Distinct profiles of anhedonia and reward processing and their prospective associations with quality of life among individuals with mood disorders.

Leading professional health bodies have called for the wider adoption of Patient Reported Outcome Measures, such as quality of life, in research and clinical practice as a means for understanding why the global burden of depression continues to climb despite increased rates of treatment use. Here, we examined whether anhedonia-an often recalcitrant and impairing symptom of depression-along with its neural correlates, was associated with longitudinal changes in patient-reported quality of life among individuals seeking treatment for mood disorders. We recruited 112 participants, including n = 80 individuals with mood disorders (58 unipolar, 22 bipolar) and n = 32 healthy controls (63.4% female). We assessed anhedonia severity along with two electroencephalographic markers of neural reward responsiveness (scalp-level 'Reward Positivity' amplitude and source-localized reward-related activation in the dorsal anterior cingulate cortex), and assessed quality of life at baseline, 3- and 6-month follow-up. Anhedonia emerged as a robust correlate of quality of life cross-sectionally and longitudinally among individuals with mood disorders. Furthermore, increased neural reward responsiveness at baseline was associated with greater improvements in quality of life over time, and this improvement was mediated by longitudinal improvements in anhedonia severity. Finally, differences in quality of life observed between individuals with unipolar and bipolar mood disorders were mediated by differences in anhedonia severity. Our findings indicate that anhedonia and its reward-related neural correlates are linked to variability in quality of life over time in individuals with mood disorders. Treatments capable of improving anhedonia and normalizing brain reward function may be necessary for improving broader health outcomes for individuals seeking treatment for depression.ClinicalTrials.gov identifier: NCT01976975.

Effects of acute stress and depression on functional connectivity between prefrontal cortex and the amygdala.

Stress is known to be a significant risk factor for the development of Major Depressive Disorder (MDD), yet the neural mechanisms that underlie this risk are poorly understood. Prior work has heavily implicated the corticolimbic system in the pathophysiology of MDD. In particular, the prefrontal cortex (PFC) and amygdala play a central role in regulating the response to stress, with dorsal PFC and ventral PFC exhibiting reciprocal excitatory and inhibitory influences on amygdala subregions. However, it remains unclear how best to disentangle the impact of stress from the impact of current MDD symptoms on this system. Here, we examined stress-induced changes in resting state functional connectivity (rsFC) within an a priori corticolimbic network in MDD patients and healthy controls (total n = 80) before and after an acute stressor or a "no stress" control condition. Using graph theoretic analysis, we found that connectivity between basolateral amygdala and dorsal prefrontal nodes of the corticolimbic network had a negative association with individual differences in chronic perceived stress at baseline. Following the acute stressor, healthy individuals showed a reduction of the amygdala node strength, while MDD patients exhibited little change. Finally, dorsal PFC-particularly dorsomedial PFC- connectivity to the basolateral amygdala was associated with the strength of the basolateral amygdala responses to loss feedback during a reinforcement learning task. These findings highlight attenuated connectivity between basolateral amygdala and prefrontal cortex in patients with MDD. In healthy individuals, acute stress exposure was found to push the corticolimbic network to a "stress-phenotype" that may be chronically present in patients with current depression and high levels of perceived stress. In sum, these results help to identify circuit mechanisms underlying the effects of acute stress and their role in mood disorders.

Aiding and Abetting Anhedonia: Impact of Inflammation on the Brain and Pharmacological Implications.

