Michael T. Treadway

Reconsidering Anhedonia in Depression: Lessons from Translational Neuroscience

Anhedonia is a core symptom of major depressive disorder (MDD), the neurobiological mechanisms of which remain poorly understood. Despite decades of speculation regarding the role of dopamine (DA) in anhedonic symptoms, empirical evidence has remained elusive, with frequent reports of contradictory findings. In the present review, we argue that this has resulted from an underspecified definition of anhedonia, which has failed to dissociate between consummatory and motivational aspects of reward behavior. Given substantial preclinical evidence that DA is involved primarily in motivational aspects of reward, we suggest that a refined definition of anhedonia that distinguishes between deficits in pleasure and motivation is essential for the purposes of identifying its neurobiological substrates. Moreover, bridging the gap between preclinical and clinical models of anhedonia may require moving away from the conceptualization of anhedonia as a steady-state, mood-like phenomena. Consequently, we introduce the term decisional anhedonia to address the influence of anhedonia on reward decision-making. These proposed modifications to the theoretical definition of anhedonia have implications for research, assessment and treatment of MDD.

Mesolimbic dopamine reward system hypersensitivity in individuals with psychopathic traits

Psychopathy is a personality disorder that is strongly linked to criminal behavior. Using [18F]fallypride positron emission tomography and blood oxygen level–dependent functional magnetic resonance imaging, we found that impulsive-antisocial psychopathic traits selectively predicted nucleus accumbens dopamine release and reward anticipation-related neural activity in response to pharmacological and monetary reinforcers, respectively. These findings suggest that neurochemical and neurophysiological hyper-reactivity of the dopaminergic reward system may comprise a neural substrate for impulsive-antisocial behavior and substance abuse in psychopathy.

Effort-Based Decision-Making in Major Depressive Disorder: A Translational Model of Motivational Anhedonia

Anhedonia is a core feature of major depressive disorder (MDD), but the precise nature of anhedonic symptoms is unknown. Whereas anhedonia has traditionally been viewed as a deficit in the experience of pleasure, more recent evidence suggests that reduced anticipation and motivation may also be a core feature of this symptom. Here, we provide data from a study in MDD patients and healthy controls using a translational measure of reward motivation, the Effort Expenditure for Rewards Task (EEfRT or effort). This task offers subjects a series of trials where they may choose to expend more or less effort for the opportunity to win varying amounts of monetary rewards. We found that MDD patients were less willing to expend effort for rewards than controls. Additionally, we observed that patients were less able to effectively use information about magnitude and probability of rewards to guide their choice behavior. Finally, within the MDD patient group, duration of the current episode was a significant negative predictor of EEfRT task performance. These findings offer novel support for theoretical models proposing that anhedonia in MDD may reflect specific impairments in motivation and reward-based decision-making.

Worth the ‘EEfRT’? The Effort Expenditure for Rewards Task as an Objective Measure of Motivation and Anhedonia

Background Of the putative psychopathological endophenotypes in major depressive disorder (MDD), the anhedonic subtype is particularly well supported. Anhedonia is generally assumed to reflect aberrant motivation and reward responsivity. However, research has been limited by a lack of objective measures of reward motivation. We present the Effort-Expenditure for Rewards Task (EEfRT or “effort”), a novel behavioral paradigm as a means of exploring effort-based decision-making in humans. Using the EEfRT, we test the hypothesis that effort-based decision-making is related to trait anhedonia. Methods/Results 61 undergraduate students participated in the experiment. Subjects completed self-report measures of mood and trait anhedonia, and completed the EEfRT. Across multiple analyses, we found a significant inverse relationship between anhedonia and willingness to expend effort for rewards. Conclusions These findings suggest that anhedonia is specifically associated with decreased motivation for rewards, and provide initial validation for the EEfRT as a laboratory-based behavioral measure of reward motivation and effort-based decision-making in humans.

Amping Up Effort: Effects of d-Amphetamine on Human Effort-Based Decision-Making

Animal studies suggest the neurotransmitter dopamine (DA) plays an important role in decision-making. In rats, DA depletion decreases tolerance for effort and probability costs, while drugs enhancing DA increase tolerance for these costs. However, data regarding the effect of DA manipulations on effort and probability costs in humans remain scarce. The current study examined acute effects of d-amphetamine, an indirect DA agonist, on willingness of healthy human volunteers to exert effort for monetary rewards at varying levels of reward value and reward probability. Based on preclinical research, we predicted amphetamine would increase exertion of effort, particularly when reward probability was low. Over three sessions, 17 healthy normal adults received placebo, d-amphetamine 10 mg, and 20 mg under counterbalanced double-blind conditions and completed the Effort Expenditure for Rewards Task. Consistent with predictions, amphetamine enhanced willingness to exert effort, particularly when reward probability was lower. Amphetamine did not alter effects of reward magnitude on willingness to exert effort. Amphetamine sped task performance, but its psychomotor effects were not strongly related to its effects on decision-making. This is the first demonstration in humans that dopaminergic manipulations alter willingness to exert effort for rewards. These findings help elucidate neurochemical substrates of choice, with implications for neuropsychiatric diseases characterized by dopaminergic dysfunction and motivational deficits.

