Adolescent major depressive disorder (MDD) is a major public health concern associated with significant morbidity and mortality. The identification of neurobiological correlates of adolescent MDD has been hampered by the disorder's heterogeneity. To address this challenge, the proposed project adapts a dimensional investigative approach focusing on anhedonia - the loss of pleasure - a core symptom of MDD. Anhedonia can be easily quantified and is tied to specific neural reward circuitry. Among adolescents with MDD, anhedonia is highly variable, with its full range of severity manifesting in this group. These characteristics make anhedonia an ideal candidate for such an approach. Converging data from our laboratory and others'suggest that peripheral activation of the immune system/inflammation and associated CNS alterations mediate anhedonia. We have studied the kynurenine pathway (KP), a central neuroimmunological pathway, which is activated by cytokines and degrades tryptophan into several neurotoxins (""""""""kynurenines""""""""). We reported increased peripheral activation of the KP and neurotoxic load in highly anhedonic MDD adolescents compared to non-anhedonic and healthy control (HC) adolescents. Further, to assess KP-associated CNS alterations, we used proton MR spectroscopy (1H MRS), a non-invasive imaging technique that measures brain metabolites reflecting different aspects of neural function. We documented associations between blood KP neurotoxins and striatal choline (membrane turnover marker) levels along with decreased anterior cingulate cortex (ACC) 3- aminobutyric acid (GABA) levels in anhedonic MDD adolescents, which were correlated with anhedonia scores in the whole MDD group. Based on these preliminary data, we propose to test the overall hypothesis that peripheral activation of the immune system and accompanying neurometabolic alterations are specifically linked to anhedonia severity. To test our hypothesis, 60 depressed adolescents (psychotropic-free) and 40 HC, ages 12-18, Tanner e 4, will be studied. Anhedonia will be measured quantitatively. Blood samples for cytokines, KP metabolites (including quinolinic acid and 3-hydroxykynurenine), kynurenine 3-monooxygenase enzyme activity (initiates the KP neurotoxic branch), and saliva samples for cortisol measures will be collected at AM after an overnight fast. Within an hour, concentrations of neurometabolites reflecting neuronal viability, GABA, and membrane turnover will be measured in the ACC and striatum, regions within the neural reward circuitry, via 1H MRS.
The current project proposes an integrated investigative strategy utilizing immunological and neurochemical imaging approaches to examine the neurobiology of anhedonia - the loss of pleasure - in depressed youth. Our focus on anhedonia as a continuous and quantitative symptom addresses the challenges of the current categorical classification schema of depression, which is based exclusively on a cluster of symptoms that often overlap with other disorders and represent distinct etiologies. This interdisciplinary approach is expected to provide novel insights into putative pathways associated with depression and anhedonia in adolescents and may provide novel targets for treatment strategies and prevention measures.
|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|
|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|
|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|
|Van Dam, Nicholas T; O'Connor, David; Marcelle, Enitan T et al. (2017) Data-Driven Phenotypic Categorization for Neurobiological Analyses: Beyond DSM-5 Labels. Biol Psychiatry 81:484-494|
|Ely, Benjamin A; Xu, Junqian; Goodman, Wayne K et al. (2016) Resting-state functional connectivity of the human habenula in healthy individuals: Associations with subclinical depression. Hum Brain Mapp 37:2369-84|
|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|
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