Exogenous administration of inflammatory stimuli to humans and laboratory animals and chronic endogenous inflammatory states lead to motivational deficits and ultimately anhedonia, a core and disabling symptom of depression present in multiple other psychiatric disorders. Inflammation impacts neurotransmitter systems and neurocircuits in subcortical brain regions including the ventral striatum, which serves as an integration point for reward processing and motivational decision-making. Many mechanisms contribute to these effects of inflammation, including decreased synthesis, release and reuptake of dopamine, increased synaptic and extrasynaptic glutamate, and activation of kynurenine pathway metabolites including quinolinic acid. Neuroimaging data indicate that these inflammation-induced neurotransmitter effects manifest as decreased activation of ventral striatum and decreased functional connectivity in reward circuitry involving ventral striatum and ventromedial prefrontal cortex. Neurocircuitry changes in turn mediate nuanced effects on motivation that include decreased willingness to expend effort for reward while maintaining the ability to experience reward. Taken together, the data reveal an inflammation-induced pathophysiologic phenotype that is agnostic to diagnosis. Given the many mechanisms involved, this phenotype represents an opportunity for development of novel and/or repurposed pharmacological strategies that target inflammation and associated cellular and systemic immunometabolic changes and their downstream effects on the brain. To date, clinical trials have failed to capitalize on the unique nature of this transdiagnostic phenotype, leaving the field bereft of interpretable data for meaningful clinical application. However, novel trial designs incorporating established targets in the brain and/or periphery using relevant outcome variables (e.g., anhedonia) are the future of targeted therapy in psychiatry. SIGNIFICANCE STATEMENT: Emerging understanding of mechanisms by which peripheral inflammation can affect the brain and behavior has created unprecedented opportunities for development of pharmacological strategies to treat deficits in motivation including anhedonia, a core and disabling symptom of depression well represented in multiple psychiatric disorders. Mechanisms include inflammation and cellular and systemic immunometabolism and alterations in dopamine, glutamate, and kynurenine metabolites, revealing a target-rich environment that nevertheless has yet to be fully exploited by current clinical trial designs and drugs employed.

Functional connectivity in reward circuitry and symptoms of anhedonia as therapeutic targets in depression with high inflammation: evidence from a dopamine challenge study.

Increased inflammation in major depressive disorder (MDD) has been associated with low functional connectivity (FC) in corticostriatal reward circuits and symptoms of anhedonia, relationships which may involve the impact of inflammation on synthesis and release of dopamine. To test this hypothesis while establishing a platform to examine target engagement of potential therapies in patients with increased inflammation, medically stable unmedicated adult MDD outpatients enrolled to have a range of inflammation (as indexed by plasma C-reactive protein [CRP] levels) were studied at two visits involving acute challenge with the dopamine precursor levodopa (L-DOPA; 250 mg) and placebo (double-blind, randomized order ~1-week apart). The primary outcome of resting-state (rs)FC in a classic ventral striatum to ventromedial prefrontal cortex reward circuit was calculated using a targeted, a priori approach. Data available both pre- and post-challenge (n = 31/40) established stability of rsFC across visits and determined CRP > 2 mg/L as a cut-point for patients exhibiting positive FC responses (post minus pre) to L-DOPA versus placebo (p < 0.01). Higher post-L-DOPA FC in patients with CRP > 2 mg/L was confirmed in all patients (n = 40) where rsFC data were available post-challenge (B = 0.15, p = 0.006), and in those with task-based (tb)FC during reward anticipation (B = 0.15, p = 0.013). While effort-based motivation outside the scanner positively correlated with rsFC independent of treatment or CRP, change in anhedonia scores negatively correlated with rsFC after L-DOPA only in patients with CRP > 2 mg/L (r = -0.56, p = 0.012). FC in reward circuitry should be further validated in larger samples as a biomarker of target engagement for potential treatments including dopaminergic agents in MDD patients with increased inflammation.

The effort-doors task: Examining the temporal dynamics of effort-based reward processing using ERPs.

