Evidence for Cortical Dysfunction in Autism: A Proton Magnetic Resonance Spectroscopic Imaging Study

Department of Medical Biophysics, The University of Western Ontario, London, Ontario, Canada.
Biological Psychiatry (Impact Factor: 10.26). 03/2007; 61(4):465-73. DOI: 10.1016/j.biopsych.2006.07.022
Source: PubMed


Although brain imaging studies have reported neurobiological abnormalities in autism, the nature and distribution of the underlying neurochemical irregularities are unknown. The purpose of this study was to examine cerebral gray and white matter cellular neurochemistry in autism with proton magnetic resonance spectroscopic imaging (MRSI).
Proton MRSI examinations were conducted in 26 males with autism (age 9.8 +/- 3.2 years) and 29 male comparison subjects (age 11.1 +/- 2.4 years). Estimates of cerebral gray and white matter concentrations of N-acetylaspartate (NAA), creatine + phosphocreatine, choline-containing compounds, myo-inositol, and glutamate + glutamine (Glx) were made by linear regression analysis of multi-slice MRSI data and compared between groups. Regional estimates of metabolite concentration were also made with multivariate linear regression, allowing for comparisons of frontal, temporal, and occipital gray matter, cerebral white matter, and the cerebellum.
Patients with autism exhibited significantly lower levels of gray matter NAA and Glx than control subjects. Deficits were widespread, affecting most cerebral lobes and the cerebellum. No significant differences were detected in cerebral white matter or cerebellar metabolite levels.
These results suggest widespread reductions in gray matter neuronal integrity and dysfunction of cortical and cerebellar glutamatergic neurons in patients with autism.

