Remote digital cognitive assessment reveals cognitive deficits related to hippocampal atrophy in autoimmune limbic encephalitis: a cross-sectional validation study.

Background: Autoimmune limbic encephalitis (ALE) is a neurological disease characterised by inflammation of the limbic regions of the brain, mediated by pathogenic autoantibodies. Because cognitive deficits persist following acute treatment of ALE, the accurate assessment of long-term cognitive outcomes is important for clinical assessments and trials. However, evaluating cognition is costly and an unmet need exists for validated digital methods. Methods: In this cross-sectional validation study, we investigated whether a remote digital platform could identify previously characterised cognitive impairments in patients with chronic ALE and whether digital metrics would correlate with standard neuropsychological assessment and hippocampal volume. Patients with ALE who had a chronic and stable presentation and received a clinical diagnosis of ALE were recruited for this study. The cognitive performance of 21 patients with ALE and 54 age-matched healthy controls - enrolled via the University of Oxford (UK) Cognitive Neurology Lab testing programme - was assessed with a battery of 12 cognitive tasks from the Cognitron online platform. The platform was optimised with National Institute for Health and Care Research (NIHR) support to be deliverable remotely to elderly and patient groups. The primary outcome measure was behavioural performance and corresponding neuroimaging and neuropsychological assessment metrics. Findings: Between February 15, 2021, and April 21, 2022, 21 patients with ALE (mean age 63.01 years, 14 males) and 54 healthy controls (mean age 65.56 years, 23 males) completed the digital cognitive assessment. Patients with ALE performed significantly worse in memory, visuospatial abilities, executive function, and language. No impairments in digit & spatial span, target detection (attention) and emotion discrimination were observed. The global score on the online cognitive tasks correlated significantly with the established Addenbrooke's Cognitive Examination III (ACE) pen-and-paper test. Deficits in visuospatial processing and language were identified in ALE compared to controls using remote digital testing but not using the ACE, highlighting higher sensitivity of computerised testing to residual cognitive impairment. Finally, the hippocampal volumes of patients with ALE and healthy controls correlated with online cognitive scores. Interpretation: These findings demonstrate that subtle cognitive deficits in patients with chronic ALE, who often show full recovery in measures of disability and dependence on daily activities, are detectable using a remote online platform, which also relates to hippocampal atrophy. Such methods may facilitate the characterisation of cognitive profiles in complex neurological diseases. Future longitudinal studies designed to assess the utility of such digital methods for further clinical characterisation are needed. Funding: The Wellcome Trust, Medical Research Council, National Institute for Health Research, Rhodes Scholarship, and the Berrow Foundation Scholarship.

Clinical assessment of parietal lobe function.

The notion of specific assessments of the function of a particular lobe of the brain is in many ways archaic. Advances in our understanding of brain network function have revealed that brain functions are underpinned by large-scale networks with long range connections between cortical distant regions. It would, therefore, be more correct to discuss the contributions of parietal areas to specific functions. Nevertheless, in clinical practice, as we show here, simple bedside assessment can still often point towards parietal dysfunction, or at least reveal an impairment in a function to which parietal regions normally contribute.

Assessment of apathy in neurological patients using the Apathy Motivation Index caregiver version.

