Dataset Information

Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder.

ABSTRACT: Currently, there are no effective pharmacologic treatments for the core symptoms of autism spectrum disorder (ASD). There is, nevertheless, potential for progress. For example, recent evidence suggests that the excitatory (E) glutamate and inhibitory (I) GABA systems may be altered in ASD. However, no prior studies of ASD have examined the 'responsivity' of the E-I system to pharmacologic challenge; or whether E-I modulation alters abnormalities in functional connectivity of brain regions implicated in the disorder. Therefore, we used magnetic resonance spectroscopy ([1H]MRS) to measure prefrontal E-I flux in response to the glutamate and GABA acting drug riluzole in adult men with and without ASD. We compared the change in prefrontal 'Inhibitory Index'-the GABA fraction within the pool of glutamate plus GABA metabolites-post riluzole challenge; and the impact of riluzole on differences in resting-state functional connectivity. Despite no baseline differences in E-I balance, there was a significant group difference in response to pharmacologic challenge. Riluzole increased the prefrontal cortex inhibitory index in ASD but decreased it in controls. There was also a significant group difference in prefrontal functional connectivity at baseline, which was abolished by riluzole within the ASD group. Our results also show, for we believe the first time in ASD, that E-I flux can be 'shifted' with a pharmacologic challenge, but that responsivity is significantly different from controls. Further, our initial evidence suggests that abnormalities in functional connectivity can be 'normalised' by targeting E-I, even in adults.

SUBMITTER: Ajram LA

PROVIDER: S-EPMC5534939 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder.

Ajram L A LA Horder J J Mendez M A MA Galanopoulos A A Brennan L P LP Wichers R H RH Robertson D M DM Murphy C M CM Zinkstok J J Ivin G G Heasman M M Meek D D Tricklebank M D MD Barker G J GJ Lythgoe D J DJ Edden R A E RAE Williams S C SC Murphy D G M DGM McAlonan G M GM

Translational psychiatry 20170523 5

Currently, there are no effective pharmacologic treatments for the core symptoms of autism spectrum disorder (ASD). There is, nevertheless, potential for progress. For example, recent evidence suggests that the excitatory (E) glutamate and inhibitory (I) GABA systems may be altered in ASD. However, no prior studies of ASD have examined the 'responsivity' of the E-I system to pharmacologic challenge; or whether E-I modulation alters abnormalities in functional connectivity of brain regions implic ...[more]

PMID: 28534874

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Project description:BackgroundIndividuals with autism spectrum disorder (ASD) often report difficulties with inhibition in everyday life. During inhibition tasks, adults with ASD show reduced activation of and connectivity between brain areas implicated in inhibition, suggesting impairments in inhibitory control at the neural level. Our study further investigated these differences by using magnetoencephalography (MEG) to examine the frequency band(s) in which functional connectivity underlying response inhibition occurs, as brain functions are frequency specific, and whether connectivity in certain frequency bands differs between adults with and without ASD.MethodsWe analysed MEG data from 40 adults with ASD (27 males; 26.94 ± 6.08 years old) and 39 control adults (27 males; 27.29 ± 5.94 years old) who performed a Go/No-go task. The task involved two blocks with different proportions of No-go trials: Inhibition (25% No-go) and Vigilance (75% No-go). We compared whole-brain connectivity in the two groups during correct No-go trials in the Inhibition vs. Vigilance blocks between 0 and 400 ms.ResultsDespite comparable performance on the Go/No-go task, adults with ASD showed reduced connectivity compared to controls in the alpha band (8-14 Hz) in a network with a main hub in the right inferior frontal gyrus. Decreased connectivity in this network predicted more self-reported difficulties on a measure of inhibition in everyday life.LimitationsMeasures of everyday inhibitory control were not available for all participants, so this relationship between reduced network connectivity and inhibitory control abilities may not be necessarily representative of all adults with ASD or the larger ASD population. Further research with independent samples of adults with ASD, including those with a wider range of cognitive abilities, would be valuable.ConclusionsOur findings demonstrate reduced functional brain connectivity during response inhibition in adults with ASD. As alpha-band synchrony has been linked to top-down control mechanisms, we propose that the lack of alpha synchrony observed in our ASD group may reflect difficulties in suppressing task-irrelevant information, interfering with inhibition in real-life situations.

