Regular drug use can lead to addiction, but not everyone who takes drugs makes this transition. How exactly drugs of abuse interact with individual vulnerability is not fully understood, nor is it clear how individuals defy the risks associated with drugs or addiction vulnerability. We used resting-state functional MRI (fMRI) in 162 participants to characterize risk- and resilience-related changes in corticostriatal functional circuits in individuals exposed to stimulant drugs both with and without clinically diagnosed drug addiction, siblings of addicted individuals, and control volunteers. The likelihood of developing addiction, whether due to familial vulnerability or drug use, was associated with significant hypoconnectivity in orbitofrontal and ventromedial prefrontal cortical-striatal circuits-pathways critically implicated in goal-directed decision-making. By contrast, resilience against a diagnosis of substance use disorder was associated with hyperconnectivity in two networks involving 1) the lateral prefrontal cortex and medial caudate nucleus and 2) the supplementary motor area, superior medial frontal cortex, and putamen-brain circuits respectively implicated in top-down inhibitory control and the regulation of habits. These findings point toward a predisposing vulnerability in the causation of addiction, related to impaired goal-directed actions, as well as countervailing resilience systems implicated in behavioral regulation, and may inform novel strategies for therapeutic and preventative interventions.

Behavioural and Clinical Neuroscience Institute Department of Psychology University of Cambridge Cambridge CB2 3EB United Kingdom

Behavioural and Clinical Neuroscience Institute Department of Psychology University of Cambridge Cambridge CB2 3EB United Kingdom Department of Psychology University of Cambridge Cambridge CB2 3EB United Kingdom

Department of Clinical Neurosciences University of Cambridge Cambridge CB2 3EB United Kingdom

Department of Psychiatry University of Cambridge Cambridge CB2 0SZ United Kingdom

Department of Psychiatry University of Cambridge Cambridge CB2 0SZ United Kingdom Behavioural and Clinical Neuroscience Institute Department of Psychology University of Cambridge Cambridge CB2 3EB United Kingdom Cambridgeshire and Peterborough National Health Service Foundation Trust Cambridge CB21 5EF United Kingdom

Department of Psychiatry University of Cambridge Cambridge CB2 0SZ United Kingdom Cambridgeshire and Peterborough National Health Service Foundation Trust Cambridge CB21 5EF United Kingdom

Department of Psychiatry University of Cambridge Cambridge CB2 0SZ United Kingdom Department of Kinanthropology and Humanities Charles University 16252 Prague Czech Republic

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