Altered white matter integrity in adults with autism spectrum disorder and an IQ >100: a diffusion tensor imaging study.

OBJECTIVE: White matter (WM) alterations have been reported in children and adults with autism spectrum disorder (ASD). In particular, impaired connectivity of limbic structures may be related to social deficits. Heterogeneous findings could be explained in terms of differences in sample characteristics and methodology. In this context, non-syndromic forms might differ substantially in WM structure from secondary ASD forms. METHOD: In an attempt to recruit a homogeneous study sample, we included adults with high-functioning ASD and an IQ > 100 to decrease the influence of syndromic forms being often associated with cognitive deficits. Diffusion tensor imaging (DTI) was performed in 30 participants with ASD and 30 pairwise-matched controls. Fractional anisotropy (FA) and mean diffusivity (MD) as surrogate imaging markers for WM integrity were calculated. RESULTS: We found a significant FA decrease in the ASD group in the genu and body of the corpus callosum (CC). Increased MD was detected in the subgenual anterior cingulate cortex (sACC). CONCLUSION: The finding of decreased WM integrity in the genu of the CC is in line with earlier studies reporting a decreased number of interhemispheric fibers in the frontal lobe of ASD. Alterations in the sACC might be associated with 'Theory of mind' deficits.

Disturbed cingulate glutamate metabolism in adults with high-functioning autism spectrum disorder: evidence in support of the excitatory/inhibitory imbalance hypothesis.

Over the last few years, awareness of autism spectrum disorder (ASD) in adults has increased. The precise etiology of ASD is still unresolved. Animal research, genetic and postmortem studies suggest that the glutamate (Glu) system has an important role, possibly related to a cybernetic imbalance between neuronal excitation and inhibition. To clarify the possible disruption of Glu metabolism in adults with high-functioning autism, we performed a magnetic resonance spectroscopy (MRS) study investigating the anterior cingulate cortex (ACC) and the cerebellum in adults with high-functioning ASD. Twenty-nine adult patients with high-functioning ASD and 29 carefully matched healthy volunteers underwent MRS scanning of the pregenual ACC and the left cerebellar hemisphere. Metabolic data were compared between groups and were correlated with psychometric measures of autistic features. We found a significant decrease in the cingulate N-acetyl-aspartate (NAA) and the combined Glu and glutamine (Glx) signals in adults with ASD, whereas we did not find other metabolic abnormalities in the ACC or the cerebellum. The Glx signal correlated significantly with psychometric measures of autism, particularly with communication deficits. Our data support the hypothesis that there is a link between disturbances of the cingulate NAA and Glx metabolism, and autism. The findings are discussed in the context of the hypothesis of excitatory/inhibitory imbalance in autism. Further research should clarify the specificity and dynamics of these findings regarding other neuropsychiatric disorders and other brain areas.

Altered cingulate and amygdala response towards threat and safe cues in attention deficit hyperactivity disorder.

BACKGROUND: Emotional dysregulation is becoming increasingly recognized as an important feature of attention deficit hyperactivity disorder (ADHD). In this study, two experiments were conducted investigating the neural response to either verbally instructed fear (IF) or uninstructed (classically conditioned) fear (UF) using the skin conductance response (SCR) and functional magnetic resonance imaging (fMRI). METHOD: In the conditioning phase of the UF experiment (17 ADHD and 17 healthy controls), subjects experienced an unconditioned stimulus (UCS, unpleasant electrodermal stimulation) paired with a former neutral conditioned stimulus (CS+), whereas a control stimulus (CS-) was never paired with the UCS. In the subsequent test phase, only the CS+ and the CS- were presented. In the IF experiment (13 ADHD and 17 healthy controls), subjects were only told that an independently experienced UCS might occur together with the CS+ but not the CS- during testing. No UCS was presented. RESULTS: Groups did not detectably differ in SCR or neural responses to UF. In IF, ADHD patients showed a trend-line decreased SCR and significantly decreased activation of the dorsal anterior cingulate cortex (dACC), a region prominently involved in fear responding, to the CS+. This was accompanied by higher amygdala activation to the CS-. CONCLUSIONS: During IF, ADHD patients showed deficits in regions centrally involved in fear learning and expression in terms of diminished CS+-related dACC and increased CS--related amygdala signals. This suggests an impaired processing of verbally transmitted aversive information, which is central for conveying fear information in social contexts. This result extends the growing literature on emotional alterations in ADHD.

Reduced cingulate glutamate/glutamine-to-creatine ratios in adult patients with attention deficit/hyperactivity disorder -- a magnet resonance spectroscopy study.

BACKGROUND: The dopaminergic system is thought to be essentially involved in the pathogenesis of attention deficit/hyperactivity disorder (ADHD). However, there is also evidence for abnormalities in the glutamatergic system and recent theories focus on a disturbed interaction between the two systems as the essential pathogenetic mechanism of ADHD. In the present study, we wanted to test the hypothesis that prefrontal glutamate signals indirectly indicate dopaminergic dysfunction in adult patients with ADHD. METHODS: Twenty-eight adult patients with ADHD and 28 group-matched healthy volunteers were studied clinically and using chemical-shift MR spectroscopy (MRS) of the prefrontal cortex covering the anterior cingulate gyrus. RESULTS: A significant reduction of the combined glutamate/glutamine to creatine ratio in the right anterior cingulate cortex in patients with ADHD was found. DISCUSSION: Glutamatergic alterations as measured with MRS might play a role in the pathogenesis of adult patients with ADHD.

H¹-MR-spectroscopy of cerebellum in adult attention deficit/hyperactivity disorder.

INTRODUCTION: Neurobiological research has implicated the cerebellum as one possible site of neurophysiological dysfunction in ADHD. Latest theoretical conceptualizations of the cerebellum as core site of the brain to model motor as well as cognitive behavior puts further weight to the assumption that it might play a key role in ADHD pathophysiology. METHODS: 30 medication free adult ADHD patients and 30 group matched (gender, age and education) healthy controls were investigated using the method of chemical shift imaging (CSI) of the cerebellum. The vermis, left and right cerebellar hemispheres were processed separately. RESULTS: We found significantly increased glutamate-glutamine (Glx) to creatine (Cre) ratios in the left cerebellar hemisphere. No other differences in measured metabolite concentrations were observed. DISCUSSION: To our knowledge this is the first evidence for neurochemical alterations in cerebellar neurochemistry in adult ADHD. They relate well to recent hypotheses that the cerebellum might control mental activities by internal models.