Aberrant reward processing is a cardinal feature of various forms of psychopathology. However, recent research indicates that aberrant reward processing may manifest at temporally distinct substages and involve interdependent subcomponents of reward processing. To improve our understanding of both the temporal dynamics and distinct subcomponents of reward processing, we added an effort manipulation to the "doors" reward-task paradigm, to derive behavioral and event-related potential (ERP) measures of effort-based reward processing. Behavioral measures consisting of reaction time, response rate, and response rate change were used to index effort expenditure, and ERP measures were used to index attention allocated toward effort-completion cues, anticipation of reward, valuation of reward, and attention toward monetary feedback. Reduced response rate and slowing of response were evident during the high effort versus the low effort condition. ERP findings indicated increased attention to signals of high- compared to low-effort completion cues-as well as reduced anticipation of rewards, and reduced attention toward feedback information following high effort expenditure. Participants showing the most response-rate slowing evidenced the greatest reward devaluation following high versus low effort. Findings demonstrate that the addition of an effort expenditure manipulation to the doors reward paradigm produced reliable ERP and behavioral measures of effort-based reward processing, providing opportunities for future researchers to utilize the effort-doors task to parse the temporal dynamics of both anticipatory and consummatory reward processing components.

Corticoinsular circuits encode subjective value expectation and violation for effortful goal-directed behavior.

We are presented with choices each day about how to invest our effort to achieve our goals. Critically, these decisions must frequently be made under conditions of incomplete information, where either the effort required or possible reward to be gained is uncertain. Such choices therefore require the development of potential value estimates to guide effortful goal-directed behavior. To date, however, the neural mechanisms for this expectation process are unknown. Here, we used computational fMRI during an effort-based decision-making task where trial-wise information about effort costs and reward magnitudes was presented separately over time, thereby allowing us to model distinct effort/reward computations as choice-relevant information unfolded. We found that ventromedial prefrontal cortex (vmPFC) encoded expected subjective value. Further, activity in dorsal anterior cingulate (dACC) and anterior insula (aI) reflected both effort discounting as well as a subjective value prediction error signal derived from trial history. While prior studies have identified these regions as being involved in effort-based decision making, these data demonstrate their specific role in the formation and maintenance of subjective value estimates as relevant information becomes available.

Gene signatures in peripheral blood immune cells related to insulin resistance and low tyrosine metabolism define a sub-type of depression with high CRP and anhedonia.

Inflammation and altered glucose metabolism are two pathways implicated in the pathophysiology of major depressive disorder (MDD). We have previously shown that high inflammation as measured by C-reactive protein (CRP) in MDD patients is associated with symptoms of anhedonia, a core symptom of MDD, along with deficits in dopaminergic reward circuitry. Increased inflammation can shift metabolic demand and reprogram cellular energy sources, which may collectively impact the brain and reward processing to contribute to symptoms of anhedonia. To determine whether immunometabolic gene signatures were enriched in immune cells of depressed patients with increased inflammation and anhedonia, we examined whole-blood gene expression microarray (Illumina HumanHT-12) data from unmedicated, medically-stable patients with MDD (n = 93). Patients were considered to have increased inflammation based on High (>3mg/L) versus Low (≤3mg/L) plasma CRP, and further classified as having a self-reported phenotype of High (n = 30, 33rd percentile) versus Low (n = 32, 67th percentile) Anhedonia. Functional enrichment of gene pathways was assessed by Gene Set Enrichment Analysis (GSEA) using the KEGG pathway database. Pathways related to glucose metabolism (insulin signaling, insulin resistance, HIF-1, PI3K/AKT signaling), cancer (e.g., genes related to insulin and PI3K/AKT signaling), and inflammation (B cell, T cell and Fc receptor signaling) were specifically enriched in patients with both High CRP and High Anhedonia (all FDR q < 0.25). Within patients with High CRP in GSEA, the insulin signaling pathway was the top enriched pathway in patients with High versus Low Anhedonia (n = 10 and 9 respectively), which was driven by genes expressed predominantly in monocytes (z = 2.95, p < 0.01). Conversely, within patients with High Anhedonia, in addition to enrichment of immunometabolic pathways, the tyrosine metabolism pathway was also reduced in patients with High versus Low CRP (n = 20 and 10 respectively). Of note, enrichment of immunometabolic pathways was confirmed in complementary linear regression analyses examining pathways associated with a CRP-by-Anhedonia interaction term while controlling for clinical covariates in all patients (n = 93). These results indicate that increased glucose and low tyrosine metabolism define a subset of depressed patients with high inflammation and anhedonia. Enrichment of cancer-related pathways driven by metabolic genes also suggests a shift in immune cell metabolism from oxidative phosphorylation to glycolysis. Together these data suggest that anhedonia in MDD with high CRP involves both immunometabolic shifts and reduced dopamine precursor availability.

