Cross-sectional and longitudinal neuroanatomical profiles of distinct clinical (adaptive) outcomes in autism.

Individuals with autism spectrum disorder (henceforth referred to as autism) display significant variation in clinical outcome. For instance, across age, some individuals' adaptive skills naturally improve or remain stable, while others' decrease. To pave the way for 'precision-medicine' approaches, it is crucial to identify the cross-sectional and, given the developmental nature of autism, longitudinal neurobiological (including neuroanatomical and linked genetic) correlates of this variation. We conducted a longitudinal follow-up study of 333 individuals (161 autistic and 172 neurotypical individuals, aged 6-30 years), with two assessment time points separated by ~12-24 months. We collected behavioural (Vineland Adaptive Behaviour Scale-II, VABS-II) and neuroanatomical (structural magnetic resonance imaging) data. Autistic participants were grouped into clinically meaningful "Increasers", "No-changers", and "Decreasers" in adaptive behaviour (based on VABS-II scores). We compared each clinical subgroup's neuroanatomy (surface area and cortical thickness at T1, ∆T (intra-individual change) and T2) to that of the neurotypicals. Next, we explored the neuroanatomical differences' potential genomic associates using the Allen Human Brain Atlas. Clinical subgroups had distinct neuroanatomical profiles in surface area and cortical thickness at baseline, neuroanatomical development, and follow-up. These profiles were enriched for genes previously associated with autism and for genes previously linked to neurobiological pathways implicated in autism (e.g. excitation-inhibition systems). Our findings suggest that distinct clinical outcomes (i.e. intra-individual change in clinical profiles) linked to autism core symptoms are associated with atypical cross-sectional and longitudinal, i.e. developmental, neurobiological profiles. If validated, our findings may advance the development of interventions, e.g. targeting mechanisms linked to relatively poorer outcomes.

Comparative transcriptomic analyses reveal activation of the epithelial-mesenchymal transition program in non-metastasizing low grade pseudomyxoma peritonei.

Epithelial-mesenchymal transition (EMT), angiogenesis, cell adhesion and extracellular matrix (ECM) interaction are essential for colorectal cancer (CRC) metastasis. Low grade mucinous neoplasia of the appendix (LAMN) and its advanced state low grade pseudomyxoma peritonei (lgPMP) show local aggressiveness with very limited metastatic potential as opposed to CRC. To better understand the underlying processes that foster or impede metastatic spread, we compared LAMN, lgPMP, and CRC with respect to their molecular profile with subsequent pathway analysis. LAMN, lgPMP and (mucinous) CRC cases were subjected to transcriptomic analysis utilizing Poly(A) RNA sequencing. Successfully sequenced cases (LAMN n = 10, 77%, lgPMP n = 13, 100% and CRC n = 8, 100%) were investigated using bioinformatic and statistical tests (differential expression analysis, hierarchical clustering, principal component analysis and gene set enrichment analysis). We identified a gene signature of 28 genes distinguishing LAMN, lgPMP and CRC neoplasias. Ontology analyses revealed that multiple pathways including EMT, ECM interaction and angiogenesis are differentially regulated. Fifty-three significantly differentially regulated gene sets were identified between lgPMP and CRC followed by CRC vs. LAMN (n = 21) and lgPMP vs. LAMN (n = 16). Unexpectedly, a substantial enrichment of the EMT gene set was observed in lgPMP vs. LAMN (FDR=0.011) and CRC (FDR=0.004). Typical EMT markers were significantly upregulated (Vimentin, TWIST1, N-Cadherin) or downregulated (E-Cadherin) in lgPMP. However, MMP1 and MMP3 levels, associated with EMT, ECM and metastasis, were considerably higher in CRC. We show that the different tumor biological behaviour and metastatic spread pattern of midgut malignancies is reflected in a different gene expression profile. We revealed a strong activation of the EMT program in non-metastasizing lgPMP vs. CRC. Hence, although EMT is considered a key step in hematogenous spread, successful EMT does not necessarily lead to hematogenous dissemination. This emphasizes the need for further pathway analyses and forms the basis for mechanistic and therapy-targeting research.

