Search

Insecticides, such as pyrethroids, have frequently been detected in runoff from urban areas, and their offsite transport can cause aquatic toxicity in urban streams and estuaries. To better understand the wash-off process of pesticide residues in urban runoff, the association of pyrethroids with sediment in runoff from residential surfaces was investigated in two watersheds located in Northern California (Sacramento County). Rainfall, flow rate, and event mean concentrations/loads of sediments and pyrethroids, collected during seasonal monitoring campaigns from 2007 to 2014, were analyzed to identify relationships among stormwater quality and rainfall characteristics, primarily using Principal Component Analysis (PCA). Pyrethroid wash-off was strongly related to sediment wash-off whenever sediment loads exceeded 10 mg; this value was conveniently selected as a threshold between dissolved and particle-bound control of off-site pyrethroid transport. A new mechanistic model for predicting pyrethroid wash-off profiles from residential surfaces at basin-scale was implemented in the Storm Water Management Model (SWMM). The accuracy of the model predictions was estimated by evaluating the root mean square error (RMSE), Nash⁻Sutcliff efficiency (NSE), and Kling⁻Gupta efficiency (KGE) for each pyrethroid detected (RMSEtot = 0.13; NSEtot = 0.28; KGEtot = 0.56). The importance of particle-bound transport revealed in this work confirms previous field investigations at a smaller scale, and it should be a key consideration when developing policies to mitigate pesticide runoff from urban areas.

Background: RASopathies are a group of disorders characterized by pathogenic mutations in the Ras/mitogen-activated protein kinase (Ras/MAPK) signaling pathway. Distinct pathogenic variants in genes encoding proteins in the Ras/MAPK pathway cause Noonan syndrome (NS) and neurofibromatosis type 1 (NF1), which are associated with increased risk for autism spectrum disorder and attention-deficit/hyperactivity disorder., Methods: This study examined the effect of RASopathies (NS and NF1) on human neuroanatomy, specifically on surface area (SA), cortical thickness (CT), and subcortical volumes. Using vertex-based analysis for cortical measures and Desikan region of interest parcellation for subcortical volumes, we compared structural T1-weighted images of children with RASopathies (n = 91, mean age = 8.81 years, SD = 2.12) to those of sex- and age-matched typically developing children (n = 74, mean age = 9.07 years, SD = 1.77)., Results: Compared with typically developing children, RASopathies had convergent effects on SA and CT, exhibiting increased SA in the precentral gyrus, decreased SA in occipital regions, and thinner CT in the precentral gyrus. RASopathies exhibited divergent effects on subcortical volumes, with syndrome-specific influences from NS and NF1. Overall, children with NS showed decreased volumes in striatal and thalamic structures, and children with NF1 displayed increased volumes in the hippocampus, amygdala, and thalamus., Conclusions: Our study reveals the converging and diverging neuroanatomical effects of RASopathies on human neurodevelopment. The convergence of cortical effects on SA and CT indicates a shared influence of Ras/MAPK hyperactivation on the human brain. Therefore, considering these measures as objective outcome indicators for targeted treatments is imperative., (Published by Elsevier Inc.)

Background: Cognitive training holds potential as a non-pharmacological intervention to decrease cognitive symptoms associated with Alzheimer's disease (AD), but more research is needed to understand individual differences that may predict maximal training benefits., Objective: We conducted a pilot study using a six-month training regimen in healthy aging adults with no cognitive decline. We investigated the effects of baseline performance and age on training and transfer improvements., Methods: Out of 43 participants aged 65-84 years, 31 successfully completed cognitive training (BrainHQ) in one of three cognitive domains: processing speed (N = 13), inhibitory control (N = 9), or episodic memory (N = 9). We used standardized assessments to measure baseline performance and transfer effects., Results: All 31 participants improved on the cognitive training regimen and age was positively associated with training improvement (p = 0.039). The processing speed group improved significantly across many near- and far-transfer tasks. In the inhibitory control group, individuals with lower baseline performance improved more on inhibitory control and cognitive flexibility tasks. In the episodic memory group, older individuals improved most on a memory task while younger individuals improved most on an executive function far-transfer task., Conclusions: Individual differences are predictive of cognitive training gains, and the impact of individual differences on training improvements is specific to the domain of training. We provide initial insight regarding how non-pharmacological interventions can be optimized to combat the onset of cognitive decline in older adults. With future research this work can inform the design of effective cognitive interventions for delaying cognitive decline in preclinical AD.

