Reduced Reward Sensitivity Research Articles

Neural Correlates of Three Promising Endophenotypes of Depression: Evidence from the EMBARC Study

Major depressive disorder (MDD) is clinically, and likely pathophysiologically, heterogeneous. A potentially fruitful approach to parsing this heterogeneity is to focus on promising endophenotypes. Guided by the NIMH Research Domain Criteria initiative, we used source localization of scalp-recorded EEG resting data to examine the neural correlates of three emerging endophenotypes of depression: neuroticism, blunted reward learning, and cognitive control deficits. Data were drawn from the ongoing multi-site EMBARC study. We estimated intracranial current density for standard EEG frequency bands in 82 unmedicated adults with MDD, using Low-Resolution Brain Electromagnetic Tomography. Region-of-interest and whole-brain analyses tested associations between resting state EEG current density and endophenotypes of interest. Neuroticism was associated with increased resting gamma (36.5-44 Hz) current density in the ventral (subgenual) anterior cingulate cortex (ACC) and orbitofrontal cortex (OFC). In contrast, reduced cognitive control correlated with decreased gamma activity in the left dorsolateral prefrontal cortex (dlPFC), decreased theta (6.5-8 Hz) and alpha2 (10.5-12 Hz) activity in the dorsal ACC, and increased alpha2 activity in the right dlPFC. Finally, blunted reward learning correlated with lower OFC and left dlPFC gamma activity. Computational modeling of trial-by-trial reinforcement learning further indicated that lower OFC gamma activity was linked to reduced reward sensitivity. Three putative endophenotypes of depression were found to have partially dissociable resting intracranial EEG correlates, reflecting different underlying neural dysfunctions. Overall, these findings highlight the need to parse the heterogeneity of MDD by focusing on promising endophenotypes linked to specific pathophysiological abnormalities.

Reward Pays the Cost of Noise Reduction in Motor and Cognitive Control

SummarySpeed-accuracy trade-off is an intensively studied law governing almost all behavioral tasks across species. Here we show that motivation by reward breaks this law, by simultaneously invigorating movement and improving response precision. We devised a model to explain this paradoxical effect of reward by considering a new factor: the cost of control. Exerting control to improve response precision might itself come at a cost—a cost to attenuate a proportion of intrinsic neural noise. Applying a noise-reduction cost to optimal motor control predicted that reward can increase both velocity and accuracy. Similarly, application to decision-making predicted that reward reduces reaction times and errors in cognitive control. We used a novel saccadic distraction task to quantify the speed and accuracy of both movements and decisions under varying reward. Both faster speeds and smaller errors were observed with higher incentives, with the results best fitted by a model including a precision cost. Recent theories consider dopamine to be a key neuromodulator in mediating motivational effects of reward. We therefore examined how Parkinson’s disease (PD), a condition associated with dopamine depletion, alters the effects of reward. Individuals with PD showed reduced reward sensitivity in their speed and accuracy, consistent in our model with higher noise-control costs. Including a cost of control over noise explains how reward may allow apparent performance limits to be surpassed. On this view, the pattern of reduced reward sensitivity in PD patients can specifically be accounted for by a higher cost for controlling noise.

Gray’s revised Reinforcement Sensitivity Theory in relation to Attention-Deficit/Hyperactivity and Tourette-like behaviors in the general population

Attention-Deficit/Hyperactivity Disorder (ADHD) and Tourette syndrome (TS) present as distinct conditions clinically; however, they show comorbidity and inhibitory control deficits have been proposed to underlie both. The role of reinforcement sensitivity in ADHD has been studied previously, but no study has addressed this in relation to TS-like behaviors in the general population. The present study examined these associations within the remit of the revised Reinforcement Sensitivity Theory (rRST). One hundred and thirty-eight participants completed psychometric measures of the rRST, and self-report checklists for ADHD- and TS-like behaviors. The results show that whilst ADHD-inattention was only linked to increased anxiety (BIS), ADHD-hyperactivity/impulsivity was linked to increased impulsivity (BAS-fun seeking), anxiety (BIS) and punishment sensitivity (FFFS), and to reduced reward sensitivity (BAS-reward responsiveness), independently of ‘comorbid’ TS-like behaviors. TS-related phonic tics were associated with increased BIS and FFFS, and TS-related obsessive–compulsive behaviors (OCBs) with increased goal-orientation (BAS-drive) and reduced impulsivity (BAS-fun seeking). However, these associations were driven by ADHD-like behaviors or OCB co-occurrence, respectively, suggesting little role of the rRST in pure TS-like behaviors. The results are discussed in light of mixed findings in the literature and the importance of distinguishing between multiple processing models of the rRST in distinct disorder phenotypes.

Adapting dialectical behavior therapy for outpatient adult anorexia nervosa--a pilot study.

