Anhedonia represents one of the most debilitating yet clinically challenging phenomenological features in psychopathology, stripping individuals of their intrinsic capacity to anticipate, experience, and integrate rewarding stimuli into adaptive behavior. Far beyond mere sadness or affective flattening, it reflects profound disruptions across distributed neurobiological systems governing motivation, reinforcement learning, and hedonic valuation.
Anhedonia
1. Concise Definition
Anhedonia is defined as the significantly diminished capacity or total inability to experience pleasure from activities, relationships, and physical sensations that are ordinarily perceived as rewarding or enjoyable. Historically classified as a unitary symptom of affective and psychotic spectrum conditions, contemporary psychiatry conceptualizes anhedonia as a multidimensional construct spanning motivational, anticipatory, and consummatory deficits within the broader neurobiology of reward processing.
In clinical nomenclature, anhedonia serves as one of the two cardinal diagnostic criteria for Major Depressive Disorder within the Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR), alongside persistently depressed mood. However, its presence extends across a diverse transdiagnostic spectrum, emerging prominently in schizophrenia, substance use disorders, post-traumatic stress disorder, Parkinson’s disease, and chronic neuroinflammatory states. Individuals experiencing anhedonia often describe their internal emotional landscape not necessarily as an acute, painful sadness, but as a hollow, blunted indifference where previously cherished passions, intellectual pursuits, social connections, and sensory pleasures cease to evoke positive affective resonance.
Modern affective neuroscience further deconstructs anhedonia into distinct behavioral components: anticipatory anhedonia, which impairs the forward-looking desire or prediction of future enjoyment, and consummatory anhedonia, which compromises the immediate, in-the-moment hedonic response to a stimulus. By analyzing how these components interact, researchers can map the underlying dysfunctions in neurochemical and circuit-level reward architecture, separating the drive to obtain rewards from the hedonic experience of receiving them.
2. Etymology & Linguistic Origin
The term anhedonia derives from the Ancient Greek prefix an- (ἀν-), denoting negation or absence ("without"), compounded with the substantive noun hēdonē (ἡδονή), meaning "pleasure," "delight," or "enjoyment." Its linguistic root is shared with the philosophical concept of hedonism, which posits pleasure as the ultimate intrinsic good or motivational drive of sentient beings.
The word was formally introduced into psychological and psychiatric nomenclature in 1896 by the French psychologist and philosopher Théodule-Armand Ribot in his foundational treatise La Psychologie des sentiments (The Psychology of the Emotions). Ribot recognized that while medical science possessed terms such as "analgesia" to describe the absence or insensitivity to physical pain, no symmetrical lexical designation existed to capture the pathological insensitivity to pleasure. Ribot coined "anhédonie" to fill this conceptual lacuna, identifying it as an affective anesthesia that could manifest either as an acute episodic disturbance or as a stable, constitutional personality trait.
3. Pronunciation & Grammatical Form
Pronunciation: The standard International Phonetic Alphabet (IPA) transcription for the term is /ˌæn.hɪˈdoʊ.ni.ə/ in American English and /ˌæn.hɪˈdəʊ.ni.ə/ in British English.
Part of Speech: Uncountable noun.
Grammatical Variants and Derivatives:
- Adjective: Anhedonic (/ˌæn.hɪˈdɒn.ɪk/), used to describe a person, affective state, phenotype, or symptom profile marked by an absence of pleasure (e.g., "anhedonic presentation," "anhedonic depression").
- Noun (Agent): Anhedonic, occasionally employed to denote an individual manifesting this trait or symptom.
- Adverb: Anhedonically, characterizing actions performed without affective pleasure or subjective reward.
4. Detailed Conceptual Explanation
To fully grasp the scope and boundaries of anhedonia, it is necessary to examine reward processing not as a monolithic event, but as a complex, iterative neurobehavioral cascade. In healthy physiological functioning, the processing of rewarding stimuli involves four interconnected phases: reward valuation (appraising the subjective utility of an outcome), motivation/anticipation (expending energy and planning to secure the reward), consummation (experiencing the in-the-moment sensory and affective pleasure), and reinforcement learning (encoding the outcome to guide future decision-making). Classical definitions focused almost exclusively on the consummatory phase, treating anhedonia simply as a deadening of positive affect upon encountering a pleasant stimulus.
