Elucidating Reward Network Modulation in Medial Forebrain Bundle Deep Brain Stimulation for Treatment Resistant Depression

Project Summary Treatment resistant depression (TRD), representing up to 30% of major depression diagnoses, is an incapacitating disability affecting millions worldwide. Limited improvement with non-invasive treatments has led to the use of deep brain stimulation (DBS) as it directly engages critical networks. Unfortunately, progress with DBS for depression has been limited seen in the failure of two clinical trials due to a lack of understanding its mechanism of action. This results from an incomplete knowledge of the network effects of chronic stimulation for depression. Overcoming this barrier necessitates understanding how changes in metabolism and functional connectivity (FC) of key mediators correlates with observed behavioral change. Within the affective network, the ventral tegmental area (VTA) is a critical integrator of both emotional and behavioral reward processing, which is dysfunctional in major depression and anhedonia (inability to experience reward/pleasure). Although direct modulation of the VTA is difficult, the supero-lateral medial forebrain bundle (MFB) is a key white matter bundle demonstrated to structurally connect the VTA through to the prefrontal/orbitofrontal cortex (PFC/OFC). For over 10 years, we have actively pursued a clinical trial on DBS to the MFB, demonstrating a rapid and significant improvement in anhedonia and depressive symptoms with 80% response rate at 5 years. Lack of uniform improvement to MFB DBS in depression, however, must be corrected and points to an incomplete understanding of network response to modulation. It is imperative that we use the results from brain imaging at a therapeutic stimulation threshold to evaluate the mechanism of reward network modulation that underlies an improvement in anhedonia. If such an imaging biomarker is identified, then it can be used to guide successful programming. If anhedonic TRD patients undergo MFB DBS and a threshold of therapeutic stimulation consistently produces key imaging findings correlated with improvement in reward processing, then this would demonstrate an objective biomarker of reward network engagement. The overall objective is to identify metabolic and functional imaging changes in the reward network secondary to therapeutic MFB DBS, which may be biomarkers of reward network modulation correlated with reversal of anhedonia. Our central hypothesis is that FC of the ventral PFC/OFC, caudate, and dorsal anterior cingulate ‘network’ is modulated by MFB DBS in an amplitude-dependent fashion. In Aim 1, we seek to characterize the temporality of reward network changes induced by MFB DBS using imaging collected at multiple time points pre-/post-surgery during stepwise amplitude titration. In Aim 2, we seek to confirm that induced reward network imaging changes are reversible during MFB DBS discontinuation and correlate with change in reward processing behavior. The proposed aims will confirm reward network modulation by MFB DBS, and by acquiring serial imaging during stepwise amplitude increments until a stimulation threshold is identified to incur a reversal of anhedonia, identify objective imaging biomarkers that can predict MFB DBS-induced reward network modulation and guide successful programming.