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 posterior-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 for resting EEG best discriminated non-mosaic FXS males via frontal theta resting relative power (AUC = 0.8759), even with data reduced to a 20-channel clinical montage (AUC = 0.9062). In the chirp task, FXS females and non-mosaic males were nearly perfectly discriminated by combined theta, alpha, and gamma power (AUC = 0.9444) and a combination of all variables (AUC = 0.9610), respectively. 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.

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.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile X syndrome.

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. These EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding post-period 1 of the study, participants who received BPN14770 in period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770 measured at the end of period 1. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of a significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Auditory N1 event-related potential amplitude is predictive of serum concentration of BPN14770 in fragile x syndrome.

Fragile X syndrome (FXS) is a rare neurodevelopmental disorder caused by a CGG repeat expansion ≥ 200 repeats in 5' untranslated region of the FMR1 gene, leading to intellectual disability and cognitive difficulties, including in the domain of communication. A recent phase 2a clinical trial testing BPN14770, a phosphodiesterase 4D inhibitor, showed improved cognition in 30 adult males with FXS on drug relative to placebo. The initial study found significant improvements in clinical measures assessing cognition, language, and daily functioning in addition to marginal improvements in electroencephalography (EEG) results for the amplitude of the N1 event-related potential (ERP) component. EEG results suggest BPN14770 improved neural hyperexcitability in FXS. The current study investigated the relationship between BPN14770 pharmacokinetics (PK) and the amplitude of the N1 ERP component from the initial data. Consistent with the original group-level finding in period 1 of the study, participants who received BPN14770 in the period 1 showed a significant correlation between N1 amplitude and serum concentration of BPN14770. These findings strengthen the validity of the original result, indicating that BPN14770 improves cognitive performance by modulating neural hyperexcitability. This study represents the first report of significant correlation between a reliably abnormal EEG marker and serum concentration of a novel pharmaceutical in FXS.

Frontal Cortex Hyperactivation and Gamma Desynchrony in Fragile X Syndrome: Correlates of Auditory Hypersensitivity.

Fragile X syndrome (FXS) is an X-linked disorder that often leads to intellectual disability, anxiety, and sensory hypersensitivity. While sound sensitivity (hyperacusis) is a distressing symptom in FXS, its neural basis is not well understood. It is postulated that hyperacusis may stem from temporal lobe hyperexcitability or dysregulation in top-down modulation. Studying the neural mechanisms underlying sound sensitivity in FXS using scalp electroencephalography (EEG) is challenging because the temporal and frontal regions have overlapping neural projections that are difficult to differentiate. To overcome this challenge, we conducted EEG source analysis on a group of 36 individuals with FXS and 39 matched healthy controls. Our goal was to characterize the spatial and temporal properties of the response to an auditory chirp stimulus. Our results showed that males with FXS exhibit excessive activation in the frontal cortex in response to the stimulus onset, which may reflect changes in top-down modulation of auditory processing. Additionally, during the chirp stimulus, individuals with FXS demonstrated a reduction in typical gamma phase synchrony, along with an increase in asynchronous gamma power, across multiple regions, most strongly in temporal cortex. Consistent with these findings, we observed a decrease in the signal-to-noise ratio, estimated by the ratio of synchronous to asynchronous gamma activity, in individuals with FXS. Furthermore, this ratio was highly correlated with performance in an auditory attention task. Compared to controls, males with FXS demonstrated elevated bidirectional frontotemporal information flow at chirp onset. The evidence indicates that both temporal lobe hyperexcitability and disruptions in top-down regulation play a role in auditory sensitivity disturbances in FXS. These findings have the potential to guide the development of therapeutic targets and back-translation strategies.

Family history of psychosis moderates early auditory cortical response abnormalities in non-psychotic bipolar disorder.

