GABA and glutamate response to social processing: a functional MRS feasibility study.

Several studies have suggested that atypical social processing in neurodevelopmental conditions (e.g. autism) is associated with differences in excitation and inhibition, through changes in the levels of glutamate and gamma-aminobutyric acid (GABA). While associations between baseline metabolite levels and behaviours can be insightful, assessing the neurometabolic response of GABA and glutamate during social processing may explain altered neurochemical function in more depth. Thus far, there have been no attempts to determine whether changes in metabolite levels are detectable using functional MRS (fMRS) during social processing in a control population. We performed Mescher-Garwood point resolved spectroscopy edited fMRS to measure the dynamic response of GABA and glutamate in the superior temporal sulcus (STS) and visual cortex (V1) while viewing social stimuli, using a design that allows for analysis in both block and event-related approaches. Sliding window analyses were used to investigate GABA and glutamate dynamics at higher temporal resolution. The changes of GABA and glutamate levels with social stimulus were largely non-significant. A small decrease in GABA levels was observed during social stimulus presentation in V1, but no change was observed in STS. Conversely, non-social stimulus elicited changes in both GABA and glutamate levels in both regions. Our findings suggest that the current experimental design primarily captures effects of visual stimulation, not social processing. Here, we discuss the feasibility of using fMRS analysis approaches to assess changes in metabolite response.

Perceptual alterations in the relationship between sensory reactivity, intolerance of uncertainty, and anxiety in autistic children with and without ADHD.

Sensory differences and anxiety disorders are highly prevalent in autistic individuals with and without ADHD. Studies have shown that sensory differences and anxiety are associated and that intolerance of uncertainty (IU) plays an important role in this relationship. However, it is unclear as to how different levels of the sensory processing pathway (i.e., perceptual, affective, or behavioral) contribute. Here, we used psychophysics to assess how alterations in tactile perception contribute to questionnaire measures of sensory reactivity, IU, and anxiety. Thirty-eight autistic children (aged 8-12 years; 27 with co-occurring ADHD) were included. Consistent with previous findings, mediation analyses showed that child-reported IU fully mediated an association between parent-reported sensory reactivity and parent-reported anxiety and that anxiety partially mediated an association between sensory reactivity and IU. Of the vibrotactile thresholds, only simultaneous frequency discrimination (SFD) thresholds correlated with sensory reactivity. Interestingly, we found that sensory reactivity fully mediated an association between SFD threshold and anxiety, and between SFD threshold and IU. Taken together, those findings suggest a mechanistic pathway whereby tactile perceptual alterations contribute to sensory reactivity at the affective level, leading in turn to increased IU and anxiety. This stepwise association can inform potential interventions for IU and anxiety in autism.

Examining the latent structure and correlates of sensory reactivity in autism: a multi-site integrative data analysis by the autism sensory research consortium.

BACKGROUND: Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these "supra-modal" traits in the autistic population. METHODS: Leveraging a combined sample of 3868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a "general response pattern" factor for each supra-modal construct and determine the added value of "modality-specific response pattern" scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO, and SEEK (sub)constructs. RESULTS: All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses supported the validity of a supra-modal HYPER construct (ωH = .800) but not a supra-modal HYPO construct (ωH = .653), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ωH = .800; 4/7 modalities). Modality-specific subscales demonstrated significant added value for all response patterns. Meta-analytic correlations varied by construct, although sensory features tended to correlate most with other domains of core autism features and co-occurring psychiatric symptoms (with general HYPER and speech HYPO demonstrating the largest numbers of practically significant correlations). LIMITATIONS: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to caregiver report of observable behaviors and excluded multisensory items that reflect many "real-world" sensory experiences. CONCLUSION: Of the three sensory response patterns, only HYPER demonstrated sufficient evidence for valid interpretation at the supra-modal level, whereas supra-modal HYPO/SEEK constructs demonstrated substantial psychometric limitations. For clinicians and researchers seeking to characterize sensory reactivity in autism, modality-specific response pattern scores may represent viable alternatives that overcome many of these limitations.

