Neurobiology of Alcohol and Nicotine Co-Addiction

Primary outcomes

1. Brain Activation During Functional Magnetic Resonance Imaging (fMRI) in Response to a Stress Modulated Cue Induced Craving Task (DSNBACK)

   Time frame: Baseline

   The DSN-back is a cognitive task used to assess working memory and attention. Participants view a sequence of letters presented on a screen, flanked by either drug-related or neutral images, and are instructed to identify matches occurring N steps earlier. Neural activation during high working memory demand condition (2-back) relative to the low working memory condition (0-back) was investigated. Inconsistent activation patterns across regions may indicate impaired neural processing in regions critical for cognitive control, emotion regulation, and reward processing, commonly reported in substance use disorders. Values closer to 0 (no change) in regions responsible for emotion regulation and cognitive control (e.g., Amygdala, ACC) may indicate reduced task-specific engagement where drug-related processes may be dominating neural activity.

2. Brain Activation During Resting State MRI.

   Time frame: Baseline

   This outcome measures resting-state functional connectivity (rsFC) of the striatum using seed-based analysis of resting-state fMRI data. FC values, expressed as Fisher z-transformed correlation coefficients, quantify the strength of synchronization between the striatum seed region and other brain areas. Positive values indicate synchronized activity, while negative values reflect anticorrelation. Altered rsFC of the striatum, a hub for reward processing, habit formation, and executive control, is linked to alcohol and nicotine use disorders and may indicate impaired regulation of cravings and heightened sensitivity to substance-related cues. Investigating rsFC patterns may identify biomarkers of addiction severity, predict treatment outcomes, and inform potential therapeutic targets.

3. Brain Cortical Thickness Assessed During MRI

   Time frame: Baseline

   This outcome measures cortical thickness (millimeters) across brain regions using structural MRI. Cortical thickness reflects the integrity of gray matter and is influenced by factors such as neurodegeneration, plasticity, and development. Reductions in cortical thickness, particularly in prefrontal and limbic regions, are associated with impaired cognitive control, emotion regulation, and decision-making in substance use disorders.

4. Brain White Matter Integrity as Assessed by Fractional Anisotropy During MRI

   Time frame: Baseline

   Fractional Anisotropy (FA) is a scalar metric derived from diffusion-weighted MRI that quantifies the degree of directional dependence (anisotropy) of water diffusion in brain white matter, with values ranging from 0 (isotropic diffusion) to 1 (maximally anisotropic diffusion). Increases in FA may reflect greater white matter organization and integrity, while decreases often indicate microstructural damage, demyelination, or axonal loss. FA measurements were averaged within predefined regions of interest (ROIs) to assess the integrity of white matter in various brain regions associated with cognitive, motor, and emotional processing. Decreased FA in tracts such as the corpus callosum or prefrontal pathways may reflect impaired communication between brain regions involved in reward processing and cognitive control in substance use disorders.