REVIEWNeurobiological basis of motivational deficits in psychopathology☆
Introduction
Although it has been recognized for some time that motivational dysfunctions are commonplace in psychopathology, this subject has been receiving increasing interest in the recent literature (Demyttenaere et al., 2005, Salamone et al., 2006, Gard et al., 2009, Barch and Dowd, 2010, Treadway and Zald, 2011, Salamone and Correa, 2012, Markou et al., 2013, Fava et al., 2013, Davis et al., 2014, Barch et al., 2014, Arango et al., 2014). The present review will provide some conceptual background on the construct of motivation, and propose a framework that is relevant for research on both normal and pathological aspects of motivation. Particular emphasis will be placed on what is known about the neurobiological basis of activational aspects of motivation, including studies from animal models and human psychopathology (i.e., depression, schizophrenia and other disorders).
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Conceptual background: motivation
Motivation has been defined in several different ways, although there are common threads to these diverse definitions. Young (1961) defined motivation as the process of arousing actions, sustaining this activity in progress, and regulating its pattern. Motivation also has been defined as the behaviorally-relevant processes that enable an organism to regulate its external and/or internal environments (Salamone, 1992, Salamone, 2010, Ryan and Deci, 2000). Motivational functions often involve
Preclinical studies of behavioral activation and effort-related aspects of motivation
One brain system that has been consistently implicated in activational aspects of motivation is the mesolimbic dopamine (DA) system (Robbins and Everitt, 2007, Salamone et al., 2006). In rats, neurotoxic depletion of DA in the nucleus accumbens (i.e., NAcc; part of ventral striatum) reduces the motor activity instigated by psychomotor stimulant drugs (Koob et al., 1978), as well as the behavioral activities induced by motivational conditions such as periodic presentation of food to
The clinical vocabulary of amotivation
Various terms are used to label impairments in activational aspects of motivation (Markou et al., 2013). One frequently used term is fatigue, which is employed to label symptoms seen in several disorders, including depression, schizophrenia, multiple sclerosis and Parkinson׳s disease (Andreasen, 1981, Kay et al., 1987, Friedman et al., 2010, Waters et al., 2013). In this context, the term does not refer to muscle fatigue, but rather to something akin to “central fatigue”, which is used to
Healthy volunteer studies
The neurobiology of motivation and reward processing has been investigated in healthy volunteers using functional magnetic resonance imaging (fMRI) during the performance of effort-based reward paradigms. The most established type of tasks used involve the money-incentive delay (MID) paradigm (Knutson et al., 2000). Each trial begins with a cue indicating whether participants stand to win or lose money. They then wait during an anticipatory delay period before responding to a target stimulus to
Human lesion and neurodegenerative studies
A significant part of what is known about the neurobiology of motivation in humans comes from instances where a degenerative process or brain lesion has led to apathy and lack of motivation. It has been suggested (Cummings, 1993) that the latter result when a fronto-striatal network comprising Brodmann areas 24 and 8 (AC and supplementary motor area respecitvely) and the ventral striatum (NAcc, ventromedial caudate, ventral putamen and olfactory tubercule) is affected. These structures project
Schizophrenia
Apathy and avolition (AA) are some of the most significant negative symptoms of schizophrenia. Factor analyses have identified AA as one of the two distinct factors explaining the largest variance in negative symptomatology (the other being diminished emotional expression, DE) (Kimhy et al., 2006, Strauss et al., 2013). The clinical relevance of this dichotomy was highlighted by recent data showing that patients expressing primarily AA vs. DE symptomatology had particularly poor functional
Treatment of negative symptoms in schizophrenia
The effects of clinical treatments can provide indirect information on the neurobiology of motivation. In patients with schizophrenia, treatment with conventional antipsychotic medication, which acts through D2 antagonism, has little positive effect on negative symptoms (Kirkpatrick et al., 2006, Leucht et al., 1999, Davis et al., 2014, Arango et al., 2014). However, clozapine may improve negative symptoms (Brar et al., 1997, Buchanan, 1995) and this has been attributed to its action on
