Motivational anhedonia?a subset of anhedonic symptoms involving dopamine-linked impairments in effort- based decision-making, reward anticipation and reinforcement learning?are common in psychiatric disorders such as major depression, and are notoriously difficult to treat. In recent years, these symptoms have been associated with alterations in dopaminergic corticostriatal circuitry, yet the underlying causes of this circuit dysfunction remain unknown. One candidate mechanism is inflammation; increased inflammatory cytokines have been reliably found in depressed patients, and administration of inflammatory cytokines or cytokine inducers has been shown to foment depressive symptoms of apathy, anhedonia and fatigue. In addition, inflammatory cytokines have been found to disrupt dopamine synthesis, alter basal-ganglia metabolism, and blunt striatal responsivity during reward anticipation. To date, however, the majority of data supporting the relationship between cytokines and symptoms in patients with major depression and other disorders is correlational in nature, and thus alternative experimental strategies are required to elucidate causal relationships. One strategy is to block inflammatory cytokines in a sample of depressed patients with high inflammation so as to determine which symptom domains are most affected and through which molecular pathways. Previously, we found that the TNF antagonist infliximab (a ?biologic? monoclonal antibody that selectively inhibits TNF) selectively reduced symptoms of motivational anhedonia, but only in depressed patients with high inflammation as reflected by plasma c-reactive protein (CRP) of at least >3mg/L. Unfortunately, not all patients in this sample exhibited high inflammation, and these associations must therefore be considered preliminary, albeit promising. More critically, this study was unable to address target engagement at the level of neural circuitry. Building off of these initial data, the current study will assess neuroimaging measures of corticostriatal circuitry before and after a placebo-controlled pharmacologic blockade of inflammation in 80 depressed patients (n = 40 per group) recruited to ensure high levels of peripheral inflammation (CRP > 3mg/L). Primary aims are to evaluate whether 1) corticostriatal function during reward motivation and anticipation are associated with change in peripheral inflammation following pharmacologic blockade relative to placebo 2) the temporal dynamics of change in inflammation, gene- expression, reward motivation and reinforcement learning behavior and motivational symptoms assessed at baseline, and 24 hours, 3 days, 1 week and two weeks post infliximab infusion, and 3) test an integrative multi- level path model to determine whether change in corticostriatal circuitry following inflammation blockade mediates the relationship between change in inflammation and change in motivational anhedonia symptoms. These data will provide further validation of inflammatory cytokines as therapeutic targets for motivational symptoms in depression and will define symptom targets and biomarkers of response for future studies.
Inflammation may contribute to the development of motivational impairments and underlying corticostriatal circuit dysfunction in a subset of patients with major depression, which affects approximately 20 million adults in the US. Through a combination of functional neuroimaging and placebo-controlled inflammation blockade in a sample of depressed patients with high levels of inflammation, this project will determine the extent to which inflammation contributes to motivational symptoms and whether corticostriatal circuit function mediates this relationship. The proposed studies will help validate the immune system and corticostriatal reward circuits as important targets for the development of novel anti-inflammatory treatment and prevention strategies, which in turn can be used to personalize treatments for patients with high inflammation and motivational deficits.
|Arulpragasam, Amanda R; Cooper, Jessica A; Nuutinen, Makiah R et al. (2018) Corticoinsular circuits encode subjective value expectation and violation for effortful goal-directed behavior. Proc Natl Acad Sci U S A 115:E5233-E5242|
|Cooper, Jessica A; Arulpragasam, Amanda R; Treadway, Michael T (2018) Anhedonia in depression: biological mechanisms and computational models. Curr Opin Behav Sci 22:128-135|
|Belleau, Emily L; Treadway, Michael T; Pizzagalli, Diego A (2018) The Impact of Stress and Major Depressive Disorder on Hippocampal and Medial Prefrontal Cortex Morphology. Biol Psychiatry :|
|Mosner, Maya G; Kinard, Jessica L; McWeeny, Sean et al. (2017) Vicarious Effort-Based Decision-Making in Autism Spectrum Disorders. J Autism Dev Disord 47:2992-3006|
|Lasselin, Julie; Treadway, Michael T; Lacourt, Tamara E et al. (2017) Lipopolysaccharide Alters Motivated Behavior in a Monetary Reward Task: a Randomized Trial. Neuropsychopharmacology 42:801-810|
|Zald, David H; Treadway, Michael T (2017) Reward Processing, Neuroeconomics, and Psychopathology. Annu Rev Clin Psychol 13:471-495|
|Treadway, Michael T; Admon, Roee; Arulpragasam, Amanda R et al. (2017) Association Between Interleukin-6 and Striatal Prediction-Error Signals Following Acute Stress in Healthy Female Participants. Biol Psychiatry 82:570-577|
|Felger, Jennifer C; Treadway, Michael T (2017) Inflammation Effects on Motivation and Motor Activity: Role of Dopamine. Neuropsychopharmacology 42:216-241|
|Beard, C; Millner, A J; Forgeard, M J C et al. (2016) Network analysis of depression and anxiety symptom relationships in a psychiatric sample. Psychol Med 46:3359-3369|