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Altered brain connectivity and atypical neural oscillations have been observed in autism, yet their relationship with autistic traits in non-clinical populations remains underexplored. Here, we employ electroencephalography (EEG) to examine functional connectivity, oscillatory power, and broadband aperiodic activity during a dynamic facial emotion processing (FEP) task in 101 typically developing children aged 4-12 years. We investigate associations between these electrophysiological measures of brain dynamics and autistic traits as assessed by the Social Responsiveness Scale, 2nd Edition (SRS-2). Our results revealed that increased FEP-related connectivity across theta (4-7 Hz) and beta (13-30 Hz) frequencies correlated positively with higher SRS-2 scores, predominantly in right-lateralized (theta) and bilateral (beta) cortical networks. Additionally, a steeper 1/ f -like aperiodic slope (spectral exponent) across fronto-central electrodes was associated with higher SRS-2 scores. Greater aperiodic-adjusted theta and alpha oscillatory power further correlated with both higher SRS-2 scores and steeper aperiodic slopes. These findings underscore important links between FEP-related brain dynamics and autistic traits in typically developing children. Future work could extend these findings to assess these EEG-derived markers as potential mechanisms underlying behavioural difficulties in autism., Competing Interests: Conflict of Interest Disclosure: The authors have no conflicts of interest to declare. This research was supported by an Australian Research Council Future Fellowship (PGE; FT160100077). LMO is supported by the NIMH Intramural Research Program (ZIAMH002955). The opinions expressed in this article are the authors’ own and do not reflect the views of the National Institutes of Health, the Department of Health and Human Services, or the United States government.

Sensory deficits are a feature of autism and schizophrenia, as well as the upper end of their non-clinical spectra. The mismatch negativity (MMN), an index of pre-attentive auditory processing, is particularly sensitive in detecting such deficits; however, little is known about the relationship between the visual MMN (vMMN) to facial emotions and autism and schizophrenia spectrum symptom domains. We probed the vMMN to happy, sad, and neutral faces in 61 healthy adults (18-40 years, 32 female), and evaluated their degree of autism and schizophrenia spectrum traits using the Autism Spectrum Quotient (AQ) and Schizotypal Personality Questionnaire (SPQ). The vMMN to happy faces was significantly larger than the vMMNs to sad and neutral faces. The vMMN to happy faces was associated with interpersonal difficulties as indexed by AQ Communication and Attention to Detail subscales, and SPQ associated with more interpersonal difficulties. These data suggest that pre-attentive processing of positive affect might be more specific to the interpersonal features associated with autism and schizophrenia. These findings add valuable insights into the growing body of literature investigating symptom-specific neurobiological markers of autism and schizophrenia spectrum conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Ford, Hugrass and Jack.)

Introduction: There are no well-established biomedical treatments for the core symptoms of autism spectrum disorder (ASD). A small number of studies suggest that repetitive transcranial magnetic stimulation (rTMS), a non-invasive brain stimulation technique, may improve clinical and cognitive outcomes in ASD. We describe here the protocol for a funded multicentre randomised controlled clinical trial to investigate whether a course of rTMS to the right temporoparietal junction (rTPJ), which has demonstrated abnormal brain activation in ASD, can improve social communication in adolescents and young adults with ASD., Methods and Analysis: This study will evaluate the safety and efficacy of a 4-week course of intermittent theta burst stimulation (iTBS, a variant of rTMS) in ASD. Participants meeting criteria for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition ASD (n=150, aged 14-40 years) will receive 20 sessions of either active iTBS (600 pulses) or sham iTBS (in which a sham coil mimics the sensation of iTBS, but no active stimulation is delivered) to the rTPJ. Participants will undergo a range of clinical, cognitive, epi/genetic, and neurophysiological assessments before and at multiple time points up to 6 months after iTBS. Safety will be assessed via a structured questionnaire and adverse event reporting. The study will be conducted from November 2020 to October 2024., Ethics and Dissemination: The study was approved by the Human Research Ethics Committee of Monash Health (Melbourne, Australia) under Australia's National Mutual Acceptance scheme. The trial will be conducted according to Good Clinical Practice, and findings will be written up for scholarly publication., Trial Registration Number: Australian New Zealand Clinical Trials Registry (ACTRN12620000890932)., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Atypical white matter (WM) microstructure is commonly implicated in the neuropathophysiology of autism spectrum disorder (ASD). Fixel based analysis (FBA), at the cutting-edge of diffusion-weighted imaging, can account for crossing WM fibers and can provide indices of both WM micro- and macrostructure. We applied FBA to investigate WM structure between 25 (12 males, 13 females) adults with ASD and 24 (12 males, 12 females) matched controls. As the role of biological sex on the neuropathophysiology of ASD is of increasing interest, this was also explored. There were no significant differences in WM micro- or macrostructure between adults with ASD and matched healthy controls. When data were stratified by sex, females with ASD had reduced fiber density and cross-section (FDC), a combined metric comprised of micro- and macrostructural measures, in the corpus callosum, a finding not detected between the male sub-groups. We conclude that micro- and macrostructural WM aberrations are present in ASD, and may be influenced by biological sex., (Copyright © 2020 Kirkovski, Fuelscher, Hyde, Donaldson, Ford, Rossell, Fitzgerald and Enticott.)

