The role of the human hippocampus in decision-making under uncertainty.

The role of the hippocampus in decision-making is beginning to be more understood. Because of its prospective and inferential functions, we hypothesized that it might be required specifically when decisions involve the evaluation of uncertain values. A group of individuals with autoimmune limbic encephalitis-a condition known to focally affect the hippocampus-were tested on how they evaluate reward against uncertainty compared to reward against another key attribute: physical effort. Across four experiments requiring participants to make trade-offs between reward, uncertainty and effort, patients with acute limbic encephalitis demonstrated blunted sensitivity to reward and effort whenever uncertainty was considered, despite demonstrating intact uncertainty sensitivity. By contrast, the valuation of these two attributes (reward and effort) was intact on uncertainty-free tasks. Reduced sensitivity to changes in reward under uncertainty correlated with the severity of hippocampal damage. Together, these findings provide evidence for a context-sensitive role of the hippocampus in value-based decision-making, apparent specifically under conditions of uncertainty.

Dissociable behavioural signatures of co-existing impulsivity and apathy in decision-making.

Apathy and impulsivity are expressed in a wide range of neuropsychiatric disorders, and, to a less severe extent, in healthy people too. Although traditionally considered to be opposite extremes of a single motivational spectrum, recent epidemiological questionnaire-based data suggest that both traits can in fact co-exist within the same individual. Here, we sought to investigate the relationship between these constructs in healthy people within a controlled task environment that examines the ability to make a decision under temporal uncertainty and measures the vigour of the response. Sixty participants performed a new version of the Traffic Light Task and completed self-report questionnaire measures of apathy and impulsivity. The task required individuals to make rapid decision-making for time-sensitive reward by squeezing a hand-held dynamometer as quickly as possible after a predictable event occurred (a traffic light turning green). Although apathy and impulsivity were positively correlated in questionnaire assessments, the two traits were associated with distinct behavioural signatures on the task. Impulsivity was expressed as an inflexible tendency to generate rapid anticipatory responses, regardless of cost-benefit information. Apathy, on the other hand, was associated with a blunted effect of reward on response vigour. These findings reveal how apathy and impulsivity are related to distinct dimensions of goal-directed behaviour, explaining how these traits might co-exist in the same individuals.

Hyperreactivity to uncertainty is a key feature of subjective cognitive impairment.

With an increasingly ageing global population, more people are presenting with concerns about their cognitive function, but not all have an underlying neurodegenerative diagnosis. Subjective cognitive impairment (SCI) is a common condition describing self-reported deficits in cognition without objective evidence of cognitive impairment. Many individuals with SCI suffer from depression and anxiety, which have been hypothesised to account for their cognitive complaints. Despite this association between SCI and affective features, the cognitive and brain mechanisms underlying SCI are poorly understood. Here, we show that people with SCI are hyperreactive to uncertainty and that this might be a key mechanism accounting for their affective burden. Twenty-seven individuals with SCI performed an information sampling task, where they could actively gather information prior to decisions. Across different conditions, SCI participants sampled faster and obtained more information than matched controls to resolve uncertainty. Remarkably, despite their 'urgent' sampling behaviour, SCI participants were able to maintain their efficiency. Hyperreactivity to uncertainty indexed by this sampling behaviour correlated with the severity of affective burden including depression and anxiety. Analysis of MRI resting functional connectivity revealed that SCI participants had stronger insular-hippocampal connectivity compared to controls, which also correlated with faster sampling. These results suggest that altered uncertainty processing is a key mechanism underlying the psycho-cognitive manifestations in SCI and implicate a specific brain network target for future treatment.

Age-related decline in cortical inhibitory tone strengthens motor memory.

Ageing disrupts the finely tuned excitation/inhibition balance (E:I) across cortex via a natural decline in inhibitory tone (γ-amino butyric acid, GABA), causing functional decrements. However, in young adults, experimentally lowering GABA in sensorimotor cortex enhances a specific domain of sensorimotor function: adaptation memory. Here, we tested the hypothesis that as sensorimotor cortical GABA declines naturally with age, adaptation memory would increase, and the former would explain the latter. Results confirmed this prediction. To probe causality, we used brain stimulation to further lower sensorimotor cortical GABA during adaptation. Across individuals, how stimulation changed memory depended on sensorimotor cortical E:I. In those with low E:I, stimulation increased memory; in those with high E:I stimulation reduced memory. Thus, we identified a form of motor memory that is naturally strengthened by age, depends causally on sensorimotor cortex neurochemistry, and may be a potent target for motor skill preservation strategies in healthy ageing and neurorehabilitation.

The computational cost of active information sampling before decision-making under uncertainty.

