The neurobiology of anhedonia and other reward-related deficits

doi:10.1016/j.tins.2011.11.005

Trends in Neurosciences

Volume 35, Issue 1, January 2012, Pages 68-77

https://doi.org/10.1016/j.tins.2011.11.005 Get rights and content

Anhedonia, or markedly diminished interest or pleasure, is a hallmark symptom of major depression, schizophrenia and other neuropsychiatric disorders. Over the past three decades, the clinical definition of anhedonia has remained relatively unchanged, although cognitive psychology and behavioral neuroscience have expanded our understanding of other reward-related processes. Here, we review the neural bases of the construct of anhedonia that reflects deficits in hedonic capacity and also closely linked to the constructs of reward valuation, decision-making, anticipation and motivation. The neural circuits subserving these reward-related processes include the ventral striatum, prefrontal cortical regions, and afferent and efferent projections. An understanding of anhedonia and other reward-related constructs will facilitate the diagnosis and treatment of disorders that include reward deficits as key symptoms.

Introduction

For it is then that we have need of pleasure, when we feel pain owing to the absence of pleasure. Epicurus (341–270 B.C.) [1]

Anhedonia, or loss of interest or pleasure in all or almost all activities, is a prominent symptom of many neuropsychiatric disorders, most notably major depressive disorder (MDD) and schizophrenia (see Glossary) [2]. Greek philosophers, such as Epicurus, contemplated the nature of pleasure (and the absence of pleasure) over 2000 years ago. Today, however, reward-related deficits experienced by individuals with MDD, schizophrenia and other neuropsychiatric disorders involve more than just an absence or loss of pleasure. Anhedonia is a core feature of reward deficits because the capacity to feel pleasure is a critical step during the normal processing of rewards. However, having the motivation to seek out pleasurable experiences and making appropriate decisions based on those previous experiences are important processes that are equally, if not more in some cases, disturbed in individuals with MDD or schizophrenia. Deficits in these reward processes are often inappropriately labeled under the umbrella of anhedonia. The current preclinical and clinical literature regarding the neural bases of the various aspects of reward processing, and the contribution of deficits in these reward processes to the clinical symptom of anhedonia, is reviewed here.

Section snippets

A brief history of anhedonia

Anhedonia as a psychopathological symptom was first noted in the early 19th century. Haslam, who documented the first complete study of a psychiatric patient in 1809 (suffering from schizophrenia), noted a ‘neglect [of] those objects and pursuits which formerly proved sources of delight and instruction’ [3]. The term anhedonie was later introduced by the French psychologist Ribot in 1896 to describe the counterpart to analgesia in his patients, for whom ‘it was impossible to find the least

Reward deficits beyond anhedonia

There are numerous published studies documenting the neurobiological changes associated with MDD, schizophrenia and other neuropsychiatric disorders characterized by anhedonia, but relatively few that specifically examined the presence or severity of anhedonia. Considering that MDD and schizophrenia are characterized by various symptoms, it is unlikely that the neural circuits mediating anhedonia are also involved in, for example, hallucinations or feelings of guilt. Thus, it is challenging to

Assessments of anhedonia in humans and experimental animals

Traditional subjective self-report measures of anhedonia assess the ability to experience pleasurable events. In these assessments, individuals respond to statements such as ‘I would enjoy being with my family or close friends’ [Snaith-Hamilton Pleasure Scale (SHAPS)]. The preclinical analogs to these anhedonia scales, and the procedures most commonly used to assess depression-like behavior in rodents, are the sucrose intake and preference tests, whereby decreased intake of or preference for a

Dissecting the circuits of anhedonia and other reward-related deficits

The majority of studies in humans to assess the neurobiology of anhedonia have involved MDD or schizophrenia patients, although we could extrapolate that the same circuits are likely to be involved in anhedonia exhibited in other neuropsychiatric disorders, such as PD and AD. Although anhedonia in clinical populations is primarily defined by subjective responses to self-report questionnaires, these purported measures of anhedonia may also reflect deficits in other reward processes, such as

Constructing the circuits for anhedonia, anticipation, valuation, decision-making and avolition