B vitamins are essential for optimal brain and body function, and are particularly important for cortical metabolic processes that have downstream effects on mitigating oxidative stress. Oxidative stress has been linked to poor psychological outcomes including psychological distress, which has wide-reaching implications for the community and the workplace. Given work-related stress has been associated with poor mental health outcomes, high-dose B vitamin supplementation may be effective in improving brain function and psychological outcomes via attenuation of oxidative stress. This randomized, double-blind, placebo-controlled study investigated psychological outcomes following 6-month supplementation of a high-B-vitamin multivitamin in a large sample of healthy adults ( n = 108, aged 30-70 years), as well as changes in default mode network functional connectivity in a subset of the original sample ( n = 28). Improvements in occupational stress, general health, perceived stress, depressive symptoms, and mood profiles were identified for both active and placebo groups over time ( p < 0.05 corrected ). Seed-based functional connectivity analysis centered on the posterior cingulate cortex (PCC) showed that connectivity between the PCC and the caudate increased for the active treatment group, but decreased for the placebo group ( p < 0.05 corrected ). These findings reveal a substantial intervention effect for both active and placebo treatments, which could in part be associated with a placebo effect in subjective measures. There was, however, a significant treatment effect in the objective measure of functional connectivity, suggesting that reduced psychological stress and high-B-vitamin multivitamin supplementation may lead to an increase in DMN and caudate functional connectivity, which might reflect a strengthening of neurocircuitry within areas associated with reward and emotion at rest. Future studies should consider a placebo run-in methodology to reduce the placebo effect on the subjective measures of stress., (Copyright © 2019 Downey, Simpson, Ford, McPhee, Suo, Myers, Oliver and Stough.)

A diet rich in B-group vitamins is essential for optimal body and brain function, and insufficient amounts of such vitamins have been associated with higher levels of neural inflammation and oxidative stress, as marked by increased blood plasma homocysteine. Neural biomarkers of oxidative stress quantified through proton magnetic spectroscopy (1H-MRS) are not well understood, and the relationship between such neural and blood biomarkers is seldom studied. The current study addresses this gap by investigating the direct effect of 6-month high-dose B-group vitamin supplementation on neural and blood biomarkers of metabolism. Using a randomized, double-blind, placebo-controlled design, 32 healthy adults (20 female, 12 male) aged 30⁻65 years underwent blood tests (vitamin B6, vitamin B12, folate, and homocysteine levels) and 1H-MRS of the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) before and after supplementation. Results confirmed the supplement was effective in increasing vitamin B6 and vitamin B12 levels and reducing homocysteine, whereas there was no change in folate levels. There were significant relationships between vitamin B6 and N -acetylaspartate (NAA), choline, and creatine, as well as between vitamin B12 and creatine ( p s < 0.05), whereas NAA in the PCC increased, albeit not significantly ( p > 0.05). Together these data provide preliminary evidence for the efficacy of high-dose B-group supplementation in reducing oxidative stress and inflammation through increasing oxidative metabolism. It may also promote myelination, cellular metabolism, and energy storage.

