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.

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.

Auditory structural connectivity in preterm and healthy term infants during the first postnatal year.

Assessing language development in the first postnatal year is difficult, as receptive and expressive skills are rudimentary. Although outward manifestations of change are limited, the auditory language system is thought to undergo critical development at this age, as the foundations are laid for the rapid onset of spoken language in the second and third years. We recruited 11 infants, 7 healthy controls (gestational age = 40.69 ± 0.56; range from 40 to 41.43) and preterm babies (gestational age = 28.04 ± 0.95; range from 27.43 to 29.43) who underwent a Magnetic Resonance Imaging study during the first postnatal year (age at scan = 194.18 ± 97.98). We assessed white matter tracts using diffusion-weighted magnetic resonance imaging with probabilistic tractography. Fractional anisotropy was found to be largely mature even at one month, although there was a little further increase during the first postnatal year in both the acoustic radiation and the direct brainstem-Heschl's pathway.

Adult-like processing of naturalistic sounds in auditory cortex by 3- and 9-month old infants.

Functional neuroimaging has been used to show that the developing auditory cortex of very young human infants responds, in some way, to sound. However, impoverished stimuli and uncontrolled designs have made it difficult to attribute brain responses to specific auditory features, and thus made it difficult to assess the maturity of feature tuning in auditory cortex. To address this, we used functional magnetic resonance imaging (fMRI) to measure the brain activity evoked by naturalistic sounds (a series of sung lullabies) in two groups of infants (3 and 9 months) and adults. We developed a novel analysis method - inter-subject regression (ISR) - to quantify the similarity of cortical responses between infants and adults, and to decompose components of the response due to different auditory features. We found that the temporal pattern of activity in infant auditory cortex shared similarity with adults. Some of this shared response could be attributed to simple acoustic features, such as frequency, pitch, envelope, but other parts were not, suggesting that even more complex adult-like features are represented in auditory cortex in early infancy.

Using Functional Magnetic Resonance Imaging to Detect Preserved Function in a Preterm Infant with Brain Injury.

We studied developmental plasticity using functional magnetic resonance imaging (fMRI) in a preterm infant with brain injury on structural MRI. fMRI showed preserved brain function and subsequent neurodevelopment was within the normal range. Multimodal neuroimaging including fMRI can improve understanding of neural plasticity after preterm birth and brain injury.

Cognitive, psychophysical, and neural correlates of vulvar pain in primary and secondary provoked vestibulodynia: a pilot study.

INTRODUCTION: Provoked vestibulodynia (PVD) is a common condition characterized by localized, provoked pain that can be present since first vaginal penetration attempt (primary) or can develop after a period of pain-free penetration (secondary). Research has demonstrated psychosocial and psychophysical differences between women with these subtypes of PVD, but the question of whether neural responses to pain also differ remains to be investigated. AIM: This study aims to examine whether cognitive, psychophysical, and neural responses to vulvar pressure pain differ between women with PVD1 and PVD2. METHODS: Women with PVD1 and PVD2 were compared for group differences using multiple modalities, including questionnaires, psychophysical testing, and neuroimaging. Pain ratings were held constant across groups, rather than amount of pressure applied. MAIN OUTCOME MEASURES: Demographics, sexual functioning, four questionnaires examining anxiety and catastrophizing, quantitative sensory testing at the vulvar vestibule using a vulvalgesiometer, and functional and structural magnetic resonance imaging (MRI). RESULTS: Findings suggest that women with PVD1 are more anxious and that they catastrophize more about their vulvar and nonvulvar pain than women with PVD2. Overall, MRI results demonstrated structural and functional similarities to other chronic pain findings for both groups of women. Gray matter (GM) density also differed between groups: women with PVD1 showed significant decreases in GM throughout areas associated with pain processing. Functionally, between-groups differences were found during painful vulvar stimulation despite lower pressures applied to the vulva for women with PVD1 because of their heightened sensitivity; the determination of the level of vulvar pressure to elicit pain was based on subjective ratings. CONCLUSIONS: Findings are limited by sample size and liberal alpha values; however, future research is certainly warranted based on the preliminary findings of this study suggesting both similarities and differences between PVD1 and PVD2. Overall, women with PVD1 seem to fare worse on several pain-related and psychosocial variables compared with women with PVD2.

