Subcortical alterations in newly diagnosed epilepsy and associated changes in brain connectivity and cognition

Objectives Patients with chronic focal epilepsy commonly exhibit subcortical atrophy, particularly of the thalamus. The timing of these alterations remains uncertain, though preliminary evidence suggests that observable changes may already be present at diagnosis. It is also not yet known how these morphological changes are linked to the coherence of white matter pathways throughout the brain, or to neuropsychological function often compromised before anti-seizure medication treatment. This study investigates localised atrophy in subcortical regions using surface shape analysis in individuals with newly diagnosed focal epilepsy (NDfE) and assesses their implications on brain connectivity and cognitive function. Methods We collected structural (T1w) and diffusion weighted MRI, as well as neuropsychological data from 104 patients with NDfE and 45 healthy controls (HC) matched for age, sex and education. A vertex-based shape analysis was performed on subcortical structures to compare patients with NDfE and HC, adjusting for age, sex and intracranial volume. The mean deformation of significance areas (pcor < 0.05) was used to identify white matter pathways associated with overall shape alterations in patients relative to controls using correlational tractography. Additionally, the relationship between significant subcortical shape values and neuropsychological outcomes was evaluated using a generalised canonical correlation approach. Results Shape analysis revealed bilateral focal inward deformation (a proxy for localised atrophy) in anterior areas of the right and left thalamus and right pallidum in patients with NDfE compared to HC (FWE corrected). No structures showed areas of outward deformation in patients. The connectometry analysis revealed that fractional anisotropy (FA) was positively correlated with thalamic and pallidal shape deformation, i.e., reduced FA was associated with inward deformation in tracts proximal to and or connecting with the thalamus including the fornix, frontal, parahippocampal and corticothalamic pathways. Thalamic and pallidal shape changes were also related to with increased depression and anxiety, and reduced memory and cognitive function. Discussion These findings suggest that atrophy of the thalamus, which has previously been associated with the generation and maintenance of focal seizures, may present at epilepsy diagnosis and relate to alterations in both white matter connectivity and cognitive performance. We suggest that at least some alterations in brain structure and consequent impact on cognitive and affective processes are the result of early epileptogenic processes rather than exclusively due to the chronicity of longstanding epilepsy, recurrent seizures, and treatment with anti-seizure medication. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement A UK Medical Research Council (MRC) research grant (MR/S00355X/1) ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: the study was approved by the North West, Liverpool East Research Ethics Committee (19/NW/0384) through the Integrated Research Application System (Project ID 260623). Health Research Authority (HRA) approval was provided and the project was sponsored by the UoL (UoL001449). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors