Changes in Brain Activity Immediately Post-Exercise Indicate a Role for Central Fatigue in the Volitional Termination of Exercise.

Electroencephalography (EEG) allows for the evaluation of real time changes in brain (electrocortical) activity during exercise. A few studies have examined changes in electrocortical activity using stationary cycling, but the findings have been mixed. Some of these studies have found increases in brain activity following exercise, while others have found decreases in brain activity following exercise. Hence, it is of importance to identify post-exercise changes in brain activity. Sixteen healthy, untrained subjects (8 males; 8 females) participated in the study. All 16 participants performed a graded exercise test (GXT) to volitional exhaustion on an upright cycle ergometer. Continuous EEG recordings were sampled before (PRE) and immediately following (IP) the GXT. Regions of interest were primarily the dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), and left and right motor cortex (MC). In the DLPFC, a frontal asymmetry index was also identified. There was a statistically significant increase in theta power in the DLPFC, VLPFC, and left and right MC from PRE to IP (all p < 0.05). There was also a shift towards right hemisphere asymmetry at the IP time point in the DLPFC (p < 0.05). Finally, there was an increase in alpha power from PRE to IP in the right MC (p < 0.05). EEG could prove to be an important way to measure the effects of central fatigue on brain activity before and immediately following exercise.

Validating brain activity measures as reliable indicators of individual diagnostic group and genetically mediated sub-group membership Fragile X Syndrome.

Recent failures translating preclinical behavioral treatment effects to positive clinical trial results in humans with Fragile X Syndrome (FXS) support refocusing attention on biological pathways and associated measures, such as electroencephalography (EEG), with strong translational potential and small molecule target engagement. This study utilized guided machine learning to test promising translational EEG measures (resting power and auditory chirp oscillatory variables) in a large heterogeneous sample of individuals with FXS to identify best performing EEG variables for reliably separating individuals with FXS, and genetically-mediated subgroups within FXS, from typically developing controls. Best performing variables included resting relative frontal theta power, all combined whole-head resting power bands, posterior peak alpha frequency (PAF), combined PAF across all measured regions, combined theta, alpha, and gamma power during the chirp, and all combined chirp oscillatory variables. Sub-group analyses best discriminated non-mosaic FXS males via whole-head resting relative power (AUC = .9250), even with data reduced to a 20-channel clinical montage. FXS females were nearly perfectly discriminated by combined theta, alpha, and gamma power during the chirp (AUC = .9522). Results support use of resting and auditory oscillatory tasks to reliably identify neural deficit in FXS, and to identify specific translational targets for genetically-mediated sub-groups, supporting potential points for stratification.

Hypersensitivity to Distractors in Fragile X Syndrome from Loss of Modulation of Cortical VIP Interneurons.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in humans and mice with FXS but not in typically developing controls. In both species, males and females were examined. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the poststimulus period during early distractor trials in WT mice, consistent with their known role as error signals. Strikingly, however, VIP cells from Fmr1 -/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells could be a potential therapeutic target for attentional difficulties in FXS.SIGNIFICANCE STATEMENT Sensory hypersensitivity, impulsivity, and persistent inattention are among the most consistent clinical features of FXS, all of which impede daily functioning and create barriers to learning. However, the neural mechanisms underlying sensory over-reactivity remain elusive. To overcome a significant challenge in translational FXS research we demonstrate a compelling alignment of sensory over-reactivity in both humans with FXS and Fmr1 -/- mice (the principal animal model of FXS) using a novel analogous distractor task. Two-photon microscopy in mice revealed that lack of modulation by VIP cells contributes to susceptibility to distractors. Implementing research efforts we describe here can help identify dysfunctional neural mechanisms associated not only with sensory issues but broader impairments, including those in learning and cognition.

Neuropsychiatric feature-based subgrouping reveals neural sensory processing spectrum in female FMR1 premutation carriers: A pilot study.

Introduction: Fragile X Syndrome (FXS) is rare genetic condition characterized by a repeat expansion (CGG) in the Fragile X messenger ribonucleoprotein 1 (FMR1) gene where individuals with greater than 200 repeats are defined as full mutation. FXS clinical presentation often includes intellectual disability, and autism-like symptoms, including anxiety and sensory hypersensitivities. Individuals with 55 to <200 CGG repeats are said to have the FMR1 premutation, which is not associated with primary characteristics of the full mutation, but with an increased risk for anxiety, depression, and other affective conditions, as well as and impaired cognitive processing differences that vary in severity. Defining subgroups of premutation carriers based on distinct biological features may identify subgroups with varying levels of psychiatric, cognitive, and behavioral alterations. Methods: The current pilot study utilized 3 cluster subgroupings defined by previous k means cluster analysis on neuropsychiatric, cognitive, and resting EEG variables in order to examine basic sensory auditory chirp task-based EEG parameters from 33 females with the FMR1 premutation (ages 17-78). Results: Based on the predefined, neuropsychiatric three-cluster solution, premutation carriers with increased neuropsychiatric features and higher CGG repeat counts (cluster 1) showed decreased stimulus onset response, similar to previous ERP findings across a number of psychiatric disorders but opposite to findings in individuals with full mutation FXS. Premutation carriers with increased executive dysfunction and resting gamma power (cluster 2) exhibited decreased gamma phase locking to a chirp stimulus, similar to individuals with full mutation FXS. Cluster 3 members, who were relatively unaffected by psychiatric or cognitive symptoms, showed the most normative task-based EEG metrics. Discussion: Our findings suggest a spectrum of sensory processing characteristics present in subgroups of premutation carriers that have been previously understudied due to lack of overall group differences. Our findings also further validate the pre-defined clinical subgroups by supporting links between disturbances in well-defined neural pathways and behavioral alterations that may be informative for identifying the mechanisms supporting specific risk factors and divergent therapeutic needs in individuals with the FMR1 premutation.