However, contemporary clinical neuroscience distinguishes between the motivational component of reward—frequently referred to as "wanting" or incentive salience—and the affective component—termed "liking." Converging psychophysiological evidence reveals that many individuals with psychiatric disorders who report profound anhedonia on retrospective self-report scales retain preserved "liking" capacity when presented with immediate, evocative stimuli in controlled laboratory environments. Their deficit lies predominantly within the domain of "wanting": an inability to anticipate reward, compute the effort-to-reward ratio, maintain positive mental representations over time, and translate hedonic anticipation into goal-directed motoric action.
At the neurobiological level, anhedonia reflects structural and functional abnormalities within cortico-striatal-limbic circuits. The mesolimbic and mesocortical dopamine pathways, originating in the ventral tegmental area (VTA) and projecting forward to the ventral striatum (incorporating the nucleus accumbens) and the prefrontal cortex, are fundamental to the calculation of reward prediction errors and incentive motivation. When dopamine neurotransmission within these circuits is blunted or dysregulated, individuals lose the neurochemical drive required to initiate behavior toward potentially rewarding outcomes.
Concurrently, the consummatory hedonic "hotspots"—specialized, highly localized subregions within the nucleus accumbens shell and ventral pallidum—rely on endogenous opioid, endocannabinoid, and gamma-aminobutyric acid (GABA) signaling rather than dopamine. In individuals demonstrating authentic consummatory deficits, disruptions within these discrete subcortical hotspots impede the generation of positive hedonic impact. Furthermore, altered connectivity between the ventral striatum and the orbitofrontal cortex (OFC), anterior cingulate cortex (ACC), and ventromedial prefrontal cortex (vmPFC) compromises the cognitive evaluation of reward magnitude, rendering patients unable to properly calibrate effort expenditure against expected hedonic return.
5. Historical Development
The historical trajectory of anhedonia reflects evolving perspectives on psychopathology, moving from qualitative philosophical psychopathology to descriptive psychiatry, and ultimately to contemporary computational and cognitive neuroscience.
Following Théodule-Armand Ribot’s initial coining of the term in 1896, early psychiatric pioneers integrated anhedonia into foundational frameworks of major psychiatric illnesses. Emil Kraepelin observed that patients suffering from dementia praecox (later termed schizophrenia) exhibited a profound loss of interest in external affairs and an incapacity to derive pleasure from their surrounding environment. Kraepelin categorized these disruptions as foundational deficits in emotional volition and affective life, foreshadowing modern models of negative symptom domains.
In the mid-20th century, psychoanalyst Sándor Radó elevated anhedonia to a central etiologic position in his adaptational psychodynamics. In 1956, Radó posited that an innate or acquired "pleasure deficiency" constituted the core hereditary defect predisposing individuals to schizophrenia. Radó argued that without an intact primary pleasure apparatus to reinforce reality-based adaptations and buffer against psychic distress, the individual would inevitably manifest disorganized thinking, emotional withdrawal, and social fragmentation.
During the 1970s and 1980s, Paul Meehl expanded upon Radó’s ideas, introducing the concept of "hypokrisia" and arguing that anhedonia was a genetically determined, neurobehavioral vulnerability marker for the schizophrenia spectrum (the "schizotypic diathesis"). Around the same period, Loren and Jean Chapman developed psychometric instruments designed to systematically quantify physical and social anhedonia, demonstrating that enduring anhedonic traits could identify individuals at elevated statistical risk for psychosis.
Simultaneously, descriptive psychiatry codified anhedonia as an essential pillar of mood disorders. The publication of the Research Diagnostic Criteria (RDC) in 1978 and the DSM-III in 1980 firmly cemented anhedonia as a required core symptom for the diagnosis of major depressive episodes and melancholic depression. In recent decades, the advent of the National Institute of Mental Health’s Research Domain Criteria (RDoC) initiative has further reshaped the landscape, liberating anhedonia from categorical diagnostic silos and conceptualizing it as a continuous, transdiagnostic disruption within the Positive Valence Systems domain.
6. Theoretical Foundations
Several theoretical frameworks explain how anhedonia emerges, persists, and impacts overall psychosocial functioning.
