James W. Murrough - US grants

DESCRIPTION (provided by applicant): The long-term objective of this Patient-Oriented Mentored Career Development Award (K23) is to support the career development of the candidate in functional neuroimaging and experimental therapeutics in mood disorders. This will be accomplished through a structured supervised research experience and formal instruction that will focus on the training areas of (1) Clinical Research Methodology, Biostatistics and Ethics; (2) Functional Neuroimaging Methodology; and (3) Affective and Cognitive Neuroscience. The specific objective of the proposed research strategy is to characterize the function of emotion-processing neural networks in vivo in patients with treatment-resistant depression (TRD), and to identify functional changes in these networks that are specific to rapid antidepressant response. Conventional antidepressant treatments are slow to result in therapeutic benefit, and 20-30% of patients with major depression fail to achieve an adequate therapeutic response (i.e., experience TRD). Recent findings of rapid and robust antidepressant effects of the anesthetic agent ketamine, a N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, present a unique opportunity to test hypotheses regarding the mechanisms of rapid-acting therapeutic action. The proposed research will utilize advanced cognitive neuroscience techniques and functional magnetic resonance imaging (fMRI) to investigate the specific functional contributions of key neural systems supporting emotion generation/regulation, including the prefrontal cortex (PFC), anterior cingulate cortex (ACC) and associated subcortical structures, in TRD and rapid antidepressant response to ketamine. TRD subjects will undergo fMRI at baseline (in the depressed state) and then again 24 hours following a single IV infusion of ketamine or a control treatment. The fMRI strategy will utilize both a well-validated probe of negative emotion bias (sad facial expressions), and a probe of emotion regulation (cognitive reappraisal), which specifically recruits PFC/ACC structures implicated in mechanisms of antidepressant action. This research will test specific hypotheses regarding the role of emotion generation (e.g. subcortical) and regulation (e.g. PFC/ACC) neural systems in the depressed state in patients with TRD, and changes in the function of these systems associated with changes in depressive symptoms resulting from ketamine. The skills and data acquired and research methods developed during the K23 award period will provide the candidate with the tools required to achieve the long- term goal of becoming an independent investigator in clinical neuroscience research in mood disorders.

Depression is among the most disabling human illnesses worldwide, and current treatments fall short of what is required to meet this large public health need. Anhedonia ? the markedly diminished response to pleasure ? is a core feature of depression and is linked to impaired psychosocial functioning, poor treatment outcome, suicidal behavior and often persists despite treatment with a serotonin selective reuptake inhibitor. Increased signaling of pro-inflammatory cytokines, including interleukin 6 (IL-6), lead to anhedonic behavior in animals, patients with depression are characterized by elevated levels of IL-6 and other cytokines, and administration of pro-inflammatory cytokines triggers depressive symptoms and changes in brain responses to reward in human subjects. Despite these data, there is significant heterogeneity in the literature and it is now clear that there is not a one-to-one mapping of pro-inflammatory cytokines to depressive symptoms. The current proposal seeks to go beyond linking inflammation to depressive phenotypes by testing the relationships between peripheral inflammatory factors and neural and behavioral responses to reward and social stimuli in patients with anhedonia across a range of depressive disorders. The proposal leverages state-of-the-art immunological techniques to examine inflammatory response profiles of leukocytes harvested from patients and stimulated ex vivo. Our goal is to characterize meaningful immune-brain-behavior profiles underlying the phenotype of anhedonia in humans in order to promote novel diagnostic and treatment development efforts. We will confirm and expand on our previous published finding of elevated basal levels of IL-6 in patients with major depressive disorder (MDD) by examining IL-6 augmented with a board panel of cytokines in patients enriched for anhedonia across a spectrum of depression in both un-stimulated (basal) and stimulated conditions (Aim 1). Building on the peripheral immune profiles developed in Aim 1, we will use quantitative computer-based assessments of reward learning [probabilistic reward task (PRT)] and functional magnetic resonance imaging (fMRI) with monetary incentive [incentive flanker task (IFT)] and positive social emotion [positive faces task (PFT) 10] tasks to develop immune-brain-behavior multimodal profiles of anhedonia (Aim 2). Supporting these aims, our pilot work show that (a) high IL-6 is linked to poor reward learning, (b) high IL-6 is linked to reduced response to positive emotion within the rostral anterior cingluate cortex (rACC), and (c) high IL-6 is linked to reduced response to monetary incentives (reward outcome) within the ventromedial prefrontal cortex (vmPFC). Our project has the potential to have a major public health impact by developing multimodal immune-brain- behavior profiles in order to advance novel diagnostic and treatment development.