Frontostriatal and Dopamine Markers of Individual Differences in Reinforcement Learning: A Multi-modal Investigation.

Prior studies have shown that dopamine (DA) functioning in frontostriatal circuits supports reinforcement learning (RL), as phasic DA activity in ventral striatum signals unexpected reward and may drive coordinated activity of striatal and orbitofrontal regions that support updating of action plans. However, the nature of DA functioning in RL is complex, in particular regarding the role of DA clearance in RL behavior. Here, in a multi-modal neuroimaging study with healthy adults, we took an individual differences approach to the examination of RL behavior and DA clearance mechanisms in frontostriatal learning networks. We predicted that better RL would be associated with decreased striatal DA transporter (DAT) availability and increased intrinsic functional connectivity among DA-rich frontostriatal regions. In support of these predictions, individual differences in RL behavior were related to DAT binding potential in ventral striatum and resting-state functional connectivity between ventral striatum and orbitofrontal cortex. Critically, DAT binding potential had an indirect effect on reinforcement learning behavior through frontostriatal connectivity, suggesting potential causal relationships across levels of neurocognitive functioning. These data suggest that individual differences in DA clearance and frontostriatal coordination may serve as markers for RL, and suggest directions for research on psychopathologies characterized by altered RL.

Distinct Trajectories of Cortisol Response to Prolonged Acute Stress Are Linked to Affective Responses and Hippocampal Gray Matter Volume in Healthy Females.

The development of robust laboratory procedures for acute stress induction over the last decades has greatly advanced our understanding of stress responses in humans and their underlying neurobiological mechanisms. Nevertheless, attempts to uncover linear relationships among endocrine, neural, and affective responses to stress have generally yielded inconsistent results. Here, 79 healthy females completed a well established laboratory procedure of acute stress induction that was modified to prolong its effect. Endocrinological and subjective affect assessments revealed stress-induced increases in cortisol release and negative affect that persisted 65 and 100 min after stress onset, respectively, confirming a relatively prolonged acute stress induction. Applying latent class linear mixed modeling on individuals' patterns of cortisol responses identified three distinct trajectories of cortisol response: the hyper-response (n = 10), moderate-response (n = 21), and mild-response (n = 48) groups. Notably, whereas all three groups exhibited a significant stress-induced increase in cortisol release and negative affect, the hyper-response and mild-response groups both reported more negative affect relative to the moderate-response group. Structural MRI revealed no group differences in hippocampal and amygdala volumes, yet a continuous measure of cortisol response (area under the curve) showed that high and low levels of stress-induced cortisol release were associated with less hippocampal gray matter volume compared with moderate cortisol release. Together, these results suggest that distinct trajectories of cortisol response to prolonged acute stress among healthy females may not be captured by conventional linear analyses; instead, quadratic relations may better describe links between cortisol response to stress and affective responses, as well as hippocampal structural variability.SIGNIFICANCE STATEMENT Despite substantial research, it is unclear whether and how individual neuroendocrine stress response patterns are linked to affective responses to stress and structural variability in neuroendocrine regulatory brain regions. By applying latent class linear mixed modeling on individuals' patterns of cortisol responses to a prolonged acute stressor, we identified three distinct trajectories of cortisol response. Relative to the group showing a moderate cortisol response, groups characterized by hyper and mild cortisol response were both associated with more negative affect. Moreover, a continuous measure of cortisol response showed that high and low levels of stress-induced cortisol release correlated with reduced hippocampal gray matter volume. Given that neuroendocrine stress responses are conceptualized as biomarkers of stress susceptibility, these insights may have clinical implications.

