A transdiagnostic examination of cognitive heterogeneity in children and adolescents with neurodevelopmental disorders.

Children and adolescents with neurodevelopmental disorders demonstrate extensive cognitive heterogeneity that is not adequately captured by traditional diagnostic systems, emphasizing the need for alternative assessment and classification techniques. Using a transdiagnostic approach, a retrospective cohort study of cognitive functioning was conducted using a large heterogenous sample (n = 1529) of children and adolescents 7 to 18 years of age with neurodevelopmental disorders. Measures of short-term memory, verbal ability, and reasoning were administered to participants with attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), comorbid ADHD/ASD, and participants without neurodevelopmental disorders (non-NDD) using a 12-task, web-based neurocognitive testing battery. Unsupervised machine learning techniques were used to create a self-organizing map, an artificial neural network, in conjunction with k-means clustering to identify data-driven subgroups. The study aims were to: 1) identify cognitive profiles in the sample using a data-driven approach, and 2) determine their correspondence with traditional diagnostic statuses. Six clusters representing different cognitive profiles were identified, including participants with varying forms of cognitive impairment. Diagnostic status did not correspond with cluster-membership, providing evidence for the application of transdiagnostic approaches to understanding cognitive heterogeneity in children and adolescents with neurodevelopmental disorders. Additionally, the findings suggest that many typically developing participants may have undiagnosed learning difficulties, emphasizing the need for accessible cognitive assessment tools in school-based settings.

Crystallographic Fragment Screen of Coxsackievirus A16 2A Protease identifies new opportunities for the development of broad-spectrum anti-enterovirals.

Enteroviruses are the causative agents of paediatric hand-foot-and-mouth disease, and a target for pandemic preparedness due to the risk of higher order complications in a large-scale outbreak. The 2A protease of these viruses is responsible for the self-cleavage of the poly protein, allowing for correct folding and assembly of capsid proteins in the final stages of viral replication. These 2A proteases are highly conserved between Enterovirus species, such as Enterovirus A71 and Coxsackievirus A16 . Inhibition of the 2A protease deranges capsid folding and assembly, preventing formation of mature virions in host cells and making the protease a valuable target for antiviral activity. Herein, we describe a crystallographic fragment screening campaign that identified 75 fragments which bind to the 2A protease including 38 unique compounds shown to bind within the active site. These fragments reveal a path for the development of non-peptidomimetic inhibitors of the 2A protease with broad-spectrum anti-enteroviral activity.

A design for life: Predicting cognitive performance from lifestyle choices.

Maintaining cognitive capacity through adulthood has been the target of many recent studies that have examined the influence of lifestyle choices such as exercise, diet, and sleeping habits. Many of these studies have focused on a single factor (e.g., diet) and its effect on cognitive abilities; however, humans make numerous lifestyle choices every single day, many of which interact and influence each other. Here, we investigated whether combinations of lifestyle choices can predict better or worse cognitive performance in the general population, and whether optimal combinations of choices existed depending on the cognitive domain. Specifically, we examined 20 self-reported lifestyle choices, such as playing video games, drinking alcohol, and amount of exercise taken, in a sample of almost 10,000 participants. All participants also completed 12 cognitive tests that have been shown to generate three composite cognitive domain scores pertaining to short-term memory, verbal abilities, and reasoning. Using recursive feature elimination and random forest regression, we were able to explain 9% of the variance in short-term memory scores, 8% of the variance in reasoning scores, and 7% of the variance in verbal ability scores. While the regression model provided predictive power in all three domains, these levels indicate that even when considering a large number of lifestyle choices, there remains a considerable degree of variability in predicting short-term memory, reasoning and verbal abilities. Thus, while some modifiable lifestyle factors may have an impact on cognitive capacity, there likely exists no single optimal design for life.

Predicting neurologic recovery after severe acute brain injury using resting-state networks.