This 5-year R61/R33 phased-innovation award, ?Developing KCNQ Channel Modulators for Mood Disorders,? is designed to efficiently examine the neuronal KCNQ2/3 potassium (K+) channel subtype as a novel treatment target for depression and related conditions. Depressive disorders are among the most disabling medical conditions worldwide and currently available treatments fall short of addressing this large public health burden. Dysfunction within the brain reward system is emerging as a core feature of depressive disorders, in particular giving rise to deficits in motivation, interest, and response to pleasure (e.g., anhedonia). The proposed R61/R33 project capitalizes on a series of preclinical studies from our group that highlight the KCNQ subtype of neuronal potassium (K+) channel as a novel target for the treatment of depressive disorders. In model systems, up-regulation of KCNQ channels normalizes pathological functioning within the brain reward circuit, reversing an anhedonic phenotype. Building on these data, the current project will assess reward circuit activity following treatment with the KCNQ-selective channel opener ezogabine in depressed patients with anhedonia [Aim 1], and will examine the relationship between change in reward circuit activity and clinically relevant symptom and behavior outcomes [Aim 2]. Our project capitalizes on recent advances in conceptualizing and measuring reward-processing alterations across species, and utilizes the Research Domain Criteria (RDoC) domain of Positive Valence Systems (PVS) as a unifying framework. In particular, our animal and human work indicate that enhancing KCNQ channel function within the reward circuit normalizes behavioral processes that map to the PVS constructs of approach motivation (reward expectancy) and initial responsiveness to reward. The project takes advantage of (1) availability of ezogabine (Potiga, GlaxoSmithKline) for human use as a unique first-in-class KCNQ channel opener [FDA-approved for the treatment of seizure disorders], and (2) availability of reliable methods for measuring reward processing at the level of neural, behavioral, and clinical levels in humans. The proposed studies have significant potential to advance treatment discovery for depression within an RDoC framework.

Anxiety and stress-related disorders, including panic disorder (PD), generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD), are among the most disabling neuropsychiatric conditions in the United States. A core feature of these disorders is pathological anxiety (i.e., maladaptive arousal and fear). Animal models point strongly towards shared mechanisms underlying pathological anxiety to involve the locus coeruleus (LC), the primary source of norepinephrine in the CNS, and modulator of the regulation of arousal and response to threat. However, the specific role of the LC in human pathological anxiety is not known, due in part to past technical limitations of non-invasive imaging for small nuclei such as the LC. Thus, despite the prevailing hypothesis of the role of the LC, the pathophysiology of anxiety disorders remains largely undiscovered. This gap impedes translational research aimed at developing more biologically based models of human anxiety and stress-related disorders, precluding precision medicine for these disorders. In order to address this gap, we propose to the first transdiagnostic in vivo study of LC in anxiety, leveraging cutting-edge 7 Tesla (7 T) MRI in patients with PD, PTSD, GAD. Our central hypothesis is that LC dysregulation underlies shared dimensions of psychopathology across neuropsychiatric disorders that are characterized by pathological anxiety. Here we develop and apply MRI innovations for 7 T structural, connectomic, and functional characterization of the LC in terms of drivers of pathological anxiety across diagnostic boundaries. Our 7 T MRI approach affords on the order of three-fold higher resolution and sensitivity over 3 T MRI for multi- modal imaging the LC in patient populations. Our preliminary 7 T MRI data demonstrate the neuroanatomical and functional architecture of LC and connected cortico-subcortical circuitry robustly characterized in both patients and controls. Using quantitative magnetization transfer (MT) imaging and neurite orientation dispersion density imaging (NODDI), our proposal will allow for the precise localization, quantification and microstructural characterization of the LC in humans. Building on our pilot data, Aim 1 will establish the role of LC microstructure in pathological anxiety. Aim 2 will establish the relationship between LC functional and anatomical connectivity and pathological anxiety. Aim 3 will establish the role of LC in functional response to threat in pathological anxiety. In each case, co-variance between imaging measures of the LC and dimensional measures of anxiety will be examined trans-diagnostically across four study groups [PTSD (n=30), PD (n=30), GAD (n=30), healthy controls (N=30)] in a cross-sectional design. Secondarily, between-group differences will be examined. Finally, in Aim 4, we will use a data-driven approach to explore how specific measures of LC microstructure, connectivity, and function relate to specific dimensional clinical features across diagnoses.

