Social gaze behavior and hyperarousal in young females with fragile X syndrome: A within-person approach.

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.

Aerobic Exercise, Cognitive Performance, and Brain Activity in Adolescents with Attention-Deficit/Hyperactivity Disorder.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder for which behavioral treatments such as exercise are recommended as part of a multidisciplinary treatment program. Exercise improves executive function in individuals with ADHD, but limited information exists regarding the mechanisms involved in the response. We examined task-evoked brain responses during exercise and seated rest in 38 adolescents ( n = 15 ADHD; age, 13.6 ± 1.9; male, 73.3%; n = 23 typically developing (TD; age, 13.3 ± 2.1; male, 56.5%)). METHODS: Participants completed a working memory and inhibitory task while cycling at a moderate intensity for 25 min (i.e., exercise condition) and while seated on the bike without pedaling (i.e., control condition). Conditions were randomized and counterbalanced. Functional near-infrared spectroscopy measured relative changes in oxygenated hemoglobin concentration in 16 brain regions of interest. Brain activity for each cognitive task and condition was examined using linear mixed-effects models with a false discovery rate (FDR) correction. RESULTS: The ADHD group had slower response speeds for all tasks and lower response accuracy in the working memory task during exercise compared with the TD group ( P < 0.05). For the inhibitory task, the ADHD group had lower brain activity in the inferior/superior parietal gyrus during exercise compared with the control condition, whereas the opposite was true for TD (FDR corrected , P < 0.05). For the working memory task, higher brain activity during exercise was observed, regardless of group, in the middle and inferior frontal gyrus and the temporoparietal junction (FDR corrected , P < 0.05). CONCLUSIONS: Dual-task performance is challenging for adolescents with ADHD, and exercise may modulate neuronal resources in regions such as the temporoparietal junction and frontal areas known to be hypoactive in this population. Future research should examine how these relationships change over time.

Aberrant Neural Response During Face Processing in Girls With Fragile X Syndrome: Defining Potential Brain Biomarkers for Treatment Studies.

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.

Cortical activation predicts posttraumatic improvement in youth treated with TF-CBT or CCT.

BACKGROUND: Identifying neural activation patterns that predict youths' treatment response may aid in the development of imaging-based assessment of emotion dysregulation following trauma and foster tailored intervention. Changes in cortical hemodynamic activity measured with functional near-infrared spectroscopy (fNIRS) may provide a time and cost-effective option for such work. We examined youths' PTSD symptom change following treatment and tested if previously identified activation patterns would predict treatment response. METHODS: Youth (N = 73, mean age = 12.97, SD = 3.09 years) were randomly assigned to trauma-focused cognitive behavioral therapy (TF-CBT), cue-centered therapy (CCT), or treatment as usual (TAU). Parents and youth reported on youth's PTSD symptoms at pre-intervention, post-intervention, and follow-up. Neuroimaging data (N = 31) assessed at pre-intervention were obtained while youth engaged in an emotion expression task. Treatment response slopes were calculated for youth's PTSD symptoms. RESULTS: Overall, PTSD symptoms decreased from pre-intervention through follow-up across conditions, with some evidence of relative benefit of TF-CBT and CCT over TAU but significant individual variation in treatment response. Cortical activation patterns were correlated with PTSD symptom improvement slopes (r = 0.53). In particular, cortical responses to fearful and neutral facial stimuli in six fNIRS channels in the bilateral dlPFC were important predictors of PTSD symptom improvement. CONCLUSIONS: The use of fNIRS provides a method of monitoring and assessing cortical activation patterns in a relatively inexpensive and portable manner. Associations between functional activation and youths' PTSD symptoms improvement may be a promising avenue for understanding emotion dysregulation in clinical populations.

Aberrant brain network and eye gaze patterns during natural social interaction predict multi-domain social-cognitive behaviors in girls with fragile X syndrome.

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.

Functional near-infrared spectroscopy brain imaging predicts symptom severity in youth exposed to traumatic stress.