Common and Dissociable Neural Activity After Mindfulness-Based Stress Reduction and Relaxation Response Programs.

OBJECTIVE: We investigated common and dissociable neural and psychological correlates of two widely used meditation-based stress reduction programs. METHODS: Participants were randomized to the Relaxation Response (RR; n = 18; 56% female) or the Mindfulness-Based Stress Reduction (MBSR; n = 16; 56% female) programs. Both programs use a "bodyscan" meditation; however, the RR program explicitly emphasizes physical relaxation during this practice, whereas the MBSR program emphasizes mindful awareness with no explicit relaxation instructions. After the programs, neural activity during the respective meditation was investigated using functional magnetic resonance imaging. RESULTS: Both programs were associated with reduced stress (for RR, from 14.1 ± 6.6 to 11.3 ± 5.5 [Cohen's d = 0.50; for MBSR, from 17.7 ± 5.7 to 11.9 ± 5.0 [Cohen's d = 1.02]). Conjunction analyses revealed functional coupling between ventromedial prefrontal regions and supplementary motor areas (p < .001). The disjunction analysis indicated that the RR bodyscan was associated with stronger functional connectivity of the right inferior frontal gyrus-an important hub of intentional inhibition and control-with supplementary motor areas (p < .001, family-wise error [FWE] rate corrected). The MBSR program was uniquely associated with improvements in self-compassion and rumination, and the within-group analysis of MBSR bodyscan revealed significant functional connectivity of the right anterior insula-an important hub of sensory awareness and salience-with pregenual anterior cingulate during bodyscan meditation compared with rest (p = .03, FWE corrected). CONCLUSIONS: The bodyscan exercises in each program were associated with both overlapping and differential functional coupling patterns, which were consistent with each program's theoretical foundation. These results may have implications for the differential effects of these programs for the treatment of diverse conditions.

Reward Processing, Neuroeconomics, and Psychopathology.

Abnormal reward processing is a prominent transdiagnostic feature of psychopathology. The present review provides a framework for considering the different aspects of reward processing and their assessment, and highlights recent insights from the field of neuroeconomics that may aid in understanding these processes. Although altered reward processing in psychopathology has often been treated as a general hypo- or hyperresponsivity to reward, increasing data indicate that a comprehensive understanding of reward dysfunction requires characterization within more specific reward-processing domains, including subjective valuation, discounting, hedonics, reward anticipation and facilitation, and reinforcement learning. As such, more nuanced models of the nature of these abnormalities are needed. We describe several processing abnormalities capable of producing the types of selective alterations in reward-related behavior observed in different forms of psychopathology, including (mal)adaptive scaling and anchoring, dysfunctional weighting of reward and cost variables, competition between valuation systems, and reward prediction error signaling.

Inflammatory markers are associated with decreased psychomotor speed in patients with major depressive disorder.

Previous data have demonstrated that administration of inflammatory cytokines or their inducers leads to altered basal ganglia function associated with reduced psychomotor speed. Decreased psychomotor speed, referred to clinically as psychomotor retardation, is a cardinal symptom of major depressive disorder (MDD) and has been associated with poor antidepressant treatment response. We therefore examined the association between plasma inflammatory markers and psychomotor speed in ninety-three un-medicated patients with MDD. Psychomotor speed was assessed by a range of neuropsychological tests from purely motor tasks (e.g. movement latency and finger tapping) to those that involved motor activity with increasing cognitive demand and cortical participation (e.g. Trails A and Digit Symbol Substitution Task (DSST)). Linear regression analyses were performed to determine the relationship of inflammatory markers and psychomotor task performance controlling for age, race, sex, education, body mass index, and severity of depression. MDD patients exhibited decreased psychomotor speed on all tasks relative to normative standards. Increased IL-6 was associated with decreased performance on simple and choice movement time tasks, whereas MCP-1 was associated with decreased performance on the finger tapping task and DSST. IL-10 was associated with increased performance on the DSST. In an exploratory principle component analysis including all psychomotor tasks, IL-6 was associated with the psychomotor speed factor. Taken together, the data indicate that a peripheral inflammatory profile including increased IL-6 and MCP-1 is consistently associated with psychomotor speed in MDD. These data are consistent with data demonstrating that inflammation can affect basal ganglia function, and indicate that psychomotor speed may be a viable outcome variable for anti-inflammatory therapies in depression and other neuropsychiatric disorders with increased inflammation.