OBJECTIVE: There is a lack of reliable tools used to predict functional recovery in unresponsive patients following a severe brain injury. The objective of the study is to evaluate the prognostic utility of resting-state functional magnetic resonance imaging for predicting good neurologic recovery in unresponsive patients with severe brain injury in the intensive-care unit. METHODS: Each patient underwent a 5.5-min resting-state scan and ten resting-state networks were extracted via independent component analysis. The Glasgow Outcome Scale was used to classify patients into good and poor outcome groups. The Nearest Centroid classifier used each patient's ten resting-state network values to predict best neurologic outcome within 6 months post-injury. RESULTS: Of the 25 patients enrolled (mean age = 43.68, range = [19-69]; GCS ≤ 9; 6 females), 10 had good and 15 had poor outcome. The classifier correctly and confidently predicted 8/10 patients with good and 12/15 patients with poor outcome (mean = 0.793, CI = [0.700, 0.886], Z = 2.843, p = 0.002). The prediction performance was largely determined by three visual (medial: Z = 3.11, p = 0.002; occipital pole: Z = 2.44, p = 0.015; lateral: Z = 2.85, p = 0.004) and the left frontoparietal network (Z = 2.179, p = 0.029). DISCUSSION: Our approach correctly identified good functional outcome with higher sensitivity (80%) than traditional prognostic measures. By revealing preserved networks in the absence of discernible behavioral signs, functional connectivity may aid in the prognostic process and affect the outcome of discussions surrounding withdrawal of life-sustaining measures.

Anatomical correlates of category-selective visual regions have distinctive signatures of connectivity in neonates.

The ventral visual stream is shaped during development by innate proto-organization within the visual system, such as the strong input from the fovea to the fusiform face area. In adults, category-selective regions have distinct signatures of connectivity to brain regions beyond the visual system, likely reflecting cross-modal and motoric associations. We tested if this long-range connectivity is part of the innate proto-organization, or if it develops with postnatal experience, by using diffusion-weighted imaging to characterize the connectivity of anatomical correlates of category-selective regions in neonates (N = 445), 1-9 month old infants (N = 11), and adults (N = 14). Using the HCP data we identified face- and place- selective regions and a third intermediate region with a distinct profile of selectivity. Using linear classifiers, these regions were found to have distinctive connectivity at birth, to other regions in the visual system and to those outside of it. The results support an extended proto-organization that includes long-range connectivity that shapes, and is shaped by, experience-dependent development.

Disentangling the cognitive, physical, and mental health sequelae of COVID-19.

As COVID-19 cases exceed hundreds of millions globally, many survivors face cognitive challenges and prolonged symptoms. However, important questions about the cognitive effects of COVID-19 remain unresolved. In this cross-sectional online study, 478 adult volunteers who self-reported a positive test for COVID-19 (mean = 30 days since most recent test) perform significantly worse than pre-pandemic norms on cognitive measures of processing speed, reasoning, verbal, and overall performance, but not short-term memory, suggesting domain-specific deficits. Cognitive differences are even observed in participants who did not require hospitalization. Factor analysis of health- and COVID-related questionnaires reveals two clusters of symptoms-one that varies mostly with physical symptoms and illness severity, and one with mental health. Cognitive performance is positively correlated with the global measure encompassing physical symptoms, but not the one that broadly describes mental health, suggesting that the subjective experience of "long COVID" relates to physical symptoms and cognitive deficits, especially executive dysfunction.

Discovery of novel druggable pockets on polyomavirus VP1 through crystallographic fragment-based screening to develop capsid assembly inhibitors.