Anorexia Nervosa (AN) is associated with excessive self-control. This iterative case series describes the augmentation of Dialectical Behavior Therapy (DBT) for outpatient adult AN with skills addressing emotional and behavioral overcontrol. An overly controlled style is theorized to develop from the transaction between an individual with heightened threat sensitivity and reduced reward sensitivity, interacting with an environment reinforcing overcontrol and punishing imperfection. Case Series 1 utilized standard DBT, resulting in retention of 5/6 patients and a body mass index (BMI) effect size increase of d = -0.5 from pre- to post-treatment. Case series 2, using standard DBT augmented with skills addressing overcontrol, resulted in retention of 8/9 patients with an effect size increase in BMI at post-treatment that was maintained at 6- and 12-months follow-up (d = -1.12, d = -0.87, and d = -1.12). Findings suggest that skills training targeting rigidity and increasing openness and social connectedness warrant further study of this model and treatment for AN.

The link between dopamine function and apathy in cannabis users: an [18F]-DOPA PET imaging study

Cannabis is the most widely used illicit drug in the world, and regular use has been associated with reduced motivation, i.e. apathy. Regular long-term cannabis use has been associated with reduced dopamine synthesis capacity. The mesolimbic dopaminergic system mediates the processing of incentive stimuli by modifying their motivational value, which in turn is modulated by endocannabinoid signalling. Thus, it has been proposed that dopaminergic dysfunction underlies the apathy associated with chronic cannabis use. The aim of this study was to examine the relationship between dopaminergic function and subjective apathy in cannabis users. We measured dopamine synthesis capacity (indexed as the influx rate constant K i(cer)) via 3,4-dihydroxy-6-[(18)F]-fluoro-l-phenylalanine positron emission tomography and subjective apathy using the self-rated Apathy Evaluation Scale (AES-S) in 14 regular cannabis users. All subjects scored in excess of 34 points on the AES-S (median [interquartile range] 59.5 [7.5]), indicative of significant apathy based on normative data. K i (cer) was inversely correlated to AES-S score in the whole striatum and its associative functional subdivision (Spearman's rho = -0.64, p = 0.015 [whole striatum]; rho = -0.69, p = 0.006 [associative]) but not in the limbic or sensorimotor striatal subdivisions. There were no significant relationships between AES-S and current cannabis consumption (rho = 0.28, p = 0.34) or age of first cannabis use (rho = 0.25, p = 0.40). These findings indicate that the reduction in striatal dopamine synthesis capacity associated with chronic cannabis use may underlie reduced reward sensitivity and a motivation associated with chronic cannabis use.

Do different fairness contexts and facial emotions motivate ‘irrational’ social decision-making in major depression? An exploratory patient study

Although ‘irrational’ decision-making has been linked to depression, the contribution of biases in information processing to these findings remains unknown. To investigate the impact of cognitive biases and aberrant processing of facial emotions on social decision-making, we manipulated both context-related and emotion-related information in a modified Ultimatum Game. Unfair offers were (1) paired with different unselected alternatives, establishing the context in which an offer was made, and (2) accompanied by emotional facial expressions of proposers. Responder behavior was assessed in patients with major depressive disorder and healthy controls. In both groups alike, rejection rates were highest following unambiguous signals of unfairness, i.e. an angry proposer face or when an unfair distribution had deliberately been chosen over an equal split. However, depressed patients showed overall higher rejection rates than healthy volunteers, without exhibiting differential processing biases. This suggests that depressed patients were, as healthy individuals, basing their decisions on informative, salient features and differentiating between (i) fair and unfair offers, (ii) alternatives to unfair offers and (iii) proposers' facial emotions. Although more fundamental processes, e.g. reduced reward sensitivity, might underlie increased rejection in depression, the current study provides insight into mechanisms that shape fairness considerations in both depressed and healthy individuals.

Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis

BackgroundDepression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge.MethodsSix behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate.ResultsMDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate.ConclusionReward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior.

Reduced Sensitivity to Immediate Reward during Decision-Making in Older than Younger Adults

We examined whether older adults differ from younger adults in the degree to which they favor immediate over delayed rewards during decision-making. To examine the neural correlates of age-related differences in delay discounting we acquired functional MR images while participants made decisions between smaller but sooner and larger but later monetary rewards. The behavioral results show age-related reductions in delay discounting. Less impulsive decision-making in older adults was associated with lower ventral striatal activations to immediate reward. Furthermore, older adults showed an overall higher percentage of delayed choices and reduced activity in the dorsal striatum than younger adults. This points to a reduced reward sensitivity of the dorsal striatum in older adults. Taken together, our findings indicate that less impulsive decision-making in older adults is due to a reduced sensitivity of striatal areas to reward. These age-related changes in reward sensitivity may result from transformations in dopaminergic neuromodulation with age.