Background: The autism and schizophrenia spectra overlap to a large degree in the social and interpersonal domains. Similarly, abnormal excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) neurotransmitter concentrations have been reported for both spectra, with the interplay of these neurotransmitters important for cortical excitation to inhibition regulation. This study investigates whether these neurotransmitter abnormalities are specific to the shared symptomatology, and whether the degree of abnormality increases with increasing symptom severity. Hence, the relationship between the glutamate/GABA ratio and autism and schizophrenia spectrum traits in an unmedicated, subclinical population was investigated., Methods: A total of 37 adults (19 female, 18 male) aged 18-38 years completed the Autism Spectrum Quotient (AQ) and Schizotypal Personality Questionnaire (SPQ), and participated in the resting state proton magnetic resonance spectroscopy study in which sequences specific for quantification of glutamate and GABA+ concentration were applied to a right and left superior temporal voxel., Results: There were significant, moderate, positive relationships between right superior temporal glutamate/GABA+ ratio and AQ, SPQ and AQ+SPQ total scores (p<0.05), SPQ subscales Social Anxiety, No Close Friend, Constricted Affect, Odd Behaviour, Odd Speech, Ideas of Reference and Suspiciousness, and AQ subscales Social Skills, Communication and Attention Switching (p<0.05); increased glutamate/GABA+ coinciding with higher scores on these subscales. Only the relationships between glutamate/GABA+ ratio and Social Anxiety, Constricted Affect, Social Skills and Communication survived multiple comparison correction (p< 0.004). Left superior temporal glutamate/GABA+ ratio reduced with increasing restricted imagination (p<0.05)., Conclusion: These findings demonstrate evidence for an association between excitatory/inhibitory neurotransmitter concentrations and symptoms that are shared between the autism and schizophrenia spectra.

Autism and schizophrenia are multi-dimensional spectrum disorders that have substantial phenotypic overlap. This overlap is readily identified in the non-clinical population, and has been conceptualised as Social Disorganisation (SD). This study investigates the balance of excitatory glutamate and inhibitory γ -aminobutyric acid (GABA) concentrations in a non-clinical sample with high and low trait SD, as glutamate and GABA abnormalities are reported across the autism and schizophrenia spectrum disorders. Participants were 18 low (10 females) and 19 high (9 females) SD scorers aged 18 to 40 years who underwent 1 H-MRS for glutamate and GABA+macromolecule (GABA+) concentrations in right and left hemisphere superior temporal (ST) voxels. Reduced GABA+ concentration ( p  = 0.03) and increased glutamate/GABA+ ratio ( p  = 0.003) in the right ST voxel for the high SD group was found, and there was increased GABA+ concentration in the left compared to right ST voxel ( p  = 0.047). Bilateral glutamate concentration was increased for the high SD group ( p  = 0.006); there was no hemisphere by group interaction ( p  = 0.772). Results suggest that a higher expression of the SD phenotype may be associated with increased glutamate/GABA+ ratio in the right ST region, which may affect speech prosody processing, and lead behavioural characteristics that are shared within the autistic and schizotypal spectra.

Social Disorganisation (SD) is a shared autistic and schizotypal phenotype that is present in the subclinical population. Auditory processing deficits, particularly in mismatch negativity/field (MMN/F) have been reported across both spectrum disorders. This study investigates differences in MMN/F cortical spatio-temporal source activity between higher and lower quintiles of the SD spectrum. Sixteen low (9 female) and 19 high (9 female) SD subclinical adults (18-40years) underwent magnetoencephalography (MEG) during an MMF paradigm where standard tones (50ms) were interrupted by infrequent duration deviants (100ms). Spatio-temporal source cluster analysis with permutation testing revealed no difference between the groups in source activation to the standard tone. To the deviant tone however, there was significantly reduced right hemisphere fronto-temporal and insular cortex activation for the high SD group ( p = 0.038). The MMF, as a product of the cortical response to the deviant minus that to the standard, did not differ significantly between the high and low Social Disorganisation groups. These data demonstrate a deficit in right fronto-temporal processing of an auditory change for those with more of the shared SD phenotype, indicating that right fronto-temporal auditory processing may be associated with psychosocial functioning.

Neuroimaging studies of neuropsychiatric behavior biomarkers across spectrum disorders are typically based on diagnosis, thus failing to account for the heterogeneity of multi-dimensional spectrum disorders such as autism (ASD). Control group trait phenotypes are also seldom reported. Proton magnetic resonance spectroscopy ((1)H-MRS) measures the abundance of neurochemicals such as neurotransmitters and metabolites and hence can probe disorder phenotypes at clinical and sub-clinical levels. This detailed review summarizes and critiques the current (1)H-MRS research in ASD. The literature reports reduced N-acetylaspartate (NAA), glutamate and glutamine (Glx), γ-aminobutyric acid (GABA), creatine and choline, and increased glutamate for children with ASD. Adult studies are few and results are inconclusive. Overall, the literature has several limitations arising from differences in (1)H-MRS methodology and sample demographics. We argue that more consistent methods and greater emphasis on phenotype studies will advance understanding of underlying cortical metabolite disturbance in ASD, and the detection, diagnosis, and treatment of ASD and other multi-dimensional psychiatric disorders.

