Adolescence is a critical developmental period during which many psychiatric symptoms first emerge. It has been argued that common alterations within the reward circuitry underlie the development of adolescent-onset psychiatric conditions. Addressing a critical need for the identification of biomarkers early in the course of psychopathologies, this RDoC project examines the neuroimmunology of specific reward processes in adolescents. Specifically, we focus on the clinical phenomenology of anhedonia, a salient feature across psychiatric conditions that often presents as a prodromal psychiatric symptom. However, anhedonia represents a final clinical outcome of several distinct PVS deficits. Therefore, this project examines Reward Expectancy (RE) versus Initial Responsiveness to Reward Attainment (IRRA), reflecting reward anticipation and receipt. This research investigates a novel theory hypothesizing that peripheral inflammation and associated striatal metabolic changes induce specific alterations in the reward circuitry that clinically manifest as anhedonia. We have studied the neuroimmunology and neuronal circuitry of anhedonia and found positive associations between peripheral activity of the kynurenine pathway (KP)-a central neuroimmunological pathway-and anhedonia severity in adolescents. Using MR spectroscopy (1H MRS), we documented associations between blood KP neurotoxins and striatal choline (biomarker for lipid peroxidation) in anhedonic adolescents along with inverse relationships between brain glutathione (antioxidant) and anhedonia severity in adults. Using fMRI, we mapped and identified distinct striatal-based intrinsic functional connectivity (iFC) associated with anhedonia. Additionally, we developed the reward flanker task (RFT) that distinguishes between RE and IRRA. Building upon these compelling preliminary data, we propose a multimodal study to examine the neuroimmunology of specific PVS deficits. We will study 100 psychotropic-free adolescents with diverse psychiatric symptomology (NOS, or full syndromes) and 30 healthy controls group-matched, ages 12-18, Tanner e 4. The study will consist of comprehensive, systematic diagnostic procedures that include dimensional assessments of anhedonia, negative affect, fatigue, and sleep. Peripheral inflammatory measures will include KP activity along with activation status of innate and adaptive immune compartments and responses to both psychological and biological stresses. HPA axis will be indexed by saliva cortisol levels. CNS inflammation will be probed by 1H MRS by measuring chemicals reflecting oxidative stress, lipid peroxidation and mitochondrial function in the striatum, a key region within the reward circuitry. Specific reward processes will be studied using the RFT and striatal based iFC.

Public Health Relevance

This Research Domain Criteria project utilizes an integrated, investigative strategy that combines immunological and molecular approaches with neurochemical and functional imagining techniques to test an innovative theory implicating inflammation in specific PVS deficits. It focuses on anhedonia and reward circuitry disturbances across adolescent psychiatric conditions to examine a critical developmental period during which psychopathology often emerges. This interdisciplinary approach is expected to provide new insights into putative pathways associated with specific PVS deficits early on, and subsequently may provide novel targets for treatment strategies and prevention measures.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZMH1)
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Garvey, Marjorie A
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Icahn School of Medicine at Mount Sinai
Schools of Medicine
New York
United States
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Bradley, Kailyn A; Alonso, Carmen M; Mehra, Lushna M et al. (2018) Elevated striatal ?-aminobutyric acid in youth with major depressive disorder. Prog Neuropsychopharmacol Biol Psychiatry 86:203-210
DeWitt, Samuel J; Bradley, Kailyn A; Lin, Na et al. (2018) A pilot resting-state functional connectivity study of the kynurenine pathway in adolescents with depression and healthy controls. J Affect Disord 227:752-758
Freed, Rachel D; Mehra, Lushna M; Laor, Daniel et al. (2018) Anhedonia as a clinical correlate of inflammation in adolescents across psychiatric conditions. World J Biol Psychiatry :1-11
Gabbay, V; Bradley, K A; Mao, X et al. (2017) Anterior cingulate cortex ?-aminobutyric acid deficits in youth with depression. Transl Psychiatry 7:e1216
Freed, Rachel D; Hollenhorst, Cecilia N; Weiduschat, Nora et al. (2017) A pilot study of cortical glutathione in youth with depression. Psychiatry Res Neuroimaging 270:54-60
Bradley, Kailyn A L; Case, Julia A C; Freed, Rachel D et al. (2017) Neural correlates of RDoC reward constructs in adolescents with diverse psychiatric symptoms: A Reward Flanker Task pilot study. J Affect Disord 216:36-45
Bradley, K A L; Mao, X; Case, J A C et al. (2016) Increased ventricular cerebrospinal fluid lactate in depressed adolescents. Eur Psychiatry 32:1-8
Bradley, Kailyn A L; Colcombe, Stan; Henderson, Sarah E et al. (2016) Neural correlates of self-perceptions in adolescents with major depressive disorder. Dev Cogn Neurosci 19:87-97
Yaseen, Zimri S; Galynker, Igor I; Briggs, Jessica et al. (2016) Functional domains as correlates of suicidality among psychiatric inpatients. J Affect Disord 203:77-83
Parvaz, Muhammad A; Gabbay, Vilma; Malaker, Pias et al. (2016) Objective and specific tracking of anhedonia via event-related potentials in individuals with cocaine use disorders. Drug Alcohol Depend 164:158-165

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