P01-299 Reward sensitivity and response to treatment in major depression

Rationale:Anhedonia, or the lack of reactivity to a pleasurable stimuli is expressed as reduced reward sensitivity in patients with major depressive disorder (MDD) (1). Reward experience might discriminate between depressed patients who respons to treatment and those who do not (2).Objective:The purpose of this study was to test the hypothesis that patients non-responsive to treatment show reduced reward sensitivity compared to responsive patients.Method:A probabilistic computer task was used to measure reward sensitivity objectively (3). Twenty-eight medicated inpatients meeting DSM-IV criteria for MDD performed the reward task within the first week after submission and again after eight weeks. The response to treatment was assessed with the Hamilton Depression rating Scale (HDRS). Patients with scores less that ten or a fifty percent reduction on the HDRS after 8 weeks were considered responders to treatment. Sixteen healthy subjects were recruited as controls.Results:When considering reward sensitivity at baseline, the control group was significantly more sensitive to reward than the responders group and the non-responders group, who were the least reward sensitive (F = 11.88; p < 0.01). After 8 weeks, responders showed an almost similar reward dependence to controls on the task, however non-responders still preformed significantly worse compared to both responders and controls (F= 8.71; p< 0.01).Conclusion:These results support the hypothesis that impairment of reward responsiveness might influence response to treatment in patients with MDD.

Effects of serotonin depletion on the hippocampal GR/MR and BDNF expression during the stress adaptation

Increased serotonin (5-hydroxytryptamine, 5-HT) release in the hippocampus induced by repeated stress is thought to be critical for the neuroadaptation that alleviates the adverse effects of stressors on emotion and behavior. A failure in this process may be one of the primary neuropathological mechanisms underlying the development of stress-related disorders. The para-chloroamphetamine ( p-PCA) was used to deplete 5-HT in the rat prior to repeated restraint stress (6 h/day for 10 days), and determined the consequences of 5-HT depletion on stress-induced alterations of animal behaviors, hippocampal corticosteroid receptor immunoreactivity and the brain-derived neurotrophic factor (BDNF) mRNA expression. Behavioral tests indicate that the stressed rats with 5-HT depletion showed pronounced anxiety, reduced reward sensitivity and enhanced learned-helplessness. In addition, they also developed learning impairments in Morris water maze tests. These results suggest that hippocampal 5-HT depletion compromised adaptation to chronic stress. Furthermore, repeated stress caused a lesser degree of glucocorticoid receptor increase and down-regulation of BDNF mRNA. The study suggest that 5-HT deficiency in the adult hippocampus may impair stress adaptation by suppressing hippocampal GR and BDNF expression.

Gene–gene interaction associated with neural reward sensitivity

Reward processing depends on dopaminergic neurotransmission and is modulated by factors affecting dopamine (DA) reuptake and degradation. We used fMRI and a guessing task sensitive to reward-related activation in the prefrontal cortex and ventral striatum to study how individual variation in genes contributing to DA reuptake [DA transporter (DAT)] and degradation [catechol-o-methyltransferase (COMT)] influences reward processing. Prefrontal activity, evoked by anticipation of reward irrespective of reward probability and magnitude, was COMT genotype-dependent. Volunteers homozygous for the Met allele, associated with lower enzyme activity and presumably greater DA availability, showed larger responses compared with volunteers homozygous for the Val allele. A similar COMT effect was observed in the ventral striatum. As reported previously, the ventral striatum was also found to code gain-related expected value, i.e., the product of reward magnitude and gain probability. Individual differences in ventral striatal sensitivity for value were in part explained by an epistatic gene-gene interaction between COMT and DAT. Although most genotype combinations exhibited the expected activity increase with more likely and larger rewards, two genotype combinations (COMT Met/Met DAT 10R and COMT Val/Val 9R) were associated with blunted ventral striatal responses. In view of a consistent relationship between reduced reward sensitivity and addiction, our findings point to a potential genetic basis for vulnerability to addiction.

Behavioral characteristics of rats predisposed to learned helplessness: Reduced reward sensitivity, increased novelty seeking, and persistent fear memories

The congenitally helpless rat strain, which was selectively bred for increased susceptibility to learned helplessness, may model the predisposition to affective disorders, including depression and post-traumatic stress disorder. Other than the selected trait, the behavior of this strain is not well characterized. In this study, we assessed congenitally helpless rats on several behavioral tests. First, we assessed reward sensitivity by measuring their consumption of a 5% sucrose solution. Next, we assessed exploratory behavior and fearfulness in both a novel and familiar open field, and in a light–dark test. Finally, we assessed fear conditioning by exposing the animals to 4 tone-shock pairs on 1 day (acquisition) and then presenting 60 tones over the next 2 days (extinction). Compared to normal Sprague–Dawley controls, congenitally helpless rats showed less consumption of the sucrose solution and more exploratory behavior in the novel, but not the familiar, open fields. They also showed less fearfulness in the light–dark test, but more conditioned freezing to the tone predicting shock. Moreover, this freezing was resistant to extinction; congenitally helpless rats not only failed to show a fear decrement during extinction, but actually showed increased fear, a phenomenon termed “paradoxical enhancement.” Thus, congenitally helpless rats appear to have a behavioral phenotype characterized by reduced sensitivity to reward, increased drive to explore novel environments, and increased propensity to form and maintain fear-associated memories. This behavioral phenotype is discussed as resembling the personality of humans vulnerable to post-traumatic stress disorder.