Corrigendum: 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.

[This corrects the article DOI: 10.3389/fpsyt.2023.1278823.].

Safety, tolerability, and clinical and neural effects of single-dose psilocybin in obsessive-compulsive disorder: protocol for a randomized, double-blind, placebo-controlled, non-crossover trial.

Background: Psilocybin may help treat obsessive-compulsive disorder (OCD). To date, only one open-label study of psilocybin for OCD exists, necessitating further investigation with a randomized controlled design. The neural correlates of psilocybin's effects on OCD have also not been studied. Objectives: This first-of-its-kind trial aims to evaluate the feasibility, safety, and tolerability of psilocybin in the treatment of OCD, provide preliminary evidence on the effects of psilocybin on OCD symptoms, and elucidate neural mechanisms that may mediate psilocybin's effects on OCD. Design: We use a randomized (1:1), double-blind, placebo-controlled, non-crossover design to examine the clinical and neural effects of either a single dose of oral psilocybin (0.25 mg/kg) or active placebo-control agent (250 mg of niacin) on OCD symptoms. Methods and analysis: We are enrolling 30 adult participants at a single site in Connecticut, USA who have failed at least one trial of standard care treatment (medication/psychotherapy) for OCD. All participants will also receive unstructured, non-directive psychological support during visits. Aside from safety, primary outcomes include OCD symptoms over the past 24 h, assessed by the Acute Yale-Brown Obsessive-Compulsive Scale and Visual Analog Scale ratings. These are collected by blinded, independent raters at baseline and the primary endpoint of 48 h post-dosing. Total follow-up is 12 weeks post-dosing. Resting state neuroimaging data will be collected at baseline and primary endpoint. Participants randomized to placebo will be offered the chance to return for an open-label dose of 0.25 mg/kg. Ethics statement: All participants will be required to provide written informed consent. The trial (protocol v. 5.2) was approved by the institutional review board (HIC #2000020355) and registered with ClinicalTrials.gov (NCT03356483). Discussion: This study may represent an advance in our ability to treat refractory OCD, and pave the way for future studies of neurobiological mechanisms of OCD that may respond to psilocybin.

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.

Cortical gradients during naturalistic processing are hierarchical and modality-specific.

Understanding cortical topographic organization and how it supports complex perceptual and cognitive processes is a fundamental question in neuroscience. Previous work has characterized functional gradients that demonstrate large-scale principles of cortical organization. How these gradients are modulated by rich ecological stimuli remains unknown. Here, we utilize naturalistic stimuli via movie-fMRI to assess macroscale functional organization. We identify principal movie gradients that delineate separate hierarchies anchored in sensorimotor, visual, and auditory/language areas. At the opposite/heteromodal end of these perception-to-cognition axes, we find a more central role for the frontoparietal network along with the default network. Even across different movie stimuli, movie gradients demonstrated good reliability, suggesting that these hierarchies reflect a brain state common across different naturalistic conditions. The relative position of brain areas within movie gradients showed stronger and more numerous correlations with cognitive behavioral scores compared to resting state gradients. Together, these findings provide an ecologically valid representation of the principles underlying cortical organization while the brain is active and engaged in multimodal, dynamic perceptual and cognitive processing.

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.

Background: To 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. Objectives: This 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. Design: A 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 analysis: This 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. Ethics: Written informed consent will be obtained from participants. The institutional review board has approved this trial (protocol v. 1.7; HIC #2000032623). Discussion: This 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.

Linear discriminant analysis of phenotypic data for classifying autism spectrum disorder by diagnosis and sex.

