A shared spatial topography links the functional connectome correlates of cocaine use disorder and dopamine D2/3 receptor densities

Abstract

BackgroundThe biological mechanisms that contribute to cocaine and other substance use disorders involve an array of cortical and subcortical systems. Prior work on the development and maintenance of substance use has largely focused on cortico-striatal circuits, with relatively less attention on alterations within and across large-scale functional brain networks, and associated aspects of the dopamine system. The brain-wide pattern of temporal co-activation between distinct brain regions, referred to as the functional connectome, underpins individual differences in behavior. Critically, the functional connectome correlates of substance use and their specificity to dopamine receptor densities relative to other metabotropic receptors classes remains to be established. MethodsWe comprehensively characterized brain-wide differences in functional connectivity across multiple scales, including individual connections, regions, and networks in participants with cocaine use disorder (CUD; n=69) and healthy matched controls (n=62), Further, we studied the relationship between the observed functional connectivity signatures of CUD and the spatial distribution of a broad range of normative neurotransmitter receptor and transporter bindings as assessed through 18 different normative positron emission tomography (PET) maps. ResultsOur analyses identified a widespread profile of functional connectivity differences between individuals with CUD and matched healthy comparison participants (8.8% of total edges; 8,185 edges; pFWE=0.025). We largely find lower connectivity preferentially linking default network and subcortical regions, and higher within-network connectivity in the default network in participants with CUD. Furthermore, we find consistent and replicable associations between signatures of CUD and normative spatial density of dopamine D2/3 receptors. ConclusionsOur analyses revealed a widespread profile of altered connectivity in individuals with CUD that extends across the functional connectome and implicates multiple circuits. This profile is robustly coupled with normative dopamine D2/3 receptors densities. Underscoring the translational potential of connectomic approaches for the study of in vivo brain functions, CUD- linked aspects of brain function were spatially coupled to disorder relevant neurotransmitter systems. Key PointsO_ST_ABSQuestionC_ST_ABSAre there group differences in whole brain functional connectivity between individuals with and without cocaine use disorder, and to what extent do these connectivity patterns relate to the spatial distribution of dopamine (D2/3) receptor densities? FindingsThe presence of cocaine use disorder is associated with brain-wide functional connectivity alterations that are spatially coupled to the density of dopamine (D2/3) receptors. MeaningA preferential and replicable link exists between the functional connectome correlates of cocaine use disorder and dopamine receptor densities across the brain.