The foremost framework is Kent Berridge and Terry Robinson’s Incentive Salience Theory. This model differentiates between "wanting" (incentive salience attributed to reward representations, mediated primarily by mesolimbic dopamine) and "liking" (the qualitative experience of pleasure, mediated by localized opioid and cannabinoid hedonic hotspots). Under this paradigm, classic depressive and psychotic anhedonia is primarily understood as a disorder of incentive salience: the "wanting" mechanism fails to energize behavior toward rewards, even though the fundamental "liking" system may remain intact when stimuli are encountered directly.
A second framework stems from Reinforcement Learning and Computational Psychiatry. This model asserts that hedonic perception is fundamentally dynamic, guided by the computation of Reward Prediction Errors (RPEs)—the mathematical difference between an expected outcome and the actual outcome. Dopaminergic firing in the striatum signals these discrepancies. In anhedonic individuals, blunted neural responses to RPEs impair their ability to update representations of reward value. As a result, even if an activity yields pleasure, the individual fails to integrate that information into long-term behavioral strategies, leading to a persistent expectation that future efforts will be unrewarding.
A third perspective involves Effort-Based Decision-Making models, popularized by Michael Treadway and colleagues. This framework conceptualizes anhedonia as a distortion in cost-benefit valuation. Rather than an inability to register sensory pleasure, anhedonia reflects a pathological increase in perceived effort costs or a failure of reward magnitude to override effort thresholds. When confronted with tasks that require cognitive or physical exertion, individuals with high levels of anhedonia show a blunted willingness to allocate effort for potential rewards, retreating into behavioral passivity.
Finally, the Neuroinflammatory Model provides a crucial biological framework. Peripheral systemic inflammation—evidenced by elevated inflammatory cytokines such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP)—triggers neuroinflammation within the central nervous system. These cytokines alter microglial activation, accelerate the conversion of tryptophan to kynurenine (depleting serotonin and producing neurotoxic metabolites), and suppress both presynaptic dopamine synthesis and vesicular storage. Consequently, neuroinflammation induces sickness behavior, an evolutionary defense mechanism characterized by lethargy, social withdrawal, and profound anhedonia.
7. Key Components, Types & Dimensions
Anhedonia is an umbrella term encompassing multiple subtypes and dimensions across affective, cognitive, and social domains:
- Anticipatory Anhedonia: The inability to forecast, expect, or imagine future enjoyment from upcoming events. This deficit directly impairs goal setting, forward planning, and proactive engagement in hobbies, social events, or occupational activities.
- Consummatory Anhedonia: The reduction or complete absence of experiential pleasure during direct contact with a rewarding stimulus, such as savoring a meal, listening to music, or experiencing tactile affection.
- Physical Anhedonia: A marked diminution in the capacity to derive pleasure from physical, sensory, or somatic inputs, including gustatory (food), olfactory (fragrances), tactile (touch), auditory (music), and sexual stimuli.
- Social Anhedonia: A persistent lack of pleasure derived from interpersonal relationships, social interactions, conversational exchanges, belonging to peer groups, or engaging in reciprocal emotional bonds.
- Trait vs. State Anhedonia: Trait anhedonia represents an enduring, lifelong temperamental baseline characteristic, often associated with schizotypy or genetic vulnerability. State anhedonia represents a time-limited, episodic exacerbation that emerges during acute psychiatric conditions, such as major depressive episodes or severe stress.
- Motivational Anhedonia (Avolitional Component): A failure of reward-related cues to elicit behavioral motivation and motor readiness, resulting in significant passivity and diminished goal-directed activity.
8. Examples & Illustrative Cases
To contextualize anhedonia across clinical presentations, consider the following illustrative profiles reflecting affective and psychotic manifestations:
Case Vignette 1: Major Depressive Disorder with Melancholic Features
A 44-year-old software architect presents with a four-month history of severe vegetative depression. He reports an absolute inability to experience joy, describing his mental state as a "gray vacuum." An accomplished amateur pianist and avid marathon runner, he has entirely abandoned these activities. When urged by family members to sit at the piano, he touches the keys but notes that the music "sounds completely dead and flat" to him; it elicits no emotional resonance whatsoever (consummatory anhedonia). Furthermore, he cannot imagine experiencing satisfaction from completing a work project or attending his daughter’s graduation (anticipatory anhedonia), which leads to profound avolition and psychomotor slowing. He clarifies that he is not necessarily weeping or actively desperate, but rather feels entirely depleted of emotional color and reward responsiveness.
