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.

An adaptation and exploratory factor analysis of the smoking-related weight and eating episodes test (SWEET) for electronic cigarette users.

INTRODUCTION: Smoking for weight control is a well-documented behavior. There is emerging evidence to suggest electronic cigarettes (e-cigarettes) may be used for similar motivations yet measure development for the use of e-cigarettes for weight control has received less attention. The objective of the current study was to adapt and explore the psychometric properties of The Smoking-Related Weight and Eating Episodes Test (SWEET) for e-cigarette users. METHODS: Young adult (N=1875) current cigarette, e-cigarette, and dual users completed the original SWEET (SWEET-C) and/or adapted SWEET for e-cigarette use (SWEET-EC) based on current tobacco product use. Demographics, associated e-cigarette characteristics, nicotine dependence, outcome expectancies, and eating disorder behaviors were also assessed. Participants were recruited online and measures were completed via self-report. RESULTS: Four exploratory factor analyses using principal components extraction and direct oblimin rotation methods were run to explore the SWEET-C and SWEET-EC. A one-factor solution explaining 66 % of the variance was retained for the SWEET-C, and a one-factor solution explaining 73 % of the variance was retained for the SWEET-EC. Both measures exhibited excellent internal consistency. Higher SWEET-EC scores were observed among dual users, and were associated with daily e-cigarette use, JUUL use, self-reported vaping for weight control, older age, higher body mass index, and problematic eating behaviors. CONCLUSION: Our findings support the adaptation of the SWEET-EC to measure e-cigarette use for weight control. The SWEET-EC will help to better understand how individuals use e-cigarettes to curb eating behavior and for weight control.

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.

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.

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.

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.

Youth use of e-cigarettes: Does dependence vary by device type?

INTRODUCTION: Youth nicotine dependence may vary by e-cigarette device used. METHODS: E-cigarette device type ("JUUL," "similar pod/JUUL like device (i.e., pod mod)," or "other type of e-cigarette" (i.e., tank, mod)), nicotine dependence (Hooked on Nicotine Checklist; HONC), frequency of e-cigarette use (i.e., weekly, daily, monthly), and covariates were examined via a convenience sample of youth who use e-cigarettes in the United States via an online Qualtrics panel survey from April 2019 to May 2019. RESULTS: Youth aged 13-17 (Mean age = 15.9 years, SD = 1.0 year; n = 185) were mostly 72.4% female. Primary device used by category was endorsed as follows: JUUL n = 87, pod mod n = 42, and other type of e-cigarette n = 56. Participants endorsed an average of 4.5 / 10 HONC symptoms (SD = 3.6). Compared to other e-cigarettes, youth who used JUUL and pod mod devices endorsed more dependence symptoms, even when adjusting for current smoking status (JUUL IRR = 1.96, 95% CI 1.30-2.97; pod mod device IRR = 1.76, 95% CI 1.08-2.87). In total, HONC symptoms significantly differed by device for 8/10 symptoms, with JUUL and pod mod users reporting higher frequency of items compared to other e-cigarette devices. CONCLUSIONS: Features of nicotine dependence experienced by youth (i.e., feeling a stronger urge to vape) differed by primary device used, with those using JUUL and pod-mods reporting a greater level of dependence. Regulation of features of e-cigarette devices that may increase nicotine delivery and subsequent development of dependence among youth warrant urgent consideration.

The TRPA1 Ion Channel Contributes to Sensory-Guided Avoidance of Menthol in Mice.

The flavoring agent menthol elicits complex orosensory and behavioral effects including perceived cooling at low concentrations and irritation and ingestive avoidance at higher intensities. Oral menthol engages the cold-activated transient receptor potential (TRP) ion channel TRP melastatin 8 (TRPM8) on trigeminal fibers, although its aversive feature was discussed to involve activation of TRP ankyrin 1 (TRPA1) associated with nociceptive processing. Here, we studied the roles of TRPM8 and TRPA1 in orosensory responding to menthol by subjecting mice gene deficient for either channel to brief-access exposure tests, which measure immediate licking responses to fluid stimuli to capture sensory/tongue control of behavior. Stimuli included aqueous concentration series of (-)-menthol [0 (water), 0.3, 0.5, 0.7, 1.0, 1.5, and 2.3 mM] and the aversive bitter taste stimulus quinine-HCl (0, 0.01, 0.03, 0.1, 0.3, 1, and 3 mM). Concentration-response data were generated from daily brief-access tests conducted in lickometers, which recorded the number of licks water-restricted mice emitted to a randomly selected stimulus concentration over a block of several 10-s stimulus presentations. Wild-type mice showed aversive orosensory responses to menthol above 0.7 mM. Oral aversion to menthol was reduced in mice deficient for TRPA1 but not TRPM8. Oral aversion to quinine was similar between TRPA1 mutant and control mice but stronger than avoidance of menthol. This implied menthol avoidance under the present conditions represented a moderate form of oral aversion. These data reveal TRPA1 contributes to the oral sensory valence of menthol and have implications for how input from TRPA1 and TRPM8 shapes somatosensory-guided behaviors.