OBJECTIVES: Bipolar I disorder is a disabling illness affecting 1% of people worldwide. Family and twin studies suggest that psychotic bipolar disorder (BDP) represents a homogeneous subgroup with an etiology distinct from non-psychotic bipolar disorder (BDNP) and partially shared with schizophrenia. Studies of auditory electrophysiology [e.g., paired-stimulus and oddball measured with electroencephalography (EEG)] consistently report deviations in psychotic groups (schizophrenia, BDP), yet such studies comparing BDP and BDNP are sparse and, in some cases, conflicting. Auditory EEG responses are significantly reduced in unaffected relatives of psychosis patients, suggesting that they may relate to both psychosis liability and expression. METHODS: While 64-sensor EEGs were recorded, age- and gender-matched samples of 70 BDP, 35 BDNP {20 with a family history of psychosis [BDNP(+)]}, and 70 psychiatrically healthy subjects were presented with typical auditory paired-stimuli and auditory oddball paradigms. RESULTS: Oddball P3b reductions were present and indistinguishable across all patient groups. P2s to paired stimuli were abnormal only in BDP and BDNP(+). Conversely, N1 reductions to stimuli in both paradigms and P3a reductions were present in both BDP and BDNP(-) groups but were absent in BDNP(+). CONCLUSIONS: Although nearly all auditory neural response components studied were abnormal in BDP, BDNP abnormalities at early- and mid-latencies were moderated by family psychosis history. The relationship between psychosis expression, heritable psychosis risk, and neurophysiology within bipolar disorder, therefore, may be complex. Consideration of such clinical disease heterogeneity may be important for future investigations of the pathophysiology of major psychiatric disturbance.

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.

Double dissociation between P300 components and task switch error type in healthy but not psychosis participants.

Event-related potentials (ERPs) during oddball tasks and the behavioral performance on the Penn Conditional Exclusion Task (PCET) measure context-appropriate responding: P300 ERPs to oddball targets reflect detection of input changes and context updating in working memory, and PCET performance indexes detection, adherence, and maintenance of mental set changes. More specifically, PCET variables quantify cognitive functions including inductive reasoning (set 1 completion), mental flexibility (perseverative errors), and working memory maintenance (regressive errors). Past research showed that both P300 ERPs and PCET performance are disrupted in psychosis. This study probed the possible neural correlates of 3 PCET abnormalities that occur in participants with psychosis via the overlapping cognitive demands of the two study paradigms. In a two-tiered analysis, psychosis (n = 492) and healthy participants (n = 244) were first divided based on completion of set 1 - which measures subjects' ability to use inductive reasoning to arrive at the correct set. Results showed that participants who failed set 1 produced lower parietal P300, independent of clinical status. In the second tier of analysis, a double dissociation was found among healthy set 1 completers: frontal P300 amplitudes were negatively associated with perseverative errors, and parietal P300 was negatively associated with regressive errors. In contrast, psychosis participants showed global P300 reductions regardless of PCET performance. From this we conclude that in psychosis, overall activations evoked by the oddball task are reduced while the cognitive functions required by PCET are still somewhat supported, showing some level of independence or compensatory physiology in psychosis between neural activities underlying the two tasks.

Empirical Frequency Bound Derivation Reveals Prominent Mid-Frontal Alpha Associated with Neurosensory Dysfunction in Fragile X Syndrome.

The FMR1 gene is inactive in Fragile X syndrome (FXS), resulting in low levels of FMRP and consequent neurochemical, synaptic, and local circuit neurophysiological alterations in the fmr1 KO mouse. In FXS patients, electrophysiological studies have demonstrated a marked reduction in global alpha activity and regional increases in gamma oscillations associated with intellectual disability and sensory hypersensitivity. Since alpha activity is associated with a thalamocortical function with widely distributed modulatory effects on neocortical excitability, insight into alpha physiology may provide insight into systems-level disease mechanisms. Herein, we took a data-driven approach to clarify the temporal and spatial properties of alpha and theta activity in participants with FXS. High-resolution resting-state EEG data were collected from participants affected by FXS (n = 65) and matched controls (n = 70). We used a multivariate technique to empirically classify neural oscillatory bands based on their coherent spatiotemporal patterns. Participants with FXS demonstrated: 1) redistribution of lower-frequency boundaries indicating a "slower" dominant alpha rhythm, 2) an anteriorization of alpha frequency activity, and 3) a correlation of increased individualized alpha power measurements with auditory neurosensory dysfunction. These findings suggest an important role for alterations in thalamocortical physiology for the well-established neocortical hyper-excitability in FXS and, thus, a role for neural systems level disruption to cortical hyperexcitability that has been studied primarily at the local circuit level in animal models.

Independent evaluation of the harvard automated processing pipeline for Electroencephalography 1.0 using multi-site EEG data from children with Fragile X Syndrome.

