Neuro-Immune Biotypes of Depression: Towards Pathophysiology-Based Diagnosis and Personalized Treatment

The current study aims to conduct a high impact, advanced neuro-immune imaging project designed to integrate clinical, neuroimaging and immunological assessments in order to ultimately advance therapeutic discovery for a specific neuro-immune biotype of major depressive disorder (MDD). MDD accounts for more disability than any other disease worldwide, yet many patients continue to suffer symptoms as current drug discovery efforts are largely stalled due to lack of clearly defined novel drug targets. Critically, recent preclinical work points toward a key role for stress-sensitive integrity of the blood-brain barrier (BBB) in regulating the influence of peripheral immune mediators on brain circuit function leading to a pro-depressive phenotype. Building on this data, the proposed highly translational study will use advanced neuroimaging techniques to characterize the relationship between peripheral immune profiles, neural circuits, and integrity of the stress-sensitive BBB across MDD patients and healthy non-depressed volunteers. Our mechanistic model posits that depression arises in a subgroup of patients through up-regulation of peripheral immune factors and convergent breakdown of the BBB, possibly through a stress-dependent mechanism. The study Aims and hypotheses are as follows. Aim 1. To link peripheral immune profiles to symptom-specific neurocircuit perturbations in patients with a high-inflammatory biotype of MDD. In Aim 1, we will characterize the connectivity of the VTA-NAc circuit, and additional key circuits that regulate mood, across three study groups: (1) high-inflammatory MDD (n=20), (2) low-inflammatory MDD (n=20), and (3) non-depressed health control (HC) (n=20), and link these neurocircuit measures to specific profiles of circulating immune factors. Hypothesis 1. MDD patients in the high- inflammatory subgroup have abnormal hyper-connectivity within the reward neurocircuit, comprised of the ventral tegmental area (VTA), nucleus accumbens (NAc), and medial prefrontal cortex (mPFC), circuits that regulate anhedonia. Aim 2. To characterize the role of blood-brain barrier (BBB) integrity in patients with a high-inflammatory biotype of MDD. In Aim 2, we will characterize BBB integrity across the three study groups from Aim 1: (1) high-inflammatory MDD, (2) low-inflammatory MDD, and (3) HC, and test a mechanistic model whereby peripheral circulating immune factors influence the VTA-NAc and other circuits as a function of BBB integrity in order to cause symptoms of anhedonia and other symptoms of depression in a high-inflammatory MDD subtype of depression. Hypothesis 2.1. MDD patients in the high- inflammatory subgroup have reduced integrity of the BBB (i.e., greater leakiness), compared to low-inflammatory MDD and HC. Hypothesis 2.2. Reduced BBB integrity in MDD is associated with hyper-connectivity within the reward neurocircuit and anhedonia.