Patterns of Brain Maturation in Autism and Their Molecular Associations.

Importance: In the neurotypical brain, regions develop in coordinated patterns, providing a fundamental scaffold for brain function and behavior. Whether altered patterns contribute to clinical profiles in neurodevelopmental conditions, including autism, remains unclear. Objectives: To examine if, in autism, brain regions develop differently in relation to each other and how these differences are associated with molecular/genomic mechanisms and symptomatology. Design, Setting, and Participants: This study was an analysis of one the largest deep-phenotyped, case-control, longitudinal (2 assessments separated by approximately 12-24 months) structural magnetic resonance imaging and cognitive-behavioral autism datasets (EU-AIMS Longitudinal European Autism Project [LEAP]; study dates, February 2014-November 2017) and an out-of-sample validation in the Brain Development Imaging Study (BrainMapASD) independent cohort. Analyses were performed during the 2022 to 2023 period. This multicenter study included autistic and neurotypical children, adolescents, and adults. Autistic participants were included if they had an existing autism diagnosis (DSM-IV/International Statistical Classification of Diseases and Related Health Problems, Tenth Revision or DSM-5 criteria). Autistic participants with co-occurring psychiatric conditions (except psychosis/bipolar disorder) and those taking regular medications were included. Exposures: Neuroanatomy of neurotypical and autistic participants. Main Outcomes and Measures: Intraindividual changes in surface area and cortical thickness over time, analyzed via surface-based morphometrics. Results: A total of 386 individuals in the LEAP cohort (6-31 years at first visit; 214 autistic individuals, mean [SD] age, 17.3 [5.4] years; 154 male [72.0%] and 172 neurotypical individuals, mean [SD] age, 16.35 [5.7] years; 108 male [62.8%]) and 146 individuals in the BrainMapASD cohort (11-18 years at first visit; 49 autistic individuals, mean [SD] age, 14.31 [2.4] years; 42 male [85.7%] and 97 neurotypical individuals, mean [SD] age, 14.10 [2.5] years; 58 male [59.8%]). Maturational between-group differences in cortical thickness and surface area were established that were mostly driven by sensorimotor regions (eg, across features, absolute loadings for early visual cortex ranged from 0.07 to 0.11, whereas absolute loadings for dorsolateral prefrontal cortex ranged from 0.005 to 0.06). Neurodevelopmental differences were transcriptomically enriched for genes expressed in several cell types and during various neurodevelopmental stages, and autism candidate genes (eg, downregulated genes in autism, including those regulating synaptic transmission; enrichment odds ratio =3.7; P =2.6 × -10). A more neurotypical, less autismlike maturational profile was associated with fewer social difficulties and more typical sensory processing (false discovery rate P <.05; Pearson r ≥0.17). Results were replicated in the independently collected BrainMapASD cohort. Conclusions and Relevance: Results of this case-control study suggest that the coordinated development of brain regions was altered in autism, involved a complex interplay of temporally sensitive molecular mechanisms, and may be associated with both lower-order (eg, sensory) and higher-order (eg, social) clinical features of autism. Thus, examining maturational patterns may provide an analytic framework to study the neurobiological origins of clinical profiles in neurodevelopmental/mental health conditions.

Frontal and occipital brain glutathione levels are unchanged in autistic adults.

