Abstract

Introduction The anterior limb of the internal capsule (ALIC) is a major white matter highway connecting prefrontal cortical (PFC) regions to the thalamus, brainstem, and subthalamic nucleus. Structural and functional abnormalities within the ALIC circuit have been associated with many neuropsychiatric disorders, including obsessive-compulsive disorder (OCD) and depression, and deep brain stimulation (DBS) may provide effective treatment to some of these patients. However, it remains unclear whether the well-characterized topographic organization of the ALIC observed in healthy individuals and preclinical models is preserved in treatment-resistant psychiatric populations. Methods We first used diffusion tractography to evaluate the topography of PFC and subcortical fibers through the ALIC in patients with treatment-resistant OCD (n=18) and depression (n=5). In depression patients, we also evaluated ALIC topography using cerebro-cerebral evoked potentials (CCEPs) elicited by single-pulse electrical stimulation (SPES) of DBS leads in the ALIC and recordings in the ventral PFC (vPFC). Results The topographic organization of PFC and subcortical projections is preserved in the ALIC among treatment-resistant psychiatric patients, consistent with patterns observed in healthy individuals and preclinical models. CCEP recordings in the ventral PFC showed a ventral ALIC to medial vPFC/dorsal ALIC to lateral vPFC response pattern in the left hemisphere, but not in the right. Conclusion Our findings confirm that topographic patterns within the ALIC previously identified using preclinical models and healthy controls are preserved in treatment-resistant psychiatric patients. Furthermore, by linking white matter topography to stimulation effects, this work supports more precise and individualized neuromodulatory strategies for neuropsychiatric disorders. ### Competing Interest Statement EAS reports receiving research funding to his institution from the Ream Foundation, International OCD Foundation, and NIH. He receives direct funding from the International OCD Foundation as well as MHNTI for providing trainings on treating obsessive-compulsive disorder with psychotherapy. He was a consultant for Brainsway and Biohaven Pharmaceuticals in the past 36 months. He owns stock options less than $5000 in NView(for distribution of the Y-BOCS and CY-BOCS) and receives royalties from OCD Scales LLC (for distribution of the Y-BOCS and CY-BOCS). He receives book royalties from Elsevier, Wiley, Oxford, American Psychological Association, Guildford, Springer, Routledge, and Jessica Kingsley. NP reports personal fees from Abbott Laboratories and Boston Scientific. WKG declares royalties from Nview, LLC and OCDscales, LLC. SAS reports consulting/advising for Boston Scientific, Zimmer Biomet, Abbott, Koh Young Technology, NeuroPace Inc, and co-founding Motif Neurotech. SJM has served as a consultant to Allergan, Alkermes, Almatica Pharma, Axsome Therapeutics, BioXcel Therapeutics, Clexio Biosciences, COMPASS Pathways, Eleusis, EMA Wellness, Engrail Therapeutics, Greenwich Biosciences, Intra-Cellular Therapies, Janssen, Levo Therapeutics, Perception Neurosciences, Praxis Precision Medicines, Neumora, Neurocrine, Relmada Therapeutics, Sage Therapeutics, Seelos Therapeutics, Signant Health, Sunovion and Worldwide Clinical Trials. He reports research support from Biohaven Pharmaceuticals, Boehringer-Ingelheim, Janssen, Merck, Sage Therapeutics, and VistaGen Therapeutics. NIH Common Fund, https://ror.org/001d55x84, UH3NS103549 NIH Common Fund, https://ror.org/001d55x84, R01MH1340597 NIH Common Fund, https://ror.org/001d55x84, UH3NS100549 Robert and Janice McNair Foundation, https://ror.org/01pg81m90