Microstructural Impairments in a Topologically Distinct Prefrontal-Habenular Connection in Cocaine Addiction

Drug addiction is characterized by neuroadaptations in mesocorticolimbic networks regulating reward and inhibitory control. The habenula (Hb) is central to adaptive reward and aversion-driven behaviors, serving as a hub connecting emotion/cognitive processing regions including the prefrontal cortex (PFC). However, its role in human drug addiction has not been fully explored. Using diffusion tractography, we detailed PFC structural connectivity with three regions, namely the Hb, ventral tegmental area (VTA), and anterior thalamus (AT), and quantified the tract-specific microstructural integrity using diffusion tensor imaging within the anterior limb of the internal capsule (ALIC) in healthy and cocaine-addicted individuals. White matter microstructure in cocaine-addicted individuals was uniquely impaired in PFC-Hb projections in the ALIC, distinguishable from adjacent PFC-VTA and PFC-AT projections, with more pronounced abnormalities in short-term abstinence. These findings extend preclinical evidence of PFC-Hb circuit impairments in addiction and contextualize the plausible existence of a similar PFC-Hb connection in the human brain.