Polyomaviruses are a family of ubiquitous double-stranded DNA viruses many of which are human pathogens. These include BK polyomavirus which causes severe urinary tract infection in immunocompromised patients and Merkel cell polyomavirus associated with aggressive cancers. The small genome of polyomaviruses lacks conventional drug targets, and no specific drugs are available at present. Here we focus on the main structural protein VP1 of BK polyomavirus which is responsible for icosahedral capsid formation. To provide a foundation towards rational drug design, we crystallized truncated VP1 pentamers and subjected them to a high-throughput screening for binding drug-like fragments through a direct X-ray analysis. To enable a highly performant screening, rigorous optimization of the crystallographic pipeline and processing with the latest generation PanDDA2 software were necessary. As a result, a total of 144 binding hits were established. Importantly, the hits are well clustered in six surface pockets. Three pockets are located on the outside of the pentamer and map on the regions where the 'invading' C-terminal arm of another pentamer is attached upon capsid assembly. Another set of three pockets is situated within the wide pore along the five-fold axis of the VP1 pentamer. These pockets are situated at the interaction interface with the minor capsid protein VP2 which is indispensable for normal functioning of the virus. Here we systematically analyse the three outside pockets which are highly conserved across various polyomaviruses, while point mutations in these pockets are detrimental for viral replication. We show that one of the pockets can accommodate antipsychotic drug trifluoperazine. For each pocket, we derive pharmacophore features which enable the design of small molecules preventing the interaction between VP1 pentamers and therefore inhibiting capsid assembly. Our data lay a foundation towards a rational development of first-in-class drugs targeting polyomavirus capsid.

Parametric Cognitive Load Reveals Hidden Costs in the Neural Processing of Perfectly Intelligible Degraded Speech.

Speech is often degraded by environmental noise or hearing impairment. People can compensate for degradation, but this requires cognitive effort. Previous research has identified frontotemporal networks involved in effortful perception, but materials in these works were also less intelligible, and so it is not clear whether activity reflected effort or intelligibility differences. We used functional magnetic resonance imaging to assess the degree to which spoken sentences were processed under distraction and whether this depended on speech quality even when intelligibility of degraded speech was matched to that of clear speech (close to 100%). On each trial, male and female human participants either attended to a sentence or to a concurrent multiple object tracking (MOT) task that imposed parametric cognitive load. Activity in bilateral anterior insula reflected task demands; during the MOT task, activity increased as cognitive load increased, and during speech listening, activity increased as speech became more degraded. In marked contrast, activity in bilateral anterior temporal cortex was speech selective and gated by attention when speech was degraded. In this region, performance of the MOT task with a trivial load blocked processing of degraded speech, whereas processing of clear speech was unaffected. As load increased, responses to clear speech in these areas declined, consistent with reduced capacity to process it. This result dissociates cognitive control from speech processing; substantially less cognitive control is required to process clear speech than is required to understand even very mildly degraded, 100% intelligible speech. Perceptual and control systems clearly interact dynamically during real-world speech comprehension.SIGNIFICANCE STATEMENT Speech is often perfectly intelligible even when degraded, for example, by background sound, phone transmission, or hearing loss. How does degradation alter cognitive demands? Here, we use fMRI to demonstrate a novel and critical role for cognitive control in the processing of mildly degraded but perfectly intelligible speech. We compare speech that is matched for intelligibility but differs in putative control demands, dissociating cognitive control from speech processing. We also impose a parametric cognitive load during perception, dissociating processes that depend on tasks from those that depend on available capacity. Our findings distinguish between frontal and temporal contributions to speech perception and reveal a hidden cost to processing mildly degraded speech, underscoring the importance of cognitive control for everyday speech comprehension.

Cognitive Impairment Early After Initiating Maintenance Hemodialysis: A Cross Sectional Study.

Background: Abnormalities in cognitive function are almost universal in patients receiving hemodialysis (HD) and are associated with worse quality of life, impaired decision making, increased healthcare utilization and mortality. While cognitive impairment in the HD population is increasingly recognized, it is unclear how quickly it develops after starting HD. Methods: This was a cross-sectional study of a cohort of low dialysis vintage HD patients (<12 months). We used the validated Cambridge Brain Science (CBS) battery of web-based tests to evaluate cognition compared to age- and sex matched controls across three cognitive domains: verbal processing, reasoning and short-term memory. Results: Forty-nine HD patients were included in this study; 43 completed the full battery of tests. The average scores for HD patients were consistently below the age and sex-matched controls. Fifty-five percent of HD patients had cognitive impairment in verbal skills, 43% in reasoning and 18% in short-term memory. Conclusions: There is a high prevalence of CI evident early after starting HD, with the largest deficits seen in reasoning and verbal processing. These deficits may be attributable to the HD treatment itself. Further studies are needed to characterize the natural history of CI in this patient population and to test interventions aimed at preventing or slowing its progression.

