Co-activation pattern alterations in autism spectrum disorder-A volume-wise hierarchical clustering fMRI study.

INTRODUCTION: There has been a growing effort to characterize the time-varying functional connectivity of resting state (RS) fMRI brain networks (RSNs). Although voxel-wise connectivity studies have examined different sliding window lengths, nonsequential volume-wise approaches have been less common. METHODS: Inspired by earlier co-activation pattern (CAP) studies, we applied hierarchical clustering (HC) to classify the image volumes of the RS-fMRI data on 28 adolescents with autism spectrum disorder (ASD) and their 27 typically developing (TD) controls. We compared the distribution of the ASD and TD groups' volumes in CAPs as well as their voxel-wise means. For simplification purposes, we conducted a group independent component analysis to extract 14 major RSNs. The RSNs' average z-scores enabled us to meaningfully regroup the RSNs and estimate the percentage of voxels within each RSN for which there was a significant group difference. These results were jointly interpreted to find global group-specific patterns. RESULTS: We found similar brain state proportions in 58 CAPs (clustering interval from 2 to 30). However, in many CAPs, the voxel-wise means differed significantly within a matrix of 14 RSNs. The rest-activated default mode-positive and default mode-negative brain state properties vary considerably in both groups over time. This division was seen clearly when the volumes were partitioned into two CAPs and then further examined along the HC dendrogram of the diversifying brain CAPs. The ASD group network activations followed a more heterogeneous distribution and some networks maintained higher baselines; throughout the brain deactivation state, the ASD participants had reduced deactivation in 12/14 networks. During default mode-negative CAPs, the ASD group showed simultaneous visual network and either dorsal attention or default mode network overactivation. CONCLUSION: Nonsequential volume gathering into CAPs and the comparison of voxel-wise signal changes provide a complementary perspective to connectivity and an alternative to sliding window analysis.

Attention and Working Memory in Adolescents with Autism Spectrum Disorder: A Functional MRI Study.

The present study examined attention and memory load-dependent differences in the brain activation and deactivation patterns between adolescents with autism spectrum disorders (ASDs) and typically developing (TD) controls using functional magnetic resonance imaging. Attentional (0-back) and working memory (WM; 2-back) processing and load differences (0 vs. 2-back) were analysed. WM-related areas activated and default mode network deactivated normally in ASDs as a function of task load. ASDs performed the attentional 0-back task similarly to TD controls but showed increased deactivation in cerebellum and right temporal cortical areas and weaker activation in other cerebellar areas. Increasing task load resulted in multiple responses in ASDs compared to TD and in inadequate modulation of brain activity in right insula, primary somatosensory, motor and auditory cortices. The changes during attentional task may reflect compensatory mechanisms enabling normal behavioral performance. The inadequate memory load-dependent modulation of activity suggests diminished compensatory potential in ASD.

Resting state fMRI reveals a default mode dissociation between retrosplenial and medial prefrontal subnetworks in ASD despite motion scrubbing.

In resting state functional magnetic resonance imaging (fMRI) studies of autism spectrum disorders (ASDs) decreased frontal-posterior functional connectivity is a persistent finding. However, the picture of the default mode network (DMN) hypoconnectivity remains incomplete. In addition, the functional connectivity analyses have been shown to be susceptible even to subtle motion. DMN hypoconnectivity in ASD has been specifically called for re-evaluation with stringent motion correction, which we aimed to conduct by so-called scrubbing. A rich set of default mode subnetworks can be obtained with high dimensional group independent component analysis (ICA) which can potentially provide more detailed view of the connectivity alterations. We compared the DMN connectivity in high-functioning adolescents with ASDs to typically developing controls using ICA dual-regression with decompositions from typical to high dimensionality. Dual-regression analysis within DMN subnetworks did not reveal alterations but connectivity between anterior and posterior DMN subnetworks was decreased in ASD. The results were very similar with and without motion scrubbing thus indicating the efficacy of the conventional motion correction methods combined with ICA dual-regression. Specific dissociation between DMN subnetworks was revealed on high ICA dimensionality, where networks centered at the medial prefrontal cortex and retrosplenial cortex showed weakened coupling in adolescents with ASDs compared to typically developing control participants. Generally the results speak for disruption in the anterior-posterior DMN interplay on the network level whereas local functional connectivity in DMN seems relatively unaltered.

Valence scaling of dynamic facial expressions is altered in high-functioning subjects with autism spectrum disorders: an fMRI study.

