Brain lesions disrupting addiction map to a common human brain circuit

Substance use disorders (SUDs) affect a substantial portion of the adult population and represent a major public health crisis. Current treatments are insufficient, highlighting the urgent need for new therapeutic approaches. Neuromodulation techniques like deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and surgical lesioning have been explored, but optimal targets remain unclear. The Food and Drug Administration (FDA) recently approved a TMS device for smoking cessation targeting multiple brain regions, indicating the complexity of the issue. To improve neuromodulation therapies, a better understanding of the brain regions causally involved in addiction remission is crucial. A valuable source of information comes from cases where brain damage, such as stroke, leads to addiction remission, providing a causal link between neuroanatomy and therapeutic benefit. While lesions in various brain locations have been linked to addiction remission, their precise localization remains ambiguous. This study utilizes the human connectome to investigate whether lesions in different locations converge on a common neuroanatomical substrate associated with addiction remission.

Previous research has indicated the insula's involvement in addiction remission, particularly for nicotine addiction. However, lesions outside the insula have also been associated with remission, highlighting the need for a more comprehensive understanding of the underlying brain networks. Recent advancements allow researchers to link lesions in different brain locations to a common neuroanatomical substrate using the human connectome, a map of human brain connectivity. This approach has successfully identified effective therapeutic targets in other neurological conditions. This study applies this approach to lesions resulting in addiction remission to identify a common circuit.

Two independent cohorts of patients with acquired brain lesions and active daily nicotine smoking (cohort 1 n=67; cohort 2 n=62) were analyzed. Lesion locations were mapped onto a brain atlas. Lesion network mapping (LNM) was used to compute the brain network functionally connected to each lesion location using human connectome data (n=1000). Associations with addiction remission were identified using voxel-wise lesion-symptom mapping (VLSM) and LNM. Generalizability was assessed using an independent cohort (n=186) with focal brain damage and alcohol addiction risk scores. Specificity was assessed by comparing the results to 37 other neuropsychological variables. LNM analysis involved comparing connectivity patterns between lesion locations resulting in smoking addiction remission and those from non-quitters. Structural connectivity analysis examined damage to white matter tracts associated with addiction remission. The generalizability of the findings was assessed using an independent cohort of patients with lesions and alcohol addiction risk scores. The study also analyzed case reports of lesions affecting addiction to substances other than nicotine. Finally, the study identified brain voxels with connectivity profiles best matching the profile of lesion locations associated with addiction remission, suggesting potential neuromodulation targets. Statistical analyses included general linear models, permutation tests, and multivariate analysis of variance.

The study found that lesions causing addiction remission occurred in various locations but shared a specific connectivity pattern. This pattern involved positive connectivity to the dorsal cingulate, lateral prefrontal cortex, and insula, and negative connectivity to the medial prefrontal and temporal cortex. This circuit was consistent across independent cohorts and correlated with reduced alcohol addiction risk, demonstrating generalizability. The connectivity pattern was robust to various factors, such as lesion size, age, and the method of lesion identification. The study also found no significant differences in neuropsychological tests between patients who experienced remission and those who did not, suggesting that remission might be achieved through subtle behavioral changes across multiple domains. Analysis of structural connectivity revealed damage to white matter tracts, specifically fronto-insular tracts, was also associated with remission, further supporting the identified circuit. Lesions associated with lower alcoholism risk demonstrated similar connectivity to lesions that disrupted nicotine addiction. This network similarity was specific to addiction risk and did not extend to other neuropsychological variables. The analysis of case reports further corroborated the identified connectivity pattern. Hubs with connectivity profiles that best matched the remission profile included the left frontal opercular cortex, paracingulate gyrus, and medial fronto-polar cortex. These locations align with previously identified targets for addiction treatment, suggesting therapeutic relevance.

This study demonstrates that lesions leading to addiction remission, while geographically diverse, converge on a specific brain circuit, rather than a single brain region. This finding reconciles previous conflicting results. The identified circuit aligns with neuroimaging findings and existing circuit-based models of addiction, adding causal evidence to these models. The contrasting connectivity patterns observed, mirrored in the striatum and prefrontal cortex, support clinical and pre-clinical data suggesting an imbalance between brain networks underlies addiction vulnerability and relapse. The concordance between functional and structural connectome analyses provides complementary information, with functional connectivity potentially mapping to polysynaptic networks and structural connectivity to single white matter connections. The identification of specific brain regions best matching the connectivity profile for addiction remission provides testable targets for neuromodulation therapies. The findings align well with existing treatment targets and may refine them, suggesting potential clinical applications of the results.

This study identifies a common human brain circuit causally linked to addiction remission, regardless of lesion location. The consistency of this circuit across different addiction types and its alignment with promising neuromodulation targets offers valuable insights for developing effective addiction treatments. Future research should explore the identified hubs for therapeutic neuromodulation and investigate the potential side effects associated with these interventions. Furthermore, studies could focus on integrating functional and structural connectome data to better understand the complex interplay between brain networks in addiction.

The retrospective nature of the study and the reliance on previously collected data may limit the generalizability of the findings. The definition of addiction remission relied on self-reported data and might not capture the full spectrum of remission outcomes. Additionally, the study primarily focused on smoking cessation and alcoholism, and further research is needed to validate the findings across other types of substance use disorders. The use of group connectomes as approximations for individual connectivity introduces potential inaccuracies. The study does not explicitly address the temporal dynamics of circuit changes involved in addiction remission.