RESUMO
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.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Glutationa , Lobo Occipital , Humanos , Masculino , Feminino , Glutationa/metabolismo , Glutationa/análise , Adulto , Lobo Occipital/metabolismo , Lobo Occipital/diagnóstico por imagem , Transtorno do Espectro Autista/metabolismo , Transtorno Autístico/metabolismo , Adulto Jovem , Espectroscopia de Prótons por Ressonância Magnética , Lobo Frontal/metabolismo , Estresse Oxidativo , Pessoa de Meia-Idade , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/diagnóstico por imagemRESUMO
Importance: The use of evidence-based standardized outcome measures is increasingly recognized as key to guiding clinical decision-making in mental health. Implementation of these measures into clinical practice has been hampered by lack of clarity on what to measure and how to do this in a reliable and standardized way. Objective: To develop a core set of outcome measures for specific neurodevelopmental disorders (NDDs), such as attention-deficit/hyperactivity disorder (ADHD), communication disorders, specific learning disorders, and motor disorders, that may be used across a range of geographic and cultural settings. Evidence Review: An international working group composed of clinical and research experts and service users (n = 27) was convened to develop a standard core set of accessible, valid, and reliable outcome measures for children and adolescents with NDDs. The working group participated in 9 video conference calls and 8 surveys between March 1, 2021, and June 30, 2022. A modified Delphi approach defined the scope, outcomes, included measures, case-mix variables, and measurement time points. After development, the NDD set was distributed to professionals and service users for open review, feedback, and external validation. Findings: The final set recommends measuring 12 outcomes across 3 key domains: (1) core symptoms related to the diagnosis; (2) impact, functioning, and quality of life; and (3) common coexisting problems. The following 14 measures should be administered at least every 6 months to monitor these outcomes: ADHD Rating Scale 5, Vanderbilt ADHD Diagnostic Rating Scale, or Swanson, Nolan, and Pelham Rating Scale IV; Affective Reactivity Index; Children's Communication Checklist 2; Colorado Learning Disabilities Questionnaire; Children's Sleep Habits Questionnaire; Developmental-Disability Children's Global Assessment Scale; Developmental Coordination Disorder Questionnaire; Family Strain Index; Intelligibility in Context Scale; Vineland Adaptive Behavior Scale or Repetitive Behavior Scale-Revised and Social Responsiveness Scale; Revised Child Anxiety and Depression Scales; and Yale Global Tic Severity Scale. The external review survey was completed by 32 professionals and 40 service users. The NDD set items were endorsed by more than 70% of professionals and service users in the open review survey. Conclusions and Relevance: The NDD set covers outcomes of most concern to patients and caregivers. Use of the NDD set has the potential to improve clinical practice and research.
Assuntos
Consenso , Transtornos do Neurodesenvolvimento , Avaliação de Resultados em Cuidados de Saúde , Humanos , Transtornos do Neurodesenvolvimento/diagnóstico , Criança , Adolescente , Técnica Delphi , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , FemininoRESUMO
BACKGROUND: The underlying neurobiology of the complex autism phenotype remains obscure, although accumulating evidence implicates the serotonin system and especially the 5HT2A receptor. However, previous research has largely relied upon association or correlation studies to link differences in serotonin targets to autism. To directly establish that serotonergic signalling is involved in a candidate brain function our approach is to change it and observe a shift in that function. We will use psilocybin as a pharmacological probe of the serotonin system in vivo. We will directly test the hypothesis that serotonergic targets of psilocybin - principally, but not exclusively, 5HT2A receptor pathways-function differently in autistic and non-autistic adults. METHODS: The 'PSILAUT' "shiftability" study is a case-control study autistic and non-autistic adults. How neural responses 'shift' in response to low doses (2 mg and 5 mg) of psilocybin compared to placebo will be examined using multimodal techniques including functional MRI and EEG. Each participant will attend on up to three separate visits with drug or placebo administration in a double-blind and randomized order. RESULTS: This study will provide the first direct evidence that the serotonin targets of psilocybin function differently in the autistic and non-autistic brain. We will also examine individual differences in serotonin system function. CONCLUSIONS: This work will inform our understanding of the neurobiology of autism as well as decisions about future clinical trials of psilocybin and/or related compounds including stratification approaches. TRIAL REGISTRATION: NCT05651126.
