The role of GABA-B in sensorigating processing disorders in rat models, an autoradiographic study

INTRODUCTION: The process of sensorimotor gating is a neurological phenomenon referring to the brain’s ability to process and filter out stimuli in order to prevent an overflow of information. This phenomenon can be operationally measured by prepulse inhibition, which is the attenuation of a stimulus-induced startle response by introducing a milder preceding stimulus. Studies have shown that impairment of prepulse inhibition (PPI) has been correlated with diseases such as schizophrenia and autism spectrum disorder. Many brain areas, including the superior colliculus (SC), inferior colliculus (IC), mediodorsal thalamus (MD), basolateral amygdala (BLA), anterior cingulate cortex (ACC), and ventral hippocampus (VHPC), have been implicated in playing important roles in prepulse inhibition. While many studies have implicated GABA-A receptors in playing a role in PPI regulation, little work has been done on GABA-B receptors. An established rat model with induced prepulse inhibition impairment was used in this study. PPI impairment was induced via injection of the glutamate receptor antagonist dizocilpine. A subgroup of rats was also treated with the antihistamine pyrilamine to reverse the effects of dizocilpine. OBJECTIVES: The aims of this study are to: 1. Expand the understanding of prepulse inhibition in the context of neurological and developmental diseases such as autism spectrum disorder (ASD) and schizophrenia; 2. Identify potential significant differences within GABA-B receptor densities in the rat SC, IC, MD, BLA, ACC, or VHPC between treatment groups with and without dizocilpine and groups with and without pyrilamine. METHODS: Histological brain slides harvested from 36 Sprague-Dawley rats were provided by Dr. Edward Levin from Duke University’s Neurobehavioral Research Lab for this study. The brain slides were incubated in a radioligand solution specific for GABA-B receptors and exposed to autoradiograph film for approximately 12 weeks. The films were developed in a dark room and scanned electronically. GABA-B receptor densities were measured from the images and the data was analyzed using ANOVA and independent T tests. RESULTS: ANOVA testing revealed significant differences between treatment groups in the MD and VHPC. However, only the MD was found to have significant GABA-B receptor differences when comparing the dizocilpine and pyrilamine treatment groups to the control group. The VHPC was found to have significant differences in GABA-B receptor densities when directly comparing the dizocilpine group to the pyrilamine treatment group, rather than to the control group. There were no significant differences in GABA-B receptor densities as a result of either dizocilpine or pyrilamine treatment in the SC, IC, BLA, ACC, or VHPC. CONCLUSION: Changes in GABA-B receptor levels appear to play a role in both the impairment and rescue of PPI in the rat MD. It does not appear to play a role in the SC, IC, BLA, ACC, or VHPC for either the impairment or rescue of PPI function

Comparative Multimodal Meta-analysis of Structural and Functional Brain Abnormalities in Autism Spectrum Disorder and Obsessive-Compulsive Disorder

BACKGROUND: Autism spectrum disorder (ASD) and obsessive-compulsive disorder (OCD) share inhibitory control deficits possibly underlying poor control over stereotyped and repetitive and compulsive behaviors, respectively. However, it is unclear whether these symptom profiles are mediated by common or distinct neural profiles. This comparative multimodal meta-analysis assessed shared and disorder-specific neuroanatomy and neurofunction of inhibitory functions. METHODS: A comparative meta-analysis of 62 voxel-based morphometry and 26 functional magnetic resonance imaging (fMRI) studies of inhibitory control was conducted comparing gray matter volume and activation abnormalities between patients with ASD (structural MRI: 911; fMRI: 188) and OCD (structural MRI: 928; fMRI: 247) and control subjects. Multimodal meta-analysis compared groups across voxel-based morphometry and fMRI. RESULTS: Both disorders shared reduced function and structure in the rostral and dorsomedial prefrontal cortex including the anterior cingulate. OCD patients had a disorder-specific increase in structure and function of left basal ganglia (BG) and insula relative to control subjects and ASD patients, who had reduced right BG and insula volumes versus OCD patients. In fMRI, ASD patients showed disorder-specific reduced left dorsolateral-prefrontal activation and reduced posterior cingulate deactivation, whereas OCD patients showed temporoparietal underactivation. CONCLUSIONS: The multimodal comparative meta-analysis shows shared and disorder-specific abnormalities. Whereas the rostrodorsomedial prefrontal cortex was smaller in structure and function in both disorders, this was concomitant with increased structure and function in BG and insula in OCD patients, but a reduction in ASD patients, presumably reflecting a disorder-specific frontostriatoinsular dysregulation in OCD in the form of poor frontal control over overactive BG, and a frontostriatoinsular maldevelopment in ASD with reduced structure and function in this network. Disorder-differential mechanisms appear to drive overlapping phenotypes of inhibitory control abnormalities in patients with ASD and OCD

Elevated glutamatergic compounds in pregenual anterior cingulate in pediatric autism spectrum disorder demonstrated by 1H MRS and 1H MRSI.