Aim: We investigated neuropsychiatric outcomes in children with Noonan syndrome and addressed limitations in previous research with a focus on prepubertal children, comparison to typically developing children, comprehensive neuropsychiatric evaluation, and controlling for overall cognitive abilities., Method: Forty-five children with Noonan syndrome (mean = 8 years 6 months, SD = 2 years 2 months; 29 females) and 40 typically developing children (mean = 8 years 9 months, SD = 2 years; 22 females) were evaluated with objective, parent-report, and psychiatric interview measures., Results: Children with Noonan syndrome demonstrated elevated symptoms across attention-deficit/hyperactivity disorder (ADHD) (attention, hyperactivity, and inhibition), autism spectrum disorder (ASD) (maintaining social relationships, behavioral rigidity, and sensory sensitivity), and oppositional defiant disorder (ODD) (aggression) symptom clusters relative to typically developing children (all p < 0.05). Group differences in nearly all parent-report measures were significant after accounting for variations in intellectual functioning, suggesting that increased neurodevelopmental symptoms are not simply driven by overall intelligence. Twenty out of 42 children with Noonan syndrome met criteria for ADHD, eight out of 42 for ODD, and 11 out of 43 demonstrated clinically significant symptoms seen in children with ASD., Interpretation: Children with Noonan syndrome are at increased risk for a range of ADHD, ASD, and ODD associated symptoms. A dimensional approach reveals significant ASD symptoms in Noonan syndrome that do not emerge when using the currently accepted categorical diagnostic approach., What This Paper Adds: Neuropsychiatric disorders occur in more than half of children with Noonan syndrome. Children with Noonan syndrome demonstrate highly variable neurodevelopmental symptom profiles. Children with Noonan syndrome display variable impairments in attention, hyperactivity, and inhibition. Specific social concerns include behavioral rigidity, transitions, and difficulties maintaining social relationships. Children with Noonan syndrome display variably elevated levels of aggression and emotional dysregulation., (© 2023 Mac Keith Press.)

Children with fragile X syndrome (FXS) often avoid eye contact, a behavior that is potentially related to hyperarousal. Prior studies, however, have focused on between-person associations rather than coupling of within-person changes in gaze behaviors and arousal. In addition, there is debate about whether prompts to maintain eye contact are beneficial for individuals with FXS. In a study of young females (ages 6-16), we used eye tracking to assess gaze behavior and pupil dilation during social interactions in a group with FXS ( n = 32) and a developmentally similar comparison group ( n = 23). Participants engaged in semi-structured conversations with a female examiner during blocks with and without verbal prompts to maintain eye contact. We identified a social-behavioral and psychophysiological profile that is specific to females with FXS; this group exhibited lower mean levels of eye contact, significantly increased mean pupil dilation during conversations that included prompts to maintain eye contact, and showed stronger positive coupling between eye contact and pupil dilation. Our findings strengthen support for the perspective that gaze aversion in FXS reflects negative reinforcement of social avoidance behavior. We also found that behavioral skills training may improve eye contact, but maintaining eye contact appears to be physiologically taxing for females with FXS.

