Lymphocytic Extracellular Signal-Regulated Kinase Dysregulation in Autism Spectrum Disorder.

OBJECTIVE: Extracellular signal-regulated kinase (ERK1/2) is a conserved central intracellular signaling cascade involved in many aspects of neuronal development and plasticity. Converging evidence support investigation of ERK1/2 activity in autism spectrum disorder (ASD). We previously reported enhanced baseline lymphocytic ERK1/2 activation in autism, and now we extend our work to investigate the early phase kinetics of lymphocytic ERK1/2 activation in idiopathic ASD. METHOD: Study participants included 67 individuals with ASD (3-25 years of age), 65 age- and sex-matched typical developing control (TDC) subjects, and 36 age-, sex-, and IQ-matched developmental disability control (DDC) subjects matched to those with ASD and IQ <90. We completed an additional analysis comparing results from ASD, TDC, and DDC groups with data from 37 individuals with Fragile X syndrome (FXS). All subjects had blood lymphocyte samples analyzed by flow cytometry following stimulation with phorbol ester and sequentially analyzed for ERK1/2 activation (phosphorylation) at several time points. RESULTS: The ASD group (mean = 5.81 minutes; SD = 1.5) had a significantly lower (more rapid) mean ERK1/2 T1/2 activation value than both the DDC group (mean = 6.78 minutes; SD = 1.6; p = .00078) and the TDC group (mean = 6.4 minutes; SD = 1.5; p = .025). More rapid ERK1/2 T1/2 activation times did correlate with increased social impairment across all study groups including the ASD cohort. Differences in ERK1/2 T1/2 activation were more pronounced in younger than in older individuals in the primary analysis. The ASD group additionally had more rapid activation times than the FXS group, and the FXS group activation kinetics did not differ from those of the TDC and DDC groups. CONCLUSION: Our findings indicate that lymphocytic ERK1/2 activation kinetics are dysregulated in persons with ASD, marked by more rapid early phase activation. Group differences in ERK1/2 activation kinetics appear to be driven by findings from the youngest children analyzed. DIVERSITY & INCLUSION STATEMENT: We worked to ensure sex and gender balance in the recruitment of human participants. We actively worked to promote sex and gender balance in our author group. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work.

Hypoglossal Nerve Stimulation in Veterans With Comorbid Insomnia and Sleep Apnea.

OBJECTIVE: Insomnia and sleep apnea frequently co-occur, with additive effects of both disorders presenting clinicians with unique treatment challenges compared to one disorder alone. The hypoglossal nerve stimulator (HNS) is a promising treatment for patients with comorbid insomnia and sleep apnea (COMISA), many of whom have positive airway pressure (PAP) intolerance. Our aim was to determine adherence to and efficacy of HNS in veterans with COMISA refractory to PAP therapy compared to those with obstructive sleep apnea alone (OSA only). STUDY DESIGN: Retrospective case series. SETTING: A single, academic Veterans Affairs medical center. METHODS: Review of clinical records, pre- and postoperative polysomnography, and clinical measures of obstructive sleep apnea (OSA), sleepiness, and insomnia was conducted in 53 consecutive cases of veterans with OSA undergoing HNS implantation. HNS adherence was obtained at postoperative visits. HNS adherence and efficacy were compared between individuals with COMISA and OSA only. RESULTS: COMISA was noted in 30 of 53 (56.6%) veterans studied. There was no significant difference between HNS adherence in patients with COMISA and OSA only (5.6 vs 6.4 h/night, P = .17). HNS implantation improved polysomnographic and clinical measures of OSA and sleepiness in both COMISA and OSA only, and 56.5% (13/23) of patients with COMISA self-reported improvement in insomnia after surgery. CONCLUSION: HNS was successful in treating a complex veteran population with COMISA refractory to PAP when examining measures of treatment adherence and efficacy. Future studies of patients with COMISA undergoing HNS will examine effective combination therapy targeting insomnia and a multidisciplinary effort to optimize treatment adherence.

Investigational drugs in early-stage clinical trials for autism spectrum disorder.

Introduction: Pharmacologic interventions in Autism Spectrum Disorder (ASD) have historically focused on symptom-based approaches. However, a treatment for the core social deficits has remained unidentified. While a definitive theory for the cause of ASD is not yet known, recent advances in our understanding of ASD pathophysiology have opened the door for research on new pharmaceutical methods to target core symptomology. Areas covered: Herein, we review the novel pharmacologic therapies undergoing early-stage clinical trials for the treatment of the social symptoms associated with ASD. Specifically, these strategies center on altering neurologic excitatory and inhibitory imbalance, neuropeptide abnormalities, immunologic dysfunction, and biochemical deficiencies in ASD. Expert opinion: Utilizing the growing field of knowledge regarding the pathological mechanisms and altered neurobiology of individuals with ASD has led to the development of many innovative pharmaceutical interventions. Clinical trials for neurobiologic and immunologic targets show promise in impacting the social behavior and processing deficits in ASD but need evaluation in larger clinical trials and continued biomarker development to more effectively and consistently assess pharmacologic effects. Additionally, evaluating patient-specific drug responsivity and integrating behavioral intervention in conjunction with pharmacologic treatment is crucial to developing a successful approach to ASD treatment.