Apathy is a common, disabling neuropsychiatric syndrome that occurs across many brain disorders and may be associated with diminished motivation in behavioural, cognitive, emotional and social domains. Assessment is complicated by the variability of symptoms across apathy domains and self-report from patients, which can be misleading due to their lack of insight. Independent evaluation by clinicians also has limitations though if it has to be performed with limited time. Caregiver reports are a viable alternative, but current assessments for them either do not distinguish between different apathy domains or are interview-based and take long to administer. In this study, we developed a brief caregiver questionnaire version of the recently developed Apathy Motivation Index (AMI), which is a self-report tool. We confirmed three apathy factors in this new caregiver measure (AMI-CG) that were also present in the AMI: Behavioural Activation, Emotional Sensitivity and Social Motivation. Furthermore, we validated the scores against more extensive caregiver interviews using the established Lillle apathy rating scale as well as patient self-reports of apathy, measures of depression, anhedonia, cognition, activities of daily living and caregiver burden across four different neurological conditions: Parkinson's disease, Alzheimer's disease, subjective cognitive impairment and limbic encephalitis. The AMI-CG showed good internal reliability, external validity and diagnostic accuracy. It also uncovered cases of social apathy overlooked by traditional instruments. Crucially, patients who under-rated their apathy compared to informants were more likely to have difficulties performing everyday activities and to be a greater burden to caregivers. The findings provide evidence for a multidimensional conceptualization of apathy and an instrument for efficient detection of apathy based on caregiver reports for use in clinical practice.

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.

Task-irrelevant financial losses inhibit the removal of information from working memory.

The receipt of financial rewards or penalties - though task-irrelevant - may exert an obligatory effect on manipulating items in working memory (WM) by constraining a forthcoming shift in attention or reinforcing attentional shifts that have previously occurred. Here, we adjudicate between these two hypotheses by varying - after encoding- the order in which task-irrelevant financial outcomes and cues indicating which items need to be retained in memory are presented (so called retrocues). We employed a "what-is-where" design that allowed for the fractionation of WM recall into separate components: identification, precision and binding (between location and identity). Principally, valence-dependent effects were observed only for precision and binding, but only when outcomes were presented before, rather than after, the retrocue. Specifically, task-irrelevant financial losses presented before the retrocue caused a systematic breakdown in binding (misbinding), whereby the features of cued and non-cued memoranda became confused, i.e., the features that made up relevant memoranda were displaced by those of non-cued (irrelevant) items. A control experiment, in which outcomes but no cues were presented, failed to produce the same effects, indicating that the inclusion of retrocues were necessary for generating this effect. These results show that the receipt of financial penalties - even when uncoupled to performance - can prevent irrelevant information from being effectively pruned from WM. These results illustrate the importance of reward-related processing to controlling the contents of WM.

Neurocomputational mechanisms underlying subjective valuation of effort costs.

In everyday life, we have to decide whether it is worth exerting effort to obtain rewards. Effort can be experienced in different domains, with some tasks requiring significant cognitive demand and others being more physically effortful. The motivation to exert effort for reward is highly subjective and varies considerably across the different domains of behaviour. However, very little is known about the computational or neural basis of how different effort costs are subjectively weighed against rewards. Is there a common, domain-general system of brain areas that evaluates all costs and benefits? Here, we used computational modelling and functional magnetic resonance imaging (fMRI) to examine the mechanisms underlying value processing in both the cognitive and physical domains. Participants were trained on two novel tasks that parametrically varied either cognitive or physical effort. During fMRI, participants indicated their preferences between a fixed low-effort/low-reward option and a variable higher-effort/higher-reward offer for each effort domain. Critically, reward devaluation by both cognitive and physical effort was subserved by a common network of areas, including the dorsomedial and dorsolateral prefrontal cortex, the intraparietal sulcus, and the anterior insula. Activity within these domain-general areas also covaried negatively with reward and positively with effort, suggesting an integration of these parameters within these areas. Additionally, the amygdala appeared to play a unique, domain-specific role in processing the value of rewards associated with cognitive effort. These results are the first to reveal the neurocomputational mechanisms underlying subjective cost-benefit valuation across different domains of effort and provide insight into the multidimensional nature of motivation.

Distinct Subtypes of Apathy Revealed by the Apathy Motivation Index.