Boys with fragile X syndrome (FXS), the leading known genetic cause of autism spectrum disorder (ASD), demonstrate significant impairments in social gaze and associated weaknesses in communication, social interaction, and other areas of adaptive functioning. Little is known, however, concerning the impact of behavioral treatments for these behaviors on functional brain connectivity in this population. As part of a larger study, boys with FXS (mean age 13.23 ± 2.31 years) and comparison boys with ASD (mean age 12.15 ± 2.76 years) received resting-state functional magnetic resonance imaging scans prior to and following social gaze training administered by a trained behavior therapist in our laboratory. Network-agnostic connectome-based predictive modeling of pretreatment resting-state functional connectivity data revealed a set of positive (FXS > ASD) and negative (FXS < ASD) edges that differentiated the groups significantly and consistently across all folds of cross-validation. Following administration of the brief training, the FXS and ASD groups demonstrated reorganization of connectivity differences. The divergence in the spatial pattern of reorganization response, based on functional connectivity differences pretreatment, suggests a unique pattern of response to treatment in the FXS and ASD groups. These results provide further support for implementing targeted behavioral treatments to ameliorate syndrome-specific behavioral features in FXS., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study, we used functional near-infrared spectroscopy to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population., Methods: Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function, and autism symptoms. Functional near-infrared spectroscopy was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects., Results: Compared with the control group, girls with FXS showed significant hyperactivation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition, including executive function, autism symptoms, depression, and anxiety., Conclusions: These findings strongly support a hypothesis of neural hyperactivation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker end point for improving treatment trial evaluation in girls with this condition., (Copyright © 2021 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Background: Epidemiological studies suggest that exposure to p,p'-dichloro-diphenyl-trichloroethane (p,p'-DDT) is associated with poorer cognitive function in children and adolescents, but the neural mechanisms underlying this association remain unclear., Objective: We investigated associations of prenatal and childhood exposure to p,p'-DDT and its metabolite p,p'-dichloro-diphenyl-dichloroethylene (p,p'-DDE) with cortical activation in adolescents using functional near-infrared spectroscopy (fNIRS)., Methods: We administered fNIRS to 95 adolescents from the Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS) aged 15-17 years. We assessed cortical activity in the frontal, temporal, and parietal brain regions while participants completed tasks of executive function, language comprehension, and social cognition. We measured serum p,p'-DDT and -DDE concentrations at age 9 years and then estimated exposure-outcome associations using linear regression models adjusted for sociodemographic characteristics. In secondary analyses, we back-extrapolated prenatal concentrations using prediction models and examined their association with cortical activation., Results: Median (P25-P75) p,p'-DDT and -DDE concentrations in childhood were 1.4 (1-2.3) and 141.5 (75.0-281.3) ng/g lipid, respectively. We found that childhood exposure to p,p'-DDT and -DDE was associated with altered patterns of brain activation during tasks of cognition and executive functions. For example, we observed increased activity in the left frontal lobe during a language comprehension task (β per 10 ng/g lipid increase of serum p,p'-DDE at age 9 years = 3.4; 95% CI: 0.0, 6.9 in the left inferior frontal lobe; and β = 4.2; 95% CI: 0.9, 7.5 in the left superior frontal lobe). We found no sex differences in the associations of childhood p,p'-DDT and -DDE concentrations with neural activity. Associations between prenatal p,p'-DDT and p,p'-DDE concentrations and brain activity were similar to those observed for child p,p'-DDT and -DDE concentrations., Conclusions: Childhood p,p'-DDT and -DDE exposure may impact cortical brain activation, which could be an underlying mechanism for its previously reported associations with poorer cognitive function., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Girls with fragile X syndrome (FXS) often manifest significant symptoms of avoidance, anxiety, and arousal, particularly in the context of social interaction. However, little is currently known about the associations among neurobiological, biobehavioral such as eye gaze pattern, and social-cognitive dysfunction in real-world settings. In this study, we sought to characterize brain network properties and eye gaze patterns in girls with FXS during natural social interaction. Participants included 42 girls with FXS and 31 age- and verbal IQ-matched girls (control). Portable functional near-infrared spectroscopy (fNIRS) and an eye gaze tracker were used to investigate brain network alterations and eye gaze patterns associated with social-cognitive dysfunction in girls with FXS during a structured face-to-face conversation. Compared to controls, girls with FXS showed significantly increased inter-regional functional connectivity and greater excitability within the prefrontal cortex (PFC), frontal eye field (FEF) and superior temporal gyrus (STG) during the conversation. Girls with FXS showed significantly less eye contact with their conversational partner and more unregulated eye gaze behavior compared to the control group. We also demonstrated that a machine learning approach based on multimodal data, including brain network properties and eye gaze patterns, was predictive of multiple domains of social-cognitive behaviors in girls with FXS. Our findings expand current knowledge of neural mechanisms and eye gaze behaviors underlying naturalistic social interaction in girls with FXS. These results could be further evaluated and developed as intermediate phenotypic endpoints for treatment trial evaluation in girls with FXS., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Fragile X syndrome is a genetic condition associated with alterations in brain and subsequent cognitive development. However, due to a milder phenotype relative to males, females with fragile X syndrome are underrepresented in research studies. In the current study, we investigate neuroanatomical differences in young females (age range: 6.03-16.32 years) with fragile X syndrome (N = 46) as compared to age-, sex-, and verbal abilities-matched participants (comparison group; N = 35). Between-group analyses of whole-brain and regional brain volumes were assessed using voxel-based morphometry. Results demonstrate significantly larger total gray and white matter volumes in girls with fragile X syndrome compared to a matched comparison group (Ps < 0.001). In addition, the fragile X group showed significantly larger gray matter volume in a bilateral parieto-occipital cluster and a right parieto-occipital cluster (Ps < 0.001). Conversely, the fragile X group showed significantly smaller gray matter volume in the bilateral gyrus rectus (P < 0.03). Associations between these regional brain volumes and key socio-emotional variables provide insight into gene-brain-behavior relationships underlying the fragile X syndrome phenotype in females. These findings represent the first characterization of a neuroanatomical phenotype in a large sample of girls with fragile X syndrome and expand our knowledge about potential neurodevelopmental mechanisms underlying cognitive-behavioral outcomes in this condition., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We tested whether empathy is impaired and associated with anxiety in girls with fragile X syndrome (FXS). We measured parent-reported empathy and self-reported anxiety in young girls with FXS and in a developmentally-matched comparison group. Girls with FXS received higher parent-reported scores on cognitive and affective empathy but also self-reported more severe anxiety symptoms, particularly separation anxiety and phobia symptoms, than girls in the comparison group. Girls with FXS who received higher cognitive empathy scores, however, appeared buffered against risk for separation anxiety and phobia symptoms. Girls with FXS experience elevated empathy and anxiety relative to their developmentally-matched peers. Higher cognitive empathy in girls with FXS may indicate resilience against specific forms of anxiety that are commonly observed in FXS., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Mounting evidence supports the role of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway in neurodevelopmental disorders. Here, the authors used a genetics-first approach to examine how Ras/MAPK pathogenic variants affect the functional organization of the brain and cognitive phenotypes including weaknesses in attention and inhibition. Functional MRI was used to examine resting state functional connectivity (RSFC) in association with Ras/MAPK pathogenic variants in children with Noonan syndrome (NS). Participants (age 4-12 years) included 39 children with NS (mean age 8.44, SD = 2.20, 25 females) and 49 typically developing (TD) children (mean age 9.02, SD = 9.02, 33 females). Twenty-eight children in the NS group and 46 in the TD group had usable MRI data and were included in final analyses. The results indicated significant hyperconnectivity for the NS group within canonical visual, ventral attention, left frontoparietal and limbic networks (p < 0.05 FWE). Higher connectivity within canonical left frontoparietal and limbic networks positively correlated with cognitive function within the NS but not the TD group. Further, the NS group demonstrated significant group differences in seed-based striatal-frontal connectivity (Z > 2.6, p < 0.05 FWE). Hyperconnectivity within canonical brain networks may represent an intermediary phenotype between Ras/MAPK pathogenic variants and cognitive phenotypes, including weaknesses in attention and inhibition. Altered striatal-frontal connectivity corresponds with smaller striatal volume and altered white matter connectivity previously documented in children with NS. These results may indicate delayed maturation and compensatory mechanisms and they are important for understanding the pathophysiology underlying cognitive phenotypes in NS and in the broader population of children with neurodevelopmental disorders., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Aging is the major risk factor for neurodegenerative diseases and affects neurite distributions throughout the brain, yet underlying neurobiological mechanisms remain unclear. Multi-shell diffusion-weighted imaging and neurite orientation dispersion and density imaging (NODDI) now provide in vivo biophysical measurements that explain these biological processes in the cortex and white matter. In this study, neurite distributions were evaluated in the cortex and white matter in healthy older adults and patients with amnestic mild cognitive impairment (aMCI) that provides fundamental contributions regarding healthy aging and neurodegeneration. Older age was associated with reduced neurite density and neurite orientation dispersion (ODI) in widespread cortical regions. In contrast, increased ODI was only observed in the right thalamus and hippocampus with age. For the first time, we also reported a widespread age-associated decrease in neurite density along major white matter tracts correlated with decreased cortical neurite density in the tract endpoints in healthy older adults. We further examined alterations in cortical and white matter neurite microstructures in aMCI patients and found significant neurite morphology deficits in memory networks correlated with memory performance. Our findings indicate that neurite parameters provide valuable information regarding cortical and white matter microstructure and complement myeloarchitectural information in healthy aging and aMCI., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Healthy and pathological aging influence brain microstructure via complex processes. Discerning these processes requires measurements that are sensitive to specific biological properties of brain tissue. We integrated a novel quantitative R1 measure with multi-shell diffusion weighted imaging to map age-associated changes in macromolecular tissue volume (MTV) along major white matter tracts in healthy older adults and patients with amnestic Mild Cognitive Impairment (aMCI). Reduced MTV in association tracts was associated with older age in healthy aging, was correlated with memory performance, and distinguished aMCI from controls. We also mapped changes in gray matter tissue properties using quantitative R1 measurements. We documented a widespread decrease in R1 with advancing age across the cortex and decreased R1 in aMCI compared with controls in regions implicated in episodic memory. Our data are the first to characterize MTV loss along major white matter tracts in aMCI and suggest that qMRI is a sensitive measure for detecting subtle degeneration of white and gray matter tissue that cannot be detected by conventional MRI and diffusion measures., Competing Interests: Declaration of Competing Interest The authors declare that they have no competing interests., (Copyright © 2021. Published by Elsevier Inc.)

