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Objective: To assess whether the antiseizure medication levetiracetam may improve cognition in individuals with Alzheimer's disease who have not previously experienced a seizure. Methods: We performed a randomized, double‐blind, placebo‐controlled crossover pilot study in individuals with mild‐to‐moderate Alzheimer's disease. Electroencephalography was performed at baseline and those with active epileptiform discharges were excluded. Eligible participants were randomized to placebo for 12 weeks or an active arm of oral levetiracetam (4 weeks up‐titration to levetiracetam 500 mg twice daily, 4 weeks maintained on this dose followed by 4 weeks down‐titration to nil). Participants then crossed over to the other arm. The primary outcome was change in cognitive function assessed by the Oxford Memory Task, a task sensitive to hippocampal memory binding. Secondary outcomes included tolerability, other neuropsychological scales, and general questionnaires. Results: Recruitment numbers were severely limited owing to restrictions from the COVID‐19 pandemic at the time of the study. Eight participants completed both arms of the study (mean age 68.4 years [SD = 9.2]; 5 females [62.5%]). No participants withdrew from the study and there was no significant difference between reported side effects in the active levetiracetam or placebo arm. Measures of mood and quality of life were also not significantly different between the two arms based on participant or carer reports. In limited data analysis, there was no statistically significant difference between participants in the active levetiracetam and placebo arm on the memory task. Significance: This pilot study demonstrates that levetiracetam was well tolerated in individuals with Alzheimer's disease who do not have a history of seizures and has no detrimental effect on mood or quality of life. Larger studies are needed to assess whether levetiracetam may have a positive effect on cognitive function in subsets of individuals with Alzheimer's disease. Plain Language Summary: Abnormal electrical activity within the brain, such as is seen in seizures, might contribute to memory problems in people with dementia. We completed a clinical trial to see if an antiseizure medication, levetiracetam, could help with memory difficulties in people with Alzheimer's disease (the most common cause of dementia). In this pilot study, we could not prove whether levetiracetam helped memory function. We did show that the drug is safe and well tolerated in people with dementia who have not had a seizure. This work, therefore, offers a platform for future research exploring antiseizure medications in people with dementia. [ABSTRACT FROM AUTHOR]

Introduction: The pupillary light reflex (PLR) is the constriction of the pupil in response to light. The PLR in response to a pulse of light follows a complex waveform that can be characterized by several parameters. It is a sensitive marker of acute neurological deterioration, but is also sensitive to the background illumination in the environment in which it is measured. To detect a pathological change in the PLR, it is therefore necessary to separate the contributions of neuro-ophthalmic factors from ambient illumination. Illumination varies over several orders of magnitude and is difficult to control due to diurnal, seasonal, and location variations. Methods and results: We assessed the sensitivity of seven PLR parameters to differences in ambient light, using a smartphone-based pupillometer (Al Pupillometer, Solvemed Inc.). Nine subjects underwent 345 measurements in ambient conditions ranging from complete darkness (<5 Ix) to bright lighting (<10,000 Ix). Lighting most strongly affected the initial pupil size, constriction amplitude, and velocity. Nonlinear models were fitted to find the correction function that maximally stabilized PLR parameters across different ambient light levels. Next, we demonstrated that the lighting-corrected parameters still discriminated reactive from unreactive pupils. Ten patients underwent PLR testing in an ophthalmology outpatient clinic setting following the administration of tropicamide eye drops, which rendered the pupils unreactive. The parameters corrected for lighting were combined as predictors in a machine learning model to produce a scalar value, the Pupil Reactivity (PuRe) score, which quantifies Pupil Reactivity on a scale 0-5 (0, non-reactive pupil; 0-3, abnormal/'sluggish" response; 3-5, normal/brisk response). The score discriminated unreactive pupils with 100% accuracy and was stable under changes in ambient illumination across four orders of magnitude. Discussion: This is the first time that a correction method has been proposed to effectively mitigate the confounding influence of ambient light on PLR measurements, which could improve the reliability of pupillometric parameters both in pre-hospital and inpatient care settings. In particular, the PuRe score offers a robust measure of Pupil Reactivity directly applicable to clinical practice. Importantly, the formulae behind the score are openly available for the benefit of the clinical research community. [ABSTRACT FROM AUTHOR]