Although distinct neural regions code for separate reward processes, the circuits connecting these regions allow an individual to: (i) sense a pleasant stimulus; (ii) compute reward value and associated costs; (iii) determine effort requirements to obtain that stimulus; (iv) decide to obtain that stimulus; and (v) anticipate and increase motivation to obtain that stimulus (Figure 2). The hedonic perception of rewards is mediated primarily by endogenous opioid, GABA and endocannabinoid systems

Concluding remarks and future considerations

The focus on neurobiological markers of specific behaviors, rather than entire disorders, has led to significant advances in our understanding of anhedonia and related reward deficits in neuropsychiatric disorders. One advantage for clinical researchers is that preclinical research has provided a wealth of information regarding the neurobiology of reward-related processes, from perceiving pleasure to coding reward value, assessing costs and benefits, learning from prior reinforcement,

Disclosure statement

A.M. has received contract research support from Lundbeck, Bristol-Myers Squibb Co., F. Hoffman-La Roche, Pfizer, and Astra-Zeneca, and honoraria/consulting fees from Abbott GmbH and Company, AstraZeneca, and Pfizer during the past 3 years. A.M. has a patent application on the use of metabotropic glutamate compounds for the treatment of nicotine dependence.

Acknowledgments

This work was supported by National Institutes of Health grants R01MH62527 and R01MH087989 (to A.M.), and a National Research Service Award Individual Postdoctoral fellowship F32MH080585 (to A.D.) from the National Institute of Mental Health. The authors would like to thank Ms. Janet Hightower for her assistance with graphics.

Glossary

Anhedonia: markedly diminished interest or pleasure in all, or almost all, activities
Avolition: a reduction or difficulty in the ability to initiate and persist in goal-directed behavior; lack of motivation.
Chapman Physical and Social Anhedonia Scales (CPAS/CSAS): self-report anhedonia scales that differentiate between physical (eating, sex) and social (expressing feelings and interacting with people) pleasures.
Deep brain stimulation (DBS): clinical procedure involving surgical implantation of

References (132)

A. Markou
Neurobiological similarities in depression and drug dependence: a self-medication hypothesis
Neuropsychopharmacology
(1998)
C. Davis et al.
Sensitivity to the rewarding effects of food and exercise in the eating disorders
Compr. Psychiatry
(2002)
M. Leboyer
Psychiatric genetics: search for phenotypes
Trends Neurosci.
(1998)
K. Matthews
Sucrose consumption as an hedonic measure following chronic unpredictable mild stress
Physiol. Behav.
(1995)
I. Berlin
Measures of anhedonia and hedonic responses to sucrose in depressive and schizophrenic patients in comparison with healthy subjects
Eur. Psychiatry
(1998)
A.E. Kelley
Opioid modulation of taste hedonics within the ventral striatum
Physiol. Behav.
(2002)
P.A. Keedwell
The neural correlates of anhedonia in major depressive disorder
Biol. Psychiatry
(2005)
P.O. Harvey
Functional neural substrates of self-reported physical anhedonia in non-clinical individuals and in patients with schizophrenia
J. Psychiatr. Res.
(2010)
I.H. Park
Medial prefrontal default-mode hypoactivity affecting trait physical anhedonia in schizophrenia
Psychiatry Res.
(2009)
J. Wacker
The role of the nucleus accumbens and rostral anterior cingulate cortex in anhedonia: integration of resting EEG, fMRI, and volumetric techniques
Neuroimage
(2009)

I.M. Rosso

Regional prefrontal cortex gray matter volumes in youth at familial risk for schizophrenia from the Harvard Adolescent High Risk Study

Schizophr. Res.

(2010)

F. Zijlstra

Neurobiological substrates of cue-elicited craving and anhedonia in recently abstinent opioid-dependent males

Drug Alcohol Depend.

(2009)

H.S. Mayberg

Regional metabolic effects of fluoxetine in major depression: serial changes and relationship to clinical response

Biol. Psychiatry

(2000)

H.S. Mayberg

Deep brain stimulation for treatment-resistant depression

Neuron

(2005)

F. Grabenhorst et al.

Value, pleasure and choice in the ventral prefrontal cortex

Trends Cogn. Sci.