Hypersensitivity to distractors in Fragile X syndrome from loss of modulation of cortical VIP interneurons.

Attention deficit is one of the most prominent and disabling symptoms in Fragile X Syndrome (FXS). Hypersensitivity to sensory stimuli contributes to attention difficulties by overwhelming and/or distracting affected individuals, which disrupts activities of daily living at home and learning at school. We find that auditory or visual distractors selectively impair visual discrimination performance in both humans and mice with FXS, but not their typically developing controls. Vasoactive intestinal polypeptide (VIP) neurons were significantly modulated by incorrect responses in the post-stimulus period during early distractor trials in WT mice, consistent with their known role as 'error' signals. Strikingly, however, VIP cells from Fmr1-/- mice showed little modulation in error trials, and this correlated with their poor performance on the distractor task. Thus, VIP interneurons and their reduced modulatory influence on pyramidal cells, could be a potential therapeutic target for attentional difficulties in FXS.

Electrophysiological resting state brain network and episodic memory in healthy aging adults.

Recent studies have emphasized the changes in large-scale brain networks related to healthy aging, with the ultimate purpose to aid in differentiating normal neurocognitive aging from neurodegenerative disorders that also arise with age. Emerging evidence from functional Magnetic Resonance Imaging (fMRI) indicates that connectivity patterns within specific brain networks, especially the Default Mode Network (DMN), distinguish those with Alzheimer's disease from healthy individuals. In addition, disruptive alterations in the large-scale brain systems that support high-level cognition are shown to accompany cognitive decline at the behavioral level, which is commonly observed in the aging populations, even in the absence of disease. Although fMRI is useful for assessing functional changes in brain networks, its high costs and limited accessibility discourage studies that need large populations. In this study, we investigated the aging-effect on large-scale networks of the human brain using high-density electroencephalography and electrophysiological source imaging, which is a less costly and more accessible alternative to fMRI. In particular, our study examined a group of healthy subjects in the age range from middle- to older-aged adults, which is an under-studied range in the literature. Employing a high-resolution computation model, our results revealed age associations in the connectivity pattern of DMN in a consistent manner with previous fMRI findings. Particularly, in combination with a standard battery of cognitive tests, our data showed that in the posterior cingulate / precuneus area of DMN higher brain connectivity was associated with lower performance on an episodic memory task. The findings demonstrate the feasibility of using electrophysiological imaging to characterize large-scale brain networks and suggest that changes in network connectivity are associated with normal aging.

Effects of shifts in response preferences on characteristics of representation and real-time processing: An application to the Hering illusion.

The multidimensional generalization of signal detection theory known as General Recognition Theory (GRT, Ashby & Townsend, Psychological Review, 93, 154-179 1986) has been used to model and characterize the ways in which changes in encoded perceptual information and the application of decisional operators can produce patterns in behavior that are consistent with notions such as configural processing and representation. In particular, a set of studies (e.g., Cornes et al.,, 2011; Wenger & Ingvalson; 2002, 2003) have shown how decisional influences might exert themselves in situations of configural perception, such that effects such as the Thatcher illusion can be obtained by way of shifts in decisional criteria. The present investigation brought to bear the combined tools of GRT and Systems Factorial Technology (SFT, Little et al.,, 2017; Townsend & Nozawa, 1995) with a classical illusion, to show that it is possible to induce a shift in a decisional criterion by way of varying payoffs and that this shift is accompanied by regular changes in the workload capacity statistic. The combined sets of analyses on the same stimuli reveal orderly effects on the decisional criteria (i.e., the signal detection parameter c), report independence (suggesting perceptual independence), invariant measures of sensitivity (i.e., the signal detection parameter [Formula: see text]),and exhaustive parallel processing accompanied by super capacity. We therefore propose wider use of the combined sets of tools, further exploration of the ability of decisional alterations to affect processing times while leaving accuracy largely unscathed, and reaching out to explore more of the information processing mechanisms of classical illusions.

Auditory EEG Biomarkers in Fragile X Syndrome: Clinical Relevance.