Project Summary/Abstract Stress is a leading risk factor for a multitude of the most prevalent mental health illnesses worldwide, including major depressive disorder (MDD). Current treatments fall short of what is required to meet the ever increasing disease burden and opportunity cost. In addition, current treatment paradigms fail to alleviate underlying pathophysiologies and a significant percentage of patients become refractory to treatment. The purpose of Research Project 2 is to investigate whether a well-characterized polyphenol enrich botanical supplement can provide an alternative approach to suppress the pathological effects of stress that increase an individual's susceptibility to developing certain psychiatric disorders. Emerging evidence has demonstrated that susceptibility to stress is a function of both central and peripheral immune activity. In particular, select inflammatory mediators, such as interleukin (IL)-6, have recently been recognized as key mechanistic contributory factors of stress-induced anxiety and depression. Supporting this principle are clinical observations that show that a subset of patients with treatment-resistant depression exhibit increased expression of IL-6 in the plasma. We show in a model system of stress-induced depression that specific bioavailable metabolites of our botanical supplement suppress stress-induced production of IL-6 from leukocytes and, further, provide resilience to stress-induced psychological impairment. Therefore, the first objective of Research Project 2 will be to thoroughly the pharmacokinetic and steady state properties of our botanical supplement to confirm that the bioactive compounds that were found to modulate IL-6 expression in rodents are also bioavailable and reach a bioactive concentration in humans. We will conduct a double blind, randomized, placebo-controlled (untreated control), dose ranging study in healthy volunteers using a low dose, intermediate dose, and high dose of BDPP, based upon our work with animals and from the scientific literature. Project 2 then investigate the association between metabolites of our botanical supplement and the expression of inflammatory cytokines in healthy subjects. Our proposed experiments will then characterize whether BDPP metabolites prevent upregulation of IL-6 in response to the Trier Social Stress Test: a well-validated model of psychological stress. Moreover, by integrating a multivariate adaptive regression splines (MARS) statistical method we can determine which metabolite, or combination of metabolites, may be responsible for suppressing IL-6 in a clinical setting in response to stress. Objectives from Research Project 2 will inform a future clinical trial by providing guidance on the optimal product dose, treatment timing, outcome markers of bioavailability; will verify metabolites that suppress IL-6 expression are present at bioactive concentrations in plasma, and establish whether anti-inflammatory properties of BDPP observed in model systems of stress- induced depression can be recapitulated in a clinical model of stress.

Summary Abstract The studies proposed in this U19 application titled ?The Influence of Dietary Botanical Supplements on Biological and Behavioral Resilience? represent a cohesive program of integrated and interdisciplinary research approaches that comprehensively address the objectives and purpose of RFA-OD-19-001. In particular, the principal objective of this botanical dietary supplement research center (BDSRC) is to provide valuable insight, through both pre-clinical and clinical lines of investigation that may inform a future clinical trial designed to determine if dietary polyphenol supplements can provide resilience against stress-induced psychological impairment. We have shown through rigorous feasibility studies utilizing stress-induced models of depression that supplementation with BDPP promotes resilience to depression-like behaviors. We have identified biomolecular systems associated with immune function and neuronal activity that specific bioavailable metabolites of BDPP influence to promote resilience to stress. We note that bioavailable metabolites suppressed production of peripheral leukocytes derived inflammatory cytokines, in particular IL-6, which is important to consider given studies that find production of IL-6 is a critical response that confers susceptibility to stress. Whether or not metabolites of BDPP suppress the downstream pathophysiological effects of stress-induced IL-6 that directly affect neuron function and behavior has yet to be established. Therefore, Project 1 of this BDSRC will characterize if our botanical supplement provides resilience against physiological pathways elicited by stress that are associated with increased IL-6 activity and that confer susceptibility to the onset of depressive-like behavior. Project 1 will also identify biological targets in microglia, interneurons, and blood brain barrier cells influenced by BDPP metabolites by state-of-the-art cell-specific RNA-sequencing and imaging techniques. Project 2 will directly synergize with Project 1 by first providing an assessment of the clinical properties of BDPP, and whether they parallel those observed in rodents. We will conduct a pharmacokinetic and steady-state profile to define bioavailable metabolites found in human plasma, and to confirm the presence of metabolites that exert biological effects against IL-6 production. Project 2 will also utilize a multivariate adaptive regression splines model to identify specific metabolites or combinations of BDPP metabolites responsible for modulating IL-6 expression. In addition, Project 2 will validate plasma IL-6 as a marker of biological resilience in response to BDPP treatment by testing if BDPP promotes resilience against upregulation of plasma IL-6 in response to the Trier Social Stress Test in humans. The proposed Projects are designed and optimized to synergize with each other, and to integrate seamlessly with the two Scientific Cores. Together, this proposal offers to provide critical information of the mechanism of action and the clinical properties of BDPP and its metabolites that ?ll the most critical gaps in the existing body of data needed to optimally design a future clinical trial to test resilient properties of BDPP in response to stress.