Introduction: The pupillary light reflex (PLR) is the constriction of the pupil in response to light. The PLR in response to a pulse of light follows a complex waveformthat can be characterized by several parameters. It is a sensitivemarker of acute neurological deterioration, but is also sensitive to the background illumination in the environment in which it is measured. To detect a pathological change in the PLR, it is therefore necessary to separate the contributions of neuro-ophthalmic factors from ambient illumination. Illumination varies over several orders of magnitude and is difficult to control due to diurnal, seasonal, and location variations. Methods and results: We assessed the sensitivity of seven PLR parameters to di􀀀erences in ambient light, using a smartphone-based pupillometer (AI Pupillometer, Solvemed Inc.). Nine subjects underwent 345 measurements in ambient conditions ranging from complete darkness (<5 lx) to bright lighting (.10,000 lx). Lighting most strongly a􀀀ected the initial pupil size, constriction amplitude, and velocity. Nonlinear models were fitted to find the correction function that maximally stabilized PLR parameters across di􀀀erent ambient light levels. Next, we demonstrated that the lighting-corrected parameters still discriminated reactive from unreactive pupils. Ten patients underwent PLR testing in an ophthalmology outpatient clinic setting following the administration of tropicamide eye drops, which rendered the pupils unreactive. The parameters corrected for lighting were combined as predictors in a machine learning model to produce a scalar value, the Pupil Reactivity (PuRe) score, which quantifies Pupil Reactivity on a scale 0-5 (0, non-reactive pupil; 0-3, abnormal/"sluggish" response; 3-5, normal/brisk response). The score discriminated unreactive pupils with 100% accuracy and was stable under changes in ambient illumination across four orders of magnitude. Discussion: This is the first time that a correction method has been proposed to effectively mitigate the confounding influence of ambient light on PLR measurements, which could improve the reliability of pupillometric parameters both in pre-hospital and inpatient care settings. In particular, the PuRe score offers a robust measure of Pupil Reactivity directly applicable to clinical practice. Importantly, the formulae behind the score are openly available for the benefit of the clinical research community. [ABSTRACT FROM AUTHOR]

When facing an unfamiliar environment, animals need to explore to gain new knowledge about which actions provide reward, but also put the newly acquired knowledge to use as quickly as possible. Optimal reinforcement learning strategies should therefore assess the uncertainties of these action–reward associations and utilise them to inform decision making. We propose a novel model whereby direct and indirect striatal pathways act together to estimate both the mean and variance of reward distributions, and mesolimbic dopaminergic neurons provide transient novelty signals, facilitating effective uncertainty-driven exploration. We utilised electrophysiological recording data to verify our model of the basal ganglia, and we fitted exploration strategies derived from the neural model to data from behavioural experiments. We also compared the performance of directed exploration strategies inspired by our basal ganglia model with other exploration algorithms including classic variants of upper confidence bound (UCB) strategy in simulation. The exploration strategies inspired by the basal ganglia model can achieve overall superior performance in simulation, and we found qualitatively similar results in fitting model to behavioural data compared with the fitting of more idealised normative models with less implementation level detail. Overall, our results suggest that transient dopamine levels in the basal ganglia that encode novelty could contribute to an uncertainty representation which efficiently drives exploration in reinforcement learning. Author summary: Humans and other animals learn from rewards and losses resulting from their actions to maximise their chances of survival. In many cases, a trial-and-error process is necessary to determine the most rewarding action in a certain context. During this process, determining how much resource should be allocated to acquiring information ("exploration") and how much should be allocated to utilising the existing information to maximise reward ("exploitation") is key to the overall effectiveness, i.e., the maximisation of total reward obtained with a certain amount of effort. We propose a theory whereby an area within the mammalian brain called the basal ganglia integrates current knowledge about the mean reward, reward uncertainty and novelty of an action in order to implement an algorithm which optimally allocates resources between exploration and exploitation. We verify our theory using behavioural experiments and electrophysiological recording, and show in simulations that the model also achieves good performance in comparison with established benchmark algorithms. [ABSTRACT FROM AUTHOR]

Working memory (WM) impairments are reported to occur in patients with Parkinson's disease (PD). However, the mechanisms are unclear. Here, we investigate several putative factors that might drive poor performance, by examining the precision of recall, the order in which items are recalled and whether memories are corrupted by random guessing (attentional lapses). We used two separate tasks that examined the quality of WM recall under different loads and retention periods, as well as a traditional digit span test. Firstly, on a simple measure of WM recall, where patients were asked to reproduce the orientation of a centrally presented arrow, overall recall was not significantly impaired. However, there was some evidence for increased guessing (attentional lapses). On a new analogue version of the Corsi‐span task, where participants had to reproduce on a touchscreen the exact spatial pattern of presented stimuli in the order and locations in which they appeared, there was a reduction in the precision of spatial WM at higher loads. This deficit was due to misremembering item order. At the highest load, there was reduced recall precision, whereas increased guessing was only observed at intermediate set sizes. Finally, PD patients had impaired backward, but not forward, digit spans. Overall, these results reveal the task‐ and load‐dependent nature of WM deficits in PD. On simple low‐load tasks, attentional lapses predominate, whereas at higher loads, in the spatial domain, the corruption of mnemonic information—both order item and precision—emerge as the main driver of impairment. [ABSTRACT FROM AUTHOR]

