Fronto-Striatal Glutamate in Autism Spectrum Disorder and Obsessive Compulsive Disorder.

Autism spectrum disorders (ASDs) and obsessive compulsive disorder (OCD) are often comorbid with the overlap based on compulsive behaviors. Although previous studies suggest glutamatergic deficits in fronto-striatal brain areas in both disorders, this is the first study to directly compare the glutamate concentrations across the two disorders with those in healthy control participants using both categorical and dimensional approaches. In the current multi-center study (four centers), we used proton magnetic resonance spectroscopy in 51 children with ASD, 29 with OCD, and 53 healthy controls (aged 8-13 years) to investigate glutamate (Glu) concentrations in two regions of the fronto-striatal circuit: midline anterior cingulate cortex (ACC) and left dorsal striatum. Spectra were processed with Linear Combination Model. Group comparisons were performed with one-way analyses of variance including sex, medication use, and scanner site as covariates. In addition, a dimensional analysis was performed, linking glutamate with a continuous measure of compulsivity across disorders. There was a main group effect for ACC glutamate (p=0.019). Contrast analyses showed increased glutamate both in children with ASD and OCD compared with controls (p=0.007), but no differences between the two disorders (p=0.770). Dimensional analyses revealed a positive correlation between compulsive behavior (measured with the Repetitive Behavior Scale) and ACC glutamate (rho=0.24, p=0.03). These findings were robust across sites. No differences were found in the striatum. The current findings confirm overlap between ASD and OCD in terms of glutamate involvement. Glutamate concentration in ACC seems to be associated with the severity of compulsive behavior.

Developmentally stable whole-brain volume reductions and developmentally sensitive caudate and putamen volume alterations in those with attention-deficit/hyperactivity disorder and their unaffected siblings.

IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder. It has been linked to reductions in total brain volume and subcortical abnormalities. However, owing to heterogeneity within and between studies and limited sample sizes, findings on the neuroanatomical substrates of ADHD have shown considerable variability. Moreover, it remains unclear whether neuroanatomical alterations linked to ADHD are also present in the unaffected siblings of those with ADHD. OBJECTIVE: To examine whether ADHD is linked to alterations in whole-brain and subcortical volumes and to study familial underpinnings of brain volumetric alterations in ADHD. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, we included participants from the large and carefully phenotyped Dutch NeuroIMAGE sample (collected from September 2009-December 2012) consisting of 307 participants with ADHD, 169 of their unaffected siblings, and 196 typically developing control individuals (mean age, 17.21 years; age range, 8-30 years). MAIN OUTCOMES AND MEASURES: Whole-brain volumes (total brain and gray and white matter volumes) and volumes of subcortical regions (nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, thalamus, and brainstem) were derived from structural magnetic resonance imaging scans using automated tissue segmentation. RESULTS: Regression analyses revealed that relative to control individuals, participants with ADHD had a 2.5% smaller total brain (ß = -31.92; 95% CI, -52.69 to -11.16; P = .0027) and a 3% smaller total gray matter volume (ß = -22.51; 95% CI, -35.07 to -9.96; P = .0005), while total white matter volume was unaltered (ß = -10.10; 95% CI, -20.73 to 0.53; P = .06). Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. Significant age-by-diagnosis interactions showed that older age was linked to smaller caudate (P < .001) and putamen (P = .01) volumes (both corrected for total brain volume) in control individuals, whereas age was unrelated to these volumes in participants with ADHD and their unaffected siblings. Attention-deficit/hyperactivity disorder was not significantly related to the other subcortical volumes. CONCLUSIONS AND RELEVANCE: Global differences in gray matter volume may be due to alterations in the general mechanisms underlying normal brain development in ADHD. The age-by-diagnosis interaction in the caudate and putamen supports the relevance of different brain developmental trajectories in participants with ADHD vs control individuals and supports the role of subcortical basal ganglia alterations in the pathophysiology of ADHD. Alterations in total gray matter and caudate and putamen volumes in unaffected siblings suggest that these volumes are linked to familial risk for ADHD.

Exploration of scanning effects in multi-site structural MRI studies.