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.

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.

Effortful listening: the processing of degraded speech depends critically on attention.

The conditions of everyday life are such that people often hear speech that has been degraded (e.g., by background noise or electronic transmission) or when they are distracted by other tasks. However, it remains unclear what role attention plays in processing speech that is difficult to understand. In the current study, we used functional magnetic resonance imaging to assess the degree to which spoken sentences were processed under distraction, and whether this depended on the acoustic quality (intelligibility) of the speech. On every trial, adult human participants attended to one of three simultaneously presented stimuli: a sentence (at one of four acoustic clarity levels), an auditory distracter, or a visual distracter. A postscan recognition test showed that clear speech was processed even when not attended, but that attention greatly enhanced the processing of degraded speech. Furthermore, speech-sensitive cortex could be parcellated according to how speech-evoked responses were modulated by attention. Responses in auditory cortex and areas along the superior temporal sulcus (STS) took the same form regardless of attention, although responses to distorted speech in portions of both posterior and anterior STS were enhanced under directed attention. In contrast, frontal regions, including left inferior frontal gyrus, were only engaged when listeners were attending to speech and these regions exhibited elevated responses to degraded, compared with clear, speech. We suggest this response is a neural marker of effortful listening. Together, our results suggest that attention enhances the processing of degraded speech by engaging higher-order mechanisms that modulate perceptual auditory processing.

Is the link between anatomical structure and function equally strong at all cognitive levels of processing?

Whereas low-level sensory processes can be linked to macroanatomy with great confidence, the degree to which high-level cognitive processes map onto anatomy is less clear. If function respects anatomy, more accurate intersubject anatomical registration should result in better functional alignment. Here, we use auditory functional magnetic resonance imaging and compare the effectiveness of affine and nonlinear registration methods for aligning anatomy and functional activation across subjects. Anatomical alignment was measured using normalized cross-correlation within functionally defined regions of interest. Functional overlap was assessed using t-statistics from the group analyses and the degree to which group statistics predict high and consistent signal change in individual data sets. In regions related to early stages of auditory processing, nonlinear registration resulted in more accurate anatomical registration and stronger functional overlap among subjects compared with affine. In frontal and temporal areas reflecting high-level processing of linguistic meaning, nonlinear registration also improved the accuracy of anatomical registration. However, functional overlap across subjects was not enhanced in these regions. Therefore, functional organization, relative to anatomy, is more variable in the frontal and temporal areas supporting meaning-based processes than in areas devoted to sensory/perceptual auditory processing. This demonstrates for the first time that functional variability increases systematically between regions supporting lower and higher cognitive processes.

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.

Human auditory cortex is sensitive to the perceived clarity of speech.

Feedback connections among auditory cortical regions may play an important functional role in processing naturalistic speech, which is typically considered a problem solved through serial feed-forward processing stages. Here, we used fMRI to investigate whether activity within primary auditory cortex (PAC) is sensitive to the perceived clarity of degraded sentences. A region-of-interest analysis using probabilistic cytoarchitectonic maps of PAC revealed a modulation of activity, in the most primary-like subregion (area Te1.0), related to the intelligibility of naturalistic speech stimuli that cannot be driven by stimulus differences. Importantly, this effect was unique to those conditions accompanied by a perceptual increase in clarity. Connectivity analyses suggested sources of input to PAC are higher-order temporal, frontal and motor regions. These findings are incompatible with feed-forward models of speech perception, and suggest that this problem belongs amongst modern perceptual frameworks in which the brain actively predicts sensory input, rather than just passively receiving it.

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.

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.

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).

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.