Apathy is a debilitating but poorly understood disorder characterized by a reduction in motivation. As well as being associated with several brain disorders, apathy is also prevalent in varying degrees in healthy people. Whilst many tools have been developed to assess levels of apathy in clinical disorders, surprisingly there are no measures of apathy suitable for healthy people. Moreover, although apathy is commonly comorbid with symptoms of depression, anhedonia and fatigue, how and why these symptoms are associated is unclear. Here we developed the Apathy-Motivation Index (AMI), a brief self-report index of apathy and motivation. Using exploratory factor analysis (in a sample of 505 people), and then confirmatory analysis (in a different set of 479 individuals), we identified subtypes of apathy in behavioural, social and emotional domains. Latent profile analyses showed four different profiles of apathy that were associated with varying levels of depression, anhedonia and fatigue. The AMI is a novel and reliable measure of individual differences in apathy and might provide a useful means of probing different mechanisms underlying sub-clinical lack of motivation in otherwise healthy individuals. Moreover, associations between apathy and comorbid states may be reflective of problems in different emotional, social and behavioural domains.

Shared Neural Mechanisms for the Evaluation of Intense Sensory Stimulation and Economic Reward, Dependent on Stimulation-Seeking Behavior.

UNLABELLED: Why are some people strongly motivated by intense sensory experiences? Here we investigated how people encode the value of an intense sensory experience compared with economic reward, and how this varies according to stimulation-seeking preference. Specifically, we used a novel behavioral task in combination with computational modeling to derive the value individuals assigned to the opportunity to experience an intense tactile stimulus (mild electric shock). We then examined functional imaging data recorded during task performance to see how the opportunity to experience the sensory stimulus was encoded in stimulation-seekers versus stimulation-avoiders. We found that for individuals who positively sought out this kind of sensory stimulation, there was common encoding of anticipated economic and sensory rewards in the ventromedial prefrontal cortex. Conversely, there was robust encoding of the modeled probability of receiving such stimulation in the insula only in stimulation-avoidant individuals. Finally, we found preliminary evidence that sensory prediction error signals may be positively signed for stimulation-seekers, but negatively signed for stimulation-avoiders, in the posterior cingulate cortex. These findings may help explain why high intensity sensory experiences are appetitive for some individuals, but not for others, and may have relevance for the increased vulnerability for some psychopathologies, but perhaps increased resilience for others, in high sensation-seeking individuals. SIGNIFICANCE STATEMENT: People vary in their preference for intense sensory experiences. Here, we investigated how different individuals evaluate the prospect of an unusual sensory experience (electric shock), compared with the opportunity to gain a more traditional reward (money). We found that in a subset of individuals who sought out such unusual sensory stimulation, anticipation of the sensory outcome was encoded in the same way as that of monetary gain, in the ventromedial prefrontal cortex. Further understanding of stimulation-seeking behavior may shed light on the etiology of psychopathologies such as addiction, for which high or low sensation-seeking personality has been identified as a risk factor.

Resource allocation models of auditory working memory.

Auditory working memory (WM) is the cognitive faculty that allows us to actively hold and manipulate sounds in mind over short periods of time. We develop here a particular perspective on WM for non-verbal, auditory objects as well as for time based on the consideration of possible parallels to visual WM. In vision, there has been a vigorous debate on whether WM capacity is limited to a fixed number of items or whether it represents a limited resource that can be allocated flexibly across items. Resource allocation models predict that the precision with which an item is represented decreases as a function of total number of items maintained in WM because a limited resource is shared among stored objects. We consider here auditory work on sequentially presented objects of different pitch as well as time intervals from the perspective of dynamic resource allocation. We consider whether the working memory resource might be determined by perceptual features such as pitch or timbre, or bound objects comprising multiple features, and we speculate on brain substrates for these behavioural models. This article is part of a Special Issue entitled SI: Auditory working memory.

The role of cognitive effort in subjective reward devaluation and risky decision-making.

