Retinal GABAergic Alterations in Adults with Autism Spectrum Disorder.

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 30 Hz flickering protocol, and (3) the photopic negative response protocol. Participants were administered an oral dose of placebo, 15 or 30 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.

Exploratory evidence for differences in GABAergic regulation of auditory processing in autism spectrum disorder.

Altered reactivity and responses to auditory input are core to the diagnosis of autism spectrum disorder (ASD). Preclinical models implicate ϒ-aminobutyric acid (GABA) in this process. However, the link between GABA and auditory processing in humans (with or without ASD) is largely correlational. As part of a study of potential biosignatures of GABA function in ASD to inform future clinical trials, we evaluated the role of GABA in auditory repetition suppression in 66 adults (n = 28 with ASD). Neurophysiological responses (temporal and frequency domains) to repetitive standard tones and novel deviants presented in an oddball paradigm were compared after double-blind, randomized administration of placebo, 15 or 30 mg of arbaclofen (STX209), a GABA type B (GABAB) receptor agonist. We first established that temporal mismatch negativity was comparable between participants with ASD and those with typical development (TD). Next, we showed that temporal and spectral responses to repetitive standards were suppressed relative to responses to deviants in the two groups, but suppression was significantly weaker in individuals with ASD at baseline. Arbaclofen reversed weaker suppression of spectral responses in ASD but disrupted suppression in TD. A post hoc analysis showed that arbaclofen-elicited shift in suppression was correlated with autistic symptomatology measured using the Autism Quotient across the entire group, though not in the smaller sample of the ASD and TD group when examined separately. Thus, our results confirm: GABAergic dysfunction contributes to the neurophysiology of auditory sensory processing alterations in ASD, and can be modulated by targeting GABAB activity. These GABA-dependent sensory differences may be upstream of more complex autistic phenotypes.

Differences in social brain function in autism spectrum disorder are linked to the serotonin transporter: A randomised placebo-controlled single-dose crossover trial.

BACKGROUND: Alterations in the serotonergic control of brain pathways responsible for facial emotion processing in people with autism spectrum disorder (ASD) may be a target for intervention. However, the molecular underpinnings of autistic-neurotypical serotonergic differences are challenging to access in vivo. Receptor-Enriched Analysis of functional Connectivity by Targets (REACT) has helped define molecular-enriched functional magnetic resonance imaging (fMRI) brain networks based on a priori information about the spatial distribution of neurochemical systems from available PET templates. METHODS: We used REACT to estimate the dominant fMRI signal related to the serotonin (5-HT) transporter (SERT) distribution during processing of aversive facial emotion in adults with and without ASD. We first predicted a group difference in baseline (placebo) functioning of this system. We next used a single 20 mg oral dose of citalopram, a serotonin reuptake inhibitor, to test the hypothesis that network activity in people with and without ASD would respond differently to inhibition of SERT. To confirm the specificity of our findings, we also repeated the analysis with 5-HT1A, 5-HT1B, 5-HT2A and 5-HT4 receptor maps. RESULTS: Using REACT with the SERT map, we found a baseline group difference in the SERT-enriched response to faces in the ventromedial prefrontal cortex. A single oral dose of citalopram 'shifted' the response in the ASD group towards the neurotypical baseline but did not alter response in the control group. Similar differences in SERT-enriched response were observed after controlling for other 5-HT maps. CONCLUSIONS: Our findings suggest that the SERT-enriched functional network is dynamically different in ASD during processing of socially relevant stimuli. Whether this acute neurobiological response to citalopram in ASD translates to a clinical target will be an important next step.

Impact of physiological factors on longitudinal structural MRI measures of the brain.

Longitudinal MRI is used in clinical research studies to examine illness progression, neurodevelopment, and the effect of medical interventions. Such studies typically report changes in brain volume of less than 5%. However, there is a concern that these findings could be obscured or confounded by small changes in brain volume estimates caused by physiological factors such as, dehydration, blood pressure, caffeine levels, and circadian rhythm. In this study, MRI scans using the ADNI-III protocol were acquired from 20 participants (11 female) at two time points (mean interval = 20.3 days). Hydration, systolic and diastolic blood pressure, caffeine intake, and time of day were recorded at both visits. Images were processed using FreeSurfer. Three a priori hypothesised brain regions (hippocampus, lateral ventricles, and total brain) were selected, and an exploratory analysis was conducted on FreeSurfer's auto-segmented brain regions. There was no significant effect of the physiological factors on changes in the hypothesised brain regions. We provide estimates for the maximum percentage change in regional brain volumes that could be expected to occur from normal variation in each of the physiological measures. In this study, normal variations in physiological parameters did not have a detectable effect on longitudinal changes in brain volume.

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.

Reliability of structural MRI measurements: The effects of scan session, head tilt, inter-scan interval, acquisition sequence, FreeSurfer version and processing stream.

BACKGROUND: Large-scale longitudinal and multi-centre studies are used to explore neuroimaging markers of normal ageing, and neurodegenerative and mental health disorders. Longitudinal changes in brain structure are typically small, therefore the reliability of automated techniques is crucial. Determining the effects of different factors on reliability allows investigators to control those adversely affecting reliability, calculate statistical power, or even avoid particular brain measures with low reliability. This study examined the impact of several image acquisition and processing factors and documented the test-retest reliability of structural MRI measurements. METHODS: In Phase I, 20 healthy adults (11 females; aged 20-30 years) were scanned on two occasions three weeks apart on the same scanner using the ADNI-3 protocol. On each occasion, individuals were scanned twice (repetition), after re-entering the scanner (reposition) and after tilting their head forward. At one year follow-up, nine returning individuals and 11 new volunteers were recruited for Phase II (11 females; aged 22-31 years). Scans were acquired on two different scanners using the ADNI-2 and ADNI-3 protocols. Structural images were processed using FreeSurfer (v5.3.0, 6.0.0 and 7.1.0) to provide subcortical and cortical volume, cortical surface area and thickness measurements. Intra-class correlation coefficients (ICC) were calculated to estimate test-retest reliability. We examined the effect of repetition, reposition, head tilt, time between scans, MRI sequence and scanner on reliability of structural brain measurements. Mean percentage differences were also calculated in supplementary analyses. RESULTS: Using the FreeSurfer v7.1.0 longitudinal pipeline, we observed high reliability for subcortical and cortical volumes, and cortical surface areas at repetition, reposition, three weeks and one year (mean ICCs>0.97). Cortical thickness reliability was lower (mean ICCs>0.82). Head tilt had the greatest adverse impact on ICC estimates, for example reducing mean right cortical thickness to ICC=0.74. In contrast, changes in ADNI sequence or MRI scanner had a minimal effect. We observed an increase in reliability for updated FreeSurfer versions, with the longitudinal pipeline consistently having a higher reliability than the cross-sectional pipeline. DISCUSSION: Longitudinal studies should monitor or control head tilt to maximise reliability. We provided the ICC estimates and mean percentage differences for all FreeSurfer brain regions, which may inform power analyses for clinical studies and have implications for the design of future longitudinal studies.