Autism Spectrum Disorder (ASD) is a developmental condition characterized by social and communication differences. Recent research suggests ASD affects 1-in-44 children in the United States. ASD is diagnosed more commonly in males, though it is unclear whether this diagnostic disparity is a result of a biological predisposition or limitations in diagnostic tools, or both. One hypothesis centers on the 'female protective effect,' which is the theory that females are biologically more resistant to the autism phenotype than males. In this examination, phenotypic data were acquired and combined from four leading research institutions and subjected to multivariate linear discriminant analysis. A linear discriminant model was trained on the training set and then deployed on the test set to predict group membership. Multivariate analyses of variance were performed to confirm the significance of the overall analysis, and individual analyses of variance were performed to confirm the significance of each of the resulting linear discriminant axes. Two discriminant dimensions were identified between the groups: a dimension separating groups by the diagnosis of ASD (LD1: 87% of variance explained); and a dimension reflective of a diagnosis-by-sex interaction (LD2: 11% of variance explained). The strongest discriminant coefficients for the first discriminant axis divided the sample in domains with known differences between ASD and comparison groups, such as social difficulties and restricted repetitive behavior. The discriminant coefficients for the second discriminant axis reveal a more nuanced disparity between boys with ASD and girls with ASD, including executive functioning and high-order behavioral domains as the dominant discriminators. These results indicate that phenotypic differences between males and females with and without ASD are identifiable using parent report measures, which could be utilized to provide additional specificity to the diagnosis of ASD in female patients, potentially leading to more targeted clinical strategies and therapeutic interventions. The study helps to isolate a phenotypic basis for future empirical work on the female protective effect using neuroimaging, EEG, and genomic methodologies.

Getting the nod: Pediatric head motion in a transdiagnostic sample during movie- and resting-state fMRI.

Head motion continues to be a major problem in fMRI research, particularly in developmental studies where an inverse relationship exists between head motion and age. Despite multifaceted and costly efforts to mitigate motion and motion-related signal artifact, few studies have characterized in-scanner head motion itself. This study leverages a large transdiagnostic public dataset (N = 1388, age 5-21y, The Healthy Brain Network Biobank) to characterize pediatric head motion in space, frequency, and time. We focus on practical aspects of head motion that could impact future study design, including comparing motion across groups (low, medium, and high movers), across conditions (movie-watching and rest), and between males and females. Analyses showed that in all conditions, high movers exhibited a different pattern of motion than low and medium movers that was dominated by x-rotation, and z- and y-translation. High motion spikes (>0.3mm) from all participants also showed this pitch-z-y pattern. Problematic head motion is thus composed of a single type of biomechanical motion, which we infer to be a nodding movement, providing a focused target for motion reduction strategies. A second type of motion was evident via spectral analysis of raw displacement data. This was observed in low and medium movers and was consistent with respiration rates. We consider this to be a baseline of motion best targeted in data preprocessing. Further, we found that males moved more than, but not differently from, females. Significant cross-condition differences in head motion were found. Movies had lower mean motion, and especially in high movers, movie-watching reduced within-run linear increases in head motion (i.e., temporal drift). Finally, we used intersubject correlations of framewise displacement (FD-ISCs) to assess for stimulus-correlated motion trends. Subject motion was more correlated in movie than rest, and 8 out of top 10 FD-ISC windows had FD below the mean. Possible reasons and future implications of these findings are discussed.

Increased amygdala and decreased frontolimbic r esting- s tate functional connectivity in children with aggressive behavior.

Childhood maladaptive aggression is associated with disrupted functional connectivity within amygdala-prefrontal circuitry. In this study, neural correlates of childhood aggression were probed using the intrinsic connectivity distribution, a voxel-wise metric of global resting-state brain connectivity. This sample included 38 children with aggressive behavior (26 boys, 12 girls) ages 8-16 years and 21 healthy controls (14 boys, 6 girls) matched for age and IQ. Functional MRI data were acquired during resting state, and differential patterns of intrinsic functional connectivity were tested in a priori regions of interest implicated in the pathophysiology of aggressive behavior. Next, correlational analyses tested for associations between functional connectivity and severity of aggression measured by the Reactive-Proactive Aggression Questionnaire in children with aggression. Children with aggressive behavior showed increased global connectivity in the bilateral amygdala relative to controls. Greater severity of aggressive behavior was associated with decreasing global connectivity in the dorsal anterior cingulate and ventromedial prefrontal cortex. Follow-up seed analysis revealed that aggression was also positively correlated with left amygdala connectivity with the dorsal anterior cingulate, ventromedial and dorsolateral prefrontal cortical regions. These results highlight the potential role of connectivity of the amygdala and medial prefrontal and anterior cingulate cortices in modulating the severity of aggressive behavior in treatment-seeking children.

A neurogenetic analysis of female autism.

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8-17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n = 45) brain response to human motion, relative to matched typically developing female youth (n = 45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n = 47) and typically developing males (n = 47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n = 61), versus males (n = 66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n = 2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.

