Depression and metabolic disorder (MetD) are two of the most common and debilitating disorders worldwide, occurring with significant rates of comorbidity. This is a major clinical challenge as the outcomes of both conditions are worsened. Studies have uncovered that depression and metabolic disorder are associated with chronic, low-grade inflammation. In brain circuit level, patients with depression are characterized with aberrant frontostriatal (FS) circuit connectivity and reduced activity level that also associated with metabolic comorbidity. BD patients also showed functional anomalies in the VS and FS circuits with reduced neural flexibility of hedonic signaling in response to stress. The dysfunctional FS circuits also link to the metabolic comorbidities in patients with mood disorders. Regarding metabolic control, the FS functional connectivity changes affect food craving. And the altered reciprocal loop from the medial prefrontal cortex could regulate eating behavior and metabolic disturbance. In neurotransmitter level, the dopaminergic pathway, that could be feedback regulated by immune and metabolic factors, has long been known to involve in emotional and metabolic homeostasis. More importantly, this dopamine (DA) input is critical to shaping the FS circuit-level dynamic connectivity and plasticity. Disruptions in the dopamine (DA) system have been observed in psychiatric disorders. MDD might involve DA reductions that could result from either diminished DA release from presynaptic neurons or impaired signal transduction, either due to changes in receptor number or function and/or altered intracellular signal processing. Therefore this study hypothesizes that inflammatory and metabolic dysregulations on DA transmission link to the aberrant FS function that cause depression and MetD. To clarify the underlying mechanisms, unipolar and bipolar depression patients will be enrolled to measure the FS functional connectivity and activation, before and after receiving 10 Hz repetitive transcranial magnetic stimulation (rTMS) to left dorsolateral prefrontal cortex. Then systemically analyze participants' clinical symptomology, neurocognitive function, inflammation and metabolic status. Possible correlations between indices, the effects of rTMS and the possible differences between unipolar and bipolar depression patients will be tested. Results could provide a chance for further understanding the pathophysiology and better treatment of depression with MetD, finding biomarkers for subgrouping depression between unipolar depression and bipolar depression, predicting outcomes to brain circuit based personalized rTMS treatment for depression with MetD.
The specific aims of the project are:
Aim 1: To find the biological homogeneousness among depression with MetD by investigate the associations between (1) FS circuit connectivity and clinical (mood and metabolic) symptoms, and (2) FS circuit activation and clinical (mood and metabolic) symptoms in both unipolar and bipolar depressed individuals.
Aim 2: To confirm the role of FS in depression with MetD by applying rTMS to test its effects on (1) clinical symptoms, (2) FS circuit activation, (3) FS circuit connectivity and (4) find predictors for the rTMS treatment response.
Aim 3: To study the bidirectional inflammatory and metabolic feedback regulations of the DA transmission in FS circuit in depression with MetD by investigate the associations between (1) FS circuit activation, and (2) FS circuit connectivity and systemic inflammatory/ metabolic regulators both before and after rTMS treatments.
