REVIEW
Neurobiological basis of motivational deficits in psychopathology

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Abstract

In recent years, there has been increasing emphasis on the importance of motivational symptoms in depression, schizophrenia and other disorders. The present review discusses the conceptual background related to the construct of motivation, and provides a framework that for research on both physiological and pathological aspects of motivation. Particular emphasis is placed on what is known about the neurobiological basis of activational aspects of motivation, including studies from animal models. The role of limbic/prefrontal/striatal circuitry in behavioral activation and effort-related functions is examined, and the utility of behavioral tasks of effort-based decision making as models of motivational symptoms is discussed. We also review the neurobiology of motivational symptoms in relation to psychopathology, and issues related to the language used to characterize motivational dysfunctions are considered. The literature suggests that research on the neurobiology of motivational dysfunction in psychopathology, at both clinical and preclinical levels, could inform the development of novel and more effective treatments for a range of CNS disorders.

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).

Section snippets

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.

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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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