Clashing Diagnostic Approaches: DSM-ICD Versus RDoC.

Since at least the middle of the past century, one overarching model of psychiatric classification has reigned supreme, namely, that of the Diagnostic and Statistical Manual of Mental Disorders and the International Statistical Classification of Diseases and Related Health Problems (herein referred to as DSM-ICD). This DSM-ICD approach embraces an Aristotelian view of mental disorders as largely discrete entities that are characterized by distinctive signs, symptoms, and natural histories. Over the past several years, however, a competing vision, namely, the Research Domain Criteria (RDoC) initiative launched by the National Institute of Mental Health, has emerged in response to accumulating anomalies within the DSM-ICD system. In contrast to DSM-ICD, RDoC embraces a Galilean view of psychopathology as the product of dysfunctions in neural circuitry. RDoC appears to be a valuable endeavor that holds out the long-term promise of an alternative system of mental illness classification. We delineate three sets of pressing challenges--conceptual, methodological, and logistical/pragmatic--that must be addressed for RDoC to realize its scientific potential. We conclude with a call for further research, including investigation of a rapprochement between Aristotelian and Galilean approaches to psychiatric classification.

Effect of failure/success feedback and the moderating influence of personality on reward motivation.

While motivation to pursue goals is often assumed to be a trait-like characteristic, it is influenced by a variety of situational factors. In particular, recent experiences of success or failure, as well as cognitive responses to these outcomes, may shape subsequent willingness to expend effort for future rewards. To date, however, these effects have not been explicitly tested. In the present study, 131 healthy individuals received either failure or success feedback on a cognitive task. They were then instructed to either ruminate or distract themselves from their emotions. Finally, they completed the Effort Expenditure for Rewards Task, a laboratory measure of reward motivation. Results indicate that participants who received failure feedback relied more strongly on the reward magnitude when choosing whether to exert greater effort to obtain larger rewards, though this effect only held under conditions of significant uncertainty about whether the effort would be rewarded. Further, participants with high levels of trait inhibition were less responsive to reward value and probability when choosing whether to expend greater effort, results that echo past studies of effort-based decision-making in psychological disorders.

Using Computational Phenotyping to Identify Divergent Strategies for Effort Allocation Across the Psychosis Spectrum.

BACKGROUND AND HYPOTHESIS: Disturbances in effort-cost decision-making have been highlighted as a potential transdiagnostic process underpinning negative symptoms in individuals with schizophrenia. However, recent studies using computational phenotyping show that individuals employ a range of strategies to allocate effort, and use of different strategies is associated with unique clinical and cognitive characteristics. Building on prior work in schizophrenia, this study evaluated whether effort allocation strategies differed in individuals with distinct psychotic disorders. STUDY DESIGN: We applied computational modeling to effort-cost decision-making data obtained from individuals with psychotic disorders (n = 190) who performed the Effort Expenditure for Rewards Task. The sample included 91 individuals with schizophrenia/schizoaffective disorder, 90 individuals with psychotic bipolar disorder, and 52 controls. STUDY RESULTS: Different effort allocation strategies were observed both across and within different disorders. Relative to individuals with psychotic bipolar disorder, a greater proportion of individuals with schizophrenia/schizoaffective disorder did not use reward value or probability information to guide effort allocation. Furthermore, across disorders, different effort allocation strategies were associated with specific clinical and cognitive features. Those who did not use reward value or probability information to guide effort allocation had more severe positive and negative symptoms, and poorer cognitive and community functioning. In contrast, those who only used reward value information showed a trend toward more severe positive symptoms. CONCLUSIONS: These findings indicate that similar deficits in effort-cost decision-making may arise from different computational mechanisms across the psychosis spectrum.

