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 (BPND), voxel-wise, and compared MDD and CTL samples with respect to BPND in the striatum. Using striatal regions that showed significant between-group BPND 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 BPND from these regions. We observed increased BPND in the ventral striatum, bilaterally, and in the right dorsal striatum in the depressed participants. Further, we found that as BPND 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.
Highlights
Researchers conducting neuroimaging-based investigations of major depressive disorder (MDD) have generated significant and useful brain-based conceptualizations of this illness
For the left ventral striatal region showing increased BPND in MDD, we found in the MDD group that as BPND increased, functional connectivity between this region and several nodes of the default-mode network decreased
Right dorsal striatum For the right dorsal striatal region in which we observed increased BPND in MDD, we found in the MDD group a negative relation between BPND in this region and functional connectivity with three nodes of the salience network
Summary
Researchers conducting neuroimaging-based investigations of major depressive disorder (MDD) have generated significant and useful brain-based conceptualizations of this illness. As the corpus of functional neuroimaging data from depressed samples has expanded, we have identified a variety of robust neural irregularities in MDD. Multi-center integrations of functional neuroimaging data from depressed samples have allowed for neuro-typing that predicts response to treatment in MDD2. In a meta-analysis of functional neuroimaging investigations of depression we identified a reliable failure of response of the striatum in MDD for both positively and negatively valenced stimuli[5]. Based on the valence-independent nature of this finding, in addition to observed decrements in the integration of reinforcement histories in MDD6, we proposed that there is a tonic deficit in dopaminergically-mediated neural transmission through the striatum in depression[5]. Four studies have found reduced dopamine activity[7,8,9,10], one found increased activity[11], and seven found no differences in dopamine activity between depressed an healthy samples[12,13,14,15,16,17]
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