BACKGROUND: The neurobiological underpinnings of Autism Spectrum Disorder (ASD) are diverse and likely multifactorial. One possible mechanism is increased oxidative stress leading to altered neurodevelopment and brain function. However, this hypothesis has mostly been tested in post-mortem studies. So far, available in vivo studies in autistic individuals have reported no differences in glutathione (GSH) levels in frontal, occipital, and subcortical regions. However, these studies were limited by the technically challenging quantification of GSH, the main brain antioxidant molecule. This study aimed to overcome previous studies' limitations by using a GSH-tailored spectroscopy sequence and optimised quantification methodology to provide clarity on GSH levels in autistic adults. METHODS: We used spectral editing proton-magnetic resonance spectroscopy (1H-MRS) combined with linear combination model fitting to quantify GSH in the dorsomedial prefrontal cortex (DMPFC) and medial occipital cortex (mOCC) of autistic and non-autistic adults (male and female). We compared GSH levels between groups. We also examined correlations between GSH and current autism symptoms, measured using the Autism Quotient (AQ). RESULTS: Data were available from 31 adult autistic participants (24 males, 7 females) and 40 non-autistic participants (21 males, 16 females); the largest sample to date. The GSH levels did not differ between groups in either region. No correlations with AQ were observed. CONCLUSION: GSH levels as measured using 1H-MRS are unaltered in the DMPFC and mOCC regions of autistic adults, suggesting that oxidative stress in these cortical regions is not a marked neurobiological signature of ASD.

Differences in Intrinsic Gray Matter Connectivity and Their Genomic Underpinnings in Autism Spectrum Disorder.

BACKGROUND: Autism is a heterogeneous neurodevelopmental condition accompanied by differences in brain connectivity. Structural connectivity in autism has mainly been investigated within the white matter. However, many genetic variants associated with autism highlight genes related to synaptogenesis and axonal guidance, thus also implicating differences in intrinsic (i.e., gray matter) connections in autism. Intrinsic connections may be assessed in vivo via so-called intrinsic global and local wiring costs. METHODS: Here, we examined intrinsic global and local wiring costs in the brain of 359 individuals with autism and 279 healthy control participants ages 6 to 30 years from the EU-AIMS LEAP (Longitudinal European Autism Project). FreeSurfer was used to derive surface mesh representations to compute the estimated length of connections required to wire the brain within the gray matter. Vertexwise between-group differences were assessed using a general linear model. A gene expression decoding analysis based on the Allen Human Brain Atlas was performed to link neuroanatomical differences to putative underpinnings. RESULTS: Group differences in global and local wiring costs were predominantly observed in medial and lateral prefrontal brain regions, in inferior temporal regions, and at the left temporoparietal junction. The resulting neuroanatomical patterns were enriched for genes that had been previously implicated in the etiology of autism at genetic and transcriptomic levels. CONCLUSIONS: Based on intrinsic gray matter connectivity, the current study investigated the complex neuroanatomy of autism and linked between-group differences to putative genomic and/or molecular mechanisms to parse the heterogeneity of autism and provide targets for future subgrouping approaches.

Structural neuroimaging phenotypes and associated molecular and genomic underpinnings in autism: a review.

Autism has been associated with differences in the developmental trajectories of multiple neuroanatomical features, including cortical thickness, surface area, cortical volume, measures of gyrification, and the gray-white matter tissue contrast. These neuroimaging features have been proposed as intermediate phenotypes on the gradient from genomic variation to behavioral symptoms. Hence, examining what these proxy markers represent, i.e., disentangling their associated molecular and genomic underpinnings, could provide crucial insights into the etiology and pathophysiology of autism. In line with this, an increasing number of studies are exploring the association between neuroanatomical, cellular/molecular, and (epi)genetic variation in autism, both indirectly and directly in vivo and across age. In this review, we aim to summarize the existing literature in autism (and neurotypicals) to chart a putative pathway from (i) imaging-derived neuroanatomical cortical phenotypes to (ii) underlying (neuropathological) biological processes, and (iii) associated genomic variation.

The neuroanatomical substrates of autism and ADHD and their link to putative genomic underpinnings.