Brain-based graph-theoretical predictive modeling to map the trajectory of anhedonia, impulsivity, and hypomania from the human functional connectome.

Clinical assessments often fail to discriminate between unipolar and bipolar depression and identify individuals who will develop future (hypo)manic episodes. To address this challenge, we developed a brain-based graph-theoretical predictive model (GPM) to prospectively map symptoms of anhedonia, impulsivity, and (hypo)mania. Individuals seeking treatment for mood disorders (n = 80) underwent an fMRI scan, including (i) resting-state and (ii) a reinforcement-learning (RL) task. Symptoms were assessed at baseline as well as at 3- and 6-month follow-ups. A whole-brain functional connectome was computed for each fMRI task, and the GPM was applied for symptom prediction using cross-validation. Prediction performance was evaluated by comparing the GPM to a corresponding null model. In addition, the GPM was compared to the connectome-based predictive modeling (CPM). Cross-sectionally, the GPM predicted anhedonia from the global efficiency (a graph theory metric that quantifies information transfer across the connectome) during the RL task, and impulsivity from the centrality (a metric that captures the importance of a region) of the left anterior cingulate cortex during resting-state. At 6-month follow-up, the GPM predicted (hypo)manic symptoms from the local efficiency of the left nucleus accumbens during the RL task and anhedonia from the centrality of the left caudate during resting-state. Notably, the GPM outperformed the CPM, and GPM derived from individuals with unipolar disorders predicted anhedonia and impulsivity symptoms for individuals with bipolar disorders. Importantly, the generalizability of cross-sectional models was demonstrated in an external validation sample. Taken together, across DSM mood diagnoses, efficiency and centrality of the reward circuit predicted symptoms of anhedonia, impulsivity, and (hypo)mania, cross-sectionally and prospectively. The GPM is an innovative modeling approach that may ultimately inform clinical prediction at the individual level.

A randomized proof-of-mechanism trial of TNF antagonism for motivational anhedonia and related corticostriatal circuitry in depressed patients with high inflammation.

Chronic, low-grade inflammation has been associated with motivational deficits in patients with major depression (MD). In turn, impaired motivation has been linked to poor quality of life across psychiatric disorders. We thus determined effects of the anti-inflammatory drug infliximab-a potent tumor necrosis factor (TNF) antagonist-on behavioral and neural measures of motivation in 42 medically stable, unmedicated MD patients with a C-reactive protein > 3mg/L. All patients underwent a double-blind, placebo-controlled, single-dose, randomized clinical trial with infliximab (5mg/kg) versus placebo. Behavioral performance on an effort-based decision-making task, self-report questionnaires, and neural responses during event-related functional magnetic resonance imaging were assessed at baseline and 2 weeks following infusion. We found that relative to placebo, patients receiving infliximab were more willing to expend effort for rewards. Moreover, increase in effortful choices was associated with reduced TNF signaling as indexed by decreased soluble TNF receptor type 2 (sTNFR2). Changes in effort-based decision-making and sTNFR2 were also associated with changes in task-related activity in a network of brain areas, including dmPFC, ventral striatum, and putamen, as well as the functional connectivity between these regions. Changes in sTNFR2 also mediated the relationships between drug condition and behavioral and neuroimaging measures. Finally, changes in self-reported anhedonia symptoms and effort-discounting behavior were associated with greater responses of an independently validated whole-brain predictive model (aka "neural signature") sensitive to monetary rewards. Taken together, these data support the use of anti-inflammatory treatment to improve effort-based decision-making and associated brain circuitry in depressed patients with high inflammation.