BACKGROUND: The Harvard Automatic Processing Pipeline for Electroencephalography (HAPPE) is a computerized EEG data processing pipeline designed for multiple site analysis of populations with neurodevelopmental disorders. This pipeline has been validated in-house by the developers but external testing using real-world datasets remains to be done. NEW METHOD: Resting and auditory event-related EEG data from 29 children ages 3-6 years with Fragile X Syndrome as well as simulated EEG data was used to evaluate HAPPE's noise reduction techniques, data standardization features, and data integration compared to traditional manualized processing. RESULTS: For the real EEG data, HAPPE pipeline showed greater trials retained, greater variance retained through independent component analysis (ICA) component removal, and smaller kurtosis than the manual pipeline; the manual pipeline had a significantly larger signal-to-noise ratio (SNR). For simulated EEG data, correlation between the pure signal and processed data was significantly higher for manually-processed data compared to HAPPE-processed data. Hierarchical linear modeling showed greater signal recovery in the manual pipeline with the exception of the gamma band signal which showed mixed results. COMPARISON WITH EXISTING METHODS: SNR and simulated signal retention was significantly greater in the manually-processed data than the HAPPE-processed data. Signal reduction may negatively affect outcome measures. CONCLUSIONS: The HAPPE pipeline benefits from less active processing time and artifact reduction without removing segments. However, HAPPE may bias toward elimination of noise at the cost of signal. Recommended implementation of the HAPPE pipeline for neurodevelopmental populations depends on the goals and priorities of the research.

Toward a Multidimensional Understanding of Misophonia Using Cluster-Based Phenotyping.

Misophonia is a condition characterized by hypersensitivity and strong emotional reactivity to specific auditory stimuli. Misophonia clinical presentations are relatively complex and reflect individualized experiences across clinical populations. Like some overlapping neurodevelopmental and neuropsychiatric disorders, misophonia is potentially syndromic where symptom patterns rather than any one symptom contribute to diagnosis. The current study conducted an exploratory k-means cluster analysis to evaluate symptom presentation in a non-clinical sample of young adult undergraduate students (N = 343). Individuals participated in a self-report spectrum characteristics survey indexing misophonia, tinnitus severity, sensory hypersensitivity, and social and psychiatric symptoms. Results supported a three-cluster solution that split participants on symptom presentation: cluster 1 presented with more severe misophonia symptoms but few overlapping formally diagnosed psychiatric co-occurring conditions; cluster 3 was characterized by a more nuanced clinical presentation of misophonia with broad-band sensory hypersensitivities, tinnitus, and increased incidence of social processing and psychiatric symptoms, and cluster 2 was relatively unaffected by misophonia or other sensitivities. Clustering results illustrate the spectrum characteristics of misophonia where symptom patterns range from more "pure" form misophonia to presentations that involve more broad-range sensory-related and psychiatric symptoms. Subgroups of individuals with misophonia may characterize differential neuropsychiatric risk patterns and stem from potentially different causative factors, highlighting the importance of exploring misophonia as a multidimensional condition of complex etiology.

The multiple indicator multiple cause model for cognitive neuroscience: An analytic tool which emphasizes the behavior in brain-behavior relationships.

Cognitive neuroscience has inspired a number of methodological advances to extract the highest signal-to-noise ratio from neuroimaging data. Popular techniques used to summarize behavioral data include sum-scores and item response theory (IRT). While these techniques can be useful when applied appropriately, item dimensionality and the quality of information are often left unexplored allowing poor performing items to be included in an itemset. The purpose of this study is to highlight how the application of two-stage approaches introduces parameter bias, differential item functioning (DIF) can manifest in cognitive neuroscience data and how techniques such as the multiple indicator multiple cause (MIMIC) model can identify and remove items with DIF and model these data with greater sensitivity for brain-behavior relationships. This was performed using a simulation and an empirical study. The simulation explores parameter bias across two separate techniques used to summarize behavioral data: sum-scores and IRT and formative relationships with those estimated from a MIMIC model. In an empirical study participants performed an emotional identification task while concurrent electroencephalogram data were acquired across 384 trials. Participants were asked to identify the emotion presented by a static face of a child across four categories: happy, neutral, discomfort, and distress. The primary outcomes of interest were P200 event-related potential (ERP) amplitude and latency within each emotion category. Instances of DIF related to correct emotion identification were explored with respect to an individual's neurophysiology; specifically an item's difficulty and discrimination were explored with respect to an individual's average P200 amplitude and latency using a MIMIC model. The MIMIC model's sensitivity was then compared to popular two-stage approaches for cognitive performance summary scores, including sum-scores and an IRT model framework and then regressing these onto the ERP characteristics. Here sensitivity refers to the magnitude and significance of coefficients relating the brain to these behavioral outcomes. The first set of analyses displayed instances of DIF within all four emotions which were then removed from all further models. The next set of analyses compared the two-stage approaches with the MIMIC model. Only the MIMIC model identified any significant brain-behavior relationships. Taken together, these results indicate that item performance can be gleaned from subject-specific biomarkers, and that techniques such as the MIMIC model may be useful tools to derive complex item-level brain-behavior relationships.