(2011)

E.C. Dowd et al.

Anhedonia and emotional experience in schizophrenia: neural and behavioral indicators

Biol. Psychiatry

(2010)

K.C. Berridge et al.

What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?

Brain Res. Brain Res. Rev.

(1998)

T.E. Hazy

Neural mechanisms of acquired phasic dopamine responses in learning

Neurosci. Biobehav. Rev.

(2010)

J.D. Salamone

Anhedonia or anergia? Effects of haloperidol and nucleus accumbens dopamine depletion on instrumental response selection in a T-maze cost/benefit procedure

Behav. Brain Res.

(1994)

M. Correa

Nucleus accumbens dopamine and work requirements on interval schedules

Behav. Brain Res.

(2002)

J.D. Salamone

Beyond the reward hypothesis: alternative functions of nucleus accumbens dopamine

Curr. Opin. Pharmacol.

(2005)

F. Weiss

Basal extracellular dopamine levels in the nucleus accumbens are decreased during cocaine withdrawal after unlimited-access self-administration

Brain Res.

(1992)

A.A. Harrison

Fluoxetine combined with a serotonin-1A receptor antagonist reversed reward deficits observed during nicotine and amphetamine withdrawal in rats

Neuropsychopharmacology

(2001)

A.K. Stoker et al.

Withdrawal from chronic cocaine administration induces deficits in brain reward function in C57BL/6J mice

Behav. Brain Res.

(2011)

A.M. Barr et al.

Increased successive negative contrast in rats withdrawn from an escalating-dose schedule of d-amphetamine

Pharmacol. Biochem. Behav.

(2002)

A. Santamaria et al.

Neurochemical and behavioral effects elicited by bupropion and diethylpropion in rats

Behav. Brain Res.

(2010)

A. Egerton

Acute effect of the anti-addiction drug bupropion on extracellular dopamine concentrations in the human striatum: an [¹¹C]raclopride PET study

Neuroimage

(2010)

D.A. Malone

Deep brain stimulation of the ventral capsule/ventral striatum for treatment-resistant depression

Biol. Psychiatry

(2009)

B.H. Bewernick

Nucleus accumbens deep brain stimulation decreases ratings of depression and anxiety in treatment-resistant depression

Biol. Psychiatry

(2010)

B.W. Balleine et al.

Parallel incentive processing: an integrated view of amygdala function

Trends Neurosci.

(2006)

E.A. Murray

The amygdala, reward and emotion

Trends Cogn. Sci.

(2007)

P. Skolnick

Glutamate-based antidepressants: 20 years on

Trends Pharmacol. Sci.

(2009)

R.M. Berman

Antidepressant effects of ketamine in depressed patients

Biol. Psychiatry

(2000)

R.S. Duman et al.

Signaling pathways underlying the pathophysiology and treatment of depression: novel mechanisms for rapid acting agents

Trends Neurosci.

(2012)

M.E. Liechti et al.

Interactive effects of the mGlu5 receptor antagonist MPEP and the mGlu2/3 receptor antagonist LY341495 on nicotine self-administration and reward deficits associated with nicotine withdrawal in rats

Eur. J. Pharmacol.

(2007)

L. Ossewaarde

Two-week administration of the combined serotonin–noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits

Biol. Psychiatry

(2011)

M. El Yacoubi

Chronic agomelatine and fluoxetine induce antidepressant-like effects in H/Rouen mice, a genetic mouse model of depression

Pharmacol. Biochem. Behav.

(2011)

E. Dremencov

Hyperfunctionality of serotonin-2C receptor-mediated inhibition of accumbal dopamine release in an animal model of depression is reversed by antidepressant treatment

Neuropharmacology

(2005)

A. Sartorius

Remission of major depression under deep brain stimulation of the lateral habenula in a therapy-refractory patient

Biol. Psychiatry

(2010)

N.H. Naqvi et al.

The hidden island of addiction: the insula

Trends Neurosci.

(2009)

J.W. Kable et al.