Fragile X syndrome (FXS) is the leading known inherited cause for intellectual disability. Due to mutations in the FMR1 gene, affected individuals are at risk for serious cognitive and behavioral symptoms and developmental disability. Clinical presentation varies considerably, and investigation of genetic factors not directly related to FMR1 may help better understand variability. The present study examined the BclI polymorphism of the glucocorticoid receptor gene NR3C1 in 43 individuals with FXS (28 females, age 16 to 25). Females with FXS who presented with one or more G alleles demonstrated attenuated symptoms of anxiety/depression (p = 0.038) and externalizing behaviors (p = 0.042) relative to individuals with the C/C allele. In the combined sample (males and females) structural neuroimaging data differentiated individuals with a G allele from those with the C/C genotype (p < 0.001). Key components of anxiety/fear neurocircuitry (amygdala, insula) contributed more (relative to other regions) to the model differentiating groups. These results indicate that GR polymorphisms are associated with an altered pattern of behavioral and brain development in FXS. This information is important for understanding and treating mood disorders and altered brain development among individuals with FXS. With further research, these findings could be informative for understanding anxiety and mood disorders more broadly., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Smartphones and other modern technologies have introduced multiple new forms of distraction that color the modern driving experience. While many smartphone functions aim to improve driving by providing the driver with real-time navigation and traffic updates, others, such as texting, are not compatible with driving and are often the cause of accidents. Because both functions elicit driver attention, an outstanding question is the degree to which drivers' naturalistic interactions with navigation and texting applications differ in regard to brain and behavioral indices of distracted driving. Here, we employed functional near-infrared spectroscopy to examine the cortical activity that occurs under parametrically increasing levels of smartphone distraction during naturalistic driving. Our results highlight a significant increase in bilateral prefrontal and parietal cortical activity that occurs in response to increasingly greater levels of smartphone distraction that, in turn, predicts changes in common indices of vehicle control.