Achieving Efficient Fragment Screening at XChem Facility at Diamond Light Source.

In fragment-based drug discovery, hundreds or often thousands of compounds smaller than ~300 Da are tested against the protein of interest to identify chemical entities that can be developed into potent drug candidates. Since the compounds are small, interactions are weak, and the screening method must therefore be highly sensitive; moreover, structural information tends to be crucial for elaborating these hits into lead-like compounds. Therefore, protein crystallography has always been a gold-standard technique, yet historically too challenging to find widespread use as a primary screen. Initial XChem experiments were demonstrated in 2014 and then trialed with academic and industrial collaborators to validate the process. Since then, a large research effort and significant beamtime have streamlined sample preparation, developed a fragment library with rapid follow-up possibilities, automated and improved the capability of I04-1 beamline for unattended data collection, and implemented new tools for data management, analysis and hit identification. XChem is now a facility for large-scale crystallographic fragment screening, supporting the entire crystals-to-deposition process, and accessible to academic and industrial users worldwide. The peer-reviewed academic user program has been actively developed since 2016, to accommodate projects from as broad a scientific scope as possible, including well-validated as well as exploratory projects. Academic access is allocated through biannual calls for peer-reviewed proposals, and proprietary work is arranged by Diamond's Industrial Liaison group. This workflow has already been routinely applied to over a hundred targets from diverse therapeutic areas, and effectively identifies weak binders (1%-30% hit rate), which both serve as high-quality starting points for compound design and provide extensive structural information on binding sites. The resilience of the process was demonstrated by continued screening of SARS-CoV-2 targets during the COVID-19 pandemic, including a 3-week turn-around for the main protease.

Cognition across the Lifespan: Investigating Age, Sex, and Other Sociodemographic Influences.

Maintaining cognitive health across the lifespan has been the focus of a multi-billion-dollar industry. In order to guide treatment and interventions, a clear understanding of the way that proficiency in different cognitive domains develops and declines in both sexes across the lifespan is necessary. Additionally, there are sex differences in a range of other factors, including psychiatric illnesses such as anxiety, depression, and substance use, that are also known to affect cognition, although the scale of this interaction is unknown. Our objective was to assess differences in cognitive function across the lifespan in men and women in a large, representative sample. Leveraging online cognitive testing, a sample of 9451 men and 9451 women ranging in age from 12 to 69 (M = 28.21) matched on socio-demographic factors were studied. Segmented regression was used to model three cognitive domains-working memory, verbal abilities, and reasoning. Sex differences in all three domains were minimal; however, after broadening the sample in terms of socio-demographic factors, sex differences appeared. These results suggest that cognition across the lifespan differs for men and women, but is greatly influenced by environmental factors. We discuss these findings within a framework that describes sex differences in cognition as likely guided by a complex interplay between biology and environment.

Brain training habits are not associated with generalized benefits to cognition: An online study of over 1000 "brain trainers".

The foundational tenet of brain training is that general cognitive functioning can be enhanced by completing computerized games, a notion that is both intuitive and appealing. Moreover, there is strong incentive to improve our cognitive abilities, so much so that it has driven a billion-dollar industry. However, whether brain training can really produce these desired outcomes continues to be debated. This is, in part, because the literature is replete with studies that use ill-defined criteria for establishing transferable improvements to cognition, often using single training and outcome measures with small samples. To overcome these limitations, we conducted a large-scale online study to examine whether practices and beliefs about brain training are associated with better cognition. We recruited a diverse sample of over 1000 participants, who had been using an assortment of brain training programs for up to 5 years. Cognition was assessed using multiple tests that measure attention, reasoning, working memory and planning. We found no association between any measure of cognitive functioning and whether participants were currently "brain training" or not, even for the most committed brain trainers. Duration of brain training also showed no relationship with any cognitive performance measure. This result was the same regardless of participant age, which brain training program they used, or whether they expected brain training to work. Our results pose a significant challenge for "brain training" programs that purport to improve general cognitive functioning among the general population. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Event-related potentials reflect prediction errors and pop-out during comprehension of degraded speech.

