No abstract

The anterior insular cortex (AIC) and its interconnected brain regions have been associated with both addiction and decision-making under uncertainty. However, the causal interactions in this uncertainty-encoding neurocircuitry and how these neural dynamics impact relapse remain elusive. Here, we used model-based fMRI to measure choice uncertainty in a motor decision task in 61 individuals with cocaine use disorder (CUD) and 25 healthy controls. CUD participants were assessed before discharge from a residential treatment program and followed for up to 24 weeks. We found that choice uncertainty was tracked by the AIC, dorsal anterior cingulate cortex (dACC) and ventral striatum (VS), across participants. Stronger activations in these regions measured pre-discharge predicted longer abstinence after discharge in individuals with CUD. Dynamic causal modeling revealed an AIC-to-dACC-directed connectivity modulated by uncertainty in controls, but a dACC-to-AIC connectivity in CUD participants. This reversal was mostly driven by early relapsers (<30 days). Furthermore, CUD individuals who displayed a stronger AIC-to-dACC excitatory connection during uncertainty encoding remained abstinent for longer periods. These findings reveal a critical role of an AIC-driven, uncertainty-encoding neurocircuitry in protecting against relapse and promoting abstinence.

36The anterior insular cortex (AIC) and its interconnected brain regions have been associated with 37 both addiction and decision-making under uncertainty. However, the causal interactions in this 38 uncertainty-encoding neurocircuitry and how these neural dynamics impact relapse remain 39 elusive. Here, we used model-based fMRI to measure choice uncertainty in a motor decision task 40 in 61 individuals with cocaine use disorder (CUD) and 25 healthy controls. CUD participants 41 were assessed before discharge from a residential treatment program and followed for up to 24 42 weeks. We found that choice uncertainty was tracked by the AIC, dorsal anterior cingulate cortex 43 (dACC), and ventral striatum (VS), across participants. Stronger activations in these regions 44 measured pre-discharge predicted longer abstinence after discharge in individuals with CUD. 45Dynamic causal modelling revealed an AIC-to-dACC directed connectivity modulated by 46 uncertainty in controls, but a dACC-to-AIC connectivity in CUD participants. This reversal was 47

The basal ganglia are a group of interconnected subcortical nuclei that plays a key role in multiple motor and cognitive processes, in a close interplay with several cortical regions. Two conflicting theories postulate that the basal ganglia pathways can either foster or suppress the cortico–striatal output or, alternatively, they can stabilize or destabilize the cortico–striatal circuit dynamics. These different approaches significantly impact the understanding of observable behaviours and cognitive processes in healthy, as well as clinical populations. We investigated the predictions of these models in healthy participants (N = 28), using dynamic causal modeling of fMRI BOLD activity to estimate time‐ and context‐dependent changes in the indirect pathway effective connectivity, in association with repetitions or changes of choice selections. We used two multi‐option tasks that required the participants to adapt to uncontrollable environmental changes, by performing sequential choice selections, with and without value‐based feedbacks. We found that, irrespective of the task, the trials that were characterized by changes in choice selections (switch trials) were associated with a neural response that mostly overlapped with a network commonly described for the encoding of uncertainty. More interestingly, dynamic causal modeling and family‐wise model comparison identified with high likelihood a directed causal relation from the external to the internal part of the globus pallidus (i.e., the short indirect pathway in the basal ganglia), in association with the switch trials. This finding supports the hypothesis that the short indirect pathway in the basal ganglia drives instability in the network dynamics, resulting in changes in choice selection.