We have reported consistent associations of prenatal organophosphate pesticide (OP) exposure with poorer cognitive function and behavior problems in our Center for the Health Assessment of Mothers and Children of Salinas (CHAMACOS), a birth cohort of Mexican American youth in California's agricultural Salinas Valley. However, there is little evidence on how OPs affect neural dynamics underlying associations. We used functional near-infrared spectroscopy (fNIRS) to measure cortical activation during tasks of executive function, attention, social cognition, and language comprehension in 95 adolescent CHAMACOS participants. We estimated associations of residential proximity to OP use during pregnancy with cortical activation in frontal, temporal, and parietal regions using multiple regression models, adjusting for sociodemographic characteristics. OP exposure was associated with altered brain activation during tasks of executive function. For example, with a 10-fold increase in total OP pesticide use within 1 km of maternal residence during pregnancy, there was a bilateral decrease in brain activation in the prefrontal cortex during a cognitive flexibility task (β = -4.74; 95% CI: -8.18, -1.31 and β = -4.40; 95% CI: -7.96, -0.84 for the left and right hemispheres, respectively). We also found that prenatal OP exposure was associated with sex differences in brain activation during a language comprehension task. This first functional neuroimaging study of prenatal OP exposure suggests that pesticides may impact cortical brain activation, which could underlie previously reported OP-related associations with cognitive and behavioral function. Use of fNIRS in environmental epidemiology offers a practical alternative to neuroimaging technologies and enhances our efforts to assess the impact of chemical exposures on neurodevelopment., Competing Interests: The authors declare no conflict of interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Background: Fragile X syndrome, the most common inherited cause for intellectual disability, is associated with alterations in cholinergic among other neurotransmitter systems. This study investigated the effects of donepezil hydrochloride, a cholinesterase inhibitor that has potential to correct aberrant cholinergic signaling., Method: Forty-two individuals with fragile X syndrome (mean age=19.61 years) were randomized to receive 2.5-10.0 mg of donepezil ( n =20, seven females) or placebo ( n =22, eight females) per day. One individual in the active group withdrew at week 7. Outcomes included the contingency naming test, the aberrant behavior checklist, and behavior and brain activation patterns during a functional magnetic resonance imaging gaze discrimination task., Results: There were no significant differences between active and placebo groups on cognitive (contingency naming task) or behavioral (total score or subscales of the aberrant behavior checklist) outcomes. At baseline, the active and placebo groups did not differ in functional magnetic resonance imaging activation patterns during the gaze task. After 12 weeks of treatment the active group displayed reduced activation in response to the averted vs direct gaze contrast, relative to the placebo group, in the left superior frontal gyrus., Conclusions: Reduced functional brain activation for the active group may represent less arousal in response to direct eye gaze, relative to the placebo group. Change in functional magnetic resonance imaging activation patterns may serve as a more sensitive metric and predictor of response to treatment when compared to cognitive and behavioral assessments. Our results suggest that donepezil may have an impact on brain functioning, but longer term follow-up and concomitant behavioral intervention may be required to demonstrate improvement in cognition and behavior.

Fragile X syndrome (FXS) is a genetic condition known to increase the risk of cognitive impairment and socio-emotional challenges in affected males and females. To date, the vast majority of research on FXS has predominantly targeted males, who usually exhibit greater cognitive impairment compared to females. Due to their typically milder phenotype, females may have more potential to attain a higher level of independence and quality of life than their male counterparts. However, the constellation of cognitive, behavioral, and, particularly, socio-emotional challenges present in many females with FXS often preclude them from achieving their full potential. It is, therefore, critical that more research specifically focuses on females with FXS to elucidate the role of genetic, environmental, and socio-emotional factors on outcome in this often-overlooked population.

Improvements in vehicle safety require understanding of the neural systems that support the complex, dynamic task of real-world driving. We used functional near infrared spectroscopy (fNIRS) and pupilometry to quantify cortical and physiological responses during a realistic, simulated driving task in which vehicle dynamics were manipulated. Our results elucidate compensatory changes in driver behavior in response to changes in vehicle handling. We also describe associated neural and physiological responses under different levels of mental workload. The increased cortical activation we observed during the late phase of the experiment may indicate motor learning in prefrontal-parietal networks. Finally, relationships among cortical activation, steering control, and individual personality traits suggest that individual brain states and traits may be useful in predicting a driver's response to changes in vehicle dynamics. Results such as these will be useful for informing the design of automated safety systems that facilitate safe and supportive driver-car communication., (© 2018 Wiley Periodicals, Inc.)

[This corrects the article DOI: 10.1371/journal.pone.0201486.].

Demands on visuospatial working memory are a ubiquitous part of everyday life. As such, significant efforts have been made to understand how the brain responds to these demands in real-world environments. Multiple brain imaging studies have highlighted a fronto-parietal cortical network that underlies visuospatial working memory, is modulated by cognitive load, and that appears to respond uniquely to encoding versus retrieval components. Furthermore, multiple studies have identified functional connectivity in regions of the fronto-parietal network during working memory tasks. Together, these findings have helped outline important aspects of the neural architecture that underlies visuospatial working memory. Here, we provide results from the first fNIRS-based investigation of fronto-parietal signatures of cortical activation and functional connectivity during a computer-based visuospatial working memory task. Our results indicate that the local maxima of cortical activation and functional coherence do not necessarily overlap spatially, and that cortical activation is significantly more susceptible to task-specific demands compared to functional connectivity. These results highlight important and novel information regarding neurotypical signatures of cortical activation and functional connectivity during visuospatial working memory. Our findings also demonstrate the utility of fNIRS for interrogating these cognitive processes., Competing Interests: The authors have declared that no competing interests exist.

Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability. The cognitive, behavioral, and neurological phenotypes observed in affected individuals can vary considerably, making it difficult to predict outcomes and determine the need for interventions. We sought to examine early structural brain growth as a potential marker for identification of clinically meaningful subgroups. Participants included 42 very young boys with FXS who completed a T1-weighted anatomical MRI and cognitive/behavioral assessment at two longitudinal time points, with mean ages of 2.89 y and 4.91 y. Topological data analysis (TDA), an unsupervised approach to multivariate pattern analysis, was applied to the longitudinal anatomical data to identify coherent but heretofore unknown subgroups. TDA revealed two large subgroups within the study population based solely on longitudinal MRI data. Post hoc comparisons of cognition, adaptive functioning, and autism severity scores between these groups demonstrated that one group was consistently higher functioning on all measures at both time points, with pronounced and significant unidirectional differences ( P < 0.05 for time point 1 and/or time point 2 for each measure). These results support the existence of two longitudinally defined, neuroanatomically distinct, and clinically relevant phenotypes among boys with FXS. If confirmed by additional analyses, such information may be used to predict outcomes and guide design of targeted therapies. Furthermore, TDA of longitudinal anatomical MRI data may represent a useful method for reliably and objectively defining subtypes within other neuropsychiatric disorders., Competing Interests: The authors declare no conflict of interest.

