two independent sites, and mapped INT changes in patients relative to controls across hippocampal, subcortical, and neocortical regions. We examined region-specific associations to structural alterations and explored effects of age and epilepsy duration. A supervised machine learning paradigm assessed utility of INT for classifying patients- vs -controls and seizure focus lateralization. Results Relative to controls, TLE showed marked INT reductions across multiple regions bilaterally, indexing faster changing resting activity, with strongest effects in ipsilateral medial and lateral temporal regions, and sensorimotor cortices. Findings were consistent in each site and robust, albeit with reduced effect sizes, when correcting for structural alterations. TLE-related INT reductions increased with advancing disease duration, yet findings differed from aging effects seen in controls. Classifiers based on INT distinguished patients- vs -controls (balanced accuracy, 5-fold: 76±2.65%; cross-site, 72-83%) and lateralized the focus in TLE (balanced accuracy, 5-fold: 96±2.10%; cross-site, 95-97%) with high accuracies and generalization. Conclusions Our findings robustly demonstrate atypical macroscale function in TLE in a topography that extends beyond mesiotemporal epicenters. INT measurements can assist in TLE diagnosis, seizure focus lateralization, and monitoring of disease progression, which suggests clinical utility.

ABSTRACT B ackground Temporal lobe epilepsy (TLE) is typically associated with pathology of the hippocampus, a key structure involved in relational memory processes, including episodic, semantic, and spatial memory. While it is widely accepted that TLE-associated hippocampal alterations may underlie global deficits in memory, it remains poorly understood whether TLE may present with shared or unique impairment across distinct relational memory domains. M ethods We administered a recently validated behavioral paradigm to evaluate episodic, semantic, and spatial memory in 20 pharmacoresistant TLE patients and 53 age- and sex-matched healthy controls. We implemented linear mixed effects models to identify memory deficits in individuals with TLE relative to controls, and used partial least squares analysis to identify factors contributing to overall variations in relational memory performance across both cohorts. R esults TLE patients showed marked impairment in episodic memory compared to controls, while spatial and semantic memory remained relatively intact. Findings were robust, with slight decreases in effect sizes after controlling for performance on executive function tests. Via partial least squares analysis, we identified group, age, and bilateral hippocampal volumes as important variables relating to relational memory impairment. C onclusion Our behavioral framework provides a granular approach for assessing relational memory deficits in people with TLE and may inform future prognostic strategies in patients with hippocampal pathology. Our work warrants further investigations into the underlying neural substrates of relational memory.