BACKGROUND: Pooling of multi-site MRI data is often necessary when a large cohort is desired. However, different scanning platforms can introduce systematic differences which confound true effects of interest. One may reduce multi-site bias by calibrating pivotal scanning parameters, or include them as covariates to improve the data integrity. NEW METHOD: In the present study we use a source-based morphometry (SBM) model to explore scanning effects in multi-site sMRI studies and develop a data-driven correction. Specifically, independent components are extracted from the data and investigated for associations with scanning parameters to assess the influence. The identified scanning-related components can be eliminated from the original data for correction. RESULTS: A small set of SBM components captured most of the variance associated with the scanning differences. In a dataset of 1460 healthy subjects, pronounced and independent scanning effects were observed in brainstem and thalamus, associated with magnetic field strength-inversion time and RF-receiving coil. A second study with 110 schizophrenia patients and 124 healthy controls demonstrated that scanning effects can be effectively corrected with the SBM approach. COMPARISON WITH EXISTING METHOD(S): Both SBM and GLM correction appeared to effectively eliminate the scanning effects. Meanwhile, the SBM-corrected data yielded a more significant patient versus control group difference and less questionable findings. CONCLUSIONS: It is important to calibrate scanning settings and completely examine individual parameters for the control of confounding effects in multi-site sMRI studies. Both GLM and SBM correction can reduce scanning effects, though SBM's data-driven nature provides additional flexibility and is better able to handle collinear effects.

Cerebral white matter lesions and lacunar infarcts contribute to the presence of mild parkinsonian signs.

BACKGROUND AND PURPOSE: Mild parkinsonian signs (MPS) are common in elderly people and may be an early stage of parkinson(ism). They might be related to cerebral small-vessel disease, although this association remains incompletely understood. To identify subjects at early stages of the disease, we investigated whether the presence of MPS was dependent on the severity and location of small-vessel disease, including white matter lesions and lacunar infarcts. METHODS: Four hundred thirty individuals, with small-vessel disease, aged between 50 and 85 years, without dementia or parkinsonism, were included in this analysis and underwent MRI scanning. The number and location of lacunar infarcts were rated. White matter lesion volume was assessed by manual segmentation with automated delineating of different regions. Presence of MPS was based on the motor section of the Unified Parkinson's Disease Rating Scale. Associations were determined using logistic regression analysis adjusted for age, sex, and total brain volume. RESULTS: Severe white matter lesions and the presence of lacunar infarcts were independently associated with the presence of MPS (OR, 2.6; 95% CI, 1.3-4.9 and OR, 1.8; 95% CI, 1.0-3.0). Frontal and parietal white matter lesions and, to a lesser extent, lacunar infarcts in the thalamus were associated with a higher risk of MPS. The presence of lacunar infarcts was independently related to the bradykinesia category of parkinsonian signs. CONCLUSIONS: This study shows that severe small-vessel disease, especially at certain locations, is associated with MPS signs in older adults. Our findings suggest that small-vessel disease interrupts basal ganglia-thalamocortical circuits involving both the frontal and parietal lobes and hence may result in MPS.

Involvement of monkey inferior colliculus in spatial hearing.

The midbrain inferior colliculus (IC) is implicated in coding sound location, but evidence from behaving primates is scarce. Here we report single-unit responses to broadband sounds that were systematically varied within the two-dimensional (2D) frontal hemifield, as well as in sound level, while monkeys fixated a central visual target. Results show that IC neurons are broadly tuned to both sound-source azimuth and level in a way that can be approximated by multiplicative, planar modulation of the firing rate of the cell. In addition, a fraction of neurons also responded to elevation. This tuning, however, was more varied: some neurons were sensitive to a specific elevation; others responded to elevation in a monotonic way. Multiple-linear regression parameters varied from cell to cell, but the only topography encountered was a dorsoventral tonotopy. In a second experiment, we presented sounds from straight ahead while monkeys fixated visual targets at different positions. We found that auditory responses in a fraction of IC cells were weakly, but systematically, modulated by 2D eye position. This modulation was absent in the spontaneous firing rates, again suggesting a multiplicative interaction of acoustic and eye-position inputs. Tuning parameters to sound frequency, location, intensity, and eye position were uncorrelated. On the basis of simulations with a simple neural network model, we suggest that the population of IC cells could encode the head-centered 2D sound location and enable a direct transformation of this signal into the eye-centered topographic motor map of the superior colliculus. Both signals are required to generate rapid eye-head orienting movements toward sounds.