Visuomotor ability is quite crucial for everyday functioning, particularly in driving and sports. While there is accumulating evidence regarding neural correlates of visuomotor transformation, less is known about the brain regions that accommodate visuomotor mapping under different cognitive demands. We concurrently measured cortical activity and pupillary response, using functional near infrared spectroscopy (fNIRS) and eye-tracking glasses, to examine the neural systems linked to pupil dilation under varying cognitive demands. Twenty-three healthy adults performed two sessions of a navigation task, in which the cognitive load was manipulated by either reversing the visuomotor mapping or increasing the speed of the moving object. We identified a region in the right superior parietal lobule that responded to both types of visuomotor load and its activity was associated with larger pupillary response and better performance in the task. Our multimodal analyses suggest that activity in this region arises from the need for increased attentional effort and alertness for visuomotor control and is an ideal candidate for objective measurement of visuomotor cognitive load. Our data extend previous findings connecting changes in pupil diameter to neural activity under varying cognitive demand and have important implications for examining brain-behavior associations in real-world tasks such as driving and sports.

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder, is associated with significant behavioral, social, and neurocognitive deficits. Understanding structural brain network topology in FXS provides an important link between neurobiological and behavioral/cognitive symptoms of this disorder. We investigated the connectome via whole-brain structural networks created from group-level morphological correlations. Participants included 100 individuals: 50 with FXS and 50 with typical development, age 11-23 years. Results indicated alterations in topological properties of structural brain networks in individuals with FXS. Significantly reduced small-world index indicates a shift in the balance between network segregation and integration and significantly reduced clustering coefficient suggests that reduced local segregation shifted this balance. Caudate and amygdala were less interactive in the FXS network further highlighting the importance of subcortical region alterations in the neurobiological signature of FXS. Modularity analysis indicates that FXS and typically developing groups' networks decompose into different sets of interconnected sub networks, potentially indicative of aberrant local interconnectivity in individuals with FXS. These findings advance our understanding of the effects of fragile X mental retardation protein on large-scale brain networks and could be used to develop a connectome-level biological signature for FXS., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Few studies have investigated developmental strengths and weaknesses within the cognitive profile of children and adolescents with fragile X syndrome (FXS), a single-gene cause of inherited intellectual impairment. With a prospective longitudinal design and using normalized raw scores (Z scores) to circumvent floor effects, we measured cognitive functioning of 184 children and adolescents with FXS (ages 6 to 16) using the Wechsler Scale of Intelligence for Children on one to three occasions for each participant. Participants with FXS received lower raw scores relative to the Wechsler Scale of Intelligence for Children normative sample across the developmental period. Verbal comprehension, perceptual organization, and processing speed Z scores were marked by a widening gap from the normative sample, while freedom from distractibility Z scores showed a narrowing gap. Key findings include a relative strength for verbal skills in comparison with visuospatial-constructive skills arising in adolescence and a discrepancy between working memory (weakness) and processing speed (strength) in childhood that diminishes in adolescence. Results suggest that the cognitive profile associated with FXS develops dynamically from childhood to adolescence. Findings are discussed within the context of aberrant brain morphology in childhood and maturation in adolescence. We argue that assessing disorder-specific cognitive developmental profiles will benefit future disorder-specific treatment research.

Coordinated variations in brain morphology (e.g., cortical thickness) across individuals have been widely used to infer large-scale population brain networks. These structural correlation networks (SCNs) have been shown to reflect synchronized maturational changes in connected brain regions. Further, evidence suggests that SCNs, to some extent, reflect both anatomical and functional connectivity and hence provide a complementary measure of brain connectivity in addition to diffusion weighted networks and resting-state functional networks. Although widely used to study between-group differences in network properties, SCNs are inferred only at the group-level using brain morphology data from a set of participants, thereby not providing any knowledge regarding how the observed differences in SCNs are associated with individual behavioral, cognitive and disorder states. In the present study, we introduce two novel distance-based approaches to extract information regarding individual differences from the group-level SCNs. We applied the proposed approaches to a moderately large dataset (n=100) consisting of individuals with fragile X syndrome (FXS; n=50) and age-matched typically developing individuals (TD; n=50). We tested the stability of proposed approaches using permutation analysis. Lastly, to test the efficacy of our method, individual contributions extracted from the group-level SCNs were examined for associations with intelligence scores and genetic data. The extracted individual contributions were stable and were significantly related to both genetic and intelligence estimates, in both typically developing individuals and participants with FXS. We anticipate that the approaches developed in this work could be used as a putative biomarker for altered connectivity in individuals with neurodevelopmental disorders., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Fragile-X syndrome (FXS) is a neurodevelopmental disorder associated with intellectual disability and neurobiological abnormalities including white matter microstructural differences. White matter differences have been found relative to neurotypical individuals., Aims: To examine whether FXS white matter differences are related specifically to FXS or more generally to the presence of intellectual disability., Method: We used voxel-based and tract-based analytic approaches to compare individuals with FXS (n = 40) with gender- and IQ-matched controls (n = 30)., Results: Individuals with FXS had increased fractional anisotropy and decreased radial diffusivity values compared with IQ-matched controls in the inferior longitudinal, inferior fronto-occipital and uncinate fasciculi., Conclusions: The genetic variation associated with FXS affects white matter microstructure independently of overall IQ. White matter differences, found in FXS relative to IQ-matched controls, are distinct from reported differences relative to neurotypical controls. This underscores the need to consider cognitive ability differences when investigating white matter microstructure in neurodevelopmental disorders., (© The Royal College of Psychiatrists, all rights reserved.)

