Abstract
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.
Royer et al. examine mechanisms of memory impairment in temporal lobe epilepsy, and find that regions showing atypical functional connectivity during a memory task also show microstructural imbalances; that is, attenuated differences in intracortical lamination and myelination from neighbouring cortices.
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 inter-individual clinical variability, thus offering new avenues to examine the fundamental malleability of the human brain.
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.
Temporal lobe epilepsy (TLE) is the most common pharmaco-resistant epilepsy in adults. While primarily associated with mesiotemporal pathology, recent evidence suggests that brain alterations in TLE ...extend beyond the paralimbic epicenter and impact macroscale function and cognitive functions, particularly memory. Using connectome-wide manifold learning and generative models of effective connectivity, we examined functional topography and directional signal flow patterns between large-scale neural circuits in TLE at rest. Studying a multisite cohort of 95 patients with TLE and 95 healthy controls, we observed atypical functional topographies in the former group, characterized by reduced differentiation between sensory and transmodal association cortices, with most marked effects in bilateral temporo-limbic and ventromedial prefrontal cortices. These findings were consistent across all study sites, present in left and right lateralized patients, and validated in a subgroup of patients with histopathological validation of mesiotemporal sclerosis and post-surgical seizure freedom. Moreover, they were replicated in an independent cohort of 30 TLE patients and 40 healthy controls. Further analyses demonstrated that reduced differentiation related to decreased functional signal flow into and out of temporolimbic cortical systems and other brain networks. Parallel analyses of structural and diffusion-weighted MRI data revealed that topographic alterations were independent of TLE-related cortical thinning but partially mediated by white matter microstructural changes that radiated away from paralimbic circuits. Finally, we found a strong association between the degree of functional alterations and behavioral markers of memory dysfunction. Our work illustrates the complex landscape of macroscale functional imbalances in TLE, which can serve as intermediate markers bridging microstructural changes and cognitive impairment.
•We examined intrinsic functional networks in patients with temporal lobe epilepsy (TLE) and healthy controls.•We observed atypical topographic organization and signal flow in TLE, with peak effects in temporo-limbic regions.•Findings were consistent across study sites and patient subgroups, and were replicated in an independent cohort of patients and controls.•Functional alterations were independent of TLE-related cortical thinning, but were partially mediated by white matter microstructural changes.•Functional alterations correlated with behavioral markers of memory dysfunction.
Abstract
Prior research has shown a role of the medial temporal lobe, particularly the hippocampal–parahippocampal complex, in spatial cognition. Here, we developed a new paradigm, the conformational ...shift spatial task (CSST), which examines the ability to encode and retrieve spatial relations between unrelated items. This task is short, uses symbolic cues, incorporates two difficulty levels, and can be administered inside the scanner. A cohort of 48 healthy young adults underwent the CSST, together with a set of behavioral measures and multimodal magnetic resonance imaging (MRI). Inter-individual differences in CSST performance correlated with scores on an established spatial memory paradigm, but neither with episodic memory nor mnemonic discrimination, supporting specificity. Analyzing high-resolution structural MRI data, individuals with better spatial memory showed thicker medial and lateral temporal cortices. Functional relevance of these findings was supported by task-based functional MRI analysis in the same participants and ad hoc meta-analysis. Exploratory resting-state functional MRI analyses centered on clusters of morphological effects revealed additional modulation of intrinsic network integration, particularly between lateral and medial temporal structures. Our work presents a novel spatial memory paradigm and supports an integrated structure–function substrate in the human temporal lobe. Task paradigms are programmed in python and made open access.
Abstract
Background
Autism spectrum disorder (ASD) is a common neurodevelopmental diagnosis showing substantial phenotypic heterogeneity. A leading example can be found in verbal and nonverbal ...cognitive skills, which vary from elevated to impaired compared with neurotypical individuals. Moreover, deficits in verbal profiles often coexist with normal or superior performance in the nonverbal domain.
Methods
To study brain substrates underlying cognitive imbalance in ASD, we capitalized categorical and dimensional IQ profiling as well as multimodal neuroimaging.
Results
IQ analyses revealed a marked verbal to nonverbal IQ imbalance in ASD across 2 datasets (Dataset-1: 155 ASD, 151 controls; Dataset-2: 270 ASD, 490 controls). Neuroimaging analysis in Dataset-1 revealed a structure–function substrate of cognitive imbalance, characterized by atypical cortical thickening and altered functional integration of language networks alongside sensory and higher cognitive areas.