Recent research in autism spectrum disorder (ASD) has aroused interest in anterior cingulate cortex and in the neurometabolite glutamate. We report two studies of pregenual anterior cingulate cortex (pACC) in pediatric ASD. First, we acquired in vivo single-voxel proton magnetic resonance spectroscopy ((1)H MRS) in 8 children with ASD and 10 typically developing controls who were well matched for age, but with fewer males and higher IQ. In the ASD group in midline pACC, we found mean 17.7% elevation of glutamate + glutamine (Glx) (p<0.05) and 21.2% (p<0.001) decrement in creatine + phosphocreatine (Cr). We then performed a larger (26 subjects with ASD, 16 controls) follow-up study in samples now matched for age, gender, and IQ using proton magnetic resonance spectroscopic imaging ((1)H MRSI). Higher spatial resolution enabled bilateral pACC acquisition. Significant effects were restricted to right pACC where Glx (9.5%, p<0.05), Cr (6.7%, p<0.05), and N-acetyl-aspartate + N-acetyl-aspartyl-glutamate (10.2%, p<0.01) in the ASD sample were elevated above control. These two independent studies suggest hyperglutamatergia and other neurometabolic abnormalities in pACC in ASD, with possible right-lateralization. The hyperglutamatergic state may reflect an imbalance of excitation over inhibition in the brain as proposed in recent neurodevelopmental models of ASD

Brain networks underlying inhibition in Traumatic Brain Injury and in Autism Spectrum Disorders

Autism Spectrum Disorder (ASD) and Traumatic Brain Injury (TBI) are clinical populations with social cognition difficulties, exhibited by deficits in controlling impulsive or perseverative behaviors. These difficulties have been attributed to executive functioning (EF) impairments, particularly for inhibition. Thus, understanding the neural bases of inhibition is preliminary to understanding EF impairments in populations like ASD and TBI. A coordinate-based meta-analysis of functional magnetic resonance imaging (fMRI) studies was used to identify the neural basis of response inhibition in neurotypical adults to compare with TBI and ASD. Inclusion criteria for studies required reported foci for adults (17+ years of age), reported on normal mapping, and used inhibition experiential tasks that revealed activations results. Five ASD and seven TBI studies met inclusion criteria, pooling fMRI data from 1431 neurotypical subjects, 145 TBI and 71 ASD subjects engaged in inhibition tasks, yielding 98 experiments in controls and 15 experiments (9 TBI) for contrast analyses. Brain regions found to be uniquely active in the ASD or TBI and in the Control groups were further analyzed using meta-analytic connectivity modeling (MACM) to determine whether differences in these regions were functionally relevant and associated with differing behavioral patterns. The MACM analyses included 480 neurotypical experiments (6820 subjects, 7008 foci) reporting activity in the left medial frontal gyrus region of interest and 809 experiments (11568 subjects, 11855 foci) reporting activity in the right medial frontal gyrus region of interest. Results provide evidence that the brain region involved to the greatest extent for response inhibition, the medial frontal cortex, is active in individuals with TBI, with ASD and Controls. However, the groups had differences in the peaks of activity in this region. Though subtle, these differences may indicate these clinical populations are relying more on top-down, higher-level cognitive processing to accomplish response inhibition than do neurotypical controls. Results support a hypothesis that those with ASD or TBI are engaging a smaller network of brain regions, with a higher proportion of activity in the frontal lobes, and therefore less efficient than that seen in the Controls. Given the heterogeneity of TBI and ASD demographics and the variability of inhibition tasks used, these findings are speculative and require further study. This study provides support of concept for further research on functional imaging, attention, and inhibition

Decline and fall:a biological, developmental, and psycholinguistic account of deliberative language processes and ageing