Objective: To verify the effect of an intervention protocol using virtual reality (VR) on the motor performance and balance of a child with cerebral palsy (CP)., Case Description: To comply with the proposed objectives, a 7-year old child with spastic hemiplegic cerebral palsy (cP), GMFcS level I, was submitted to a physiotherapy intervention protocol of 12 45-minute sessions, twice a week, using virtual reality-based therapy. The protocol used a commercially-available console (XBOX(®)360 Kinect(®)) able to track and reproduce body movements on a screen. Prior to the intervention protocol, the child was evaluated using the Motor Development Scale (MDS) and the Pediatric Balance Scale (PBS) in order to assess motor development and balance, respectively. Two baseline assessments with a 2-week interval between each other were carried out for each tool. Then, the child was re-evaluated after the twelfth session. The results showed no changes in the two baseline scores. After the intervention protocol, the child improved his scores in both tools used: the PBS score increased by 3 points, reaching the maximal score, and the MDS increased from a much inferior motor performance to just an inferior motor performance., Comments: The evidence presented in this case supports the use of virtual reality as a promising tool to be incorporated into the rehabilitation process of patients with neuromotor dysfunction., (Copyright © 2014 Associação de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.)

Objective: The authors sought to investigate neural system habituation to face and eye gaze in fragile X syndrome, a disorder characterized by eye-gaze aversion, among other social and cognitive deficits., Method: Participants (ages 15-25 years) were 30 individuals with fragile X syndrome (females, N=14) and a comparison group of 25 individuals without fragile X syndrome (females, N=12) matched for general cognitive ability and autism symptoms. Functional MRI (fMRI) was used to assess brain activation during a gaze habituation task. Participants viewed repeated presentations of four unique faces with either direct or averted eye gaze and judged the direction of eye gaze., Results: Four participants (males, N=4/4; fragile X syndrome, N=3) were excluded because of excessive head motion during fMRI scanning. Behavioral performance did not differ between the groups. Less neural habituation (and significant sensitization) in the fragile X syndrome group was found in the cingulate gyrus, fusiform gyrus, and frontal cortex in response to all faces (direct and averted gaze). Left fusiform habituation in female participants was directly correlated with higher, more typical levels of the fragile X mental retardation protein and inversely correlated with autism symptoms. There was no evidence for differential habituation to direct gaze compared with averted gaze within or between groups., Conclusions: Impaired habituation and accentuated sensitization in response to face/eye gaze was distributed across multiple levels of neural processing. These results could help inform interventions, such as desensitization therapy, which may help patients with fragile X syndrome modulate anxiety and arousal associated with eye gaze, thereby improving social functioning.

Background: The profile of cognitive and behavioral variation observed in individuals with fragile X syndrome (FXS), the most common known cause of inherited intellectual impairment, suggests aberrant functioning of specific brain systems. Research investigating animal models of FXS, characterized by limited or lack of fragile X mental retardation protein, (FMRP), has linked brain dysfunction to deficits in the cholinergic and glutamatergic systems. Thus, we sought to examine in vivo levels of neurometabolites related to cholinergic and glutamatergic functioning in males and females with FXS., Methods: The study participants included 18 adolescents and young adults with FXS, and a comparison group of 18 individuals without FXS matched for age, sex and general intellectual functioning. Proton magnetic resonance spectroscopy (MRS) was used to assess neurometabolite levels in the caudate nucleus, a region known to be greatly enlarged and involved in abnormal brain circuitry in individuals with FXS. A general linear model framework was used to compare group differences in metabolite concentration., Results: We observed a decrease in choline (P = 0.027) and in glutamate + glutamine (P = 0.032) in the caudate nucleus of individuals with FXS, relative to individuals in the comparison group., Conclusions: This study provides evidence of metabolite differences in the caudate nucleus, a brain region of potential importance to our understanding of the neural deficits underlying FXS. These metabolic differences may be related to aberrant receptor signaling seen in animal models. Furthermore, identification of the specific neurometabolites involved in FXS dysfunction could provide critical biomarkers for the design and efficacy tracking of disease-specific pharmacological treatments.