A working taxonomy for describing the sensory differences of autism.

BACKGROUND: Individuals on the autism spectrum have been long described to process sensory information differently than neurotypical individuals. While much effort has been leveraged towards characterizing and investigating the neurobiology underlying the sensory differences of autism, there has been a notable lack of consistency in the terms being used to describe the nature of those differences. MAIN BODY: We argue that inconsistent and interchangeable terminology-use when describing the sensory differences of autism has become problematic beyond mere pedantry and inconvenience. We begin by highlighting popular terms that are currently being used to describe the sensory differences of autism (e.g. "sensitivity", "reactivity" and "responsivity") and discuss why poor nomenclature may hamper efforts towards understanding the aetiology of sensory differences in autism. We then provide a solution to poor terminology-use by proposing a hierarchical taxonomy for describing and referring to various sensory features. CONCLUSION: Inconsistent terminology-use when describing the sensory features of autism has stifled discussion and scientific understanding of the sensory differences of autism. The hierarchical taxonomy proposed was developed to help resolve lack of clarity when discussing the sensory differences of autism and to place future research targets at appropriate levels of analysis.

Examining the Latent Structure and Correlates of Sensory Reactivity in Autism: A Multi-site Integrative Data Analysis by the Autism Sensory Research Consortium.

Background Differences in responding to sensory stimuli, including sensory hyperreactivity (HYPER), hyporeactivity (HYPO), and sensory seeking (SEEK) have been observed in autistic individuals across sensory modalities, but few studies have examined the structure of these "supra-modal" traits in the autistic population. Methods Leveraging a combined sample of 3,868 autistic youth drawn from 12 distinct data sources (ages 3-18 years and representing the full range of cognitive ability), the current study used modern psychometric and meta-analytic techniques to interrogate the latent structure and correlates of caregiver-reported HYPER, HYPO, and SEEK within and across sensory modalities. Bifactor statistical indices were used to both evaluate the strength of a "general response pattern" factor for each supra-modal construct and determine the added value of "modality-specific response pattern" scores (e.g., Visual HYPER). Bayesian random-effects integrative data analysis models were used to examine the clinical and demographic correlates of all interpretable HYPER, HYPO and SEEK (sub)constructs. Results All modality-specific HYPER subconstructs could be reliably and validly measured, whereas certain modality-specific HYPO and SEEK subconstructs were psychometrically inadequate when measured using existing items. Bifactor analyses unambiguously supported the validity of a supra-modal HYPER construct (ω H = .800), whereas a coherent supra-modal HYPO construct was not supported (ω H = .611), and supra-modal SEEK models suggested a more limited version of the construct that excluded some sensory modalities (ω H = .799; 4/7 modalities). Within each sensory construct, modality-specific subscales demonstrated substantial added value beyond the supra-modal score. Meta-analytic correlations varied by construct, although sensory features tended to correlate most strongly with other domains of core autism features and co-occurring psychiatric symptoms. Certain subconstructs within the HYPO and SEEK domains were also associated with lower adaptive behavior scores. Limitations: Conclusions may not be generalizable beyond the specific pool of items used in the current study, which was limited to parent-report of observable behaviors and excluded multisensory items that reflect many "real-world" sensory experiences. Conclusion Psychometric issues may limit the degree to which some measures of supra-modal HYPO/SEEK can be interpreted. Depending on the research question at hand, modality-specific response pattern scores may represent a valid alternative method of characterizing sensory reactivity in autism.

Functional MRS studies of GABA and glutamate/Glx - A systematic review and meta-analysis.