Functional near-infrared spectroscopy (fNIRS) is a non-invasive neuroimaging technique with the potential to enable the assessment of posttraumatic stress disorder (PTSD) brain biomarkers in an affordable and portable manner. Consistent with biological models of PTSD, functional magnetic resonance imaging (fMRI) and fNIRS studies of adults with trauma exposure and PTSD symptoms suggest increased activation in the dorsolateral prefrontal cortex (dlPFC) and ventrolateral PFC (vlPFC) in response to negative emotion stimuli. We tested this theory with fNIRS assessment among youth exposed to traumatic stress and experiencing PTSD symptoms (PTSS). A portable fNIRS system collected hemodynamic responses from (N = 57) youth with PTSS when engaging in a classic emotion expression task that included fearful and neutral faces stimuli. The General Linear Model was applied to identify cortical activations associated with the facial stimuli. Subsequently, a prediction model was established via a Support Vector Regression to determine whether PTSS severity could be predicted based on fNIRS-derived cortical response measures and individual demographic information. Results were consistent with findings from adult fMRI and fNIRS studies of PTSS showing increased activation in the dlPFC and vlPFC in response to negative emotion stimuli. Subsequent prediction analysis revealed ten features (i.e., cortical responses from eight frontocortical fNIRS channels, age and sex) strongly correlated with PTSS severity (r = 0.65, p < .001). Our findings suggest the potential utility of fNIRS as a portable tool for the detection of putative PTSS brain biomarkers.

Evaluation of smartphone interactions on drivers' brain function and vehicle control in an immersive simulated environment.

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.

X-Chromosome Insufficiency Alters Receptive Fields across the Human Early Visual Cortex.

Here, we investigated processing by receptive fields, a fundamental property of neurons in the visual system, using fMRI and population receptive field (pRF) mapping in 20 human females with monosomic Turner syndrome (TS) (mean age, 10.3 ± 2.0 years) versus 22 age- and sex-matched controls (mean age, 10.4 ± 1.9 years). TS, caused by X-chromosome haploinsufficiency in females, is associated with well-recognized effects on visuospatial processing, parieto-occipital cortical anatomy, and parietal lobe function. However, it is unknown whether these effects are related to altered brain structure and function in early visual areas (V1-V3) versus downstream parietal cortical regions. Results show that girls with TS have the following: (1) smaller volume of V1-V3, (2) lower average pRF eccentricity in early visual areas, and (3) sparser pRF coverage in the periphery of the visual field. Further, we examined whether the lower volume of early visual areas, defined using retinotopic mapping, in TS is due to smaller surface area or thinner cortex. Results show that girls with TS had a general reduction in surface area relative to controls in bilateral V1 and V2. Our data suggest the possibility that the smaller cortical surface area of early visual areas in girls with TS may be associated with a lower number of neurons, which in turn, leads to lesser coverage of the peripheral visual field compared to controls. These results indicate that X-chromosome haploinsufficiency associated with TS affects the functional neuroanatomy of early visual areas, and suggest that investigating pRFs in TS may shed insights into their atypical visuospatial processing.SIGNIFICANCE STATEMENT Turner syndrome is caused by the absence of one of the two X-chromosomes in females. Using functional neuroimaging and population receptive field mapping, we find that chromosome dosage variation (X-monosomy) associated with Turner syndrome affects the functional neuroanatomy of the visual cortex. Specifically, girls with Turner syndrome have smaller early visual areas that provide lesser coverage of the peripheral visual field compared with healthy controls. Our observations provide compelling evidence that the X-chromosome affects not only parietal cortex, as described in previous studies, but also affects early visual areas. These findings suggest a paradigm change in understanding the effect of X-monosomy on the development of visuospatial abilities in humans.

Mind over motor mapping: Driver response to changing vehicle dynamics.

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.

Quantifying stochastic effects in biochemical reaction networks using partitioned leaping.

"Leaping" methods show great promise for significantly accelerating stochastic simulations of complex biochemical reaction networks. However, few practical applications of leaping have appeared in the literature to date. Here, we address this issue using the "partitioned leaping algorithm" (PLA) [L. A. Harris and P. Clancy, J. Chem. Phys. 125, 144107 (2006)], a recently introduced multiscale leaping approach. We use the PLA to investigate stochastic effects in two model biochemical reaction networks. The networks that we consider are simple enough so as to be accessible to our intuition but sufficiently complex so as to be generally representative of real biological systems. We demonstrate how the PLA allows us to quantify subtle effects of stochasticity in these systems that would be difficult to ascertain otherwise as well as not-so-subtle behaviors that would strain commonly used "exact" stochastic methods. We also illustrate bottlenecks that can hinder the approach and exemplify and discuss possible strategies for overcoming them. Overall, our aim is to aid and motivate future applications of leaping by providing stark illustrations of the benefits of the method while at the same time elucidating obstacles that are often encountered in practice.