Functional Network Development in Sagittal Craniosynostosis Treated With Whole Vault Cranioplasty.

INTRODUCTION: In this study, the authors seek to clarify the neurological changes before and after whole vault cranioplasty (WVC) in patients born with sagittal craniosynostosis. METHODS: A case control study design was performed that included thirty functional MRI scans, from 25 individual patients. Functional MRI and diffusion tension imaging data were analyzed with BioImageSuite (Yale University, USA). 9 functional brain networks were analyzed, with appropriate correlated functional regions of the brain and utilized for analysis. RESULTS: Comparing functional MRI the infants after WVC versus infants before WVC group, the after WVC group demonstrated an increased connectivity in the left frontoparietal, secondary (V2), and third (V3) visual networks (P < 0.001). The right frontoparietal (RFPN) had decreased connectivity (P < 0.001). There is also a decrease and increase in anisotropy in the cingulum and precuneus despite surgery, respectively (P < 0.05). Adolescents treated with WVC compared to controls, demonstrated an increased connectivity in the salience and decreased connectivity in the RFPN relative to adolescent controls. CONCLUSIONS: Patients born with sagittal craniosynostosis have different connections in infancy in most of the defined cerebral networks compared to controls. After surgery, there are specific connectivity changes that occur in the RFPN, left frontoparietal, V2, and V3 networks, which are areas associated with executive function and emotional control. Changes identified in white matter tract microstructure connections could be influential in changes in functional connectivity. Although, as a child with sagittal craniosynostosis develops, much of the abnormal network connections, seen in infancy preoperatively, corrects to some degree after surgery. However, some aberrancies in the salience and RFPN networks remain potentially affecting executive functioning.

Stability and similarity of the pediatric connectome as developmental measures.

Patterns of functional connectivity are unique at the individual level, enabling test-retest matching algorithms to identify a subject from among a group using only their functional connectome. Recent findings show that accuracies of these algorithms in children increase with age. Relatedly, the persistence of functional connectivity (FC) patterns across tasks and rest also increases with age. This study investigated the hypothesis that within-subject stability and between-subject similarity of the whole-brain pediatric connectome are developmentally relevant outcomes. Using data from 210 help-seeking children and adolescents, ages 6-21 years (Healthy Brain Network Biobank), we computed whole-brain FC matrices for each participant during two different movies (MovieDM and MovieTP) and two runs of task-free rest (all from a single scan session) and fed these matrices to a test-retest matching algorithm. We replicated the finding that matching accuracies for children and youth (ages 6-21 years) are low (18-44%), and that cross-state and cross-movie accuracies were the lowest. Results also showed that parcellation resolution and the number of volumes used in each matrix affect fingerprinting accuracies. Next, we calculated three measures of whole-connectome stability for each subject: cross-rest (Rest1-Rest2), cross-state (MovieDM-Rest1), and cross-movie (MovieDM-MovieTP), and three measures of within-state between-subject connectome similarity for Rest1, MovieDM, and MovieTP. We show that stability and similarity were correlated, but that these measures were not related to age. A principal component analysis of these measures yielded two components that we used to test for brain-behavior correlations with IQ, general psychopathology, and social skills measures (n = 119). The first component was significantly correlated with the social skills measure (r=-0.26, p = 0.005). Post hoc correlations showed that the social skills measure correlated with both cross-rest stability (r=-0.29, p = 0.001) and with connectome similarity during MovieDM (r=-0.28, p = 0.002). These findings suggest that the stability and similarity of the whole-brain connectome relate to the development of social skills. We infer that the maturation of the functional connectome simultaneously achieves patterns of FC that are distinct at the individual subject level, that are shared across individuals, and that are persistent across states and across runs-features which presumably combine to optimize neural processing during development. Future longitudinal work could reveal the developmental trajectories of stability and similarity of the connectome.

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.

Imaging-genetics of sex differences in ASD: distinct effects of OXTR variants on brain connectivity.