Case Vignette 2: Schizophrenia Spectrum Deficit Syndrome
A 23-year-old university student is evaluated following progressive academic decline and social withdrawal. When interviewed, the patient demonstrates profound social anhedonia. He reports that spending time with lifelong friends feels "completely pointless and exhausting," noting that interpersonal interactions provide zero emotional warmth or satisfaction. Interestingly, when administered an experimental behavioral task involving chocolate tasting, the patient rates the immediate sweetness and palatability as moderately pleasant (preserved consummatory capacity). However, when asked whether he would walk to a local cafe to purchase the same chocolate, he declines, stating that the anticipated reward does not justify the energy required to make the trip (effort-based motivational deficit).
9. Measurement & Assessment
Assessing anhedonia requires reliable diagnostic tools capable of differentiating between its dimensions and separating it from general psychological distress or depressive sadness.
Self-Report Psychometric Scales:
- Snaith-Hamilton Pleasure Scale (SHAPS): A widely utilized, 14-item clinical scale designed explicitly to measure hedonic capacity across four primary domains: interests/pastimes, social interaction, sensory experience, and food/drink. The SHAPS is prized for its brevity, unidimensional reliability, and focus on state-dependent changes rather than enduring personality traits.
- Temporal Experience of Pleasure Scale (TEPS): A 18-item questionnaire that explicitly dissociates anticipatory pleasure (e.g., "When I think about eating my favorite meal, I get excited") from consummatory pleasure (e.g., "The smell of freshly cut grass is wonderful"), making it highly valuable in modern neurocognitive research.
- Chapman Scales (Physical and Social Anhedonia Scales): Longitudinal research instruments consisting of true/false items that assess trait-like vulnerabilities, particularly in schizotypy and schizophrenia vulnerability models.
- Dimensional Anhedonia Rating Scale (DARS): A newer, highly sensitive multidimensional scale that assesses desire, motivation, effort, and consummatory pleasure across self-generated, personally meaningful reward domains.
Behavioral and Neurocognitive Paradigms:
- Effort-Expenditure for Rewards Task (EEfRT): A computerized decision-making task wherein participants choose between low-effort/low-reward options and high-effort/high-reward options at varying probability levels, directly measuring how reward magnitude influences physical effort choices.
- Probabilistic Reward Task (PRT): A signal-detection paradigm based on reinforcement schedules, designed by Diego Pizzagalli. It quantifies reward responsiveness by measuring how effectively a participant develops a response bias toward more frequently rewarded stimuli.
10. Applications & Practical Significance
Understanding anhedonia is critical for clinical diagnostics, risk stratification, and targeted treatment development.
In clinical psychiatry, the presence of persistent anhedonia is one of the most reliable predictors of poor long-term prognosis. Patients with major depression who exhibit high baseline levels of anhedonia respond significantly worse to standard first-line selective serotonin reuptake inhibitors (SSRIs), exhibit longer times to remission, experience higher relapse rates, and demonstrate greater overall functional and occupational disability. Importantly, emerging epidemiological evidence identifies severe anhedonia as an independent, robust risk factor for completed suicide, likely because the inability to anticipate future pleasure fosters profound hopelessness and existential despair.
From a pharmacological standpoint, recognizing anhedonia has catalyzed a major shift away from purely serotonergic interventions toward agents that modulate catecholaminergic, glutamatergic, and opioid circuitry. Standard SSRIs, while effective for anxiety and negative affect, can occasionally induce or exacerbate emotional blunting and anhedonia via downstream serotonergic inhibition of dopamine release in the ventral striatum and prefrontal cortex. As a result, clinicians increasingly look toward dual norepinephrine-dopamine reuptake inhibitors (such as bupropion), atypical antipsychotics with dopamine partial agonism (e.g., aripiprazole, cariprazine), and rapid-acting glutamatergic modulators such as intravenous ketamine and intranasal esketamine, which stimulate synaptogenesis and rapidly restore ventral striatal reward responsiveness.