Behavioral and cognitive dysfunction, particularly social and communication impairments, are shared between autism and schizophrenia spectrum disorders, while evidence for a diametric autism-positive schizophrenia symptom profile is inconsistent. We investigated the shared phenotype at a personality trait level, particularly its resemblance to schizoid personality disorder, as well as differential aspects of the autism-schizophrenia model. Items of the autism spectrum quotient (AQ) and schizotypal personality questionnaire (SPQ) were pseudo-randomly combined, and were completed by 449 (162 male, 287 female) non-clinical participants aged 18-40. A factor analysis revealed three factors; the first represented a shared social disorganization phenotype, the second reflected perceptual oddities specific to schizotypy while the third reflected social rigidity specific to autism. The AQ and SPQ were strongly correlated with Factor 1 (AQ: r = 0.75, p < 0.001; SPQ: r = 0.96, p < 0.001), SPQ score was correlated with Factor 2 (r = 0.51, p < 0.001), particularly in cognitive-perceptual features (r = 0.66, p < 0.001), and AQ score was strongly correlated with Factor 3 (r = 0.76, p < 0.001). Furthermore, there was no relationship between Factor 1 and Factor 2. Thus, there is robust evidence for a shared social disorganization phenotype in autistic and schizotypal tendency, which reflects the schizoid phenotype. Discriminating and independent dimensions of schizotypal and autistic tendency exist in Factors 2 and 3, respectively. Current diagnostic protocols could result in different diagnoses depending on the instrument used, suggesting the need for neuromarkers that objectively differentiate autistic and schizotypal traits and resolve the question of commonality versus co-morbidity.

Objective: The purpose of this study was to investigate the effect of exercise occurrence and intensity on albumin excretion in normotensive, normoalbuminuric patients with type 1 diabetes., Research Design and Methods: Eighteen patients (aged 29 +/- 2 years, duration of diabetes 14 +/- 2 years, blood pressure 120 +/- 2/74 +/- 1 mmHg, HbA(1c) 7.0 +/- 0.2% [mean +/- SE]) without microalbuminuria, hypertension, or anti-angiotensin II therapy participated in two exercise studies in a clinical research center. Exercise intensities were defined as moderate (50% heart rate reserve [HRR]) and intense (75% HRR) and were performed in random order. Subjects collected urine for albumin determination on the days before and after exercise. On the day of exercise, subjects exercised for 30 min on a treadmill at the assigned intensity. Timed urine collections were obtained over the day. Blood pressures were measured using an ambulatory blood pressure monitor., Results: Moderate exercise demonstrated no changes in albumin excretion. Intense exercise demonstrated a significant increase in albumin excretion during the first 4 h compared with the rest of the day (P = 0.03) but returned to normal thereafter. Albumin excretion did not exceed normal levels throughout the study. There was no difference in albumin excretion surrounding days of intense exercise. Ambulatory blood pressures demonstrated nocturnal dipping after moderate and intense exercise (P < 0.001)., Conclusions: We have demonstrated that normotensive, normoalbuminuric patients without anti-angiotensin II therapy do not have elevated albumin excretion following exercise intensities experienced by most patients with type 1 diabetes.

The effect of ligand binding upon the buoyant density of DNA in Nycodenz gradients has been studied using DNAs of differing base compositions. The effect of both intercalating ligands (ethidium bromide and proflavin) and non-intercalating ligands (distamycin A, DAPI and netropsin) has been studied. The binding of intercalating ligands to DNA has essentially no effect on the buoyant density of DNA in Nycodenz gradients. The non-intercalating ligands were found to increase the buoyant density of DNA in a base specific manner. The increase in buoyant density can be interpreted in terms of disruption of the hydration shell of the DNA molecule caused by the binding of the ligand along the minor groove of the DNA helix.

Tissue from four mouse mammary carcinomas was enzymatically disaggregated and cells from the resulting cell suspension were fractionated on a discontinuous density gradient column (5-20%) of Nycodenz (Nycomed A.S. Oslo). The cell fractions separating at the 10-15% and 15-20% interfaces (density 1.082 and 1.110 g/ml respectively) contained a mean of 83.2 +/- 10.8 (s.d.) and 79.9 +/- 17.4 tumour cells. Compared with the original cell suspension these cell bands contained less cell aggregates and cell debris. The cells in the bands also showed an equivalent ability to grow in tissue culture and to form pulmonary tumours on i.v. injection into isogenic mice, when compared with the tumour cells in the original suspension. The relatively pure preparations of carcinoma cells thus separated may be of value in limiting the unwanted effect of normal cell contamination when testing neoplastic cells in vitro for sensitivity to drugs or hormones.