HMT + mediated visual motion perception deficits in treatment-resistant depression: a neuroimaging, genomic and neurochemical perspective

Background Visual motion perception (VMP) deficit in depression is mediated by the human middle temporal complex (hMT+). However, the reorganization of neuroactivity-perception in treatment-resistant depression (TRD) and the underlying molecular basis remain unclear. Therefore, this study aimed to investigate VMP-related pathophysiological mechanism in TRD. Method Cohort 1 consisted of 72 TRD, 157 non-treatment-resistant depression (nTRD) and 85 healthy controls (HCs), while the cohort 2 was involved in 30 TRD, 30 nTRD and 30 HCs. Amplitude of low-frequency fluctuations (ALFF) and functional connectivity (FC) with left hMT+ as seed was calculated for all participants. Using psychophysical task to test VMP in the cohort 2 and comparing the differences among groups in the fMRI measures. Their associations with genetic and neurotransmitter profiles were analysed by receptor/transporter density map and Allen Human Brain Atlas (AHBA). Results In the cohort 1, the left hMT+ of TRD exhibited decreased ALFF and its FC between the left inferior parietal lobule, right inferior temporal gyrus and middle frontal gyrus, but increased FC in the right fusiform gyrus. The ALFF of the left hMT+ were negatively correlated with cognitive impairment. Cohort 2 replicated and extended partial results from the cohort 1, underscoring the VMP-related ALFF abnormality of the left hMT+ in the TRD group. Moreover, the alterations of ALFF in left hMT+ was correlated with 10 neurotransmitters and expression map of specific genes which were enriched in synaptic structure and function. Conclusion Deficits in VMP and cognitive processing of TRD are associated with hypoactivity in hMT+, accompanied by altered inter-regional connectivity. These alterations are linked to molecular and genetic factors, including the 5-HT1b receptor and PDCL3, implicating synaptic dysfunction as a potential pathophysiological basis. HMT+ is a promising neuroimaging biomarker for TRD and a novel therapeutic target for ameliorating the sensory and cognitive impairments.