Reading is a complex process involving recruitment and coordination of a distributed network of brain regions. The present study sought to establish a methodologically sound evidentiary base relating specific reading and phonological skills to neuro-metabolic concentration. Single voxel proton magnetic resonance spectroscopy was performed to measure metabolite concentration in a left hemisphere region around the angular gyrus for 31 young adults with a range of reading and phonological abilities. Correlation data demonstrated a significant negative association between phonological decoding and normalized choline concentration and as well as a trend toward a significant negative association between sight word reading and normalized choline concentration, indicating that lower scores on these measures are associated with higher concentrations of choline. Regression analyses indicated that choline concentration accounted for a unique proportion of variance in the phonological decoding measure after accounting for age, cognitive ability and sight word reading skill. This pattern of results suggests some specificity for the negative relationship between choline concentration and phonological decoding. To our knowledge, this is the first study to provide evidence that choline concentration in the angular region may be related to phonological skills independently of other reading skills, general cognitive ability, and age. These results may have important implications for the study and treatment of reading disability, a disorder which has been related to deficits in phonological decoding and abnormalities in the angular gyrus., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Ventricular assist devices (VADs) have been associated with high rates of neurologic injury in pediatric patients during the period of support, but the delayed consequences of this type of injury have not been described in the literature., Methods: In this study we assess cognitive outcomes with indices of general intellectual functioning, including working memory, processing speed, perceptual reasoning and verbal comprehension, for pediatric heart transplant recipients who required VAD support as a bridge to transplant (n = 9). We present an aggregate of these VAD patients combined with heart transplant recipients who did not require mechanical circulatory support (n = 11), and compare the performance of all transplant patients (n = 20) to typically developing, healthy comparators (n = 12). We also present a post hoc analysis of those transplant recipients with significant medical morbidity in the first year of life, referred to as the "high-risk" transplant group (n = 5), and compare them with the "low-risk" transplant group (n = 15) and the typically developing comparators (n = 12)., Results: The mean performance of the VAD patients was in the average range for each of the examined indices of cognitive functioning. A total of 11% of the VAD patients performed in the impaired range and 78% performed in the average range, with 11% in the superior range on measures of general intellectual functioning. The typically developing participants performed significantly better than the aggregated transplant recipients on all indices except verbal comprehension. Lower cognitive performance in the combined transplant group appears to be associated with medical morbidity in the first year of life., Conclusions: Despite significant neurologic risk factors, this cohort of pediatric patients who were bridged to transplant with VAD demonstrated resiliency in terms of cognitive outcomes. In this heterogeneous population, it is likely that multiple factors contributed to the cognitive outcomes. As VAD use becomes more common in pediatric patients, a prospective evaluation of cognitive outcomes is warranted., (Copyright © 2013 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

The goal of this study was to evaluate the performance of a single video camera system for measuring shoulder rotation during computer work, and to quantify the work and postural space within which the system performs optimally. Shoulder rotation angles calculated using the video system were compared with angles calculated using an active infrared LED three-dimensional motion analysis system while 10 adult volunteers simulated postures for two different trials: typical of normal computer work (freestyle) and with forced shoulder abduction (constrained). Average and absolute errors were calculated to determine the accuracy and precision of the system, respectively, for each trial, for each position, and for both the right and left hands. For the right hand, mean values for the average and absolute errors were -1 and 0 degrees, respectively. Only the absolute error increased significantly to 12 degrees for the constrained posture compared with freestyle. During normal computer work, the video system provided shoulder rotation angle values similar to those of a three-dimensional system, thus making it a viable and simple instrument to use in field studies.

The involvement of the left hemisphere occipito-temporal (OT) junction in reading has been established, yet there is current controversy over the region's specificity for reading and the nature of its role in the reading process. Recent neuroimaging findings suggest that the region is sensitive to orthographic familiarity [Kronbichler, M., Bergmann, J., Hutzler, F., Staffen, W., Mair, A., Ladurner, G., Wimmer, H. 2007. Taxi vs. Taksi: on orthographic word recognition in the left ventral occipito-temporal cortex. Journal of Cognitive Neuroscience 19, 1-11], and the present study tested that hypothesis. Using fMRI, the OT region and other regions in the reading network were localized in 28 adult, right-handed participants. The BOLD signal in these regions was measured during a phonological judgment task (i.e., "Does it sound like a word?"). Stimuli included words, pseudohomophones (phonologically familiar yet orthographically unfamiliar), and pseudowords (phonologically and orthographically unfamiliar) that were matched on lexical properties including sublexical orthography. Relative to baseline, BOLD signal in the OT region was greater for pseudohomophones than for words, suggesting that the region is sensitive to orthographic familiarity at the whole-word level. Further contrasts of orthographic frequency within the word condition revealed increased BOLD signal for low- than high-frequency words. Specialization in the OT region for recognition of frequent letter strings may support the development of reading expertise. Additionally, BOLD signal in the OT region correlates positively with reading efficiency, supporting the idea that this region is a skill zone for reading printed words. BOLD signal in the IFG and STG correlates negatively with reading efficiency, indicating that processing effort in these classic phonological regions is inversely related to reading efficiency.

The integrity of phonological representation/processing in dyslexic children was explored with a gating task in which children listened to successively longer segments (gates) of a word. At each gate, the task was to decide what the entire word was. Responses were scored for overall accuracy as well as the children's sensitivity to coarticulation from the final consonant. As a group, dyslexic children were less able than normally achieving readers to detect coarticulation present in the vowel portion of the word, particularly on the most difficult items, namely those ending in a nasal sound. Hierarchical regression and path analyses indicated that phonological awareness mediated the relation of gating and general language ability to word and pseudoword reading ability.