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 (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.

Conflict of interest statement

Wayne Drevets is an employee of Janssen Research & Development, LLC of Johnson & Johnson, and holds equity in Johnson & Johnson. The other authors declare that they have no conflict of interest.

Figures

Fig. 1

Schematic of the timing of data collection, data modelling, and participant behavior for our concurrent PET-MRI scanning paradigm

Fig. 2

Statistical map, and corresponding cluster table, showing regions of increased 11C-raclopride binding potential in the depressed relative to the control group

Fig. 3. Left ventral striatal binding potential-by-functional connectivity correlation map.

Regions showing statistically significant negative binding potential-by-functional connectivity correlations in the depressed group are shown in blue. These regions are superimposed on a map of the default-mode network (in green) as defined by Yeo and colleagues. For convenience, the left ventral striatal seed region is shown at left.

Fig. 4. Right dorsal striatal binding potential-by-functional connectivity correlation map.

Regions showing statistically significant negative binding potential-by-functional connectivity correlations in the depressed group are shown in blue. These regions are superimposed on a map of the task-positive network (salience and executive networks, in red) as defined by Yeo and colleagues. For convenience, the right dorsal striatal seed region is shown at left