BACKGROUND: Autism spectrum disorders (ASD) are neurodevelopmental conditions accompanied by differences in brain development. Neuroanatomical differences in autism are variable across individuals and likely underpin distinct clinical phenotypes. To parse heterogeneity, it is essential to establish how the neurobiology of ASD is modulated by differences associated with co-occurring conditions, such as attention-deficit/hyperactivity disorder (ADHD). This study aimed to (1) investigate between-group differences in autistic individuals with and without co-occurring ADHD, and to (2) link these variances to putative genomic underpinnings. METHODS: We examined differences in cortical thickness (CT) and surface area (SA) and their genomic associations in a sample of 533 individuals from the Longitudinal European Autism Project. Using a general linear model including main effects of autism and ADHD, and an ASD-by-ADHD interaction, we examined to which degree ADHD modulates the autism-related neuroanatomy. Further, leveraging the spatial gene expression data of the Allen Human Brain Atlas, we identified genes whose spatial expression patterns resemble our neuroimaging findings. RESULTS: In addition to significant main effects for ASD and ADHD in fronto-temporal, limbic, and occipital regions, we observed a significant ASD-by-ADHD interaction in the left precentral gyrus and the right frontal gyrus for measures of CT and SA, respectively. Moreover, individuals with ASD + ADHD differed in CT to those without. Both main effects and the interaction were enriched for ASD-but not for ADHD-related genes. LIMITATIONS: Although we employed a multicenter design to overcome single-site recruitment limitations, our sample size of N = 25 individuals in the ADHD only group is relatively small compared to the other subgroups, which limits the generalizability of the results. Also, we assigned subjects into ADHD positive groupings according to the DSM-5 rating scale. While this is sufficient for obtaining a research diagnosis of ADHD, our approach did not take into account for how long the symptoms have been present, which is typically considered when assessing ADHD in the clinical setting. CONCLUSION: Thus, our findings suggest that the neuroanatomy of ASD is significantly modulated by ADHD, and that autistic individuals with co-occurring ADHD may have specific neuroanatomical underpinnings potentially mediated by atypical gene expression.

The Link Between Autism and Sex-Related Neuroanatomy, and Associated Cognition and Gene Expression.

OBJECTIVE: The male preponderance in prevalence of autism is among the most pronounced sex ratios across neurodevelopmental conditions. The authors sought to elucidate the relationship between autism and typical sex-differential neuroanatomy, cognition, and related gene expression. METHODS: Using a novel deep learning framework trained to predict biological sex based on T1-weighted structural brain images, the authors compared sex prediction model performance across neurotypical and autistic males and females. Multiple large-scale data sets comprising T1-weighted MRI data were employed at four stages of the analysis pipeline: 1) pretraining, with the UK Biobank sample (>10,000 individuals); 2) transfer learning and validation, with the ABIDE data sets (1,412 individuals, 5-56 years of age); 3) test and discovery, with the EU-AIMS/AIMS-2-TRIALS LEAP data set (681 individuals, 6-30 years of age); and 4) specificity, with the NeuroIMAGE and ADHD200 data sets (887 individuals, 7-26 years of age). RESULTS: Across both ABIDE and LEAP, features positively predictive of neurotypical males were on average significantly more predictive of autistic males (ABIDE: Cohen's d=0.48; LEAP: Cohen's d=1.34). Features positively predictive of neurotypical females were on average significantly less predictive of autistic females (ABIDE: Cohen's d=1.25; LEAP: Cohen's d=1.29). These differences in sex prediction accuracy in autism were not observed in individuals with ADHD. In autistic females, the male-shifted neurophenotype was further associated with poorer social sensitivity and emotional face processing while also associated with gene expression patterns of midgestational cell types. CONCLUSIONS: The results demonstrate an increased resemblance in both autistic male and female individuals' neuroanatomy with male-characteristic patterns associated with typically sex-differential social cognitive features and related gene expression patterns. The findings hold promise for future research aimed at refining the quest for biological mechanisms underpinning the etiology of autism.

Experiences of student and trainee autism researchers during the COVID-19 pandemic.

