A single-system model predicts recognition memory and repetition priming in amnesia

We challenge the claim that there are distinct neural systems for explicit and implicit memory by demonstrating that a formal single-system model predicts the pattern of recognition memory (explicit) and repetition priming (implicit) in amnesia. In the current investigation, human participants with amnesia categorized pictures of objects at study and then, at test, identified fragmented versions of studied (old) and nonstudied (new) objects (providing a measure of priming), and made a recognition memory judgment (old vs new) for each object. Numerous results in the amnesic patients were predicted in advance by the single-system model, as follows: (1) deficits in recognition memory and priming were evident relative to a control group; (2) items judged as old were identified at greater levels of fragmentation than items judged new, regardless of whether the items were actually old or new; and (3) the magnitude of the priming effect (the identification advantage for old vs new items) overall was greater than that of items judged new. Model evidence measures also favored the single-system model over two formal multiple-systems models. The findings support the single-system model, which explains the pattern of recognition and priming in amnesia primarily as a reduction in the strength of a single dimension of memory strength, rather than a selective explicit memory system deficit

Targeting SxIP-EB1 interaction: An integrated approach to the discovery of small molecule modulators of dynamic binding sites

End binding protein 1 (EB1) is a key element in the complex network of protein-protein interactions at microtubule (MT) growing ends, which has a fundamental role in MT polymerisation. EB1 is an important protein target as it is involved in regulating MT dynamic behaviour, and has been associated with several disease states, such as cancer and neuronal diseases. Diverse EB1 binding partners are recognised through a conserved four amino acid motif, (serine-X-isoleucine-proline) which exists within an intrinsically disordered region. Here we report the use of a multidisciplinary computational and experimental approach for the discovery of the first small molecule scaffold which targets the EB1 recruiting domain. This approach includes virtual screening (structure- and ligand-based design) and multiparameter compound selection. Subsequent studies on the selected compounds enabled the elucidation of the NMR structures of the C-terminal domain of EB1 in the free form and complexed with a small molecule. These structures show that the binding site is not preformed in solution, and ligand binding is fundamental for the binding site formation. This work is a successful demonstration of the combination of modelling and experimental methods to enable the discovery of compounds which bind to these challenging systems

Endocannabinoid system alterations in Alzheimer's disease: a systematic review of human studies

Studies investigating alterations of the endocannabinoid system (ECS) in Alzheimer's disease (AD) in humans have reported inconsistent findings so far. We performed a systematic review of studies examining alterations of the ECS specifically within humans with AD or mild cognitive impairment (MCI), including neuroimaging studies, studies of serum and cerebrospinal fluid biomarkers, and post-mortem studies. We attempted to identify reported changes in the expression and activity of: cannabinoid receptors 1 and 2; anandamide (AEA); 2-arachidonoylglycerol (2-AG); monoacylglycerol lipase (MAGL); fatty acid amide hydrolase (FAAH); and transient receptor potential cation channel V1 (TRPV1). Twenty-two studies were identified for inclusion. Mixed findings were reported for most aspects of the ECS in AD, making it difficult to identify a particular profile of ECS alterations characterising AD. The included studies tended to be small, methodologically heterogeneous, and frequently did not control for important potential confounders, such as pathological progression of AD. Eight studies correlated ECS alterations with neuropsychometric performance measures, though studies infrequently examined behavioural and neuropsychiatric correlates. PROSPERO database identifier: CRD42018096249

‘It’s too late’. Is it really? Considerations for amblyopia treatment in older children

