Striatal dopamine deficits predict reductions in striatal functional connectivity in major depression: a concurrent ¹¹C-raclopride positron emission tomography and functional magnetic resonance imaging investigation

Abstract

Major depressive disorder (MDD) is characterized by the altered integration of reward histories and reduced responding of the striatum. We have posited that this reduced striatal activation in MDD is due to tonically decreased stimulation of striatal dopamine synapses which results in decremented propagation of information along the cortico-striatal-pallido-thalamic (CSPT) spiral. In the present investigation, we tested predictions of this formulation by conducting concurrent functional magnetic resonance imaging (fMRI) and ¹¹C-raclopride positron emission tomography (PET) in depressed and control (CTL) participants. We scanned 16 depressed and 14 CTL participants with simultaneous fMRI and ¹¹C-raclopride PET. We estimated raclopride binding potential (BP _ND), voxel-wise, and compared MDD and CTL samples with respect to BP _ND in the striatum. Using striatal regions that showed significant between-group BP _ND differences as seeds, we conducted whole-brain functional connectivity analysis using the fMRI data and identified brain regions in each group in which connectivity with striatal seed regions scaled linearly with BP _ND from these regions. We observed increased BP _ND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BP _ND increased in both the left ventral striatum and right dorsal striatum in MDD, connectivity with the cortical targets of these regions (default-mode network and salience network, respectively) decreased. Deficits in stimulation of striatal dopamine receptors in MDD could account in part for the failure of transfer of information up the CSPT circuit in the pathophysiology of this disorder.