Pharmacological induction of negative symptoms
Administration of drugs that stimulate dopamine release, such as amphetamine or cocaine, to healthy volunteers induces acute positive psychotic symptoms (Laruelle et al., 1996), but has no effect on negative symptoms. Similarly, in patients with schizophrenia, these drugs selectively exacerbate positive symptoms (Laruelle et al., 1996). In contrast, acute challenge with noncompetitive NMDA receptor antagonists such as phencyclidine (PCP) and ketamine evokes negative symptoms, as well as
Depression and related disorders
Despite the fact that depression is typically identified as an affective disorder, with cardinal symptoms that include negative affect and mood alterations, its most common and debilitating symptoms are motivational dysfunctions such as psychomotor retardation, anergia, listlessness, and fatigue (Tylee et al., 1999, Stahl, 2002, Demyttenaere et al., 2005, Salamone et al., 2006, Salamone et al., 2007). The severity of effort-related symptoms in depression is related to problems with social
Conclusions
Together with the animal studies focused on effort-related functions of forebrain circuits (Fig. 1), the clinical findings are consistent with the hypothesis that limbic/prefrontal/striatal networks are involved in behavioral activation and effort-related processes across a broad range of disorders. Generally speaking, there is considerable overlap between brain systems implicated in behavioral activation and effort-based decision-making in animals and those involved in effort-related
Role of the funding source
Editorial assistance was funded by Roche.
Contributors
All the authors were involved in the preparation of all drafts of the manuscript and contributed to, and approved, the final manuscript.
Conflict of interest
Dr. Salamone received no fee or honorarium for the writing or submission of this manuscript.
He has no conflict of interest.
Dr. Correa received no fee or honorarium for the writing or submission of this manuscript.
She has no conflict of interest.
Dr. Koychev received no fee or honorarium for the writing or submission of this manuscript.
He has no conflict of interest.
Professor McGuire received no fee or honorarium for the writing or submission of this manuscript. He has no conflict of interest.
Acknowledgments
J.S. received grants from the National Institute of Mental Health (MH094966), Prexa, and Shire. M.C. was supported by a grant from U. Jaume I (P1.1 A 2013-01). PM has received grants from Wellcome Trust (091667/Z/10/Z; R120525; 094849/Z/10/Z; 093907/Z/10/Z), MRC (MR/L011794/1; G0901885; G0700995; G1100574; MR/J012149/1; MR/L003988/1; MR/J008915/1; MR/K002813/1), and the EC (FP7-HEALTH-2013-INNOVATION-1–603196-PSYSCAN; FP7-HEALTH-F2-2010-241909-EU-GEI; FP7-Health-F2-2010-242114-OPTiMiZE). I.K.
References (196)
- et al.
Nucleus accumbens dopamine depletions make rats more sensitive to high ratio requirements but do not impair primary food reinforcement
Neuroscience
(1999) - et al.
Reward-motivated learning: mesolimbic activation precedes memory formation
Neuron
(2006) - et al.
A randomized controlled trial of sequentially bilateral prefrontal cortex repetitive transcranial magnetic stimulation in the treatment of negative symptoms in schizophrenia
Brain Stimul.
(2012) - et al.
What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?
Brain Res. Brain Res. Rev.
(1998) - et al.
Motor and cognitive aspects of motor retardation in depression
J. Affect. Disord.
(2000) - et al.
Increased ventral striatal CB1 receptor binding is related to negative symptoms in drug-free patients with schizophrenia
Neuroimage
(2013) - et al.
Fatigue in neurological disorders
Lancet
(2004) - et al.
Nucleus accumbens dopamine and work requirements on interval schedules
Behav. Brain Res.
(2002) - et al.
Nucleus accumbens dopamine depletions alter relative response allocation in a T-maze cost/benefit task
Behav. Brain Res.
(1996) - et al.
Psychopharmacology of the negative symptoms:current status and prospects for progress
Eur. Neuropsychopharmacol.
(2014)
Molecular shielding of electric field complex dissociation
Biophys. J.
Forebrain circuitry involved in effort-related choice: injections of the GABAA agonist muscimol into ventral pallidum alter response allocation in food-seeking behavior
Neuroscience
Nucleus accumbens and effort-related functions: behavioral and neural markers of the interactions between adenosine A2A and dopamine D2 receptors
Neuroscience
Neural substrates underlying effort computation in schizophrenia
Neurosci. Biobehav. Rev.