The neurobiology of decision: consensus and controversy

Neuron

(2009)

Epicurus et al.

Epicurus, The Extant Remains

(1926)

American Psychiatric Association Task Force on DSM-IV

Diagnostic and Statistical Manual of Mental Disorders: DSM-IV

(1994)

J. Haslam

Observations on Madness and Melancholy; Including Practical Remarks on those Diseases, together with Cases, and an Account of the Morbid Appearances on Dissection

(1809)

T. Ribot

La Psychologie des Sentiments

(1896)

S. Rado

Psychoanalysis of Behavior; Collected Papers

(1956)

P.E. Meehl

Schizotaxia, schizotypy, schizophrenia

Am. Psychol.

(1962)

L.J. Chapman

Scales for physical and social anhedonia

J. Abnorm. Psychol.

(1976)

D.F. Klein

Endogenomorphic depression. A conceptual and terminological revision

Arch. Gen. Psychiatry

(1974)

American Psychiatric Association Task Force on Nomenclature and Statistics and Committee on Nomenclature and Statistics

Diagnostic and Statistical Manual of Mental Disorders

(1980)

Cited by (721)

Construction of a depression risk prediction model for type 2 diabetes mellitus patients based on NHANES 2007–2014
2024, Journal of Affective Disorders
Type 2 diabetes mellitus (T2DM) is a prevalent global health issue that has been linked to an increased risk of depression. The objective of this study was to construct a nomogram model for predicting depression in T2DM patients.
A total of 4280 patients with T2DM were included in this study from the 2007–2014 NHANES. The entire dataset was split randomly into training set comprising 70 % of the data and a validation set comprising 30 % of the data. LASSO and multivariate logistic regression analyses identified predictors significantly associated with depression, and the nomogram was constructed with these predictors. The model was assessed by C-index, calibration curve, the hosmer–lemeshow test and decision curve analysis (DCA).
The nomogram model comprised of 9 predictors, namely age, gender, PIR, BMI, education attainment, smoking status, LDL-C, sleep duration and sleep disorder. The C-index of the training set was 0.780, while that of the validation set was 0.752, indicating favorable discrimination for the model. The model exhibited excellent clinical applicability and calibration in both the training and validation datasets. Moreover, the cut-off value of the nomogram is 223.
This study has shortcomings in data collection, lack of external validation, and results non-extrapolation.
Our nomogram exhibits high clinical predictability, enabling clinicians to utilize this tool in identifying high-risk depressed patients with T2DM. It has the potential to decrease the incidence of depression and significantly improve the prognosis of patients with T2DM.
Anhedonia in adolescents at transdiagnostic familial risk for severe mental illness: Clustering by symptoms and mechanisms of association with behavior
2024, Journal of Affective Disorders
Anhedonia is a transdiagnostic symptom of severe mental illness (SMI) and emerges during adolescence. Possible subphenotypes and neural mechanisms of anhedonia in adolescents at risk for SMI are understudied.
Adolescents at familial risk for SMI (N = 81) completed anhedonia (e.g., consummatory, anticipatory, social), demographic, and clinical measures and one year prior, a subsample (N = 46) completed fMRI scanning during a monetary reward task. Profiles were identified using k-means clustering of anhedonia type and differences in demographics, suicidal ideation, impulsivity, and emotional processes were examined. Moderation analyses were conducted to investigate whether levels of brain activation of reward regions moderated the relationships between anhedonia type and behaviors.
Two-clusters emerged: a high anhedonia profile (high-anhedonia), characterized by high levels of all types of anhedonia, (N = 32) and a low anhedonia profile (low-anhedonia), characterized by low levels of anhedonia types (N = 49). Adolescents in the high-anhedonia profile reported more suicidal ideation and negative affect, and less positive affect and desire for emotional closeness than low-anhedonia profile. Furthermore, more suicidal ideation, less positive affect, and less desire for emotional closeness differentiated the familial high-risk, high-anhedonia profile adolescents from the familial high-risk, low-anhedonia profile adolescents. Across anhedonia profiles, moderation analyses revealed that adolescents with high dmPFC neural activation in response to reward had positive relationships between social, anticipatory, and consummatory anhedonia and suicidal ideation.
Small subsample with fMRI data.
Profiles of anhedonia emerge transdiagnostically and vary on clinical features. Anhedonia severity and activation in frontostriatal reward areas have value for clinically important outcomes such as suicidal ideation.
Behavioral, neurochemical and neuroimmune features of RasGEF1b deficient mice
2024, Progress in Neuro-Psychopharmacology and Biological Psychiatry