Background: This paper reviews the role of deliberative processes in language: those language processes that require central resources, in contrast to the automatic processes of lexicalisation, word retrieval, and parsing. 10 Aims: We describe types of deliberative processing, and show how these processes underpin high-level processes that feature strongly in language. We focus on metalin- guistic processing, strategic processing, inhibition, and planning. We relate them to frontal-lobe function and the development of the fronto-striate loop. We then focus on the role of deliberative processes in normal and pathological development and ageing, 15 and show how these processes are particularly susceptible to deterioration with age. In particular, many of the commonly observed language impairments encountered in ageing result from a decline in deliberative processing skills rather than in automatic language processes. Main Contribution: We argue that central processing plays a larger and more important 20 role in language processing and acquisition than is often credited. Conclusions: Deliberative language processes permeate language use across the lifespan. They are particularly prone to age-related loss. We conclude by discussing implications for therapy

Change detection in children with autism: an auditory event-related fMRI study

Autism involves impairments in communication and social interaction, as well as high levels of repetitive, stereotypic and ritualistic behaviours, and extreme resistance to change. This latter dimension, whilst required for a diagnosis, has received less research attention. We hypothesise that this extreme resistance to change in autism is rooted in atypical processing of unexpected stimuli. We tested this using auditory event-related fMRI to determine regional brain activity associated with passive detection of infrequently occurring frequency-deviant and complex novel sounds in a no-task condition. Participants were twelve 10 to 15-year-old children with autism, and a group of 12 age- and sex-matched healthy controls

Disorder-specific functional abnormalities during sustained attention in youth with Attention Deficit Hyperactivity Disorder (ADHD) and with Autism

Attention Deficit Hyperactivity Disorder (ADHD) and Autism Spectrum Disorder (ASD) are often comorbid and share behavioural-cognitive abnormalities in sustained attention. A key question is whether this shared cognitive phenotype is based on common or different underlying pathophysiologies. To elucidate this question, we compared 20 boys with ADHD to 20 age and IQ matched ASD and 20 healthy boys using functional magnetic resonance imaging (fMRI) during a parametrically modulated vigilance task with a progressively increasing load of sustained attention. ADHD and ASD boys had significantly reduced activation relative to controls in bilateral striato–thalamic regions, left dorsolateral prefrontal cortex (DLPFC) and superior parietal cortex. Both groups also displayed significantly increased precuneus activation relative to controls. Precuneus was negatively correlated with the DLPFC activation, and progressively more deactivated with increasing attention load in controls, but not patients, suggesting problems with deactivation of a task-related default mode network in both disorders. However, left DLPFC underactivation was significantly more pronounced in ADHD relative to ASD boys, which furthermore was associated with sustained performance measures that were only impaired in ADHD patients. ASD boys, on the other hand, had disorder-specific enhanced cerebellar activation relative to both ADHD and control boys, presumably reflecting compensation. The findings show that ADHD and ASD boys have both shared and disorder-specific abnormalities in brain function during sustained attention. Shared deficits were in fronto–striato–parietal activation and default mode suppression. Differences were a more severe DLPFC dysfunction in ADHD and a disorder-specific fronto–striato–cerebellar dysregulation in ASD

Magnetoencephalography as a tool in psychiatric research: current status and perspective

The application of neuroimaging to provide mechanistic insights into circuit dysfunctions in major psychiatric conditions and the development of biomarkers are core challenges in current psychiatric research. In this review, we propose that recent technological and analytic advances in Magnetoencephalography (MEG), a technique which allows the measurement of neuronal events directly and non-invasively with millisecond resolution, provides novel opportunities to address these fundamental questions. Because of its potential in delineating normal and abnormal brain dynamics, we propose that MEG provides a crucial tool to advance our understanding of pathophysiological mechanisms of major neuropsychiatric conditions, such as Schizophrenia, Autism Spectrum Disorders, and the dementias. In our paper, we summarize the mechanisms underlying the generation of MEG signals and the tools available to reconstruct generators and underlying networks using advanced source-reconstruction techniques. We then survey recent studies that have utilized MEG to examine aberrant rhythmic activity in neuropsychiatric disorders. This is followed by links with preclinical research, which have highlighted possible neurobiological mechanisms, such as disturbances in excitation/inhibition parameters, which could account for measured changes in neural oscillations. In the final section of the paper, challenges as well as novel methodological developments are discussed which could pave the way for a widespread application of MEG in translational research with the aim of developing biomarkers for early detection and diagnosis