Conclusion
Although verbal and nonverbal intelligence have been considered as specifiers unrelated to autism diagnosis, our results indicate that intelligence disparities are accentuated in ASD and reflected by a consistent structure–function substrate affecting multiple brain networks. Our findings motivate the incorporation of cognitive imbalances in future autism research, which may help to parse the phenotypic heterogeneity and inform intervention-oriented subtyping in ASD.
Abstract Delusions of reference in schizophrenia are thought to result from misattributions of self-relevance to neutral events. Activation of regions within the cortical midline structures (CMS; ...e.g., medial prefrontal cortex, cingulate cortex, and precuneus) have been previously associated with self-referential processing in schizophrenia patients; however, the specificity of this pattern to individuals with current delusions of reference has yet to be determined. In the present study, we identified functional brain networks that underlie self-referential processing using task-based multivariate functional connectivity. Healthy control subjects ( n = 15) and schizophrenia patients with ( n = 14) and without ( n = 13) current delusions of reference were shown ambiguous statements while undergoing functional magnetic resonance imaging, and evaluated whether these statements were thought to be specifically about them. Our results revealed two functionally distinct CMS networks that differed between patients and controls during self-referential processing: a posterior CMS network, which showed muted deactivity in non-delusional patients; and an anterior CMS network, in which delusional patients demonstrated hyperactivity. Furthermore, activity within the anterior CMS network across the three groups showed a linear pattern of increasing activity associated with greater intensity of delusions of reference, suggesting that hyperactivity in this network may underlie delusions of reference.
Motor performance decline observed during aging is linked to changes in brain structure and function, however, the precise neural reorganization associated with these changes remains largely unknown. ...We investigated the neurophysiological correlates of this reorganization by quantifying functional and effective brain network connectivity in elderly individuals (n = 11; mean age = 67.5 years), compared to young adults (n = 12; mean age = 23.7 years), while they performed visually‐guided unimanual and bimanual handgrips inside the magnetoencephalography (MEG) scanner. Through a combination of principal component analysis and Granger causality, we observed age‐related increases in functional and effective connectivity in whole‐brain, task‐related motor networks. Specifically, elderly individuals demonstrated (i) greater information flow from contralateral parietal and ipsilateral secondary motor regions to the left primary motor cortex during the unimanual task and (ii) decreased interhemispheric temporo‐frontal communication during the bimanual task. Maintenance of motor performance and task accuracy in elderly was achieved by hyperactivation of the task‐specific motor networks, reflecting a possible mechanism by which the aging brain recruits additional resources to counteract known myelo‐ and cytoarchitectural changes. Furthermore, resting‐state sessions acquired before and after each motor task revealed that both older and younger adults maintain the capacity to adapt to task demands via network‐wide increases in functional connectivity. Collectively, our study consolidates functional connectivity and directionality of information flow in systems‐level cortical networks during aging and furthers our understanding of neuronal flexibility in motor processes.
Functional connectivity hierarchy is an important principle in the process of brain functional organization and an important feature reflecting brain development. However, atypical brain network ...hierarchy organization in Rolandic epilepsy have not been systematically investigated. We examined connectivity alteration with age and its relation to epileptic incidence, cognition, or underlying genetic factors in 162 cases of Rolandic epilepsy and 117 typically developing children, by measuring fMRI multi-axis functional connectivity gradients. Rolandic epilepsy is characterized by contracting and slowing expansion of the functional connectivity gradients, highlighting the atypical age-related change of the connectivity hierarchy in segregation properties. The gradient alterations are relevant to seizure incidence, cognition, and connectivity deficit, and development-associated genetic basis. Collectively, our approach provides converging evidence for atypical connectivity hierarchy as a system-level substrate of Rolandic epilepsy, suggesting this is a disorder of information processing across multiple functional domains, and established a framework for large-scale brain hierarchical research.
Adolescence is a critical time for the continued maturation of brain networks. Here, we assessed structural connectome development in a large longitudinal sample ranging from childhood to young ...adulthood. By projecting high-dimensional connectomes into compact manifold spaces, we identified a marked expansion of structural connectomes, with strongest effects in transmodal regions during adolescence. Findings reflected increased within-module connectivity together with increased segregation, indicating increasing differentiation of higher-order association networks from the rest of the brain. Projection of subcortico-cortical connectivity patterns into these manifolds showed parallel alterations in pathways centered on the caudate and thalamus. Connectome findings were contextualized via spatial transcriptome association analysis, highlighting genes enriched in cortex, thalamus, and striatum. Statistical learning of cortical and subcortical manifold features at baseline and their maturational change predicted measures of intelligence at follow-up. Our findings demonstrate that connectome manifold learning can bridge the conceptual and empirical gaps between macroscale network reconfigurations, microscale processes, and cognitive outcomes in adolescent development.
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