Comprehension of degraded speech requires higher-order expectations informed by prior knowledge. Accurate top-down expectations of incoming degraded speech cause a subjective semantic 'pop-out' or conscious breakthrough experience. Indeed, the same stimulus can be perceived as meaningless when no expectations are made in advance. We investigated the event-related potential (ERP) correlates of these top-down expectations, their error signals and the subjective pop-out experience in healthy participants. We manipulated expectations in a word-pair priming degraded (noise-vocoded) speech task and investigated the role of top-down expectation with a between-groups attention manipulation. Consistent with the role of expectations in comprehension, repetition priming significantly enhanced perceptual intelligibility of the noise-vocoded degraded targets for attentive participants. An early ERP was larger for mismatched (i.e. unexpected) targets than matched targets, indicative of an initial error signal not reliant on top-down expectations. Subsequently, a P3a-like ERP was larger to matched targets than mismatched targets only for attending participants-i.e. a pop-out effect-while a later ERP was larger for mismatched targets and did not significantly interact with attention. Rather than relying on complex post hoc interactions between prediction error and precision to explain this apredictive pattern, we consider our data to be consistent with prediction error minimization accounts for early stages of processing followed by Global Neuronal Workspace-like breakthrough and processing in service of task goals.

Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease.

COVID-19, caused by SARS-CoV-2, lacks effective therapeutics. Additionally, no antiviral drugs or vaccines were developed against the closely related coronavirus, SARS-CoV-1 or MERS-CoV, despite previous zoonotic outbreaks. To identify starting points for such therapeutics, we performed a large-scale screen of electrophile and non-covalent fragments through a combined mass spectrometry and X-ray approach against the SARS-CoV-2 main protease, one of two cysteine viral proteases essential for viral replication. Our crystallographic screen identified 71 hits that span the entire active site, as well as 3 hits at the dimer interface. These structures reveal routes to rapidly develop more potent inhibitors through merging of covalent and non-covalent fragment hits; one series of low-reactivity, tractable covalent fragments were progressed to discover improved binders. These combined hits offer unprecedented structural and reactivity information for on-going structure-based drug design against SARS-CoV-2 main protease.

Bilingualism Affords No General Cognitive Advantages: A Population Study of Executive Function in 11,000 People.

Whether acquiring a second language affords any general advantages to executive function has been a matter of fierce scientific debate for decades. If being bilingual does have benefits over and above the broader social, employment, and lifestyle gains that are available to speakers of a second language, then it should manifest as a cognitive advantage in the general population of bilinguals. We assessed 11,041 participants on a broad battery of 12 executive tasks whose functional and neural properties have been well described. Bilinguals showed an advantage over monolinguals on only one test (whereas monolinguals performed better on four tests), and these effects all disappeared when the groups were matched to remove potentially confounding factors. In any case, the size of the positive bilingual effect in the unmatched groups was so small that it would likely have a negligible impact on the cognitive performance of any individual.

Concussion-related deficits in the general population predict impairments in varsity footballers.

OBJECTIVE: We investigated the long-term cognitive effects of concussion in 19,261 members of the general population and a cohort of varsity American football players with a history of frequent head impacts, using tests that are known to be sensitive to small changes in performance. METHODS: We asked 19,261 participants to complete a demographic questionnaire and 12 cognitive tests measuring aspects of executive function, including inhibitory control. We compared the performance of those reporting a history of concussion (post-concussion) to those reporting no history of concussion (non-concussed) on the cognitive battery and four non-cognitive variables. We used the results of this population-level study to predict the profile of cognitive performance in varsity American football players, who completed the same cognitive tasks. RESULTS: Post-concussion and non-concussed participants did not differ on 11 of the 12 cognitive tasks employed. However, on a test of inhibitory control based on the classic Stroop paradigm, post-concussion participants showed accuracy-related impairments specific to the incongruent conditions of the task. Post-concussion participants reported higher levels of anxiety, depression, and trouble concentrating. An entirely independent sample of 74 varsity American football players demonstrated the same pattern of impairment: compared to healthy controls, they scored significantly lower on the test of inhibitory control but were indistinguishable from controls on the 11 other tasks. INTERPRETATION: Self-reported concussion is not associated with long-term general effects on cognitive function. Nevertheless, those who report at least one concussion and those who expose themselves to long-term frequent sport-related head impacts do have a modest, but statistically robust, deficit of inhibitory control.

