High-throughput functional analysis of autism genes in zebrafish identifies convergence in dopaminergic and neuroimmune pathways

Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology

Safety, feasibility, tolerability, and clinical effects of repeated psilocybin dosing combined with non-directive support in the treatment of obsessive-compulsive disorder: protocol for a randomized, waitlist-controlled trial with blinded ratings

BackgroundTo date, few randomized controlled trials of psilocybin with non-directive support exist for obsessive-compulsive disorder (OCD). Results and participant feedback from an interim analysis of an ongoing single-dose trial (NCT03356483) converged on the possibility of administering a higher fixed dose and/or more doses of psilocybin in future trials for presumably greater benefits.ObjectivesThis trial aims to evaluate the safety, feasibility, tolerability, and clinical effects of two doses of psilocybin paired with non-directive support in the treatment of OCD. This trial also seeks to examine whether two doses of psilocybin lead to greater OCD symptom reduction than a single dose, and to elucidate psychological mechanisms underlying the effects of psilocybin on OCD.DesignA randomized (1:1), waitlist-controlled design with blinded ratings will be used to examine the effects of two doses of oral psilocybin paired with non-directive support vs. waitlist control on OCD symptoms. An adaptive dose selection strategy will be implemented (i.e., first dose: 25 mg; second dose: 25 or 30 mg).Methods and analysisThis single-site trial will enroll 30 adult participants with treatment-refractory OCD. Aside from safety, feasibility, and tolerability metrics, primary outcomes include OCD symptoms assessed on the Yale-Brown Obsessive-Compulsive Scale – Second Edition (Y-BOCS-II). A blinded independent rater will assess primary outcomes at baseline and the primary endpoint at the end of the second dosing week. Participants will be followed up to 12 months post-second dosing. Participants randomized to waitlist will be rescreened after 7 weeks post-randomization, and begin their delayed treatment phase thereafter if still eligible.EthicsWritten informed consent will be obtained from participants. The institutional review board has approved this trial (protocol v. 1.7; HIC #2000032623).DiscussionThis study seeks to advance our ability to treat refractory OCD, and catalyze future research seeking to optimize the process of psilocybin treatment for OCD through understanding relevant psychological mechanisms.Clinical trial registration: ClinicalTrials.gov, identifier NCT05370911

Movies in the magnet: Naturalistic paradigms in developmental functional neuroimaging

The use of movie-watching as an acquisition state for functional connectivity (FC) MRI has recently enabled multiple groups to obtain rich data sets in younger children with both substantial sample sizes and scan durations. Using naturalistic paradigms such as movies has also provided analytic flexibility for these developmental studies that extends beyond conventional resting state approaches. This review highlights the advantages and challenges of using movies for developmental neuroimaging and explores some of the methodological issues involved in designing pediatric studies with movies. Emerging themes from movie-watching studies are discussed, including an emphasis on intersubject correlations, developmental changes in network interactions under complex naturalistic conditions, and dynamic age-related changes in both sensory and higher-order network FC even in narrow age ranges. Converging evidence suggests an enhanced ability to identify brain-behavior correlations in children when using movie-watching data relative to both resting state and conventional tasks. Future directions and cautionary notes highlight the potential and the limitations of using movies to study FC in pediatric populations. Keywords: Naturalistic viewing, Movies, Resting state, Intersubject correlations, Head motion, Childre

Infant brain responses to social sounds: A longitudinal functional near-infrared spectroscopy study

Infants are responsive to and show a preference for human vocalizations from very early in development. While previous studies have provided a strong foundation of understanding regarding areas of the infant brain that respond preferentially to social vs. non-social sounds, how the infant brain responds to sounds of varying social significance over time, and how this relates to behavior, is less well understood. The current study uniquely examined longitudinal brain responses to social sounds of differing social-communicative value in infants at 3 and 6 months of age using functional near-infrared spectroscopy (fNIRS). At 3 months, infants showed similar patterns of widespread activation in bilateral temporal cortices to communicative and non-communicative human non-speech vocalizations, while by 6 months infants showed more similar, and focal, responses to social sounds that carried increased social value (infant-directed speech and human non-speech communicative sounds). In addition, we found that brain activity at 3 months of age related to later brain activity and receptive language abilities as measured at 6 months. These findings suggest areas of consistency and change in auditory social perception between 3 and 6 months of age. Keywords: fNIRS, Infancy, Social perception, Brain development, Auditory stimul

Cortical Activation during Action Observation, Action Execution, and Interpersonal Synchrony in Adults: A functional Near-Infrared Spectroscopy (fNIRS) Study

Introduction: Humans engage in Interpersonal Synchrony (IPS) as they synchronize their own actions with that of a social partner over time. When humans engage in imitation/IPS behaviors, multiple regions in the frontal, temporal, and parietal cortices are activated including the putative Mirror Neuron Systems (Iacoboni, 2005; Buxbaum et al., 2014). In the present study, we compared fNIRS-based cortical activation patterns across three conditions of action observation (“Watch” partner), action execution (“Do” on your own), and IPS (move “Together”).Methods: Fifteen typically developing adults completed a reach and cleanup task with the right arm while cortical activation was examined using a 24-channel, Hitachi fNIRS system. Each adult completed 8 trials across three conditions (Watch, Do, and Together). For each fNIRS channel, we obtained oxy hemoglobin (HbO2) and deoxy hemoglobin (HHb) profiles. Spatial registration methods were applied to localize the cortical regions underneath each channel and to define six regions of interest (ROIs), right and left supero-anterior (SA or pre/post-central gyri), infero-posterior (IP or angular/supramarginal gyri), and infero-anterior (IA or superior/middle temporal gyri) regions.Results: In terms of task-related differences, the majority of the ROIs were more active during Do and Together compared to Watch. Only the right/ipsilateral fronto-parietal and inferior parietal cortices had greater activation during Together compared to Do.Conclusions: The similarities in cortical activation between action execution and IPS suggest that neural control of IPS is more similar to its execution than observational aspects. To be clear, the more complex the actions performed, the more difficult the IPS behaviors. Secondly, IPS behaviors required slightly more right-sided activation (vs. execution/observation) suggesting that IPS is a higher-order process involving more bilateral activation compared to its sub-components. These findings provide a neuroimaging framework to study imitation and IPS impairments in special populations such as infants at risk for and children with ASD

Neural responsivity to social rewards in autistic female youth.

Autism is hypothesized to be in part driven by a reduced sensitivity to the inherently rewarding nature of social stimuli. Previous neuroimaging studies have indicated that autistic males do indeed display reduced neural activity to social rewards, but it is unknown whether this finding extends to autistic females, particularly as behavioral evidence suggests that affected females may not exhibit the same reduction in social motivation as their male peers. We therefore used functional magnetic resonance imaging to examine social reward processing during an instrumental implicit learning task in 154 children and adolescents (ages 8-17): 39 autistic girls, 43 autistic boys, 33 typically developing girls, and 39 typically developing boys. We found that autistic girls displayed increased activity to socially rewarding stimuli, including greater activity in the nucleus accumbens relative to autistic boys, as well as greater activity in lateral frontal cortices and the anterior insula compared with typically developing girls. These results demonstrate for the first time that autistic girls do not exhibit the same reduction in activity within social reward systems as autistic boys. Instead, autistic girls display increased neural activation to such stimuli in areas related to reward processing and salience detection. Our findings indicate that a reduced sensitivity to social rewards, as assessed with a rewarded instrumental implicit learning task, does not generalize to affected female youth and highlight the importance of studying potential sex differences in autism to improve our understanding of the condition and its heterogeneity