Hemispheric Utilization of Alpha Oscillatory Dynamics as a Unique Biomarker of Neural Compensation in Females with Fragile X Syndrome.

Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by a trinucleotide expansion on the FMR1 gene and characterized by intellectual disability, sensory hypersensitivity, executive function difficulties, and social anxiety. Recently, efforts to define neural biomarkers for FXS have highlighted disruptions to power in the alpha frequency band; however the dynamic mechanisms supporting these findings are poorly understood. The current study aimed to explore the temporal and hemispheric dynamics supporting alpha phenotypes in FXS and their relationship with neural phenotypes related to auditory processing using electroencephalography during an auditory evoked task. Adolescents and adults (N = 36) with FXS and age/sex matched typically developing controls (N = 40) completed an auditory chirp task. Frontal alpha power in the prestimulus period was decomposed into "bursts" using percentile thresholding, then assessed for number of bursts per second (burst count) and burst length. Data were compared across left and right hemispheres to assess lateralization of neural activity. Individuals with FXS showed more differences in alpha power compared to TDC primarily in the right hemisphere. Notably, alpha hemisphere outcomes in males with FXS were driven by the number of times they entered a dynamically relevant period of alpha (burst count) rather than length of time spent in alpha. Females with FXS showed reduced burst counts but remained in sustained high alpha states for longer periods of time. Length of time spent in alpha may reflect a modulatory or compensatory mechanism capable of recovering sensory processing abilities in females with FXS resulting in a less severe clinical presentation. Right hemisphere abnormalities may impact sensory processing differences between males and females with FXS. The relationship between alpha burst length, count, sex, and hemisphere may shed light on underlying mechanisms for previously observed alpha power abnormalities in FXS and their variation by sex.

Neocortical localization and thalamocortical modulation of neuronal hyperexcitability contribute to Fragile X Syndrome.

Fragile X Syndrome (FXS) is a monogenetic form of intellectual disability and autism in which well-established knockout (KO) animal models point to neuronal hyperexcitability and abnormal gamma-frequency physiology as a basis for key disorder features. Translating these findings into patients may identify tractable treatment targets. Using source modeling of resting-state electroencephalography data, we report findings in FXS, including 1) increases in localized gamma activity, 2) pervasive changes of theta/alpha activity, indicative of disrupted thalamocortical modulation coupled with elevated gamma power, 3) stepwise moderation of low and high-frequency abnormalities based on female sex, and 4) relationship of this physiology to intellectual disability and neuropsychiatric symptoms. Our observations extend findings in Fmr1-/- KO mice to patients with FXS and raise a key role for disrupted thalamocortical modulation in local hyperexcitability. This systems-level mechanism has received limited preclinical attention but has implications for understanding fundamental disease mechanisms.

Preparatory activations across a distributed cortical network determine production of express saccades in humans.

Reaction time variability across trials to identical stimuli may arise from both ongoing and transient neural processes occurring before trial onset. These processes were examined with dense-array EEG as humans completed saccades in a "gap" paradigm known to elicit bimodal variability in response times, including separate populations of "express" and regular reaction time saccades. Results indicated that express reaction time trials could be differentiated from regular reaction time trials by (1) pretrial phase synchrony of occipital cortex oscillations in the 8-9 Hz (low alpha) frequency range (lower phase synchrony preceding express trials), (2) subsequent mid- and late-gap period cortical activities across a distributed occipital-parietal network (stronger activations preceding express trials), and (3) posttarget parietal activations locked to response generation (weaker preceding express trials). A post hoc path analysis suggested that the observed cortical activations leading to express saccades are best understood as an interdependent chain of events that affect express saccade production. These results highlight the importance of a distributed posterior cortical network, particularly in right hemisphere, that prepares the saccade system for rapid responding.

Evidence for Three Subgroups of Female FMR1 Premutation Carriers Defined by Distinct Neuropsychiatric Features: A Pilot Study.