Autism spectrum disorder (ASD) is more prevalent in males than in females, but the neurobiological mechanisms that give rise to this sex-bias are poorly understood. The female protective hypothesis suggests that the manifestation of ASD in females requires higher cumulative genetic and environmental risk relative to males. Here, we test this hypothesis by assessing the additive impact of several ASD-associated OXTR variants on reward network resting-state functional connectivity in males and females with and without ASD, and explore how genotype, sex, and diagnosis relate to heterogeneity in neuroendophenotypes. Females with ASD who carried a greater number of ASD-associated risk alleles in the OXTR gene showed greater functional connectivity between the nucleus accumbens (NAcc; hub of the reward network) and subcortical brain areas important for motor learning. Relative to males with ASD, females with ASD and higher OXTR risk-allele-dosage showed increased connectivity between the NAcc, subcortical regions, and prefrontal brain areas involved in mentalizing. This increased connectivity between NAcc and prefrontal cortex mirrored the relationship between genetic risk and brain connectivity observed in neurotypical males showing that, under increased OXTR genetic risk load, females with ASD and neurotypical males displayed increased connectivity between reward-related brain regions and prefrontal cortex. These results indicate that females with ASD differentially modulate the effects of increased genetic risk on brain connectivity relative to males with ASD, providing new insights into the neurobiological mechanisms through which the female protective effect may manifest.

Randomized, Sham-Controlled Trial of Real-Time Functional Magnetic Resonance Imaging Neurofeedback for Tics in Adolescents With Tourette Syndrome.

BACKGROUND: Activity in the supplementary motor area (SMA) has been associated with tics in Tourette syndrome (TS). The aim of this study was to test a novel intervention-real-time functional magnetic resonance imaging neurofeedback from the SMA-for reduction of tics in adolescents with TS. METHODS: Twenty-one adolescents with TS were enrolled in a double-blind, randomized, sham-controlled, crossover study involving two sessions of neurofeedback from their SMA. The primary outcome measure of tic severity was the Yale Global Tic Severity Scale administered by an independent evaluator before and after each arm. The secondary outcome was control over the SMA assessed in neuroimaging scans, in which subjects were cued to increase/decrease activity in SMA without receiving feedback. RESULTS: All 21 subjects completed both arms of the study and all assessments. Participants had significantly greater reduction of tics on the Yale Global Tic Severity Scale after real neurofeedback as compared with the sham control (p < .05). Mean Yale Global Tic Severity Scale Total Tic score decreased from 25.2 ± 4.6 at baseline to 19.9 ± 5.7 at end point in the neurofeedback condition and from 24.8 ± 8.1 to 23.3 ± 8.5 in the sham control condition. The 3.8-point difference is clinically meaningful and corresponds to an effect size of 0.59. However, there were no differences in changes on the secondary measure of control over the SMA. CONCLUSIONS: This first randomized controlled trial of real-time functional magnetic resonance imaging neurofeedback in adolescents with TS suggests that this neurofeedback intervention may be helpful for improving tic symptoms. However, no effects were found in terms of change in control over the SMA, the hypothesized mechanism of action.

Frustration and Emotional Regulation in Nonsyndromic Craniosynostosis: A Functional Magnetic Resonance Imaging Study.

BACKGROUND: Nonsyndromic craniosynostosis may manifest with complex behavioral, attentional, and emotional sequelae. The authors characterized higher level brain connectivity in adolescent nonsyndromic craniosynostosis patients in response to emotional frustration. METHODS: Surgically corrected patients older than 9 years with nonsyndromic craniosynostosis were age/sex/handedness matched to controls. Patients participated in a "go/no-go" task, structured as win/lose/recovery paradigms. BioImage Suite was used to analyze whole-brain intrinsic connectivity between tasks with cluster-corrected group-level t maps. A value of p < 0.05 was significant. RESULTS: Seven unilateral coronal (average age, 12.2 years), six metopic (average age, 11.5 years), and controls were included. Unilateral coronal had worse emotional regulation scores on the Behavior Rating Inventory of Executive Function survey (p = 0.065) and performed poorly on the go/no-go task (p < 0.001). Metopic had four regions of interest, with the majority having decreased activity compared with controls, and few differences between tasks. Unilateral coronal patients had 11 regions of interest; the majority decreased during the win and lose conditions, but all increased during the recovery condition. Metopic patients had decreased blood oxygenation level- dependent signal in the posterior cingulate (p = 0.017) and middle temporal gyrus (p = 0.042). Unilateral coronal had decreased signal in the posterior cingulate (p = 0.023), middle temporal gyrus (p = 0.027), and thalamus (p = 0.033), but increased signal in the cuneus (p = 0.009) and cerebellum (p = 0.009). Right unilateral coronal, but not metopic/controls, had increased right brain activity in the caudate (p = 0.030), thalamus (p = 0.011), temporal lobe (p = 0.012), and cerebellum (p = 0.029). CONCLUSIONS: Unilateral coronal patients may have emotional dysregulation in response to frustration, whereas metopic patients may have attenuated emotional reactions. Evidence of right unilateral coronal brain laterality suggests that the area of suture fusion may contribute to the mechanism of dysfunction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Reduced Amygdala-Prefrontal Functional Connectivity in Children With Autism Spectrum Disorder and Co-occurring Disruptive Behavior.