Sensory hypersensitivities are common and distressing features of Fragile X Syndrome (FXS). While there are many drug interventions that reduce behavioral deficits in Fmr1 mice and efforts to translate these preclinical breakthroughs into clinical trials for FXS, evidence-based clinical interventions are almost non-existent potentially due to lack of valid neural biomarkers. Local circuit function in sensory networks is dependent on the dynamic balance of activity in inhibitory/excitatory synapses. Studies are needed to examine the association of electrophysiological alterations in neural systems with sensory and other clinical features of FXS to establish their clinical relevance. Adolescents and adults with FXS (n = 38, Mean age = 25.5, std = 10.1; 13 females) and age matched typically developing controls (n = 40, Mean age = 27.7, std = 12.1; 17 females) completed auditory chirp and auditory habituation tasks while undergoing dense array electroencephalography (EEG). Amplitude, latency, and percent change (habituation) in N1 and P2 event-related potential (ERP) components were characterized for the habituation task; time-frequency calculations using Morlet wavelets characterized phase-locking and single trial power for the habituation and chirp tasks. FXS patients showed increased amplitude but some evidence for reduced habituation of the N1 ERP, and reduced phase-locking in the low and high gamma frequency range and increased low gamma power to the chirp stimulus. FXS showed increased theta power in both tasks. While the habituation finding was weaker than previously found, the remaining findings replicate our previous work in a new sample of patients with FXS. Females showed less deficit in the chirp task but not the habituation task. Abnormal increases in gamma power were related to more severe behavioral and psychiatric features as well as reductions in neurocognitive abilities. Replicating electrophysiological deficits in a new group of patients using different EEG equipment at a new data collection site with differing levels of environmental noise that were robust to data processing techniques utilizing multiple researchers, indicates a potential for scalability to multi-site clinical trials. Given the robust replicability, relevance to clinical measures, and preclinical evidence for sensitivity of these EEG measures to pharmacological intervention, the observed abnormalities may provide novel translational markers of target engagement and potentially outcome measures in large-scale studies evaluating new treatments targeting neural hyperexcitability in FXS.

Developmental Effects on Auditory Neural Oscillatory Synchronization Abnormalities in Autism Spectrum Disorder.

Previous studies have found alterations in 40 Hz oscillatory activity in response to auditory stimuli in adults with Autism Spectrum Disorder (ASD). The current study sought to examine the specificity and developmental trajectory of these findings by driving the cortex to oscillate at a range of frequencies in both children and adults with and without ASD. Fifteen participants with ASD (3 female, aged 6-23 years) and 15 age-matched controls (4 female, aged 6-25 years) underwent dense-array EEG as they listened to a carrier tone amplitude-modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. EEG data were analyzed for inter-trial phase coherence (ITPC) and single-trial power (STP). Older participants with ASD displayed significantly decreased ability to phase-lock to the stimulus in the low gamma frequency range relative to their typically developing (TD) counterparts, while younger ASD and TD did not significantly differ from each other. An interaction between age and diagnosis suggested that TD and ASD also show different developmental trajectories for low gamma power; TD showed a significant decrease in low gamma power with age, while ASD did not. Regardless of age, increased low gamma STP was significantly correlated with increased clinical scores for repetitive behaviors in the ASD group, particularly insistence on sameness. This study contributes to a growing body of evidence supporting alterations in auditory processing in ASD. Older ASD participants showed more pronounced low gamma deficits than younger participants, suggesting an altered developmental trajectory for neural activity contributing to auditory processing deficits that may also be more broadly clinically relevant. Future studies are needed employing a longitudinal approach to confirm findings of this cross-sectional study.

The First Order Transfer Function in the Analysis of Agrochemical Data in Honey Bees (Apis Mellifera L.): Proboscis Extension Reflex (PER) Studies.

This paper describes a mathematical model of the learning process suitable for studies of conditioning using the proboscis extension reflex (PER) in honey bees when bees are exposed to agrochemicals. Although procedural variations exist in the way laboratories use the PER paradigm, proboscis conditioning is widely used to investigate the influence of pesticides and repellents on honey bee learning. Despite the availability of several mathematical models of the learning process, no attempts have been made to apply a mathematical model to the learning curve in honey bees exposed to agrochemicals. Our model is based on the standard transfer function in the form Y=B3 e(-B2 (X-1)) +B4(1-e(-B2 (X-1))) where X is the trial number, Y is the proportion of correct responses, B2 is the learning rate, B3 is readiness to learn, and B4 is ability to learn. We reanalyze previously published data on the effect of several classes of agrochemicals including: (1) those that are considered harmless to bees (e.g., pymetrozine, essential oils, dicofol); (2) sublethal exposure to pesticides known to harm honey bees (e.g., coumaphos, cyfluthrin, fluvalinate, permethrin); and (3) putative repellents of honey bees (e.g., butyric acid, citronella). The model revealed additional effects not detected with standard statistical tests of significance.