Circumstances surrounding the COVID-19 pandemic have resulted in significant personal and professional adjustments. Students and trainees, including those in autism research, face unique challenges to accomplishing their training and career goals during this unprecedented time. In this commentary, we, as members of the International Society for Autism Research Student and Trainee Committee, describe our personal experiences, which may or may not align with those of other students and trainees. Our experiences have varied both in terms of the ease (or lack thereof) with which we adapted and the degree to which we were supported in the transition to online research and clinical practice. We faced and continue to adjust to uncertainties about future training and academic positions, for which opportunities have been in decline and have subsequently negatively impacted our mental health. Students and trainees' prospects have been particularly impacted compared to more established researchers and faculty. In addition to the challenges we have faced, however, there have also been unexpected benefits in our training during the pandemic, which we describe here. We have learned new coping strategies which, we believe, have served us well. The overarching goal of this commentary is to describe these experiences and strategies in the hope that they will benefit the autism research community moving forward. Here, we provide a set of recommendations for faculty, especially mentors, to support students and trainees as well as strategies for students and trainees to bolster their self-advocacy, both of which we see as crucial for our future careers. LAY SUMMARY: The COVID-19 pandemic has affected students and trainees, including those in autism research, in different ways. Here, we describe our personal experiences. These experiences include challenges. For example, it has been difficult to move from in-person to online work. It has also been difficult to keep up with work and training goals. Moreover, working from home has made it hard to connect with our supervisors and mentors. As a result, many of us have felt unsure about how to make the best career choices. Working in clinical services and getting to know and support our patients online has also been challenging. Overall, the pandemic has made us feel more isolated and some of us have struggled to cope with that. On the other hand, our experiences have also included benefits. For example, by working online, we have been able to join meetings all over the world. Also, the pandemic has pushed us to learn new skills. Those include technical skills but also skills for well-being. Next, we describe our experiences of returning to work. Finally, we give recommendations for trainees and supervisors on how to support each other and to build a strong community.

Specific intraoperative antibiotic therapy abrogates the negative effect of biliary contamination on the Comprehensive Complication Index after pancreatic head resection.

BACKGROUND: The effect of bacterobilia on morbidity after pancreatoduodenectomy remains unclear. The aim of this study was to examine the influence of positive intraoperative bile cultures and perioperative antibiotic prophylaxis on morbidity measured using the Comprehensive Complication Index, a weighted composite of postoperative complications. METHODS: Intraoperative bile cultures of 182 patients who underwent pancreatoduodenectomy were obtained. We examined the effect of intraoperative bile cultures and perioperative antibiotic prophylaxis on the Comprehensive Complication Index and the occurrence of postoperative complications. To this aim, we performed general linear models controlling for relevant demographic and perioperative factors. RESULTS: Positive (versus negative) intraoperative bile cultures were associated with a higher mean Comprehensive Complication Index (25.34 vs 16.81, P = .025). The mean Comprehensive Complication Index differed significantly between individuals with positive intraoperative bile cultures and bacterial strains not covered by perioperative antibiotic prophylaxis (26.2) versus positive intraoperative bile cultures and bacterial strains sensitive to perioperative antibiotic prophylaxis (22.7) (P = .045). Positive (versus negative) intraoperative bile cultures were associated with 4.75 times (95% confidence interval: 1.74-13.00, P = .002) greater odds of wound infections. The odds of wound infection were 1.93 times (95% confidence interval: .47-8.04) greater in those with positive intraoperative bile cultures and adequate perioperative antibiotic prophylaxis and 6.14 times (95% confidence interval: 2.17-17.35) greater in those with positive intraoperative bile cultures and inadequate perioperative antibiotic prophylaxis (versus negative intraoperative bile cultures) (P = .001). CONCLUSION: Bacterobilia is associated with a significant increase in Comprehensive Complication Index and wound infections after pancreatoduodenectomy, which may be reduced by administration of a specific perioperative antibiotic prophylaxis. Acquisition of bile cultures sampled through the external conduit of patients with preoperative biliary drainage could help in selecting a specific perioperative antibiotic prophylaxis and patients with bile duct stents might benefit from broad spectrum perioperative antibiotic prophylaxis.

GABAB receptor modulation of visual sensory processing in adults with and without autism spectrum disorder.