Abnormal speech articulation, psychomotor retardation, and subcortical dysfunction in major depression
J. Psychiatr. Res.
Association between cerebral glutamate and human behaviour: the sensation seeking personality trait
Neuroimage
Anhedonia in schizophrenia: distinctions between anticipatory and consummatory pleasure
Schizophr. Res.
Motivation and its relationship to neurocognition, social cognition, and functional outcome in schizophrenia
Schizophr. Res.
A placebo-controlled crossover trial of d-cycloserine added to clozapine in patients with schizophrenia
Biol. Psychiatry
Modulation of brain and serum glutamatergic concentrations following a switch from conventional neuroleptics to olanzapine
Biol. Psychiatry
Negative symptoms of schizophrenia are associated with abnormal effort-cost computations
Biol. Psychiatry
Tetrabenazine, a monoamine-depleting drug used in the treatment of hyperkinetic movement disorders
Am. J. Geriatr. Pharmacother.
Action versus valence in decision making
Trends Cogn. Sci.
Neo-striatal rCBF correlates of psychomotor slowing in patients with major depression
Psychiatry Res.
Accumbens dopamine and the regulation of effort in food-seeking behavior: modulation of work output by different ratio or force requirements
Behav. Brain Res.
Dysfunction of ventral striatal reward prediction in schizophrenia
Neuroimage
The neurobiology of decision: consensus and controversy
Neuron
Amitriptyline normalizes tetrabenazine-induced changes in cerebral microcirculation
Biol. Psychiatry
FMRI visualization of brain activity during a monetary incentive delay task
Neuroimage
A region of mesial prefrontal cortex tracks monetarily rewarding outcomes: characterization with rapid event-related fMRI
Neuroimage
Balancing reward and work: anticipatory brain activation in NAcc and VTA predict effort differentially
Neuroimage
Efficacy and extrapyramidal side-effects of the new antipsychotics olanzapine, quetiapine, risperidone, and sertindole compared to conventional antipsychotics and placebo. A meta-analysis of randomized controlled trials
Schizophr. Res.
Chronic akinetic mutism after mesencephalic-diencephalic infarction: remediated with dopaminergic medications
Neurorehabil. Neural Repair
Akinetic mutism following unilateral anterior cerebral artery occlusion
J. Neuropsychiatry Clin. Neurosci.
Scale for the Assessment of Negative Symptoms (SANS)
Negative symptoms in schizophrenia. Definition and reliability
Arch. Gen. Psychiatry
Negative v positive schizophrenia. Definition and validation
Arch. Gen. Psychiatry
Pharmacological approaches to treating negative symptoms: a review of clinical trials
Schizophr. Res.
Negative signs and symptoms secondary to antipsychotics: a double-blind, randomized trial of a single dose of placebo, haloperidol, and risperidone in healthy volunteers
Am. J. Psychiatry
Dorsolateral prefrontal cortex drives mesolimbic dopaminergic regions to initiate motivated behavior
J. Neurosci.
Goal representations and motivational drive in schizophrenia: the role of prefrontal-striatal interactions
Schizophr. Bull.
Effort, anhedonia, and function in schizophrenia: reduced effort allocation predicts amotivation and functional impairment
J. Abnorm. Psychol.
Dopamine modulates effort-based decision making in rats
Behav. Neurosci.
Regional cerebral blood flow in depression measured by positron emission tomography: the relationship with clinical dimensions
Psychol. Med.
Altered representation of expected value in the orbitofrontal cortex in mania
Hum. Brain Mapp.
The behavioural and motor consequences of focal lesions of the basal ganglia in man
Brain
Frontal-subcortical circuitry and behavior
Dialogues Clin. Neurosci.
The effects of clozapine on negative symptoms in patients with schizophrenia with minimal positive symptoms
Ann. Clin. Psychiatry
Prefrontal-subcortical and limbic circuit mediation of major depressive disorder
Semin. Clin. Neuropsychiatry
Dopamine and depression
J. Neural. Transm. Gen. Sect.
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Based on a meeting of global experts in the field of motivation and its impairment (San Francisco, October 2012).
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