In psychotherapeutic domains, traditional cognitive therapies focused primarily on cognitive restructuring often fail to adequately target anhedonia. This has led to the adoption of specialized behavioral interventions, such as Behavioral Activation (BA) and Positive Affect Treatment (PAT). These protocols systematically target reward sensitivity by scheduling intrinsically rewarding tasks, practicing hedonic savoring, training individuals to attend to positive environmental cues, and counteracting effort-avoidant decision-making.
11. Research & Empirical Evidence
Decades of neuroimaging and psychophysiological research have established that anhedonia is linked to identifiable biological alterations rather than mere cognitive pessimism.
Functional magnetic resonance imaging (fMRI) studies consistently reveal altered blood-oxygen-level-dependent (BOLD) signals in the ventral striatum of anhedonic individuals. In seminal work conducted by Diego Pizzagalli and colleagues, patients with major depressive disorder demonstrated significantly blunted striatal activation during reward anticipation and receipt compared to healthy controls. This reduced activation directly correlates with the severity of clinically measured anhedonia. Concurrently, hyperconnectivity between the subgenual anterior cingulate cortex and default mode network hubs suggests that internally focused ruminative processes continually disrupt the brain’s capacity to allocate neural resources outward toward external rewards.
Neurochemical and PET imaging studies have corroborated these functional disruptions, demonstrating lower dopamine transporter binding and reduced D2/D3 receptor availability within the striatum of anhedonic cohorts. Moreover, pharmacologic challenge paradigms indicate that administering low doses of pramipexole (a dopamine D2/D3 agonist) can partially restore reward learning capacity in anhedonic patients.
A growing body of literature focuses on immunopsychiatry. Clinical trials demonstrate that administering endotoxins or interferon-alpha (IFN-alpha) to healthy volunteers precipitates acute anhedonia, which is accompanied by reduced ventral striatal activation during reward tasks. Conversely, clinical trials exploring monoclonal antibodies targeting pro-inflammatory cytokines (such as infliximab) show notable improvements in hedonic capacity, specifically among depressed patients with elevated baseline peripheral inflammatory markers (e.g., CRP > 3 mg/L).
12. Cultural & Cross-Cultural Considerations
While anhedonia represents a biologically grounded disruption in human reward systems, its phenomenological expression, conceptualization, and reporting vary considerably across distinct sociocultural contexts.
In Western societies influenced by cultural mandates emphasizing individualism and personal fulfillment, hedonic capacity is often framed as a core component of psychological health and personal success. Consequently, a failure to experience pleasure is readily recognized, conceptualized as an internal deficit, and reported as a primary psychiatric symptom. In contrast, in societies influenced by collectivist traditions, emotional restraint, or Buddhist and Daoist philosophical frameworks, the pursuit of individual sensory pleasure may be less emphasized or viewed with ambivalence. In these cultural contexts, individuals suffering from depressive syndromes may not spontaneously report anhedonia as an emotional absence; instead, they may report distress through somatosensory metaphors—such as physical weakness, lack of physical vitality, or a loss of energy and moral motivation.
Furthermore, cross-cultural psychometric evaluations of instruments like the SHAPS and Chapman Scales reveal linguistic and behavioral variations. For instance, assessment items assessing enjoyment of sensory experiences (e.g., "a warm cup of tea," "the scent of flowers") or social leisure pastimes carry differing contextual values across socioeconomic strata and urban versus rural settings. Clinical evaluators must therefore ensure that diagnostic interviews distinguish genuine neurobiological reward dysfunction from cultural variations in hedonic display, religious asceticism, or structural limitations on accessing rewarding environmental opportunities.
13. Criticisms, Debates & Limitations
Despite significant empirical advancements, several conceptual controversies and methodological limitations remain prominent in the field.
A major debate concerns the ecological validity of laboratory assessments compared to real-world emotional experiences. While behavioral tasks like the EEfRT and PRT offer objective, quantifiable indices of reward behavior, critics argue they oversimplify the rich, multifaceted nature of human pleasure. Conversely, retrospective self-report scales are vulnerable to recall biases, where current negative mood states distort a person’s recollection of past hedonic events. To bridge this gap, modern psychiatric research increasingly utilizes Ecological Momentary Assessment (EMA), which captures real-time affective states in everyday life.
Another fundamental controversy centers on whether anhedonia represents a distinct categorical clinical entity, an endophenotype, or simply an epiphenomenon of overall psychiatric severity. Some researchers question whether anhedonia should be classified as a primary symptom or if it is secondary to other clinical factors, such as psychomotor retardation, profound emotional distress, cognitive deficits, or pharmaceutical side effects (such as SSRI-induced apathy or neuroleptic-induced indifference).