Sensory atypicalities in autism spectrum disorder (ASD) are thought to arise at least partly from differences in γ-aminobutyric acid (GABA) receptor function. However, the evidence to date has been indirect, arising from correlational studies in patients and preclinical models. Here, we evaluated the role of GABA receptor directly, in 44 adults (n = 19 ASD). Baseline concentration of occipital lobe GABA+ (GABA plus coedited macromolecules) was measured using proton magnetic resonance spectroscopy (1H-MRS). Steady-state visual evoked potential (SSVEP) elicited by a passive visual surround suppression paradigm was compared after double-blind randomized oral administration of placebo or 15 to 30 mg of arbaclofen (STX209), a GABA type B (GABAB) receptor agonist. In the placebo condition, the neurotypical SSVEP response was affected by both the foreground stimuli contrast and background interference (suppression). In ASD, however, all stimuli conditions had equal salience and background suppression of the foreground response was weaker. In the placebo condition, although there was no difference in GABA+ between groups, GABA+ concentration positively correlated with response to maximum foreground contrast during maximum background interference in neurotypicals, but not ASD. In neurotypicals, sensitivity to visual stimuli was disrupted by 30 mg of arbaclofen, whereas in ASD, it was made more "typical" and visual processing differences were abolished. Hence, differences in GABAergic function are fundamental to autistic (visual) sensory neurobiology and are modulated by GABAB activity.

Interindividual Differences in Cortical Thickness and Their Genomic Underpinnings in Autism Spectrum Disorder.

OBJECTIVE: Autism spectrum disorder (ASD) is accompanied by highly individualized neuroanatomical deviations that potentially map onto distinct genotypes and clinical phenotypes. This study aimed to link differences in brain anatomy to specific biological pathways to pave the way toward targeted therapeutic interventions. METHODS: The authors examined neurodevelopmental differences in cortical thickness and their genomic underpinnings in a large and clinically diverse sample of 360 individuals with ASD and 279 typically developing control subjects (ages 6-30 years) within the EU-AIMS Longitudinal European Autism Project (LEAP). The authors also examined neurodevelopmental differences and their potential pathophysiological mechanisms between clinical ASD subgroups that differed in the severity and pattern of sensory features. RESULTS: In addition to significant between-group differences in "core" ASD brain regions (i.e., fronto-temporal and cingulate regions), individuals with ASD manifested as neuroanatomical outliers within the neurotypical cortical thickness range in a wider neural system, which was enriched for genes known to be implicated in ASD on the genetic and/or transcriptomic level. Within these regions, the individuals' total (i.e., accumulated) degree of neuroanatomical atypicality was significantly correlated with higher polygenic scores for ASD and other psychiatric conditions, and it scaled with measures of symptom severity. Differences in cortical thickness deviations were also associated with distinct sensory subgroups, especially in brain regions expressing genes involved in excitatory rather than inhibitory neurotransmission. CONCLUSIONS: The study findings corroborate the link between macroscopic differences in brain anatomy and the molecular mechanisms underpinning heterogeneity in ASD, and provide future targets for stratification and subtyping.

Neurobiological Correlates of Change in Adaptive Behavior in Autism.

OBJECTIVE: Autism spectrum disorder (ASD) is a lifelong neurodevelopmental condition that is associated with significant difficulties in adaptive behavior and variation in clinical outcomes across the life span. Some individuals with ASD improve, whereas others may not change significantly, or regress. Hence, the development of "personalized medicine" approaches is essential. However, this requires an understanding of the biological processes underpinning differences in clinical outcome, at both the individual and subgroup levels, across the lifespan. METHODS: The authors conducted a longitudinal follow-up study of 483 individuals (204 with ASD and 279 neurotypical individuals, ages 6-30 years), with assessment time points separated by ∼12-24 months. Data collected included behavioral data (Vineland Adaptive Behavior Scale-II), neuroanatomical data (structural MRI), and genetic data (DNA). Individuals with ASD were grouped into clinically meaningful "increasers," "no-changers," and "decreasers" in adaptive behavior. First, the authors compared neuroanatomy between outcome groups. Next, they examined whether deviations from the neurotypical neuroanatomical profile were associated with outcome at the individual level. Finally, they explored the observed neuroanatomical differences' potential genetic underpinnings. RESULTS: Outcome groups differed in neuroanatomical features (cortical volume and thickness, surface area), including in "social brain" regions previously implicated in ASD. Also, deviations of neuroanatomical features from the neurotypical profile predicted outcome at the individual level. Moreover, neuroanatomical differences were associated with genetic processes relevant to neuroanatomical phenotypes (e.g., synaptic development). CONCLUSIONS: This study demonstrates, for the first time, that variation in clinical (adaptive) outcome is associated with both group- and individual-level variation in anatomy of brain regions enriched for genes relevant to ASD. This may facilitate the move toward better targeted/precision medicine approaches.