Humans often seek information to minimize the pervasive effect of uncertainty on decisions. Current theories explain how much knowledge people should gather before a decision, based on the cost-benefit structure of the problem at hand. Here, we demonstrate that this framework omits a crucial agent-related factor: the cognitive effort expended while collecting information. Using an active sampling model, we unveil a speed-efficiency trade-off whereby more informative samples take longer to find. Crucially, under sufficient time pressure, humans can break this trade-off, sampling both faster and more efficiently. Computational modelling demonstrates the existence of a cost of cognitive effort which, when incorporated into theoretical models, provides a better account of people's behaviour and also relates to self-reported fatigue accumulated during active sampling. Thus, the way people seek knowledge to guide their decisions is shaped not only by task-related costs and benefits, but also crucially by the quantifiable computational costs incurred.

Apathy in small vessel cerebrovascular disease is associated with deficits in effort-based decision making.

Patients with small vessel cerebrovascular disease frequently suffer from apathy, a debilitating neuropsychiatric syndrome, the underlying mechanisms of which remain to be established. Here we investigated the hypothesis that apathy is associated with disrupted decision making in effort-based decision making, and that these alterations are associated with abnormalities in the white matter network connecting brain regions that underpin such decisions. Eighty-two patients with MRI evidence of small vessel disease were assessed using a behavioural paradigm as well as diffusion weighted MRI. The decision-making task involved accepting or rejecting monetary rewards in return for performing different levels of physical effort (hand grip force). Choice data and reaction times were integrated into a drift diffusion model that framed decisions to accept or reject offers as stochastic processes approaching a decision boundary with a particular drift rate. Tract-based spatial statistics were used to assess the relationship between white matter tract integrity and apathy, while accounting for depression. Overall, patients with apathy accepted significantly fewer offers on this decision-making task. Notably, while apathetic patients were less responsive to low rewards, they were also significantly averse to investing in high effort. Significant reductions in white matter integrity were observed to be specifically related to apathy, but not to depression. These included pathways connecting brain regions previously implicated in effort-based decision making in healthy people. The drift rate to decision parameter was significantly associated with both apathy and altered white matter tracts, suggesting that both brain and behavioural changes in apathy are associated with this single parameter. On the other hand, depression was associated with an increase in the decision boundary, consistent with an increase in the amount of evidence required prior to making a decision. These findings demonstrate altered effort-based decision making for reward in apathy, and also highlight dissociable mechanisms underlying apathy and depression in small vessel disease. They provide clear potential brain and behavioural targets for future therapeutic interventions, as well as modelling parameters that can be used to measure the effects of treatment at the behavioural level.

The relationship between apathy and impulsivity in large population samples.

Apathy and impulsivity are debilitating conditions associated with many neuropsychiatric conditions, and expressed to variable degrees in healthy people. While some theories suggest that they lie at different ends of a continuum, others suggest their possible co-existence. Surprisingly little is known, however, about their empirical association in the general population. Here, gathering data from six large studies ([Formula: see text]), we investigated the relationship between measures of apathy and impulsivity in young adults. The questionnaires included commonly used self-assessment tools-Apathy Evaluation Scale, Barratt Impulsiveness Scale (BIS-11) and UPPS-P Scale-as well as a more recent addition, the Apathy Motivation Index (AMI). Remarkably, across datasets and assessment tools, global measures of apathy and impulsivity correlated positively. However, analysis of sub-scale scores revealed a more complex relationship. Although most dimensions correlated positively with one another, there were two important exceptions revealed using the AMI scale. Social apathy was mostly negatively correlated with impulsive behaviour, and emotional apathy was orthogonal to all other sub-domains. These results suggest that at a global level, apathy and impulsivity do not exist at distinct ends of a continuum. Instead, paradoxically, they most often co-exist in young adults. Processes underlying social and emotional apathy, however, appear to be different and dissociable from behavioural apathy and impulsivity.

A single, clinically relevant dose of the GABAB agonist baclofen impairs visuomotor learning.

KEY POINTS: Baclofen is a GABAB agonist prescribed as a treatment for spasticity in stroke, brain injury and multiple sclerosis patients, who are often undergoing concurrent motor rehabilitation. Decreasing GABAergic inhibition is a key feature of motor learning and so there is a possibility that GABA agonist drugs, such as baclofen, could impair these processes, potentially impacting rehabilitation. Here, we examined the effect of 10 mg of baclofen, in 20 young healthy individuals, and found that the drug impaired retention of visuomotor learning with no significant effect on motor sequence learning. Overall baclofen did not alter transcranial magnetic stimulation-measured GABAB inhibition, although the change in GABAB inhibition correlated with aspects of visuomotor learning retention. Further work is needed to investigate whether taking baclofen impacts motor rehabilitation in patients. ABSTRACT: The GABAB agonist baclofen is taken daily as a treatment for spasticity by millions of stroke, brain injury and multiple sclerosis patients, many of whom are also undergoing motor rehabilitation. However, decreases in GABA are suggested to be a key feature of human motor learning, which raises questions about whether drugs increasing GABAergic activity may impair motor learning and rehabilitation. In this double-blind, placebo-controlled study, we investigated whether a single 10 mg dose of the GABAB agonist baclofen impaired motor sequence learning and visuomotor learning in 20 young healthy participants of both sexes. Participants trained on visuomotor and sequence learning tasks using their right hand. Transcranial magnetic stimulation (TMS) measures of corticospinal excitability, GABAA (short-interval intracortical inhibition, 2.5 ms) and GABAB (long-interval intracortical inhibition, 150 ms) receptor activation were recorded from left M1. Behaviourally, baclofen caused a significant reduction of visuomotor aftereffect (F1,137.8  = 6.133, P = 0.014) and retention (F1,130.7  = 4.138, P = 0.044), with no significant changes to sequence learning. There were no overall changes to TMS measured GABAergic inhibition with this low dose of baclofen. This result confirms the causal importance of GABAB inhibition in mediating visuomotor learning and suggests that chronic baclofen use could negatively impact aspects of motor rehabilitation.