Illness Progression, Recent Stress, and Morphometry of Hippocampal Subfields and Medial Prefrontal Cortex in Major Depression

BACKGROUNDnLongitudinal studies of illness progression in patients with major depressive disorder (MDD) indicate that the onset of subsequent depressive episodes becomes increasingly decoupled from external stressors. A possible mechanism underlying this phenomenon is that multiple episodes induce long-lasting neurobiological changes that confer increased risk for recurrence. Prior morphometric studies have frequently reported volumetric reductions in patients with MDD--especially in medial prefrontal cortex (mPFC) and the hippocampus--but few studies have investigated whether these changes are exacerbated by prior episodes.nnnMETHODSnIn a sample of 103 medication-free patients with depression and control subjects with no history of depression, structural magnetic resonance imaging was performed to examine relationships between number of prior episodes, current stress, hippocampal subfield volume and cortical thickness. Volumetric analyses of the hippocampus were performed using a recently validated subfield segmentation approach, and cortical thickness estimates were obtained using vertex-based methods. Participants were grouped on the basis of the number of prior depressive episodes and current depressive diagnosis.nnnRESULTSnNumber of prior episodes was associated with both lower reported stress levels and reduced volume in the dentate gyrus. Cortical thinning of the left mPFC was associated with a greater number of prior depressive episodes but not current depressive diagnosis.nnnCONCLUSIONSnCollectively, these findings are consistent with preclinical models suggesting that the dentate gyrus and mPFC are especially vulnerable to stress exposure and provide evidence for morphometric changes that are consistent with stress-sensitization models of recurrence in MDD.

Early Adverse Events, HPA Activity and Rostral Anterior Cingulate Volume in MDD

Background Prior studies have independently reported associations between major depressive disorder (MDD), elevated cortisol concentrations, early adverse events and region-specific decreases in grey matter volume, but the relationships among these variables are unclear. In the present study, we sought to evaluate the relationships between grey matter volume, early adverse events and cortisol levels in MDD. Methods/Results Grey matter volume was compared between 19 controls and 19 individuals with MDD using voxel-based morphometry. A history of early adverse events was assessed using the Childhood Trauma Questionnaire. Subjects also provided salivary cortisol samples. Depressed patients showed decreased grey matter volume in the rostral ACC as compared to controls. Rostral ACC volume was inversely correlated with both cortisol and early adverse events. Conclusions These findings suggest a key relationship between ACC morphology, a history of early adverse events and circulating cortisol in the pathophysiology of MDD.

Parsing Anhedonia: Translational Models of Reward-Processing Deficits in Psychopathology

The term anhedonia has long been used in the psychiatric literature to describe reward-processing dysfunction in psychopathology, especially depression and schizophrenia. Although anhedonia literally describes a lack of pleasurable experiences in everyday life, recent advances in both the basic science and clinical literatures indicate that reward deficits in these disorders are much broader than hedonic responses. In this article, we summarize some of the recent theoretical and empirical advances in understanding deficits in reward processing and their neurobehavioral mechanisms, with a particular focus on the neural underpinnings of motivation and effort-based decision making. We also highlight the potential of translational neuroscience to enhance diagnostic clarity by defining clinical symptoms in terms of underlying pathophysiology.

Adults with autism spectrum disorders exhibit decreased sensitivity to reward parameters when making effort-based decisions

BackgroundEfficient effort expenditure to obtain rewards is critical for optimal goal-directed behavior and learning. Clinical observation suggests that individuals with autism spectrum disorders (ASD) may show dysregulated reward-based effort expenditure, but no behavioral study to date has assessed effort-based decision-making in ASD.MethodsThe current study compared a group of adults with ASD to a group of typically developing adults on the Effort Expenditure for Rewards Task (EEfRT), a behavioral measure of effort-based decision-making. In this task, participants were provided with the probability of receiving a monetary reward on a particular trial and asked to choose between either an “easy task” (less motoric effort) for a small, stable reward or a “hard task” (greater motoric effort) for a variable but consistently larger reward.ResultsParticipants with ASD chose the hard task more frequently than did the control group, yet were less influenced by differences in reward value and probability than the control group. Additionally, effort-based decision-making was related to repetitive behavior symptoms across both groups.ConclusionsThese results suggest that individuals with ASD may be more willing to expend effort to obtain a monetary reward regardless of the reward contingencies. More broadly, results suggest that behavioral choices may be less influenced by information about reward contingencies in individuals with ASD. This atypical pattern of effort-based decision-making may be relevant for understanding the heightened reward motivation for circumscribed interests in ASD.

Imaging the pathophysiology of major depressive disorder - from localist models to circuit-based analysis

The neuroimaging literature of Major Depressive Disorder (MDD) has grown substantially over the last several decades, facilitating great advances in the identification of specific brain regions, neurotransmitter systems and networks associated with depressive illness. Despite this progress, fundamental questions remain about the pathophysiology and etiology of MDD. More importantly, this body of work has yet to directly influence clinical practice. It has long been a goal for the fields of clinical psychology and psychiatry to have a means of making objective diagnoses of mental disorders. Frustratingly little movement has been achieved on this front, however, and the gold-standard’ of diagnostic validity and reliability remains expert consensus. In light of this challenge, the focus of the current review is to provide a critical summary of key findings from different neuroimaging approaches in MDD research, including structural, functional and neurochemical imaging studies. Following this summary, we discuss some of the current conceptual obstacles to better understanding the pathophysiology of depression, and conclude with recommendations for future neuroimaging research.