Functional magnetic resonance spectroscopy (fMRS) can be used to investigate neurometabolic responses to external stimuli in-vivo, but findings are inconsistent. We performed a systematic review and meta-analysis on fMRS studies of the primary neurotransmitters Glutamate (Glu), Glx (Glutamate + Glutamine), and GABA. Data were extracted, grouped by metabolite, stimulus domain, and brain region, and analysed by determining standardized effect sizes. The quality of individual studies was rated. When results were analysed by metabolite type small to moderate effect sizes of 0.29-0.47 (p < 0.05) were observed for changes in Glu and Glx regardless of stimulus domain and brain region, but no significant effects were observed for GABA. Further analysis suggests that Glu, Glx and GABA responses differ by stimulus domain or task and vary depending on the time course of stimulation and data acquisition. Here, we establish effect sizes and directionality of GABA, Glu and Glx response in fMRS. This work highlights the importance of standardised reporting and minimal best practice for fMRS research.

Could Sensory Differences Be a Sex-Indifferent Biomarker of Autism? Early Investigation Comparing Tactile Sensitivity Between Autistic Males and Females.

Sensory differences are highly prevalent in autistic individuals. However, few studies have compared their presentation between autistic males and autistic females. We used psychophysics to assess and compare tactile perceptual sensitivity between autistic and non-autistic boys and girls aged between 8 and 12 years of age. While there were sex-differences of amplitude discrimination, frequency discrimination and order judgement thresholds, these sex-differences were not autism-specific. Mean RTs and detection thresholds were elevated in autism but were comparable between the sexes. Tactile sensitivity measures that are elevated in autism but are otherwise comparable between autistic males and autistic females suggest the possibility that certain sensory features could be used as sex-indifferent markers of autism. Further investigation with larger and more representative samples should be conducted before any stronger conclusions are made.

The role of the primary motor cortex in motor imagery: A theta burst stimulation study.

While mentally simulated actions activate similar neural structures to overt movement, the role of the primary motor cortex (PMC) in motor imagery remains disputed. The aim of the study was to use continuous theta burst stimulation (cTBS) to modulate corticospinal activity to investigate the putative role of the PMC in implicit motor imagery in young adults with typical and atypical motor ability. A randomized, double blind, sham-controlled, crossover, offline cTBS protocol was applied to 35 young adults. During three separate sessions, adults with typical and low motor ability (developmental coordination disorder [DCD]), received active cTBS to the PMC and supplementary motor area (SMA), and sham stimulation to either the PMC or SMA. Following stimulation, participants completed measures of motor imagery (i.e., hand rotation task) and visual imagery (i.e., letter number rotation task). Although active cTBS significantly reduced corticospinal excitability in adults with typical motor ability, neither task performance was altered following active cTBS to the PMC or SMA, compared to performance after sham cTBS. These results did not differ across motor status (i.e., typical motor ability and DCD). These findings are not consistent with our hypothesis that the PMC (and SMA) is directly involved in motor imagery. Instead, previous motor cortical activation observed during motor imagery may be an epiphenomenon of other neurophysiological processes and/or activity within brain regions involved in motor imagery. This study highlights the need to consider multi-session theta burst stimulation application and its neural effects when probing the putative role of motor cortices in motor imagery.

Frequency and Intensity of Premonitory Urges-to-Tic in Tourette Syndrome Is Associated With Supplementary Motor Area GABA+ Levels.

BACKGROUND: Individuals with Tourette syndrome (TS) often report that they express tics as a means of alleviating the experience of unpleasant sensations. These sensations are perceived as an urge to act and are referred to as premonitory urges. Premonitory urges have been the focus of recent efforts to develop interventions to reduce tic expression in those with TS. OBJECTIVE: The aim of this study was to examine the contribution of brain γ-aminobutyric acid (GABA) and glutamate levels of the right primary sensorimotor cortex (SM1), supplementary motor area (SMA), and insular cortex (insula) to tic and urge severity in children with TS. METHODS: Edited magnetic resonance spectroscopy was used to assess GABA+ (GABA + macromolecules) and Glx (glutamate + glutamine) of the right SM1, SMA, and insula in 68 children with TS (MAge = 10.59, SDAge = 1.33) and 41 typically developing control subjects (MAge = 10.26, SDAge = 2.21). We first compared GABA+ and Glx levels of these brain regions between groups. We then explored the association between regional GABA+ and Glx levels with urge and tic severity. RESULTS: GABA+ and Glx of the right SM1, SMA, and insula were comparable between the children with TS and typically developing control subjects. In children with TS, lower levels of SMA GABA+ were associated with more severe and more frequent premonitory urges. Neither GABA+ nor Glx levels were associated with tic severity. CONCLUSIONS: These results broadly support the role of GABAergic neurotransmission within the SMA in the experience of premonitory urges in children with TS. © 2021 International Parkinson and Movement Disorder Society.

