In vivo metabotropic glutamate receptor 5 availability-associated functional connectivity alterations in drug-naïve young adults with major depression

Abstract

There has been increasing interest in glutamatergic neurotransmission as a putative underlying mechanism of depressive disorders. We performed [¹¹C]ABP688 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in drug-naïve young adult patients with major depression to examine alterations in metabotropic glutamate receptor-5 (mGluR5) availability, and to investigate their functional significance relating to neural systems-level changes in major depression. Sixteen psychotropic drug-naïve patients with major depression without comorbidity (median age: 22.8 years) and fifteen matched healthy controls underwent [¹¹C]ABP688 PET imaging and 3-T MRI. For mGluR5 availability, we quantified [¹¹C]ABP688 binding potential (BP_ND) using the simplified reference tissue model. Seed-based functional connectivity analysis was performed using rs-fMRI data with regions derived from quantitative [¹¹C]ABP688 PET analysis as seeds. In region-of-interest (ROI)-based and voxel-based analyses, the [¹¹C]ABP688 BP_ND was significantly lower in patients than in controls in the prefrontal cortex ROI and in voxel clusters within the prefrontal, temporal, and parietal cortices, and supramarginal gyrus. The [¹¹C]ABP688 BP_ND seed-based functional connectivity analysis showed significantly less negative connectivity from the inferior parietal cortex seed to the fusiform gyrus and inferior occipital cortex in patients than in controls. The correlation patterns between [¹¹C]ABP688 BP_ND and functional connectivity strength (β) for the superior prefrontal cortex seed were opposite in the depression and control groups. In conclusion, using a novel approach combining [¹¹C]ABP688 PET and rs-fMRI analyses, our study provides a first evidence of lower mGluR5 availability and related functional connectivity alterations in drug-naïve young adults with major depression without comorbidity.

Keywords: Functional magnetic resonance imaging; Major depression; Metabotropic glutamate receptor-5; Positron emission tomography; [(11)C]ABP688.