In recent years, media coverage has demonstrated instances in which families of children aged 7 and older, newly diagnosed with strabismic and/or anisometropic amblyopia through community eyecare services, were told it was ‘too late’ for their child to effectively respond to conventional amblyopia treatment (occlusion or atropine penalisation). Formal guidance pertaining to binocular vision anomalies from eyecare professional bodies does not specifically make reference to a child’s age, beyond stating the importance of early diagnosis and treatment of strabismus/amblyopia. However, there have been many changes in the way we view the recovery period for amblyopia, and it is well demonstrated both within literature and clinical practice that conventional treatment can improve amblyopic eye visual acuity in children beyond the age of 7 years. The occurrence of these media described cases within the community eyecare sphere would suggest it is worthwhile revisiting the literature on the subject of amblyopia treatment in older children (aged 7+ years), to address misconceptions and place in the spotlight current considerations facing clinicians when treating newly diagnosed amblyopia within this age group. This perspective review provides an evidence-based update covering the various considerations associated with treatment of amblyopia in older children, along with recent amblyopia treatment advances that could have an impact on treatment prospects for this patient group. Considerations include the risks, benefits and efficacy of treating newly diagnosed amblyopia in older children, monitoring density of suppression to mitigate intractable diplopia risk, and recent findings regarding binocular treatments for amblyopia

Disrupted reward processing in Parkinson's disease and its relationship with dopamine state and neuropsychiatric syndromes: a systematic review and meta-analysis

Background: Neuropsychiatric symptoms are common in Parkinson’s disease (PD) and predict poorer outcomes. Reward processing dysfunction is a candidate mechanism for the development of psychiatric symptoms including depression and impulse control disorders (ICDs). We aimed to determine whether reward processing is impaired in PD and its relationship with neuropsychiatric syndromes and dopamine replacement therapy. // Methods: The Ovid MEDLINE/PubMed, Embase and PsycInfo databases were searched for articles published up to 5 November 2020. Studies reporting reward processing task performance by patients with PD and healthy controls were included. Summary statistics comparing reward processing between groups were converted to standardised mean difference (SMD) scores and meta-analysed using a random effects model. // Results: We identified 55 studies containing 2578 participants (1638 PD and 940 healthy controls). Studies assessing three subcomponent categories of reward processing tasks were included: option valuation (n=12), reinforcement learning (n=37) and reward response vigour (n=6). Across all studies, patients with PD on medication exhibited a small-to-medium impairment versus healthy controls (SMD=0.34; 95% CI 0.14 to 0.53), with greater impairments observed off dopaminergic medication in within-subjects designs (SMD=0.43, 95% CI 0.29 to 0.57). Within-subjects subcomponent analysis revealed impaired processing off medication on option valuation (SMD=0.57, 95% CI 0.39 to 0.75) and reward response vigour (SMD=0.36, 95% CI 0.13 to 0.59) tasks. However, the opposite applied for reinforcement learning, which relative to healthy controls was impaired on-medication (SMD=0.45, 95% CI 0.25 to 0.65) but not off-medication (SMD=0.28, 95% CI −0.03 to 0.59). ICD was the only neuropsychiatric syndrome with sufficient studies (n=13) for meta-analysis, but no significant impairment was identified compared tonon-ICD patients (SMD=−0.02, 95% CI −0.43 to 0.39). // Conclusion: Reward processing disruption in PD differs according to subcomponent and dopamine medication state, and warrants further study as a potential treatment target and mechanism underlying associated neuropsychiatric syndromes

Interventions for subjective cognitive decline: systematic review and meta-analysis