OSARI, an Open-Source Anticipated Response Inhibition Task.

The stop-signal paradigm has become ubiquitous in investigations of inhibitory control. Tasks inspired by the paradigm, referred to as stop-signal tasks, require participants to make responses on go trials and to inhibit those responses when presented with a stop-signal on stop trials. Currently, the most popular version of the stop-signal task is the 'choice-reaction' variant, where participants make choice responses, but must inhibit those responses when presented with a stop-signal. An alternative to the choice-reaction variant of the stop-signal task is the 'anticipated response inhibition' task. In anticipated response inhibition tasks, participants are required to make a planned response that coincides with a predictably timed event (such as lifting a finger from a computer key to stop a filling bar at a predefined target). Anticipated response inhibition tasks have some advantages over the more traditional choice-reaction stop-signal tasks and are becoming increasingly popular. However, currently, there are no openly available versions of the anticipated response inhibition task, limiting potential uptake. Here, we present an open-source, free, and ready-to-use version of the anticipated response inhibition task, which we refer to as the OSARI (the Open-Source Anticipated Response Inhibition) task.

Is there a relationship between EEG and sTMS neurophysiological markers of the putative human mirror neuron system?

The mirror neuron system (MNS) has been theorized to play a neurobiological role in a number of social cognitive abilities and is commonly indexed putatively in humans via interpersonal motor resonance (IMR) and mu suppression. Although both indices are thought to measure similar neuronal populations (i.e., "mirror neurons"), it has been suggested that these methods are unrelated, and therefore, incompatible. However, prior studies reporting no relationships were typically conducted in small and underpowered samples. Thus, we aimed to investigate this potential association in a large sample of neurotypical adults (N = 116; 72 females). Participants underwent transcranial magnetic stimulation (TMS), electromyography (EMG), and electroencephalography (EEG) during the observation of videos of actors performing grasping actions in order to index IMR and mu suppression (in beta, lower alpha, and upper alpha bandwidths). A series of linear regressions revealed no associations between IMR and each of the mu suppression bandwidths. Supplementary Bayesian analyses provided further evidence in favor of the null (B01  = 8.85-8.93), providing further support for no association between the two indices of MNS activity. Our findings suggest that these two measures may indeed be unrelated indices that perhaps assess different neurophysiological aspects of the MNS. These results have important implications for future studies examining the MNS.

Region-specific elevations of glutamate + glutamine correlate with the sensory symptoms of autism spectrum disorders.

Individuals on the autism spectrum are often reported as being hyper- and/or hyporeactive to sensory input. These sensory symptoms were one of the key observations that led to the development of the altered excitation-inhibition (E-I) model of autism, which posits that an increase ratio of excitatory to inhibitory signaling may explain certain phenotypical expressions of autism spectrum disorders (ASD). While there has been strong support for the altered E-I model of autism, much of the evidence has come from animal models. With regard to in-vivo human studies, evidence for altered E-I balance in ASD come from studies adopting magnetic resonance spectroscopy (MRS). Spectral-edited MRS can be used to provide measures of the levels of GABA + (GABA + macromolecules) and Glx (glutamate + glutamine) in specific brain regions as proxy markers of inhibition and excitation respectively. In the current study, we found region-specific elevations of Glx in the primary sensorimotor cortex (SM1) in ASD. There were no group differences of GABA+ in either the SM1 or thalamus. Higher levels of Glx were associated with more parent reported difficulties of sensory hyper- and hyporeactivity, as well as reduced feed-forward inhibition during tactile perception in children with ASD. Critically, the finding of elevated Glx provides strong empirical support for increased excitation in ASD. Our results also provide a clear link between Glx and the sensory symptoms of ASD at both behavioral and perceptual levels.

