The study of large-scale brain connectivity is increasingly adopting unsupervised approaches that derive low-dimensional spatial representations from high-dimensional connectomes, referred to as gradient analysis. When translating this approach to study interindividual variations in connectivity, one technical issue pertains to the selection of an appropriate group-level template to which individual gradients are aligned. Here, we compared different group-level template construction strategies using functional and structural connectome data from neurotypical controls and individuals with autism spectrum disorder (ASD) to identify between-group differences. We studied multimodal magnetic resonance imaging data obtained from the Autism Brain Imaging Data Exchange (ABIDE) Initiative II and the Human Connectome Project (HCP). We designed six template construction strategies that varied in whether (1) they included typical controls in addition to ASD; or (2) they mapped from one dataset onto another. We found that aligning a combined subject template of the ASD and control subjects from the ABIDE Initiative onto the HCP template exhibited the most pronounced effect size. This strategy showed robust identification of ASD-related brain regions for both functional and structural gradients across different study settings. Replicating the findings on focal epilepsy demonstrated the generalizability of our approach. Our findings will contribute to improving gradient-based connectivity research. Author Summary Gradient-based connectivity analysis provides a compact understanding of complex connectivity patterns across the brain. One issue of the gradient analysis is to choose an appropriate group-level template in which individual gradients are aligned. Here, we assessed six different strategies for constructing group-level gradient templates, including those based on combined data from individuals with psychiatric conditions and control subjects, and data from an independent dataset of young, healthy adults. The choice of template significantly influences the outcomes of gradient analyses, with templates combining data from both groups or aligning to a high-quality independent dataset, providing more balanced results. This study emphasizes the importance of template selection in brain connectivity studies, contributing to more reliable gradient analyses.

Author Summary Epilepsy is increasingly recognized as a network disorder characterized by recurrent seizures as well as broad-ranging cognitive difficulties and affective dysfunction. Our manuscript reviews recent literature highlighting brain network substrates of cognitive and affective dysfunction in common epilepsy syndromes, namely temporal lobe epilepsy secondary to mesiotemporal sclerosis, extratemporal epilepsy secondary to malformations of cortical development, and idiopathic generalized epilepsy syndromes arising from subcortico-cortical pathophysiology. We discuss prior work that has indicated both shared and distinct brain network signatures of cognitive and affective dysfunction across the epilepsy spectrum, improves our knowledge of structure-function links and interindividual heterogeneity, and ultimately aids screening and monitoring of therapeutic strategies. Abstract Epilepsy is one of the most common chronic neurological conditions, traditionally defined as a disorder of recurrent seizures. Cognitive and affective dysfunction are increasingly recognized as core disease dimensions and can affect patient well-being, sometimes more than the seizures themselves. Connectome-based approaches hold immense promise for revealing mechanisms that contribute to dysfunction and to identify biomarkers. Our review discusses emerging multimodal neuroimaging and connectomics studies that highlight network substrates of cognitive/affective dysfunction in the common epilepsies. We first discuss work in drug-resistant epilepsy syndromes, that is, temporal lobe epilepsy, related to mesiotemporal sclerosis (TLE), and extratemporal epilepsy (ETE), related to malformations of cortical development. While these are traditionally conceptualized as ‘focal’ epilepsies, many patients present with broad structural and functional anomalies. Moreover, the extent of distributed changes contributes to difficulties in multiple cognitive domains as well as affective-behavioral challenges. We also review work in idiopathic generalized epilepsy (IGE), a subset of generalized epilepsy syndromes that involve subcortico-cortical circuits. Overall, neuroimaging and network neuroscience studies point to both shared and syndrome-specific connectome signatures of dysfunction across TLE, ETE, and IGE. Lastly, we point to current gaps in the literature and formulate recommendations for future research.