Modulation of striatal functional connectivity differences in adults with and without autism spectrum disorder in a single-dose randomized trial of cannabidivarin.

BACKGROUND: Autism spectrum disorder (ASD) has a high cost to affected individuals and society, but treatments for core symptoms are lacking. To expand intervention options, it is crucial to gain a better understanding of potential treatment targets, and their engagement, in the brain. For instance, the striatum (caudate, putamen, and nucleus accumbens) plays a central role during development and its (atypical) functional connectivity (FC) may contribute to multiple ASD symptoms. We have previously shown, in the adult autistic and neurotypical brain, the non-intoxicating cannabinoid cannabidivarin (CBDV) alters the balance of striatal 'excitatory-inhibitory' metabolites, which help regulate FC, but the effects of CBDV on (atypical) striatal FC are unknown. METHODS: To examine this in a small pilot study, we acquired resting state functional magnetic resonance imaging data from 28 men (15 neurotypicals, 13 ASD) on two occasions in a repeated-measures, double-blind, placebo-controlled study. We then used a seed-based approach to (1) compare striatal FC between groups and (2) examine the effect of pharmacological probing (600 mg CBDV/matched placebo) on atypical striatal FC in ASD. Visits were separated by at least 13 days to allow for drug washout. RESULTS: Compared to the neurotypicals, ASD individuals had lower FC between the ventral striatum and frontal and pericentral regions (which have been associated with emotion, motor, and vision processing). Further, they had higher intra-striatal FC and higher putamenal FC with temporal regions involved in speech and language. In ASD, CBDV reduced hyperconnectivity to the neurotypical level. LIMITATIONS: Our findings should be considered in light of several methodological aspects, in particular our participant group (restricted to male adults), which limits the generalizability of our findings to the wider and heterogeneous ASD population. CONCLUSION: In conclusion, here we show atypical striatal FC with regions commonly associated with ASD symptoms. We further provide preliminary proof of concept that, in the adult autistic brain, acute CBDV administration can modulate atypical striatal circuitry towards neurotypical function. Future studies are required to determine whether modulation of striatal FC is associated with a change in ASD symptoms. TRIAL REGISTRATION: clinicaltrials.gov, Identifier: NCT03537950. Registered May 25th, 2018-Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03537950?term=NCT03537950&draw=2&rank=1 .

Balancing excitation and inhibition in the autistic brain.

A metric called the Hurst exponent could be a useful biomarker for studies exploring brain differences between men and women with autism spectrum disorder.

The effect of cannabidiol (CBD) on low-frequency activity and functional connectivity in the brain of adults with and without autism spectrum disorder (ASD).