Idiopathic rapid eye movement sleep behaviour disorder (iRBD) is now established as an important marker of the prodromal stage of Parkinson's disease and related synucleinopathies. However, although dopamine transporter (DaT) SPECT has been used to demonstrate the presence of nigro-striatal deficit in iRBD, quantifiable correlates of this are currently lacking. Sensitivity to rewarding stimuli is reduced in some people with Parkinson's disease, potentially contributing to aspects of the neuropsychiatric phenotype in these individuals. Further, a role for dopaminergic degeneration is suggested by the fact that reward insensitivity can be improved by dopaminergic medications. iRBD patients present a unique opportunity to study the relationship between reward sensitivity and early dopaminergic deficit in the unmedicated state. Here, we investigate whether a non-invasive, objective measure of reward sensitivity might be a marker of dopaminergic status in prodromal Parkinson's, by comparing with SPECT/CT measurement of dopaminergic loss in the basal ganglia. Striatal dopaminergic deficits in iRBD are associated with progression to Parkinsonian disorders. Therefore, identification of a clinically measurable correlate of this degenerative process might provide a basis for the development of novel risk stratification tools. Using a recently developed incentivised eye-tracking task, we quantified reward sensitivity in a cohort of 41 patients with idiopathic RBD and compared this with data from 40 patients with Parkinson's and 41 healthy controls. iRBD patients also underwent neuroimaging with DaT SPECT/CT. Overall, reward sensitivity, indexed by pupillary response to monetary incentives, was reduced in iRBD cases compared to controls, and was not significantly different to that in Parkinson's patients. However, in iRBD patients with normal DaT SPECT/CT imaging, reward sensitivity was not significantly different to healthy controls. Across all iRBD cases, a positive association was observed between reward sensitivity and dopaminergic SPECT/CT signal in the putamen. These findings demonstrate a direct relationship between dopaminergic deficit and reward sensitivity in patients with iRBD and suggest that measurement of pupillary responses could be of value in models of risk stratification and disease progression in these individuals. [ABSTRACT FROM AUTHOR]

Attention can be allocated in working memory (WM) to select and privilege relevant content. It is unclear whether attention selects individual features or whole objects in WM. Here, we used behavioral measures, eye-tracking, and EEG to test the hypothesis that attention spreads between an object's features in WM. Twenty-six participants completed a WM task that asked them to recall the angle of one of two oriented, colored bars after a delay while EEG and eye-tracking data were collected. During the delay, an orthogonal "incidental task" cued the color of one item for a match/mismatch judgment. On congruent trials (50%), the cued item was probed for subsequent orientation recall; on incongruent trials (50%), the other memory item was probed. As predicted, selecting the color of an object in WM brought other features of the cued object into an attended state as revealed by EEG decoding, oscillatory α-power, gaze bias, and improved orientation recall performance. Together, the results show that attentional selection spreads between an object's features in WM, consistent with object-based attentional selection. Analyses of neural processing at recall revealed that the selected object was automatically compared with the probe, whether it was the target for recall or not. This provides a potential mechanism for the observed benefits of nonpredictive cueing in WM, where a selected item is prioritized for subsequent decision-making. [ABSTRACT FROM AUTHOR]

The claustrum is the most densely interconnected region in the human brain. Despite the accumulating data from clinical and experimental studies, the functional role of the claustrum remains unknown. Here, we systematically review claustrum lesion studies and discuss their functional implications. Claustral lesions are associated with an array of signs and symptoms, including changes in cognitive, perceptual and motor abilities; electrical activity; mental state; and sleep. The wide range of symptoms observed following claustral lesions do not provide compelling evidence to support prominent current theories of claustrum function such as multisensory integration or salience computation. Conversely, the lesions studies support the hypothesis that the claustrum regulates cortical excitability. We argue that the claustrum is connected to, or part of, multiple brain networks that perform both fundamental and higher cognitive functions. As a multifunctional node in numerous networks, this may explain the manifold effects of claustrum damage on brain and behaviour. [ABSTRACT FROM AUTHOR]

Visual search and working memory (WM) are tightly linked cognitive processes. Theories of attentional selection assume that WM plays an important role in top-down guided visual search. However, computational models of visual search do not model WM. Here we show that an existing model of WM can utilize its mechanisms of rapid plasticity and pattern completion to perform visual search. In this model, a search template, like a memory item, is encoded into the network's synaptic weights forming a momentary stable attractor. During search, recurrent activation between the template and visual inputs amplifies the target and suppresses non-matching features via mutual inhibition. While the model cannot outperform models designed specifically for search, it can, "off-the-shelf", account for important characteristics. Notably, it produces search display set-size costs, repetition effects, and multiple-template search effects, qualitatively in line with empirical data. It is also informative that the model fails to produce some important aspects of visual search behaviour, such as suppression of repeated distractors. Also, without additional control structures for top-down guidance, the model lacks the ability to differentiate between encoding and searching for targets. The shared architecture bridges theories of visual search and visual WM, highlighting their common structure and their differences. [ABSTRACT FROM AUTHOR]