Gambling disorder (GD) is characterized by a persistent and repetitive pattern of problematic gambling behavior that results in clinically significant emotional distress or impairment. The prevalence of this disorder is 1.6 - 1.9% of the adult population worldwide. GD is the only disorder recognized as a behavioral addiction in the current diagnostic manuals because of its clinical and neurobiological similarities to substance use disorders (SUDs).

The aim of this thesis was to study the neurobiology of GD, focusing on the fronto-striatal-thalamic circuit, due to its pivotal role in SUDs. Two independent datasets of individuals with GD and healthy controls (HC) were studied: 1) 15 individuals with GD (mean age: 43) and 17 sex- and age-matched HC, with an imaging protocol including structural MRI (gray and white matter measurements), functional MRI (task and resting-state) and PET imaging (with tracers reflecting brain dopamine, opioid, and serotonin function); 2) 20 older adults (mean age: 64) with GD and 40 sex- and age-matched HC. Structural MRI (gray and white matter measurements) from the second dataset was studied in this thesis.

In the first dataset, resting-state fMRI connectivity analysis showed that normal negative connectivity between the right nucleus accumbens and the right dorsolateral prefrontal cortex was lost in the GD group. This abnormal functional connectivity was associated with serotonin, but not with dopamine or opioid function. Task-based fMRI analysis showed an increased BOLD response in the dorsal striatum during gambling compared to neutral cues in individuals with GD compared to HC. The BOLD response in the dorsal striatum was associated with opioid, but not with serotonin or dopamine, function. In the second dataset, individuals with GD showed significantly lower gray matter thickness in the left orbitofrontal cortex and volume in the left thalamus compared to HC. In addition, the brain white matter analyses demonstrated a lower fractional anisotropy and an increased number of white matter lesions in the left anterior corona radiata in GD compared to HC.

The results of this study indicate that GD is associated with converging structural and functional brain abnormalities in the fronto-striatal-thalamic circuit. These findings provide novel information about the neurobiology of GD that can help in the development of new treatment options.