The factor RasGEF1b is a Ras guanine exchange factor involved in immune responses. Studies have also implicated RasGEF1b in the CNS development. It is still limited the understanding of the role of RasGEF1b in CNS functioning. Using RasGEF1b deficient mice (RasGEF1b-cKO), we investigated the impact of this gene deletion in behavior, cognition, brain neurochemistry and microglia morphology. We showed that RasGEF1b-cKO mice display spontaneous hyperlocomotion and anhedonia. RasGEF1b-cKO mice also exhibited compulsive-like behavior that was restored after acute treatment with the selective serotonin reuptake inhibitor (SSRI) fluoxetine (5 mg/kg). A down-regulation of mRNA of dopamine receptor (Drd1, Drd2, Drd4 and Drd5) and serotonin receptor genes (5Htr1a, 5Htr1b and 5Htr1d) was observed in hippocampus of RasGEF1b-cKO mice. These mice also had reduction of Drd1 and Drd2 in prefrontal cortex and 5Htr1d in striatum. In addition, morphological alterations were observed in RasGEF1b deficient microglia along with decreased levels of hippocampal BDNF. We provided original evidence that the deletion of RasGEF1b leads to unique behavioral features, implicating this factor in CNS functioning.
A stress-sensitive frontostriatal circuit supporting effortful reward-seeking behavior
2024, Neuron
Effort valuation—a process for selecting actions based on the anticipated value of rewarding outcomes and expectations about the work required to obtain them—plays a fundamental role in decision-making. Effort valuation is disrupted in chronic stress states and is supported by the anterior cingulate cortex (ACC), but the circuit-level mechanisms by which the ACC regulates effort-based decision-making are unclear. Here, we show that ACC neurons projecting to the nucleus accumbens (ACC-NAc) play a critical role in effort valuation behavior in mice. Activity in ACC-NAc cells integrates both reward- and effort-related information, encoding a reward-related signal that scales with effort requirements and is necessary for supporting future effortful decisions. Chronic corticosterone exposure reduces motivation, suppresses effortful reward-seeking, and disrupts ACC-NAc signals. Together, our results delineate a stress-sensitive ACC-NAc circuit that supports effortful reward-seeking behavior by integrating reward and effort signals and reinforcing effort allocation in the service of maximizing reward.
Increased brain nucleus accumbens functional connectivity in melancholic depression
2024, Neuropharmacology
Melancholic depression, marked by typical symptoms of anhedonia, is regarded as a homogeneous subtype of major depressive disorder (MDD). However, little attention was paid to underlying mechanisms of melancholic depression. This study aims to examine functional connectivity of the reward circuit associated with anhedonia symptoms in melancholic depression.
Fifty-nine patients with first-episode drug- naive MDD, including 31 melancholic patients and 28 non-melancholic patients, were recruited and underwent resting-state functional magnetic resonance imaging (rs-fMRI). Thirty-two healthy volunteers were recruited as controls. Bilateral nucleus accumbens (NAc) were selected as seed points to form functional NAc network. Then support vector machine (SVM) was used to distinguish melancholic patients from non-melancholic patients.
Relative to non-melancholic patients, melancholic patients displayed increased functional connectivity (FC) between bilateral NAc and right middle frontal gyrus (MFG) and between right NAc and left cerebellum lobule VIII. Compared to healthy controls, melancholic patients showed increased FC between right NAc and right lingual gyrus and between left NAc and left postcentral gyrus; non-melancholic patients had increased FC between bilateral NAc and right lingual gyrus. No significant correlations were observed between altered FC and clinical variables in melancholic patients. SVM results showed that FC between left NAc and right MFG could accurately distinguish melancholic patients from non-melancholic patients.
Melancholic depression exhibited different patterns of functional connectivity of the reward circuit relative to non-melancholic patients. This study highlights the significance of the reward circuit in the neuropathology of melancholic depression.
Neural reward responsiveness and daily positive affect functioning in adolescent girls
2024, International Journal of Psychophysiology
Deficits in reward processing have been implicated in the development of many forms of psychopathology, especially major depressive disorder (MDD). One facet of reward processing, known as reward responsivity, has been associated with the development and maintenance of depression across development. The reward positivity (RewP) is an event-related potential derived from electroencephalogram (EEG), which is thought to reflect reward responsivity. An attenuated RewP has been observed in both currently depressed individuals and youth at risk for depression, suggesting it may represent a biomarker of depression. Despite this, little is known about how the RewP translates to behavior and affect in the real world. In the current study, we examined how the RewP relates to real world emotional functioning, measured using ecological momentary assessment (EMA). Thirty-eight female adolescents (ages 11–16, M_age = 13.9 years) participated in the study; approximately half of the sample were considered high risk due to maternal lifetime history of MDD. Adolescents completed a monetary reward task while EEG was recorded, followed by a 10-day period of EMA assessing daily affect and emotion regulation strategy use following positive events. Results revealed that the RewP was positively associated with subjective reports of positive, but not negative, daily affect. Results also revealed that the RewP was positively associated with focusing on positive feelings following a positive event (e.g., savoring). Findings from this preliminary study highlight how neural responses to reward in the lab relate to daily life emotional functioning, supporting the RewP as an ecologically valid marker of positive affect functioning among youth.

