Disrupted functional connectivity of the brain reward system in substance use problems: a meta-analysis of functional neuroimaging studies

ABSTRACTImportanceExtensive literature suggests that the brain reward system is crucial in understanding the neurobiology of substance use disorders. However, across studies on substance use problems, evidence of reliable disruptions in functional connectivity is limited.ObjectiveTo uncover deficient functional connectivity with the brain reward system that are reliably associated with substance use problems, by meta-analytically synthesizing results of functional brain connectivity studies on substance use problems.Data SourcesIdentification of relevant functional brain connectivity studies on substance misuse was done using PubMed, Google Scholar and EMBASE (until September 2021) with the following terms: cannabis, cocaine, substance, methamphetamine, amphetamine, alcohol, tobacco, nicotine, functional connectivity, resting-state, task-based connectivity, psychophysiological interaction.Study SelectionGuidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses were followed, Publications were included if they reported stereotactic coordinates of functional brain connectivity results on individuals with substance use problems without a comorbid major mental illness or organic impairment.Data Extraction and SynthesisSpatially convergent brain regions across functional connectivity studies on subjects with substance use problems were analyzed using Activation Likelihood Estimation meta-analysis.Altered connectivity with regions of the brain reward system was performed carried out through voxelwise seed-based meta-analyses. Subanalyses were performed to examine mediating factors such as severity of illness, connectivity modalities and types of substances.Main Outcomes and MeasuresIdentification of deficits in functional brain connectivity with the reward system across studies on substance use problems.ResultsNinety-six studies using a seed-based connectivity approach were included, representing 5757 subjects with substance use problems. In subjects with substance use problems, the ventromedial prefrontal cortex exhibited hyperconnectivity with the ventral striatum, and hypoconnectivity with the amygdala and hippocampus. Executive striatum showed hyperconnectivity with motor thalamus and dorsolateral prefrontal cortex, and hypoconnectivity with anterior cingulate cortex and anterior insula. Finally, the limbic striatum was found to be hyperconnected to the orbitofrontal cortex, and hypoconnected to the precuneus, compared to healthy subjects.Conclusions and RelevanceThe current study provided meta-analytical evidence of deficient functional connectivity between brain regions of the reward system and cortico-striato-thalamocortical loops in addiction, in line with current influential neurobiological models. These results are consistent with deficits in motivation and habit formation occurring in addiction, and they also highlight alterations in brain regions involved in socio-emotional processing and attention salience.KEY POINTSQuestionWhat functional brain connectivities with the brain reward system are reliably disrupted across studies on substance use problems?FindingsSubjects with substance use problems exhibited deficient connectivity between the ventromedial prefrontal cortex and subcortical structures including the ventral striatum, amygdala, and hippocampus. Executive striatum showed hyperconnectivity with motor thalamus and dorsolateral prefrontal cortex, and hypoconnectivity with anterior cingulate cortex and anterior insula. Altered connectivity between limbic striatum and core regions of the default mode network was also observed.MeaningDeficient functional brain connectivity along the cortico-striato-thalamocortical loops may reflect deficits in habit formation, socio-emotional and salience processing in addiction.