BACKGROUND: Disruptive behaviors are prevalent in children with autism spectrum disorder (ASD) and often cause substantial impairments. However, the underlying neural mechanisms of disruptive behaviors remain poorly understood in ASD. In children without ASD, disruptive behavior is associated with amygdala hyperactivity and reduced connectivity with the ventrolateral prefrontal cortex (vlPFC). This study examined amygdala reactivity and connectivity in children with ASD with and without co-occurring disruptive behavior disorders. We also investigated differential contributions of externalizing behaviors and callous-unemotional traits to variance in amygdala connectivity and reactivity. METHODS: This cross-sectional study involved behavioral assessments and neuroimaging in three groups of children 8 to 16 years of age: 18 children had ASD and disruptive behavior, 20 children had ASD without disruptive behavior, and 19 children were typically developing control participants matched for age, gender, and IQ. During functional magnetic resonance imaging, participants completed an emotion perception task of fearful versus calm faces. Task-specific changes in amygdala reactivity and connectivity were examined using whole-brain, psychophysiological interaction, and multiple regression analyses. RESULTS: Children with ASD and disruptive behavior showed reduced amygdala-vlPFC connectivity compared with children with ASD without disruptive behavior. Externalizing behaviors and callous-unemotional traits were associated with amygdala reactivity to fearful faces in children with ASD after controlling for suppressor effects. CONCLUSIONS: Reduced amygdala-vlPFC connectivity during fear processing may differentiate children with ASD and disruptive behavior from children with ASD without disruptive behavior. The presence of callous-unemotional traits may have implications for identifying differential patterns of amygdala activity associated with increased risk of aggression in ASD. These findings suggest a neural mechanism of emotion dysregulation associated with disruptive behavior in children with ASD.

An Investigation of Brain Functional Connectivity by Form of Craniosynostosis.

PURPOSE: Long-term neurocognitive sequelae of nonsyndromic craniosynostosis (NSC) patients are just beginning to be clarified. This study uses functional MRI (fMRI) to determine if there is evidence of altered brain functional connectivity in NSC, and whether these aberrations vary by form of synostosis. METHODS: Twenty adolescent participants with surgically treated NSC (10 sagittal synostosis, 5 right unilateral coronal synostosis [UCS], 5 metopic synostosis [MSO]) were individually matched to controls by age, gender, and handedness. A subgroup of MSO was classified as severe metopic synostosis (SMS) based on the endocranial bifrontal angle. Resting state fMRI was acquired in a 3T Siemens TIM Trio scanner (Erlangen, Germany), and data were motion corrected and then analyzed with BioImage Suite (Yale School of Medicine). Resulting group-level t-maps were cluster corrected with nonparametric permutation tests. A region of interest analysis was performed based on the left Brodmann's Areas 7, 39, and 40. RESULTS: Sagittal synostosis had decreased whole-brain intrinsic connectivity compared to controls in the superior parietal lobules and the angular gyrus (P = 0.071). Unilateral coronal synostosis had decreased intrinsic connectivity throughout the prefrontal cortex (P = 0.031). The MSO cohort did not have significant findings on intrinsic connectivity, but the SMS subgroup had significantly decreased connectivity among multiple subcortical structures. CONCLUSION: Sagittal synostosis had decreased connectivity in regions associated with visuomotor integration and attention, while UCS had decreased connectivity in circuits crucial in executive function and cognition. Finally, severity of metopic synostosis may influence the degree of neurocognitive aberration. This study provides data suggestive of long-term sequelae of NSC that varies by suture type, which may underlie different phenotypes of neurocognitive impairment.