Over 200 Cytosine-guanine-guanine (CGG) trinucleotide repeats in the 5' untranslated region of the Fragile X mental retardation 1 (FMR1) gene results in a "full mutation," clinically Fragile X Syndrome (FXS), whereas 55 - 200 repeats result in a "premutation." FMR1 premutation carriers (PMC) are at an increased risk for a range of psychiatric, neurocognitive, and physical conditions. Few studies have examined the variable expression of neuropsychiatric features in female PMCs, and whether heterogeneous presentation among female PMCs may reflect differential presentation of features in unique subgroups. In the current pilot study, we examined 41 female PMCs (ages 17-78 years) and 15 age-, sex-, and IQ-matched typically developing controls (TDC) across a battery of self-report, eye tracking, expressive language, neurocognitive, and resting state EEG measures to determine the feasibility of identifying discrete clusters. Secondly, we sought to identify the key features that distinguished these clusters of female PMCs. We found a three cluster solution using k-means clustering. Cluster 1 represented a psychiatric feature group (27% of our sample); cluster 2 represented a group with executive dysfunction and elevated high frequency neural oscillatory activity (32%); and cluster 3 represented a relatively unaffected group (41%). Our findings indicate the feasibility of using a data-driven approach to identify naturally occurring clusters in female PMCs using a multi-method assessment battery. CGG repeat count and its association with neuropsychiatric features differ across clusters. Together, our findings provide important insight into potential diverging pathophysiological mechanisms and risk factors for each female PMC cluster, which may ultimately help provide novel and individualized targets for treatment options.

Inhibition of phosphodiesterase-4D in adults with fragile X syndrome: a randomized, placebo-controlled, phase 2 clinical trial.

The goal of this study was to determine whether a phosphodiesterase-4D (PDE4D) allosteric inhibitor (BPN14770) would improve cognitive function and behavioral outcomes in patients with fragile X syndrome (FXS). This phase 2 trial was a 24-week randomized, placebo-controlled, two-way crossover study in 30 adult male patients (age 18-41 years) with FXS. Participants received oral doses of BPN14770 25 mg twice daily or placebo. Primary outcomes were prespecified as safety and tolerability with secondary efficacy outcomes of cognitive performance, caregiver rating scales and physician rating scales (ClinicalTrials.gov identifier: NCT03569631 ). The study met the primary outcome measure since BPN14770 was well tolerated with no meaningful differences between the active and placebo treatment arms. The study also met key secondary efficacy measures of cognition and daily function. Cognitive benefit was demonstrated using the National Institutes of Health Toolbox Cognition Battery assessments of Oral Reading Recognition (least squares mean difference +2.81, P = 0.0157), Picture Vocabulary (+5.81, P = 0.0342) and Cognition Crystallized Composite score (+5.31, P = 0.0018). Benefit as assessed by visual analog caregiver rating scales was judged to be clinically meaningful for language (+14.04, P = 0.0051) and daily functioning (+14.53, P = 0.0017). Results from this study using direct, computer-based assessment of cognitive performance by adult males with FXS indicate significant cognitive improvement in domains related to language with corresponding improvement in caregiver scales rating language and daily functioning.

Shifted phase of EEG cross-frequency coupling in individuals with Phelan-McDermid syndrome.

BACKGROUND: Phelan-McDermid Syndrome (PMS) is a rare condition caused by deletion or mutation of the SHANK3 gene. Individuals with PMS frequently present with intellectual disability, autism spectrum disorder, and other neurodevelopmental challenges. Electroencephalography (EEG) can provide a window into network-level function in PMS. METHODS: Here, we analyze EEG data collected across multiple sites in individuals with PMS (n = 26) and typically developing individuals (n = 15). We quantify oscillatory power, alpha-gamma phase-amplitude coupling strength, and phase bias, a measure of the phase of cross frequency coupling thought to reflect the balance of feedforward (bottom-up) and feedback (top-down) activity. RESULTS: We find individuals with PMS display increased alpha-gamma phase bias (U = 3.841, p < 0.0005), predominantly over posterior electrodes. Most individuals with PMS demonstrate positive overall phase bias while most typically developing individuals demonstrate negative overall phase bias. Among individuals with PMS, strength of alpha-gamma phase-amplitude coupling was associated with Sameness, Ritualistic, and Compulsive behaviors as measured by the Repetitive Behavior Scales-Revised (Beta = 0.545, p = 0.011). CONCLUSIONS: Increased phase bias suggests potential circuit-level mechanisms underlying phenotype in PMS, offering opportunities for back-translation of findings into animal models and targeting in clinical trials.

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.

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.