
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.03.610959
preprint
1
Article
Sex-specific differences in brain activity dynamics of youth with a family history of substance use disorder
Schilling Louisa http://orcid.org/0009-0006-1303-4797

Singleton S Parker http://orcid.org/0000-0002-7102-7820

Tozlu Ceren http://orcid.org/0000-0002-6828-886X

Hédo Marie
Zhao Qingyu http://orcid.org/0000-0002-6368-0889

Pohl Kilian M http://orcid.org/0000-0001-5416-5159

Jamison Keith http://orcid.org/0000-0001-7139-6661

Kuceyeski Amy http://orcid.org/0000-0002-5050-8342

04 9 2024
2024.09.03.610959https://creativecommons.org/licenses/by-nc/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.03.610959
nihpp-2024.09.03.610959.pdf
ABSTRACT

An individual’s risk of substance use disorder (SUD) is shaped by a complex interplay of potent biosocial factors. Current neurodevelopmental models posit vulnerability to SUD in youth is due to an overreactive reward system and reduced inhibitory control. Having a family history of SUD is a particularly strong risk factor, yet few studies have explored its impact on brain function and structure prior to substance exposure. Herein, we utilized a network control theory approach to quantify sex-specific differences in brain activity dynamics in youth with and without a family history of SUD, drawn from a large cohort of substance-naïve youth from the Adolescent Brain Cognitive Development Study. We summarize brain dynamics by calculating transition energy, which probes the ease with which a whole brain, region or network drives the brain towards a specific spatial pattern of activation (i.e., brain state). Our findings reveal that a family history of SUD is associated with alterations in the brain’s dynamics wherein: i) independent of sex, certain regions’ transition energies are higher in those with a family history of SUD and ii) there exist sex-specific differences in SUD family history groups at multiple levels of transition energy (global, network, and regional). Family history-by-sex effects reveal that energetic demand is increased in females with a family history of SUD and decreased in males with a family history of SUD, compared to their same-sex counterparts with no SUD family history. Specifically, we localize these effects to higher energetic demands of the default mode network in females with a family history of SUD and lower energetic demands of attention networks in males with a family history of SUD. These results suggest a family history of SUD may increase reward saliency in males and decrease efficiency of top-down inhibitory control in females. This work could be used to inform personalized intervention strategies that may target differing cognitive mechanisms that predispose individuals to the development of SUD.
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pmc