Towards a neuro-computational account of prism adaptation.

Prism adaptation has a long history as an experimental paradigm used to investigate the functional and neural processes that underlie sensorimotor control. In the neuropsychology literature, prism adaptation behaviour is typically explained by reference to a traditional cognitive psychology framework that distinguishes putative functions, such as 'strategic control' versus 'spatial realignment'. This theoretical framework lacks conceptual clarity, quantitative precision and explanatory power. Here, we advocate for an alternative computational framework that offers several advantages: 1) an algorithmic explanatory account of the computations and operations that drive behaviour; 2) expressed in quantitative mathematical terms; 3) embedded within a principled theoretical framework (Bayesian decision theory, state-space modelling); 4) that offers a means to generate and test quantitative behavioural predictions. This computational framework offers a route towards mechanistic neurocognitive explanations of prism adaptation behaviour. Thus it constitutes a conceptual advance compared to the traditional theoretical framework. In this paper, we illustrate how Bayesian decision theory and state-space models offer principled explanations for a range of behavioural phenomena in the field of prism adaptation (e.g. visual capture, magnitude of visual versus proprioceptive realignment, spontaneous recovery and dynamics of adaptation memory). We argue that this explanatory framework can advance understanding of the functional and neural mechanisms that implement prism adaptation behaviour, by enabling quantitative tests of hypotheses that go beyond merely descriptive mapping claims that 'brain area X is (somehow) involved in psychological process Y'.

Induced sensorimotor cortex plasticity remediates chronic treatment-resistant visual neglect.

Right brain injury causes visual neglect - lost awareness of left space. During prism adaptation therapy, patients adapt to a rightward optical shift by recalibrating right arm movements leftward. This can improve left neglect, but the benefit of a single session is transient (~1 day). Here we show that tonic disinhibition of left motor cortex during prism adaptation enhances consolidation, stabilizing both sensorimotor and cognitive prism after-effects. In three longitudinal patient case series, just 20 min of combined stimulation/adaptation caused persistent cognitive after-effects (neglect improvement) that lasted throughout follow-up (18-46 days). Moreover, adaptation without stimulation was ineffective. Thus stimulation reversed treatment resistance in chronic visual neglect. These findings challenge consensus that because the left hemisphere in neglect is pathologically over-excited it ought to be suppressed. Excitation of left sensorimotor circuits, during an adaptive cognitive state, can unmask latent plastic potential that durably improves resistant visual attention deficits after brain injury.

Testing the inter-hemispheric competition account of visual extinction with combined TMS/fMRI.

Theoretical models of visual neglect and extinction entail claims about the normal functioning of attention and parietal cortex in the healthy brain: (1) 'pseudoneglect', a commonly observed attentional bias towards left space, reflects the greater dominance of parietal cortex activity of the right versus left hemisphere; (2) the capacity to distribute attention bilaterally depends causally on the relative balance of parietal activity between the hemispheres; (3) disruption of the dominant right parietal cortex shifts this inter-hemispheric balance leftward, causing a rightward shift in attentional bias. We tested these claims using low-frequency offline transcranial magnetic stimulation (TMS) to transiently inhibit activity in the right angular gyrus/intra-parietal sulcus, followed by a visual detection task to assess changes in attentional bias, and functional magnetic resonance imaging (fMRI) to test for the predicted leftward shift in brain activity. The task required participants to covertly monitor both hemifields to detect and report the location of upcoming transient visual targets that appeared on the left, right or bilaterally. In the behavioural experiment, participants exhibited a leftward attentional bias ('pseudoneglect') at baseline, which was abolished by TMS. In the fMRI experiment, participants activated an expected network of visual, parietal and frontal cortex bilaterally during the period of covert bilateral attention. TMS shifted the relative hemispheric balance of parietal activity from right to left. The consistent direction of TMS-induced behavioural and functional change indicates a causal role for parietal inter-hemispheric balance in distributing visual attention across space.