View all citing articles on Scopus

View full text

Trends in Neurosciences

ReviewSpecial Issue: Neuropsychiatric DisordersThe neurobiology of anhedonia and other reward-related deficits

Introduction

Section snippets

A brief history of anhedonia

Reward deficits beyond anhedonia

Assessments of anhedonia in humans and experimental animals

Dissecting the circuits of anhedonia and other reward-related deficits

Constructing the circuits for anhedonia, anticipation, valuation, decision-making and avolition

Concluding remarks and future considerations

Disclosure statement

Acknowledgments

Glossary

Neuropsychopharmacology

Compr. Psychiatry

Trends Neurosci.

Physiol. Behav.

Eur. Psychiatry

Physiol. Behav.

Biol. Psychiatry

J. Psychiatr. Res.

Psychiatry Res.

Neuroimage

Schizophr. Res.

Drug Alcohol Depend.

Biol. Psychiatry

Neuron

Trends Cogn. Sci.

Biol. Psychiatry

Brain Res. Brain Res. Rev.

Neurosci. Biobehav. Rev.

Behav. Brain Res.

Behav. Brain Res.

Curr. Opin. Pharmacol.

Brain Res.

Neuropsychopharmacology

Behav. Brain Res.

Pharmacol. Biochem. Behav.

Behav. Brain Res.

Neuroimage

Biol. Psychiatry

Biol. Psychiatry

Trends Neurosci.

Trends Cogn. Sci.

Trends Pharmacol. Sci.

Biol. Psychiatry

Trends Neurosci.

Eur. J. Pharmacol.

Biol. Psychiatry

Pharmacol. Biochem. Behav.

Neuropharmacology

Biol. Psychiatry

Trends Neurosci.

Neuron

Epicurus, The Extant Remains

Diagnostic and Statistical Manual of Mental Disorders: DSM-IV

Observations on Madness and Melancholy; Including Practical Remarks on those Diseases, together with Cases, and an Account of the Morbid Appearances on Dissection

La Psychologie des Sentiments

Psychoanalysis of Behavior; Collected Papers

Schizotaxia, schizotypy, schizophrenia

Am. Psychol.

Scales for physical and social anhedonia

J. Abnorm. Psychol.

Endogenomorphic depression. A conceptual and terminological revision

Arch. Gen. Psychiatry

Diagnostic and Statistical Manual of Mental Disorders

Review
Special Issue: Neuropsychiatric Disorders
The neurobiology of anhedonia and other reward-related deficits