Mental rotation performance in young adults with and without developmental coordination disorder.

While there have been consistent behavioural reports of atypical hand rotation task (HRT) performance in adults with developmental coordination disorder (DCD), this study aimed to clarify whether this deficit could be attributed to specific difficulties in motor imagery (MI), as opposed to broad deficits in general mental rotation. Participants were 57 young adults aged 18-30 years with (n = 22) and without DCD (n = 35). Participants were compared on the HRT, a measure of MI, and the letter number rotation task (LNRT), a common visual imagery task. Only participants whose behavioural performance on the HRT suggested use of a MI strategy were included in group comparisons. Young adults with DCD were significantly less efficient compared to controls when completing the HRT yet showed comparable performance on the LNRT relative to adults with typical motor ability. Our data are consistent with the view that atypical HRT performance in adults with DCD is likely to be attributed to specific difficulties engaging in MI, as opposed to deficits in general mental rotation. Based on the theory that MI provides insight into the integrity of internal action representations, these findings offer further support for the internal modelling deficit hypothesis of DCD.

Disorder-specific alterations of tactile sensitivity in neurodevelopmental disorders.

Alterations of tactile processing have long been identified in autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). However, the extent to which these alterations are disorder-specific, rather than disorder-general, and how they relate to the core symptoms of each disorder, remains unclear. We measured and compared tactile detection, discrimination, and order judgment thresholds between a large sample of children with ASD, ADHD, ASD + ADHD combined and typically developing controls. The pattern of results suggested that while difficulties with tactile detection and order judgement were more common in children with ADHD, difficulties with tactile discrimination were more common in children with ASD. Interestingly, in our subsequent correlation analyses between tactile perception and disorder-specific clinical symptoms, tactile detection and order judgment correlated exclusively with the core symptoms of ADHD, while tactile discrimination correlated exclusively with the symptoms of ASD. When taken together, these results suggest that disorder-specific alterations of lower-level sensory processes exist and are specifically related to higher-level clinical symptoms of each disorder.

A review of decreased sound tolerance in autism: Definitions, phenomenology, and potential mechanisms.

Atypical behavioral responses to environmental sounds are common in autistic children and adults, with 50-70 % of this population exhibiting decreased sound tolerance (DST) at some point in their lives. This symptom is a source of significant distress and impairment across the lifespan, contributing to anxiety, challenging behaviors, reduced community participation, and school/workplace difficulties. However, relatively little is known about its phenomenology or neurocognitive underpinnings. The present article synthesizes a large body of literature on the phenomenology and pathophysiology of DST-related conditions to generate a comprehensive theoretical account of DST in autism. Notably, we argue against conceptualizing DST as a unified construct, suggesting that it be separated into three phenomenologically distinct conditions: hyperacusis (the perception of everyday sounds as excessively loud or painful), misophonia (an acquired aversive reaction to specific sounds), and phonophobia (a specific phobia of sound), each responsible for a portion of observed DST behaviors. We further elaborate our framework by proposing preliminary neurocognitive models of hyperacusis, misophonia, and phonophobia that incorporate neurophysiologic findings from studies of autism.

Response inhibition in humans: a whistle stop review.

This Neuro Forum presents insights from recent literature on the neurophysiology and pathoneurophysiology of reactive (speed of action stopping) and proactive (slowing of action in anticipation of stopping) response inhibition. We discuss recent studies using novel brain stimulation and spectroscopy techniques that reveal the role of cortico-subcortical networks and the neurotransmitter γ-aminobutyric acid (GABA) and how these mechanisms are influenced by healthy aging. Furthermore, we also briefly discuss computational modeling approaches, which assist in establishing meaningful differences in response inhibition.