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    • "glutamate + glutamine, (Glx) ), standard 1 H-MRS studies can also reveal concentrations of other important molecules, including n-acetyl-aspartate (NAA), creatine (Cr), myoinositol (mI), and choline (Cho). Studies in persons with autism generally have revealed lower NAA concentration [DeVito et al., 2007; Hardan et al., 2008; Hashimoto et al., 1997; Otsuka, Harada, Mori, Hisaoka, & Nishitani, 1999]. NAA levels are usually interpreted as a marker of neuronal density and/or mitochondrial function [Clark, 1998], which might suggest decreased neuronal density in ASD, altered mitochondrial function, or both. "
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    ABSTRACT: Background: Gamma band oscillatory activity, as measured using EEG and magnetoencephalography (MEG), has been associated with intrinsic GABA in animal models and in combined MR spectroscopy and MEG studies. We have previously published data demonstrating that auditory gamma-band responses are reduced in people with autism and their first-degree relatives, suggesting the utility of some of the findings as endophenotypes. Independently, prior work has suggested elevation of reduction of GABA in persons with autism. The relationship between GABA concentration and auditory gamma-band activity has not yet been studied in autism. Objectives: To assess the relationship between auditory GABA concentration and auditory gamma-band power in individuals with autism, unaffected siblings of persons with autism, and in control subjects. Methods: We examined auditory transient and steady-state gamma-band responsesand auditory cortical GABA concentration in 3 groups of children and adolescents: a) healthy controls (N=25), b) people with autism spectrum disorders (N=24) and c) unaffected siblings (N=19) of older children with ASD. Auditory response data were acquired using a 248-channel magnetoencephalography (MEG) system, and glutamate concentrations were obtained from proton magnetic resonance spectroscopy (1H-MRS) using a MEGA-PRESS sequence on a 3T MRI system. All measures were restricted to the left hemisphere due to time constraints of the spectroscopy sequence. Results: Transient gamma-band power was significantly higher in the control group compared to individuals with autism (p < .01) and the sibling group (p < .05). Auditory steady-state gamma-band power was also higher in controls than in the autism and sibling groups. GABA concentration was significantly lower in the autism (p < .05) and sibling groups (p < .05) compared with controls. GABA concentration was correlated with transient gamma-band power in the control group (r = .45, p < .002). In the autism group, the association between GABA and gamma-band power approached significance, r = .35, p = .08. The sibling group also exhibited a significant association between GABA concentration and gamma-band power, r = .51, p = .02. No correlations with steady-state response power and GABA were observed. Conclusions: This study suggests that reduced GABA concentration might be related to reductions in stimulus related gamma-band power that have frequently been reported in autism. The fact that only the obligatory transient auditory gamma response was associated with GABA levels implicates different mechanisms of generation for the transient and steady-state responses, consistent with earlier literature suggesting that the steady-state responses reflect superimposition of mid-latency auditory evoked responses. GABA concentration and gamma-band power may both be related endophenotypes in autism that are related to an underlying change inhibitory function.
    Full-text · Conference Paper · May 2014
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    • " only in signal transduction , but also brain maturation and cortical or - ganization , especially neuronal migration and positioning , which is of high relevance for neurodevelopmental disor - ders . Accordingly , GABA and glutamate have been found to be involved in the pathophysiology of neurodevelopmental disorder , particularly ASD ( e . g . , DeVito et al . , 2007 ; Ecker et al . , 2013 ; Pardo & Eberhart , 2007 ) . CSF is more likely than blood to contain potential mark - ers of disorders in the central nervous system because the chemical properties of CSF more closely reflect the bio - chemistry of the brain . CSF markers have the potential to act as diagnostics tools but can also function as p"
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    ABSTRACT: Neurodevelopmental disorders affect a substantial minority of the general population. Their origins are still largely unknown, but a complex interplay of genetic and environmental factors causing disturbances of the central nervous system's maturation and a variety of higher cognitive skills is presumed. Only limited research of rather small sample size and narrow scope has been conducted in neurodevelopmental disorders using a twin-differences design. The Roots of Autism and ADHD Twin Study in Sweden (RATSS) is an ongoing project targeting monozygotic twins discordant for categorical or dimensional autistic and inattentive/hyperactive-impulsive phenotypes as well as other neurodevelopmental disorders, and typically developing twin controls. Included pairs are 9 years of age or older, and comprehensively assessed for psychopathology, medical history, neuropsychology, and dysmorphology, as well as structural, functional, and molecular brain imaging. Specimens are collected for induced pluripotent (iPS) and neuroepithelial stem cells, genetic, gut bacteria, protein-/monoamine, and electron microscopy analyses. RATSS's objective is to generate a launch pad for novel surveys to understand the complexity of genotype-environment-phenotype interactions in autism spectrum disorder and attention-deficit hyperactivity disorder (ADHD). By October 2013, RATSS had collected data from 55 twin pairs, among them 10 monozygotic pairs discordant for autism spectrum disorder, seven for ADHD, and four for other neurodevelopmental disorders. This article describes the design, recruitment, data collection, measures, collected pairs' characteristics, as well as ongoing and planned analyses in RATSS. Potential gains of the study comprise the identification of environmentally mediated biomarkers, the emergence of candidates for drug development, translational modeling, and new leads for prevention of incapacitating outcomes.
    Full-text · Article · Apr 2014 · Twin Research and Human Genetics
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    • "Furthermore, specific reductions have been found in the thalamus [Friedman et al., 2003; Hardan et al., 2008], anterior cingulate [Levitt et al., 2003], and temporal lobe [Friedman et al., 2003]; the studies reporting reduced Cho included subjects less than 13 years of age. A number of studies have failed to find any statistically significant alterations in Cho among individuals with ASD compared with controls in regions including the cingulate gyrus [Bernardi et al., 2011; Fujii et al., 2010; Hisaoka et al., 2001], frontal lobe [DeVito et al., 2007; Endo et al., 2007; Fujii et al., 2010; Hisaoka et al., 2001], parietal lobe [Bernardi et al., 2011; Hashimoto et al., 1997, 1998; Hisaoka et al., 2001; Page et al., 2006], thalamus [Bernardi et al., 2011; Perich- Alsina et al., 2002], cerebellum [DeVito et al., 2007; Endo et al., 2007; Mori et al., 2001; Otsuka et al., 1999], occipital lobe [DeVito et al., 2007], and temporal lobe [DeVito et al., 2007; Hisaoka et al., 2001], including the amygdala-hippocampal region [Endo et al., 2007; Mori et al., 2001; Otsuka et al., 1999; Page et al., 2006]. Furthermore , Murphy et al. found increased Cho in the right medial prefrontal lobe in adults with Asperger's syndrome [Murphy et al., 2002]. "
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    ABSTRACT: Proton magnetic resonance spectroscopy ((1) H-MRS) is a safe, noninvasive way of quantifying in vivo biochemical and metabolite concentration levels in individuals with Autism Spectrum Disorders (ASD). Findings to date suggest ASD is associated with widespread reduction in N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr), choline-containing compounds (Cho), myo-inositol (mI), and glutamate plus glutamine plus gamma-Aminobutyric Acid (Glx); however, variable findings, and even substantial increases, are not uncommon depending on the study and/or region-of-interest. Widespread reduction of NAA, Cr, Cho, mI, and Glx in ASD likely reflects impaired neuronal function and/or metabolism related to abnormal neurodevelopmental processes. Future studies should attempt to relate (1) H-MRS findings to histological findings and control for variability in subject age and functioning level; this would assist in evaluating the relationship between (1) H-MRS metabolic levels and neuronal and glial cell densities, as well as neurodevelopmental process associated with ASD. Furthermore, more longitudinal (1) H-MRS studies are needed in both control and ASD subjects to attempt to standardize metabolite levels across different developmental periods in well-defined endophenotypes. This will provide for a standard rubric for which metabolic aberrations (as well as treatment responses) can be measured. With higher magnetic field strengths and spectral-editing techniques capable of quantifying less-concentrated metabolites, (1) H-MRS will continue to be an important tool in ASD research. Autism Res 2013, ●●: ●●-●●. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.
    Full-text · Article · Apr 2013 · Autism Research
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