Exploring the neural correlates of touch and pain in women with provoked vestibulodynia.

Group differences in touch and pain thresholds-and their neural correlates-were studied in women with provoked vestibulodynia (PVD; N = 15), a common subtype of vulvodynia (chronic vulvar pain), and pain-free control women (N = 15). Results from quantitative sensory testing and self-report measures indicated that, as compared with control participants, women with PVD exhibited allodynia (ie, pain in response to a normally nonpainful stimulus) and hyperalgesia (ie, an increased response to a normally painful stimulus) at vulvar and nonvulvar sites. In addition, brain imaging analyses demonstrated reduced difference scores between touch and pain in the S2 area in women with PVD compared with control participants, supporting previous findings of allodynia in women with PVD. There were no significant reductions in difference scores between touch and pain for regions related to cognitive and affective processing of painful stimuli. The results of this study contribute important information to the general pain and vulvodynia literatures in elucidating the specific sensorimotor neural mechanisms that underlie hyperalgesia in a chronic pain population. These results have implications for differentiating neural processing of touch and pain for women with and without PVD. Future research should attempt to examine alterations related to hyperalgesia in commonly comorbid conditions of PVD.

Feasibility of a web-based neurocognitive battery for assessing cognitive function in critical illness survivors.

PURPOSE: To assess the feasibility of using a widely validated, web-based neurocognitive test battery (Cambridge Brain Sciences, CBS) in a cohort of critical illness survivors. METHODS: We conducted a prospective observational study in two intensive care units (ICUs) at two tertiary care hospitals. Twenty non-delirious ICU patients who were mechanically ventilated for a minimum of 24 hours underwent cognitive testing using the CBS battery. The CBS consists of 12 cognitive tests that assess a broad range of cognitive abilities that can be categorized into three cognitive domains: reasoning skills, short-term memory, and verbal processing. Patients underwent cognitive assessment while still in the ICU (n = 13) or shortly after discharge to ward (n = 7). Cognitive impairment on each test was defined as a raw score that was 1.5 or more standard deviations below age- and sex-matched norms from healthy controls. RESULTS: We found that all patients were impaired on at least two tests and 18 patients were impaired on at least three tests. ICU patients had poorer performance on all three cognitive domains relative to healthy controls. We identified testing related fatigue due to battery length as a feasibility issue of the CBS test battery. CONCLUSIONS: Use of a web-based patient-administered cognitive test battery is feasible and can be used in large-scale studies to identify domain-specific cognitive impairment in critical illness survivors and the temporal course of recovery over time.

Dissociable effects of self-reported daily sleep duration on high-level cognitive abilities.

Most people will at some point experience not getting enough sleep over a period of days, weeks, or months. However, the effects of this kind of everyday sleep restriction on high-level cognitive abilities-such as the ability to store and recall information in memory, solve problems, and communicate-remain poorly understood. In a global sample of over 10000 people, we demonstrated that cognitive performance, measured using a set of 12 well-established tests, is impaired in people who reported typically sleeping less, or more, than 7-8 hours per night-which was roughly half the sample. Crucially, performance was not impaired evenly across all cognitive domains. Typical sleep duration had no bearing on short-term memory performance, unlike reasoning and verbal skills, which were impaired by too little, or too much, sleep. In terms of overall cognition, a self-reported typical sleep duration of 4 hours per night was equivalent to aging 8 years. Also, sleeping more than usual the night before testing (closer to the optimal amount) was associated with better performance, suggesting that a single night's sleep can benefit cognition. The relationship between sleep and cognition was invariant with respect to age, suggesting that the optimal amount of sleep is similar for all adult age groups, and that sleep-related impairments in cognition affect all ages equally. These findings have significant real-world implications, because many people, including those in positions of responsibility, operate on very little sleep and may suffer from impaired reasoning, problem-solving, and communications skills on a daily basis.