BACKGROUND: The potential benefits of cannabis and its major non-intoxicating component cannabidiol (CBD) are attracting attention, including as a potential treatment in neurodevelopmental disorders such as autism spectrum disorder (ASD). However, the neural action of CBD, and its relevance to ASD, remains unclear. We and others have previously shown that response to drug challenge can be measured using functional magnetic resonance imaging (fMRI), but that pharmacological responsivity is atypical in ASD. AIMS: We hypothesized that there would be a (different) fMRI response to CBD in ASD. METHODS: To test this, task-free fMRI was acquired in 34 healthy men (half with ASD) following oral administration of 600 mg CBD or matched placebo (random order; double-blind administration). The 'fractional amplitude of low-frequency fluctuations' (fALFF) was measured across the whole brain, and, where CBD significantly altered fALFF, we tested if functional connectivity (FC) of those regions was also affected by CBD. RESULTS: CBD significantly increased fALFF in the cerebellar vermis and the right fusiform gyrus. However, post-hoc within-group analyses revealed that this effect was primarily driven by the ASD group, with no significant change in controls. Within the ASD group only, CBD also significantly altered vermal FC with several of its subcortical (striatal) and cortical targets, but did not affect fusiform FC with other regions in either group. CONCLUSION: Our results suggest that, especially in ASD, CBD alters regional fALFF and FC in/between regions consistently implicated in ASD. Future studies should examine if this affects the complex behaviours these regions modulate.

Effects of cannabidivarin (CBDV) on brain excitation and inhibition systems in adults with and without Autism Spectrum Disorder (ASD): a single dose trial during magnetic resonance spectroscopy.

Autism spectrum disorder (ASD) is a high cost neurodevelopmental condition; and there are currently no effective pharmacological treatments for its core symptoms. This has led some families and researchers to trial alternative remedies - including the non-intoxicating Cannabis sativa-derived compound cannabidivarin (CBDV). However, how CBDV affects the human brain is unknown. Previous (pre)clinical evidence suggests that CBDV may modulate brain excitatory-inhibitory systems, which are implicated in ASD. Hence, our main aim was to test, for the first time, if CBDV shifts glutamate and/or GABA metabolites - markers of the brain's primary excitatory and inhibitory system - in both the 'typical' and autistic brain. Our subsidiary aim was to determine whether, within ASD, brain responsivity to CBDV challenge is related to baseline biological phenotype. We tested this using a repeated-measures, double-blind, randomized-order, cross-over design. We used magnetic resonance spectroscopy (MRS) to compare glutamate (Glx = glutamate + glutamine) and GABA + (GABA + macromolecules) levels following placebo (baseline) and 600 mg CBDV in 34 healthy men with (n = 17) and without (n = 17) ASD. Data acquisition from regions previously reliably linked to ASD (dorsomedial prefrontal cortex, DMPFC; left basal ganglia, BG) commenced 2 h (peak plasma levels) after placebo/CBDV administration. Where CBDV significantly shifted metabolite levels, we examined the relationship of this change with baseline metabolite levels. Test sessions were at least 13 days apart to ensure CBDV wash-out. CBDV significantly increased Glx in the BG of both groups. However, this impact was not uniform across individuals. In the ASD group, and not in the typically developing controls, the 'shift' in Glx correlated negatively with baseline Glx concentration. In contrast, CBDV had no significant impact on Glx in the DMPFC, or on GABA+ in either voxel in either group. Our findings suggest that, as measured by MRS, CBDV modulates the glutamate-GABA system in the BG but not in frontal regions. Moreover, there is individual variation in response depending on baseline biochemistry. Future studies should examine the effect of CBDV on behaviour and if the response to an acute dose of CBDV could predict a potential clinical treatment response in ASD.

Intranasal Oxytocin Enhances Connectivity in the Neural Circuitry Supporting Social Motivation and Social Perception in Children with Autism.

Oxytocin (OT) has become a focus in investigations of autism spectrum disorder (ASD). The social deficits that characterize ASD may relate to reduced connectivity between brain sites on the mesolimbic reward pathway (nucleus accumbens; amygdala) that receive OT projections and contribute to social motivation, and cortical sites involved in social perception. Using functional magnetic resonance imaging and a randomized, double blind, placebo-controlled crossover design, we show that OT administration in ASD increases activity in brain regions important for perceiving social-emotional information. Further, OT enhances connectivity between nodes of the brain's reward and socioemotional processing systems, and does so preferentially for social (versus nonsocial) stimuli. This effect is observed both while viewing coherent versus scrambled biological motion, and while listening to happy versus angry voices. Our findings suggest a mechanism by which intranasal OT may bolster social motivation-one that could, in future, be harnessed to augment behavioral treatments for ASD.