Brain mechanisms underlying apathy

Abstract

The past few decades have seen growing interest in the neuropsychiatric syndrome of apathy, conceptualised as a loss of motivation manifesting as a reduction of goal-directed behaviour. Apathy occurs frequently, and with substantial impact on quality of life, in a broad range of neurological and psychiatric conditions. Apathy is also consistently associated with neuroimaging changes in specific medial frontal cortex and subcortical structures, suggesting that disruption of a common systems-level mechanism may underlie its development, irrespective of the condition that causes it. In parallel with this growing recognition of the clinical importance of apathy, significant advances have been made in understanding normal motivated behaviour in humans and animals. These developments have occurred at several different conceptual levels, from work linking neural structures and neuromodulatory systems to specific aspects of motivated behaviour, to higher order computational models that aim to unite these findings within frameworks for normal goal-directed behaviour. In this review we develop a conceptual framework for understanding pathological apathy based on this current understanding of normal motivated behaviour. We first introduce prominent theories of motivated behaviour-which often involves sequences of actions towards a goal that needs to be maintained across time. Next, we outline the behavioural effects of disrupting these processes in animal models, highlighting the specific effects of these manipulations on different components of motivated behaviour. Finally, we relate these findings to clinical apathy, demonstrating the homologies between this basic neuroscience work and emerging behavioural and physiological evidence from patient studies of this syndrome.

Keywords: apathy; cognitive neuroscience; decision making; effort; goal-directed behaviour; motivation; reward.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY. Published by BMJ.

Figures

Figure 1

Conceptual framework and brain basis of motivated behaviour. The translation of value (reinforcer) information into a behavioural response can be conceptualised as three distinct processes. (A) A valuation system computes the subjective value (ie, allowing for current internal states and costs to obtain the reinforcer) of the current and potential events. (B) A mediating system integrates this reinforcer/cost information to activate the motor system towards particular goals. (C) A motor system produces behaviour towards motivationally relevant stimuli. Furthermore, these processes occur along two distinct neurocognitive dimensions (right side of panel). (1—vertical axis) Behaviour can be activated by flexible, but computationally demanding, goal-directed systems, which actively represent the outcome of potential actions along with the costs of these actions. It can also be activated by inflexible, simpler habitual systems, which activate responses based on previously learnt stimulus-response mappings. (2—horizontal axis) Motor control functions are hierarchically organised, such that complex behaviours are represented as higher level, abstract actions (eg, fly to London) as well as the lower level subcomponent behaviours (eg, book a flight, move mouse cursor upwards…). Outcome feedback and learning occur at all hierarchical levels to inform future behaviour. Such hierarchical arrangements likely occur within both goal-directed (predominantly cortical) and habitual (predominantly subcortical) systems. (D) These processes are instantiated within a complex network of reciprocally connected cortical and subcortical brain regions, under the influence of the mesolimbic dopaminergic system. A single brain region likely contributes to more than one process, but with specialisation. Hence the value system predominantly involves the vmPFC and, the motor system predominantly pMCC, SMA, ACC and the dorsal striatum (including the caudate and the putamen), while the VS, ACC and mesolimbic dopamine (originating in VTA) form the mediating system. This gradient of function is represented in the figure by the gradual change from gold (reinforcer) to green (motor). ACC, anterior cingulate cortex; pMCC, posterior mid-cingulate cortex; SMA, supplementary motor area; vmPFC, ventromedial prefrontal cortex; VS, ventral striatum; VTA, ventral tegmental area.

Figure 2

Effects of dopaminergic and anatomical lesions on phases of motivated behaviour. (A) Motivated behaviour takes place in two distinct phases. The consummatory phase involves direct interaction with the motivational stimulus, whereas the instrumental phase describes the behaviours required to obtain this stimulus. Instrumental behaviours are both directional (towards or away from stimuli) and activational (energising), allowing organisms to overcome obstacles separating them from salient stimuli. Thus, organisms pay response ‘costs’ to access motivationally relevant goals. (B) Effort-based choice is often assessed in rodents using one of two experimental set-ups. Animals can be free to choose between pressing a lever (effort cost) a fixed number of times (ratio can be varied) to receive a preferred reinforcer, or accessing standard lab chow (less preferred reinforcer) at any point. (C) Alternatively a T-maze set-up allows animals to choose between a high-reward, high-effort cost option and a low-reward, lower cost option. (D) Both low-dose systemic dopamine antagonists and local (nucleus accumbens) dopamine depletion or antagonism bias responses towards low-effort, low-reward options, without affecting reward preference (when effort costs are equalised) or motor ability. Thus interference with the dopaminergic system reduces animals’ willingness to undertake costs to access motivationally relevant goals. (E) Anterior cingulate cortex lesions produce very similar changes in behaviour. Prior to the lesion, rodents preferred to climb a 30 cm barrier to obtain high rewards (A and B on graph). Post lesion, the behaviour changed dramatically, with rodents now choosing the low-effort, low-reward option (C). However, equalising effort costs led to rodents again choosing the high-reward option (D), indicating reward preference was not altered by the lesion. Adapted from Aberman and Salamone, 1999 (s33); Walton et al with permission. DA, dopamine; HR, high reward (arm)

Figure 3

A neurocognitive framework for apathy. (A) Apathy could result from alterations in the processes underlying the translation of value information to actions, which are often described under the term effort-based decision making. Reduced willingness to exert effort for reward (effort-based choice—’is it worth it’), as well as impaired persistence and vigour towards goals (‘is it still worth it’), could lead to the reduced goal-directed behaviour that characterises apathy. Similarly changes in learning from the reinforcing outcomes of actions could change the likelihood of the same behaviour being repeated in the future (’was it worth it’). These changes could be driven by anatomical disruption of key neural regions (such as the anterior cingulate cortex and ventral striatum) and/or changes in neuromodulators such as the mesolimbic dopaminergic system. (B) A large number of studies, across disorders and using different imaging modalities (eg, positron emission tomography), have associated disruption of the ventral striatum and anterior cingulate with apathy. (C) Reward sensitivity can be assessed by measuring the degree of pupillary dilatation to reinforcer information. Apathy is associated with impaired autonomic (pupillary) responses to reward in both genetic cerebral small vessel disease (shown) and PD. (D) Effort-based choice can be assessed by sequentially offering patients varying levels of reward in return for exerting varying levels of effort. Apathy is associated with reduced willingness to exert effort for reward. This change is not global, but is driven by reduced sensitivity to rewarding outcomes without a change in sensitivity to effort costs, in both patients with genetic small vessel disease and PD (shown). (E) Gambling tasks, in which patients select an option and are then provided feedback about whether they ‘won’ or ‘lost’, allow assessment of outcome-related physiological changes, which are thought to drive learning. PD patients with apathy show blunted outcome-related electrophysiological activity compared with non-apathetic patients. Adapted from Le Heron et al 2018, Martínez-Horta et al, Robert et al 2014 and Schroeter et al 2013 with permission. CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy; MVC, maximal voluntary contraction; PD, Parkinson’s disease.