Finally, the diagnostic conflation of "anticipatory" versus "consummatory" pleasure in legacy classification systems remains a major point of critique. Standard clinical tools frequently group together items measuring hedonic enjoyment, interest, and physical energy, obscuring the precise neurochemical mechanisms at play in an individual patient. This limits the personalization of therapeutic interventions.
14. Related Terms & Distinctions
Anhedonia must be carefully differentiated from several overlapping psychiatric, neurologic, and affective constructs:
- Apathy: Characterized by a general loss of motivation, initiative, and emotional responsiveness. While an individual with apathy lacks the goal-directed drive to initiate actions, an anhedonic individual specifically lacks the capacity to derive or anticipate pleasure from those actions, even though they may retain cognitive insight and experience frustration over this absence.
- Abulia: A severe neurological deficit of willpower, volition, and decision-making capacity, typically linked to basal ganglia or frontal lobe damage. Abulia represents a profound physical and verbal inertia, far exceeding the hedonic deficits seen in anhedonia.
- Alexithymia: A subclinical cognitive-affective trait characterized by difficulty identifying, describing, and distinguishing emotional states from bodily sensations. An alexithymic individual may experience pleasure physiologically, but cannot label or cognitively articulate their emotional state, whereas an anhedonic individual understands the concept of pleasure but is physically and affectively incapable of experiencing it.
- Dysphoria: An emotional state characterized by profound unease, dissatisfaction, and subjective distress. Dysphoria is an active, painful negative affective state, whereas anhedonia is the blunting or absence of positive affective capacity.
- Avolition: A psychological deficit characterized by a profound lack of motivation to initiate and persist in goal-directed activities. Avolition represents the behavioral consequence of impaired motivation, whereas anhedonia represents the underlying affective and predictive reward impairment.
- Depression: A broad, systemic affective syndrome encompassing cognitive, somatic, and emotional disturbances. Anhedonia is a specific core symptom and neurobiological dimension within depression, but depression also involves guilt, suicidal ideation, psychomotor changes, and negative affect.
15. Summary / Key Takeaways
Anhedonia is a multidimensional neurobiological and psychological phenomenon characterized by the inability to anticipate, experience, or pursue pleasure. Far from a simple emotional blunting, it reflects distributed network dysfunctions within cortico-striatal-limbic dopamine, opioid, and glutamatergic pathways, commonly exacerbated by systemic neuroinflammation and chronic stress. Deconstructing the symptom into anticipatory, consummatory, and effort-valuation components has transformed our understanding of reward processing.
As psychiatric neuroscience moves toward transdiagnostic frameworks like the RDoC, anhedonia stands as a prime example of an objective, circuit-based neurobehavioral deficit. Recognizing its presence is crucial for clinicians, as it signals a heightened risk for chronic treatment resistance and suicidal behavior. Addressing anhedonia demands targeted interventions—ranging from dopaminergic and rapid-acting glutamatergic pharmacotherapies to specialized, positive-affect-focused psychotherapies—aimed at re-engaging the neural circuits that bring color, motivation, and vital hedonic meaning to human experience.
References
- Berridge, K. C., & Robinson, T. E. (2003). Parsing reward. Trends in Neurosciences, 26(9), 507–513. https://doi.org/10.1016/S0166-2236(03)00233-9
- Der-Avakian, A., & Markou, A. (2012). The neurobiology of anhedonia and other reward-related deficits. Trends in Neurosciences, 35(1), 68–77. https://doi.org/10.1016/j.tins.2011.11.005
- Pizzagalli, D. A. (2014). Depression, stress, and anhedonia: Toward a synthesis and integrated model. Annual Review of Clinical Psychology, 10, 393–423. https://doi.org/10.1146/annurev-clinpsy-050212-185606
- Ribot, T. (1896). La Psychologie des sentiments. Félix Alcan.
- Treadway, M. T., & Zald, D. H. (2011). Reconsidering anhedonia in depression: Lessons from translational neuroscience. Neuroscience & Biobehavioral Reviews, 35(3), 537–555. https://doi.org/10.1016/j.neubiorev.2010.06.006