Individual differences in intracortical inhibition predict motor-inhibitory performance.

Studies in which single- and paired-pulse TMS was applied during motor task performance have shed considerable light on the functional relevance of popular TMS-derived neurophysiological biomarkers such as short-interval intracortical inhibition (SICI) and long-interval intracortical inhibition (LICI). While it has become well established that corticospinal excitability and intracortical inhibition are modulated during the enactment and cancellation of actions, it has remained unclear as to whether interindividual differences in these neurophysiological markers were associated with an individual's actual ability to restrain and cancel actions. In this study, we found that individual differences in both SICI and LICI were positively associated with relevant performance metrics on the go/no-go task and stop-signal task. Specifically, we found that individuals with greater resting SICI and LICI were faster to respond on go trials of the go/no-go task and were also more accurate at inhibiting their manual responses on both go/no-go and stop-signal tasks. These results are in support of findings from our earlier study and also provide new evidence for a general relationship between individual differences in resting-state GABAergic intracortical inhibitory functioning and motor inhibition.

Motor imagery in children with DCD: A systematic and meta-analytic review of hand-rotation task performance.

This is the first review to quantitatively summarise evidence evaluating MI functioning in children with DCD compared to controls based on the hand rotation task (HRT). Specifically, MI performance was assessed using three different behavioural performance measures on the HRT (i.e., reaction time, accuracy and efficiency). Eight studies were included for quantitative analysis, yielding data for 176 and 198 children with and without DCD respectively. While children with DCD consistently used MI across all measures of the task, they continually demonstrated reductions in HRT performance relative to controls. Additionally, group differences appeared to be strongest and more commonly detected when using the IES (mean inverse efficiency-IES) metric on the HRT. These effects did not differ statistically as a function of instruction type. In support of the internal modelling deficit hypothesis, group effects suggested children with DCD demonstrate broad reductions in HRT performance relative to controls. However, consideration of effect size and study level analysis showed the ability for an individual study to detect these effects differs considerably depending on the outcome metric adopted.

Interhemispheric Cortical Inhibition Is Reduced in Young Adults With Developmental Coordination Disorder.

INTRODUCTION: While the etiology of developmental coordination disorder (DCD) is yet to be established, brain-behavior modeling provides a cogent argument that neuropathology may subserve the motor difficulties typical of DCD. We argue that a number of the core behavioral features of the DCD profile (such as poor surround inhibition, compromised motor inhibition, and the presence of mirror movements) are consistent with difficulties regulating inhibition within the primary motor cortex (M1). This study aimed to be the first account of the integrity of cortical inhibition in motor cortices in DCD. METHOD: The sample consisted of eight adults with DCD aged (18-30 years) and 10 aged matched neurotypical controls. Participants received a common battery of single and paired-pulse transcranial magnetic stimulation from which a series of neurophysiological measures classically used to measure intra- [e.g., short-interval cortical inhibition (SICI), long-interval cortical inhibition (LICI), and cortical silent period] and inter hemispheric [e.g., ipsilateral silent period (ISP)] cortical inhibition of the M1 at rest were recorded. RESULTS: While no group differences were observed for any measure of intrahemispheric cortical inhibition, individuals with DCD demonstrated significantly reduced interhemispheric cortical inhibition relative to controls, shown by consistently lower ISPratios. CONCLUSION: Our findings are consistent with the view that regulation of cortical inhibition of M1 activity may be atypical in individuals with DCD, indicating differential GABAergic operation. This effect, however, appears to be select to cortical inhibition. Importantly, our data support the notion that reduced interhemispheric M1 cortical inhibition may at least partly explain commonly reported difficulties with bimanual motor control in DCD. The neurochemical implications and limitations of this evidence will be discussed.