Assuntos
Transtorno Autístico , Encéfalo , Imageamento por Ressonância Magnética , Psilocibina , Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Transtorno Autístico/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Estudos de Casos e Controles , Método Duplo-Cego , Eletroencefalografia , Alucinógenos/farmacologia , Alucinógenos/uso terapêutico , Psilocibina/uso terapêutico , Psilocibina/farmacologia , Receptor 5-HT2A de Serotonina/efeitos dos fármacos , Receptor 5-HT2A de Serotonina/metabolismo , Serotonina/metabolismo , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Alterations in γ-aminobutyric acid (GABA) have been implicated in sensory differences in individuals with autism spectrum disorder (ASD). Visual signals are initially processed in the retina, and in this study, we explored the hypotheses that the GABA-dependent retinal response to light is altered in individuals with ASD. Light-adapted electroretinograms were recorded from 61 adults (38 males and 23 females; n = 22 ASD) in response to three stimulus protocols: (1) the standard white flash, (2) the standard 30â Hz flickering protocol, and (3) the photopic negative response protocol. Participants were administered an oral dose of placebo, 15 or 30â mg of arbaclofen (STX209, GABAB agonist) in a randomized, double-blind, crossover order before the test. At baseline (placebo), the a-wave amplitudes in response to single white flashes were more prominent in ASD, relative to typically developed (TD) participants. Arbaclofen was associated with a decrease in the a-wave amplitude in ASD, but an increase in TD, eliminating the group difference observed at baseline. The extent of this arbaclofen-elicited shift significantly correlated with the arbaclofen-elicited shift in cortical responses to auditory stimuli as measured by using an electroencephalogram in our prior study and with broader autistic traits measured with the autism quotient across the whole cohort. Hence, GABA-dependent differences in retinal light processing in ASD appear to be an accessible component of a wider autistic difference in the central processing of sensory information, which may be upstream of more complex autistic phenotypes.
Assuntos
Transtorno do Espectro Autista , Masculino , Adulto , Feminino , Humanos , Transtorno do Espectro Autista/tratamento farmacológico , Retina , Eletroencefalografia , Ácido gama-Aminobutírico , EletrorretinografiaRESUMO
22q11.2 deletion syndrome (22q11DS) is the most frequently occurring microdeletion in humans. It is associated with a significant impact on brain structure, including prominent reductions in gray matter volume (GMV), and neuropsychiatric manifestations, including cognitive impairment and psychosis. It is unclear whether GMV alterations in 22q11DS occur according to distinct structural patterns. Then, 783 participants (470 with 22q11DS: 51% females, mean age [SD] 18.2 [9.2]; and 313 typically developing [TD] controls: 46% females, mean age 18.0 [8.6]) from 13 datasets were included in the present study. We segmented structural T1-weighted brain MRI scans and extracted GMV images, which were then utilized in a novel source-based morphometry (SBM) pipeline (SS-Detect) to generate structural brain patterns (SBPs) that capture co-varying GMV. We investigated the impact of the 22q11.2 deletion, deletion size, intelligence quotient, and psychosis on the SBPs. Seventeen GMV-SBPs were derived, which provided spatial patterns of GMV covariance associated with a quantitative metric (i.e., loading score) for analysis. Patterns of topographically widespread differences in GMV covariance, including the cerebellum, discriminated individuals with 22q11DS from healthy controls. The spatial extents of the SBPs that revealed disparities between individuals with 22q11DS and controls were consistent with the findings of the univariate voxel-based morphometry analysis. Larger deletion size was associated with significantly lower GMV in frontal and occipital SBPs; however, history of psychosis did not show a strong relationship with these covariance patterns. 22q11DS is associated with distinct structural abnormalities captured by topographical GMV covariance patterns that include the cerebellum. Findings indicate that structural anomalies in 22q11DS manifest in a nonrandom manner and in distinct covarying anatomical patterns, rather than a diffuse global process. These SBP abnormalities converge with previously reported cortical surface area abnormalities, suggesting disturbances of early neurodevelopment as the most likely underlying mechanism.
Assuntos
Síndrome de DiGeorge , Transtornos Psicóticos , Feminino , Humanos , Adolescente , Masculino , Síndrome de DiGeorge/diagnóstico por imagem , Imageamento por Ressonância Magnética , Encéfalo/diagnóstico por imagem , Transtornos Psicóticos/complicações , Substância Cinzenta/diagnóstico por imagemRESUMO
Clinical trials of pharmacological candidates targeting the core features of autism have largely failed. This is despite evidence linking differences in multiple neurochemical systems to brain function in autism. While this has in part been explained by the heterogeneity of the autistic population, the field has largely relied upon association studies to link brain chemistry to function. The only way to directly establish that a neurotransmitter or neuromodulator is involved in a candidate brain function is to change it and observe a shift in that function. This experimental approach dominates preclinical neuroscience, but not human studies. There is little direct experimental evidence describing how neurochemical systems modulate information processing in the living human brain. Thus, our understanding of how neurochemical differences contribute to neurodiversity is limited, impeding our ability to translate findings from animal studies into humans. Here, we introduce our 'shiftability' paradigm, an approach to bridge the translational gap in autism research. We provide an overview of the guiding principles and methodologies we use to directly test the hypothesis that neurochemical systems function differently in autistic and non-autistic individuals.