Project description:BackgroundDisruptive behaviors are prevalent in children with autism spectrum disorder (ASD) and often cause substantial impairments. However, the underlying neural mechanisms of disruptive behaviors remain poorly understood in ASD. In children without ASD, disruptive behavior is associated with amygdala hyperactivity and reduced connectivity with the ventrolateral prefrontal cortex (vlPFC). This study examined amygdala reactivity and connectivity in children with ASD with and without co-occurring disruptive behavior disorders. We also investigated differential contributions of externalizing behaviors and callous-unemotional traits to variance in amygdala connectivity and reactivity.MethodsThis cross-sectional study involved behavioral assessments and neuroimaging in three groups of children 8 to 16 years of age: 18 children had ASD and disruptive behavior, 20 children had ASD without disruptive behavior, and 19 children were typically developing control participants matched for age, gender, and IQ. During functional magnetic resonance imaging, participants completed an emotion perception task of fearful versus calm faces. Task-specific changes in amygdala reactivity and connectivity were examined using whole-brain, psychophysiological interaction, and multiple regression analyses.ResultsChildren with ASD and disruptive behavior showed reduced amygdala-vlPFC connectivity compared with children with ASD without disruptive behavior. Externalizing behaviors and callous-unemotional traits were associated with amygdala reactivity to fearful faces in children with ASD after controlling for suppressor effects.ConclusionsReduced amygdala-vlPFC connectivity during fear processing may differentiate children with ASD and disruptive behavior from children with ASD without disruptive behavior. The presence of callous-unemotional traits may have implications for identifying differential patterns of amygdala activity associated with increased risk of aggression in ASD. These findings suggest a neural mechanism of emotion dysregulation associated with disruptive behavior in children with ASD.

Project description:Research on the biological basis of autism spectrum disorder has yielded a list of brain abnormalities that are arguably as diverse as the set of behavioral symptoms that characterize the disorder. Among these are patterns of abnormal cortical connectivity and abnormal basal ganglia development. In attempts to integrate the existing literature, the current paper tests the hypothesis that impairments in the basal ganglia's function to flexibly select and route task-relevant neural signals to the prefrontal cortex underpins patterns of abnormal synchronization between the prefrontal cortex and other cortical processing centers observed in individuals with autism spectrum disorder (ASD). We tested this hypothesis using a Dynamic Causal Modeling analysis of neuroimaging data collected from 16 individuals with ASD (mean age=25.3 years; 6 female) and 17 age- and IQ-matched neurotypical controls (mean age=25.6, 6 female), who performed a Go/No-Go test of executive functioning. Consistent with the hypothesis tested, a random-effects Bayesian model selection procedure determined that a model of network connectivity in which basal ganglia activation modulated connectivity between the prefrontal cortex and other key cortical processing centers best fit the data of both neurotypicals and individuals with ASD. Follow-up analyses suggested that the largest group differences were observed for modulation of connectivity between prefrontal cortex and the sensory input region in the occipital lobe [t(31)=2.03, p=0.025]. Specifically, basal ganglia activation was associated with a small decrease in synchronization between the occipital region and prefrontal cortical regions in controls; however, in individuals with ASD, basal ganglia activation resulted in increased synchronization between the occipital region and the prefrontal cortex. We propose that this increased synchronization may reflect a failure in basal ganglia signal gating mechanisms, resulting in a non-selective copying of signals to prefrontal cortex. Such a failure to prioritize and filter signals to the prefrontal cortex could result in the pervasive impairments in cognitive flexibility and executive functioning that characterize autism spectrum disorder, and may offer a mechanistic explanation of some of the observed abnormalities in patterns of cortical synchronization in ASD.

Dataset Information

Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder.

Publications

Shifting brain inhibitory balance and connectivity of the prefrontal cortex of adults with autism spectrum disorder.

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