The Relationships of Peripheral Inflammation and Reward-Related Brain Function with Anhedonia, Somatic Symptoms and Functional Impairment in Adolescence

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PROJECT SUMMARY/ABSTRACT Major depression (MD) is a major source of disability affecting millions of people worldwide. Nevertheless, 30- 50% of the depressed population does not respond sufficiently to currently available treatments. Research suggests that the low treatment response rate may stem from elevated inflammatory signaling and abnormal reward processing that are not precisely targeted by currently available treatments. However, relationships of inflammation and abnormalities in reward function with a MD diagnosis are not detected consistently. Emerging research attributes the inconsistent findings to possible symptom-specific effects of inflammation and abnormalities in reward-related brain function. Indeed, inflammation and reward abnormalities have been linked with anhedonia, a cardinal feature of MD defined by decreased interest or pleasure in previously enjoyable activities, and with melancholic MD characterized by severe anhedonia, somatic symptoms, and functional impairment commonly modulated by reward function, whereas little evidence supports these abnormalities' association with cognitive symptoms (e.g., negative cognitions). This suggests a need to examine whether inflammation and reward abnormalities are relevant to only some MD symptoms. Further, inflammation may amplify the effect of reward dysfunction on these symptoms, given its role in altering reward-related dopaminergic tone and basal ganglion function. However, little work has tested these claims. Developmental stage also may contribute to inconsistent findings on the links of inflammation and reward function with MD. Adolescents may be particularly vulnerable, given the rapid changes in reward brain function and inflammatory phenotype. Thus, the proposed study seeks to test the hypotheses that elevated inflammation and low reward-related brain function, separately, and in interaction, are more strongly associated with anhedonia, somatic symptoms, and functional impairment than cognitive symptoms, during the vulnerable developmental stage of adolescence. The proposed study will recruit at least 192 14-16 year-olds varying in trait reward sensitivity who have enrolled in an assessment of peripheral inflammatory markers and reward-related neural activation and functional connectivity for my sponsor's NIMH-funded R01, prospective, longitudinal study of first-onset MD. A training plan has been designed that consists of formal coursework, workshops, experiential learning, and mentorship to develop the applicant's expertise in the pathophysiology of mood symptoms, psychoneuroimmunology, neuroimaging, and data analysis necessary to become an independent clinical neuroscientist. Utilizing the Research Domain Criteria perspective to examine inflammation, reward-related brain function, and individual MD symptoms, this study can yield greater insight into the role of inflammation and reward-related abnormalities in depressive psychopathology and clinical implications for interventions targeting inflammation and abnormal reward function. The proposed study will take place in Temple University's clinical psychology Ph.D. program, which has a successful track record of conducting impactful NIH-funded research and training clinical research scientists. 1