Motivation is underpinned by cost-benefit valuations where costs-such as physical effort or outcome risk-are subjectively weighed against available rewards. However, in many environments risks pertain not to the variance of outcomes, but to variance in the possible levels of effort required to obtain rewards (effort risks). Moreover, motivation is often guided by the extent to which cognitive-not physical-effort devalues rewards (effort discounting). Yet, very little is known about the mechanisms that underpin the influence of cognitive effort risks or discounting on motivation. We used two cost-benefit decision-making tasks to probe subjective sensitivity to cognitive effort (number of shifts of spatial attention) and to effort risks. Our results show that shifts of spatial attention when monitoring rapidly presented visual stimuli are perceived as effortful and devalue rewards. Additionally, most people are risk-averse, preferring safe, known amounts of effort over risky offers. However, there was no correlation between their effort and risk sensitivity. We show for the first time that people are averse to variance in the possible amount of cognitive effort to be exerted. These results suggest that cognitive effort sensitivity and risk sensitivity are underpinned by distinct psychological and neurobiological mechanisms.

Reward Pays the Cost of Noise Reduction in Motor and Cognitive Control.

Speed-accuracy trade-off is an intensively studied law governing almost all behavioral tasks across species. Here we show that motivation by reward breaks this law, by simultaneously invigorating movement and improving response precision. We devised a model to explain this paradoxical effect of reward by considering a new factor: the cost of control. Exerting control to improve response precision might itself come at a cost--a cost to attenuate a proportion of intrinsic neural noise. Applying a noise-reduction cost to optimal motor control predicted that reward can increase both velocity and accuracy. Similarly, application to decision-making predicted that reward reduces reaction times and errors in cognitive control. We used a novel saccadic distraction task to quantify the speed and accuracy of both movements and decisions under varying reward. Both faster speeds and smaller errors were observed with higher incentives, with the results best fitted by a model including a precision cost. Recent theories consider dopamine to be a key neuromodulator in mediating motivational effects of reward. We therefore examined how Parkinson's disease (PD), a condition associated with dopamine depletion, alters the effects of reward. Individuals with PD showed reduced reward sensitivity in their speed and accuracy, consistent in our model with higher noise-control costs. Including a cost of control over noise explains how reward may allow apparent performance limits to be surpassed. On this view, the pattern of reduced reward sensitivity in PD patients can specifically be accounted for by a higher cost for controlling noise.

Dopamine Regulates Approach-Avoidance in Human Sensation-Seeking.

BACKGROUND: Sensation-seeking is a trait that constitutes an important vulnerability factor for a variety of psychopathologies with high social cost. However, little is understood either about the mechanisms underlying motivation for intense sensory experiences or their neuropharmacological modulation in humans. METHODS: Here, we first evaluate a novel paradigm to investigate sensation-seeking in humans. This test probes the extent to which participants choose either to avoid or self-administer an intense tactile stimulus (mild electric stimulation) orthogonal to performance on a simple economic decision-making task. Next we investigate in a different set of participants whether this behavior is sensitive to manipulation of dopamine D2 receptors using a within-subjects, placebo-controlled, double-blind design. RESULTS: In both samples, individuals with higher self-reported sensation-seeking chose a greater proportion of mild electric stimulation-associated stimuli, even when this involved sacrifice of monetary gain. Computational modelling analysis determined that people who assigned an additional positive economic value to mild electric stimulation-associated stimuli exhibited speeding of responses when choosing these stimuli. In contrast, those who assigned a negative value exhibited slowed responses. These findings are consistent with involvement of low-level, approach-avoidance processes. Furthermore, the D2 antagonist haloperidol selectively decreased the additional economic value assigned to mild electric stimulation-associated stimuli in individuals who showed approach reactions to these stimuli under normal conditions (behavioral high-sensation seekers). CONCLUSIONS: These findings provide the first direct evidence of sensation-seeking behavior being driven by an approach-avoidance-like mechanism, modulated by dopamine, in humans. They provide a framework for investigation of psychopathologies for which extreme sensation-seeking constitutes a vulnerability factor.