OBJECTIVES: This review provides a broad overview of the effectiveness of interventions for subjective cognitive decline (SCD) in improving psychological well-being, metacognition and objective cognitive performance. METHODS: Databases including PubMed, Web of Science and Cochrane Systematic Reviews were searched up to August 2017 to identify randomised controlled trials evaluating interventions for SCD. Interventions were categorised as psychological, cognitive, lifestyle or pharmacological. Outcomes of interest included psychological well-being, metacognitive ability and objective cognitive performance. To assess the risk of bias, three authors independently rated study validity using criteria based on the Critical Appraisal Skills Programme. Random-effects meta-analyses were undertaken where three or more studies investigated similar interventions and reported comparable outcomes. RESULTS: Twenty studies met inclusion criteria and 16 had sufficient data for inclusion in the meta-analyses. Of these, only seven were rated as being high quality. Group psychological interventions significantly improved psychological well-being (g=0.40, 95% CI 0.03 to 0.76; p=0.03) but the improvement they conferred on metacognitive ability was not statistically significant (g=0.26, 95% CI -0.22 to 0.73; p=0.28). Overall, cognitive training interventions led to a small, statistically significant improvement in objective cognitive performance (g=0.13, 95% CI 0.01 to 0.25; p=0.03). However, the pooled effect sizes of studies using active control groups (g=0.02, 95% CI -0.19 to 0.22; p=0.85) or reporting global cognitive measures (g=0.06, 95% CI -0.19 to 0.31; p=0.66) were non-significant. CONCLUSIONS: There is a lack of high-quality research in this field. Group psychological interventions improve psychological well-being and may also improve metacognition. A large, high-quality study is indicated to investigate this further. There is no evidence to suggest that cognitive interventions improve global cognitive performance and the clinical utility of small improvements in specific cognitive domains is questionable. There is a lack of research considering lifestyle interventions and poor quality evidence for pharmacological interventions. PROSPERO REGISTRATION NUMBER: CRD42017079391

Jacobi Polynomials as su(2, 2) Unitary Irreducible Representation

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Dimension reduction for systems with slow relaxation

We develop reduced, stochastic models for high dimensional, dissipative dynamical systems that relax very slowly to equilibrium and can encode long term memory. We present a variety of empirical and first principles approaches for model reduction, and build a mathematical framework for analyzing the reduced models. We introduce the notions of universal and asymptotic filters to characterize `optimal' model reductions for sloppy linear models. We illustrate our methods by applying them to the practically important problem of modeling evaporation in oil spills.Comment: 48 Pages, 13 figures. Paper dedicated to the memory of Leo Kadanof

Myocardial changes on 3T cardiovascular magnetic resonance imaging in response to haemodialysis with fluid removal

Background: Mapping of left ventricular (LV) native T1 is a promising non-invasive, non-contrast imaging biomarker. Native myocardial T1 times are prolonged in patients requiring dialysis, but there are concerns that the dialysis process and fluctuating fluid status may confound results in this population. We aimed to assess the changes in cardiac parameters on 3T cardiovascular magnetic resonance (CMR) before and after haemodialysis, with a specific focus on native T1 mapping. Methods: This is a single centre, prospective observational study in which maintenance haemodialysis patients underwent CMR before and after dialysis (both scans within 24 h). Weight measurement, bio-impedance body composition monitoring, haemodialysis details and fluid intake were recorded. CMR protocol included cine imaging and mapping native T1 and T2. Results: Twenty-six participants (16 male, 65 ± 9 years) were included in the analysis. The median net ultrafiltration volume on dialysis was 2.3 L (IQR 1.8, 2.5), resulting in a median weight reduction at post-dialysis scan of 1.35 kg (IQR 1.0, 1.9), with a median reduction in over-hydration (as measured by bioimpedance) of 0.75 L (IQR 0.5, 1.4). Significant reductions were observed in LV end-diastolic volume (− 25 ml, p = 0.002), LV stroke volume (− 13 ml, p = 0.007), global T1 (21 ms, p = 0.02), global T2 (− 1.2 ms, p = 0.02) following dialysis. There was no change in LV mass (p = 0.35), LV ejection fraction (p = 0.13) or global longitudinal strain (p = 0.22). On linear regression there was no association between baseline over-hydration (as defined by bioimpedance) and global native T1 or global T2, nor was there an association between the change in over-hydration and the change in these parameters. Conclusions: Acute changes in cardiac volumes and myocardial native T1 are detectable on 3T CMR following haemodialysis with fluid removal. The reduction in global T1 suggests that the abnormal native T1 observed in patients on haemodialysis is not entirely due to myocardial fibrosis