What is the Functional Difference Between Sagittal With Metopic and Isolated Sagittal Craniosynotosis?

INTRODUCTION: The purpose of this study is to understand the neurological differences between patients born with combined sagittal and metopic craniosynostosis (SMc) and isolated sagittal craniosynostosis (ISc) by studying aberrations in functional brain connectivity and white matter microstructure, before surgery, utilizing functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). METHODS: The authors collected DTI and resting-state (ie, no sedation and asleep) functional connectivity MRI data in 10 infant patients preoperatively: 5 in the SMc group (4.3 ±â€Š1 months) and 5 in the ISc group (4.8 ±â€Š1.1 months). Resting state fMRI imaging and DTI data were acquired using a 3-T Siemens Trio MRI system (Erlangen, Germany) while the infant patients slept. fMRI data were corrected for movement using SPM, underwent cerebrospinal fluid and white matter signal regression and further analyzed with BioImageSuite. For the DTI data, 3 diffusion runs were averaged, processed utilizing FMRIB Software Library, and analyzed statistically using BioImageSuite. RESULTS: Comparing the SMc versus ISc groups, SMc demonstrated that there was increased connectivity, statistically significant differences, in neural networks between children with sagittal synostosis alone versus those with sagittal with metopic synostosis, in the right BA 31 and BA 23 (corresponding to the posterior cingulate cortex (PCC) (P < 0.001). Analysis of the DTI revealed increased fractional anisotropy (normal maturation of white tracts) in the SMc group in the cingulum compared to the ISc group (P < 0.05). Differences in the functional networks include increased connectivity right frontoparietal network (RFPN) in ISc and increased connectivity in the primary visual network (V1) in SMc (P < 0.001). CONCLUSION: The SMc had increased connectivity as measured by fMR in the PCC, an area associated with attention deficit hyperactivity disorder. The DTI analysis demonstrated an increase in fractional anisotropy of the cingulum in the SMc group, a white matter tract projecting from the cingulate cortex; connections of the limbic (emotional regulation) system are instrumental. In SMc, increase of connectivity in the PCC correlates with an increase in maturation of the cingulum compared to ISc. There is increased connectivity of the RFPN network in the ISc and increased connectivity of the V1 network in the SMc patients. The SMc group has increased connectivity in the PCC, the original seed of the DMN network, and decreased connectivity to the RFPN network. The pattern of increased connectivity in the area of the DMN and decreased connectivity in the RFPN network is similar to the trend when comparing ADHD patients to normal controls. SMc has more similar functional network connectivity to ADHD as compared to ISc.

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.

Understanding the Learning Disabilities Linked to Sagittal Craniosynostosis.

OBJECTIVE: The purpose of this study is to investigate further findings that corroborate similarities between corrected sagittal craniosynostosis and attention deficit hyperactivity disorder (ADHD). The aim is to further characterize the neurocognitive deficits seen in adolescents with corrected craniosynostosis by comparing it to established learning deficits such as ADHD. METHODS: A total of 30 functional magnetic resonance imaging (fMRI) of 10 sagittal nonsyndromic craniosynostosis (sNSC), 10 ADHD-combined, and 10 control adolescents were studied. The fMRI scans were analyzed utilizing Statistical Parametric Mapping (University College London, UK) and analyzed with BioImageSuite (Yale University, New Haven, CT). RESULTS: The ADHD has lower connectivity to Brodmann area (BA) 11 (Montreal Neurological Institution [MNI]: -12,26,-21), BA20 (MNI: 62,-24,-25), and BA21 (MNI: 62,-32,-23) compared to sNSC and controls (P < 0.001). The sNSC has a unique visuospatial defect, compared to ADHD, created by decreased connectivity to BA31 (MNI: -3,-68,37), BA7 (MNI: -4,-68,41), BA19 (MNI: 0,-83,31), visual association cortex (MNI: -4,-78,22), and primary visual cortex (MNI: 7,-74,21) (P < 0.001). CONCLUSION: Patients born with sNSC have different neural connections than children born with ADHD. Patients born with sNSC have decreased connections in areas of visual processing and increased connections in areas of attention and auditory processing than patients with ADHD. Therefore, children with sagittal craniosynsotosis may have learning difficulties that, similar, yet different from ADHD.