Differentiating social preference and social anxiety phenotypes in fragile X syndrome using an eye gaze analysis: a pilot study.

BACKGROUND: Fragile X syndrome (FXS) is the leading inherited cause of autism spectrum disorder, but there remains debate regarding the clinical presentation of social deficits in FXS. The aim of this study was to compare individuals with FXS to typically developing controls (TDC) and individuals with idiopathic autism spectrum disorder (ASD) across two social eye tracking paradigms. METHODS: Individuals with FXS and age- and gender-matched TDC and individuals with idiopathic ASD completed emotional face and social preference eye tracking tasks to evaluate gaze aversion and social interest, respectively. Participants completed a battery of cognitive testing and caregiver-reported measures for neurobehavioral characterization. RESULTS: Individuals with FXS exhibited reduced eye and increased mouth gaze to emotional faces compared to TDC. Gaze aversive findings were found to correlate with measures of anxiety, social communication deficits, and behavioral problems. In the social interest task, while individuals with idiopathic ASD showed significantly less social preference, individuals with FXS displayed social preference similar to TDC. CONCLUSIONS: These findings suggest fragile X syndrome social deficits center on social anxiety without the prominent reduction in social interest associated with autism spectrum disorder. Specifically designed eye tracking techniques clarify the nature of social deficits in fragile X syndrome and may have applications to improve phenotyping and evaluate interventions targeting social functioning impairments.

Atypical Social Attention and Emotional Face Processing in Autism Spectrum Disorder: Insights From Face Scanning and Pupillometry.

Social attention deficits are a hallmark characteristic within autism spectrum disorder (ASD) and have been hypothesized to have cascading effects on emotion recognition. Eye-tracking methodology has emerged as a potentially reliable, feasible, and sensitive biomarker for examining core phenotypic features of ASD; however, these findings are mixed with regards to measuring treatment change in clinical trials. The present study aimed to assess the utility of an eye-tracking paradigm to discriminate between clinical groups in social attention and emotion recognition through face scanning and pupillometry. The present study also assessed the reliability of this paradigm within the ASD sample to further our understanding of the utility of eye-tracking for future clinical trials. Participants included 42 individuals with ASD, 29 developmental disability (DD) controls, and 62 typically developing (TD) controls between 3 and 25 years of age. An emotional faces eye-tracking paradigm was administered to all participants, with the ASD group completing the paradigm a second time approximately 2 months later. Participants' average proportion of looking and number of fixations to specific areas of interest (AOI) were examined along with changes in pupil reactivity while viewing different emotional faces. Results suggest atypical face-scanning through a reduced proportion of looking and the number of fixations toward the eyes in the ASD group regardless of the emotion that was presented. Further, pupillometry measures were able to detect increases in pupil dilation to happy faces in the ASD group. Lastly, test-retest reliability coefficients varied between the poor and excellent range based on the mechanism assessed, with the proportion of looking demonstrating the highest reliability coefficients. These findings build on the promise of eye-tracking as a feasible and reliable biomarker for identifying social attention and emotion recognition deficits in ASD. Detecting differences in emotion recognition explicitly through facial scanning was not as clear. Specific mechanisms within the eye-tracking paradigm may be viable options for assessing treatment-specific outcomes.

Eye gaze and pupillary response in Angelman syndrome.

BACKGROUND: Angelman syndrome (AS) is a rare neurological disorder characterized by severe developmental disability, communication impairment, elevated seizure risk, and motor system abnormalities. AIMS: The aims of this study were to determine the feasibility of social scene eye tracking and pupillometry measures in individuals with AS and to compare the performance of AS participants to individuals with idiopathic Autism Spectrum Disorder (ASD) and typically developing controls (TDC). METHODS AND PROCEDURES: Individuals with AS and age- and gender- matched controls completed a social eye tracking paradigm. Neurobehavioral characterization of AS participants was completed via a battery of psychological testing and caregiver behavioral evaluations. OUTCOMES AND RESULTS: Eight of seventeen recruited AS participants completed the eye tracking paradigm. Compared to TDC, AS subjects demonstrated significantly less preference for social scenes than geometric shapes. Additionally, AS subjects showed less pupil dilation, compared to TDC, when viewing social scenes versus geometric shapes. There was no statistically significant difference found between AS and ASD subjects in either social eye tracking or pupillometry. CONCLUSIONS AND IMPLICATIONS: The use of eye tracking and pupillometry may represent an innovative measure for quantifying AS-associated impairments in social salience.

Esterase- and pH-responsive poly(ß-amino ester)-capped mesoporous silica nanoparticles for drug delivery.

Gating of mesoporous silica nanoparticles (MSNs) with the stimuli-responsive poly(ß-amino ester) has been achieved. This hybrid nanocarrier releases doxorubicin (DOX) under acidic conditions or in the presence of porcine liver esterase. The DOX loaded poly(ß-amino ester)-capped MSNs reduce cell viability when tested on MDA-MB-231 human breast cancer cells.