Striatal dopaminergic function and cortical functional connectivity in 22q11.2 deletion syndrome: an integrative multimodal 18F-DOPA PET and magnetic resonance imaging study.
Dopaminergic signalling is critical for regulating large-scale brain network dynamics and is implicated in the pathophysiology of psychotic disorders. 22q11.2 deletion syndrome (22q11DS), a high-penetrance genetic risk factor for schizophrenia, is associated with both dopaminergic alterations and disruptions in functional connectivity (FC), yet the degree to which these separate people with 22q11DS from healthy controls and their inter-relationship remains unclear. Eighteen individuals with 22q11DS (no history of psychosis or antipsychotic use) and 22 controls underwent [18F]-DOPA PET imaging to assess striatal dopamine synthesis (indexed by Kicer values) and resting-state fMRI to examine FC. Classification performance using FC, dopamine measures, and their combination was assessed via repeated 10-fold cross-validation. Associations between Kicer, connectivity, and psychotic symptoms were evaluated using linear regression. FC alone classified 22q11DS with 68% balanced accuracy (p = 0.004), Kicer alone with 77% (p < 0.001), and combined measures with 85% balanced accuracy (p < 0.001), indicating additive value. The somatomotor and auditory networks contributed most to group discrimination. Across individuals, higher Kicer was significantly associated with more control-like connectivity profiles (p = 0.011), with significant effects in all striatal subdivisions. No association was found between FC and subclinical psychotic symptoms. This multimodal study demonstrates a significant association between striatal dopamine synthesis capacity and functional brain network architecture in 22q11DS. Higher dopamine synthesis was linked to more normative FC, potentially suggesting FC differences reflect a compensatory, rather than pathogenic role. These findings bridge genetic risk at the 22q11.2 locus with dopamine dysfunction and large-scale networks, offering novel insights into the neurobiology of 22q11DS and related neuropsychiatric risk.