FMRI was performed with the dynamic facial expressions fear and happiness. This was done to detect differences in valence processing between 25 subjects with autism spectrum disorders (ASDs) and 27 typically developing controls. Valence scaling was abnormal in ASDs. Positive valence induces lower deactivation and abnormally strong activity in ASD in multiple regions. Negative valence increased deactivation in visual areas in subjects with ASDs. The most marked differences between valences focus on fronto-insular and temporal regions. This supports the idea that subjects with ASDs may have difficulty in passive processing of the salience and mirroring of expressions. When the valence scaling of brain activity fails, in contrast to controls, these areas activate and/or deactivate inappropriately during facial stimuli presented dynamically.

White matter in autism spectrum disorders - evidence of impaired fiber formation.

BACKGROUND: Diffusion tensor imaging (DTI) enables measurements and visualization of the microstructure of neural fiber tracts. The existing literature on autism spectrum disorders (ASDs) and DTI is heterogenous both regarding methodology and results. PURPOSE: To compare brain white matter of high-functioning individuals with ASDs and controls. MATERIAL AND METHODS: Tract-based spatial statistics (TBSS), a voxel-based approach to DTI, was used to compare 27 subjects with ASDs (mean age 14.7 years, range 11.4-17.6 years, 20 boys, 7 girls) and 26 control subjects (mean age 14.5 years, range 11.7-17.3 years, 17 boys, 9 girls). Mean fractional anisotropy (FA) image (skeleton) was created and each subject's aligned FA data were then projected onto this skeleton. Voxelwise cross-subject statistics on the skeletonized FA data, mean diffusivity (MD), and measures of diffusion direction were calculated. Importantly, the data were corrected across the whole image instead of using ROI-based methods. RESULTS: The ASD group showed significantly greater FA (P < 0.05, corrected) in the area containing clusters of optic radiation and the right inferior fronto-occipital fasciculus (iFOF). In the same area, λ(3) (representing transverse diffusion) was significantly reduced in the ASD group. No age-related changes were found. CONCLUSION: The results suggest that the reduced transverse diffusion within the iFOF is related to abnormal information flow between the insular salience processing areas and occipital visual areas.

Age-Related Differences in Functional Nodes of the Brain Cortex - A High Model Order Group ICA Study.

Functional MRI measured with blood oxygen dependent (BOLD) contrast in the absence of intermittent tasks reflects spontaneous activity of so-called resting state networks (RSN) of the brain. Group level independent component analysis (ICA) of BOLD data can separate the human brain cortex into 42 independent RSNs. In this study we evaluated age-related effects from primary motor and sensory, and, higher level control RSNs. One hundred sixty-eight healthy subjects were scanned and divided into three groups: 55 adolescents (ADO, 13.2 ± 2.4 years), 59 young adults (YA, 22.2 ± 0.6 years), and 54 older adults (OA, 42.7 ± 0.5 years), all with normal IQ. High model order group probabilistic ICA components (70) were calculated and dual-regression analysis was used to compare 21 RSN's spatial differences between groups. The power spectra were derived from individual ICA mixing matrix time series of the group analyses for frequency domain analysis. We show that primary sensory and motor networks tend to alter more in younger age groups, whereas associative and higher level cognitive networks consolidate and re-arrange until older adulthood. The change has a common trend: both spatial extent and the low frequency power of the RSN's reduce with increasing age. We interpret these result as a sign of normal pruning via focusing of activity to less distributed local hubs.

Functional mapping of dynamic happy and fearful facial expression processing in adolescents.

This paper assessed the neural systems involved in processing of dynamic facial expressions in adolescents. The processing of facial expressions changes as a function of age, and it is thus important to understand how healthy adolescent subjects process dynamic facial expressions prior to analyzing disease-related changes. We hypothesized that viewing of dynamic facial expressions with opposing valences (happy vs. fearful) induces differential activations and deactivations in the brain. 27 healthy adolescents (9 female, 18 male, mean age = 14.5 years; age range 11.6-17.3 years) were examined by using the ASSQ and K-SADS-PL and scanned with 1.5-T fMRI during viewing of dynamic facial expressions and mosaic control images. The stimuli activated the same areas as previously seen in dynamic facial expression in adults. Our results indicated that opposing-valence dynamic facial expressions had differential effects on many cortical structures but not on subcortical limbic structures. The mirror neuron system is activated more during viewing of fearful compared to happy expressions in bilateral inferior frontal gyrus (IFG) and superior temporal sulcus (STS) left dominantly. We also detected more deactivation in the ventral anterior cingulate gyrus (ACG), showing more automated attentional processing of fearful expressions during passive viewing. Females were found to deactivate the right frontal pole more than male adolescents during happy facial expressions, while there were no differences in fear processing between genders. No clear gender or age effects were detected. In conclusion fear induces stronger responses in attention and mirror neurons probably related to fear contagion.

Alterations in regional homogeneity of resting-state brain activity in autism spectrum disorders.

Measures assessing resting-state brain activity with blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) can reveal cognitive disorders at an early stage. Analysis of regional homogeneity (ReHo) measures the local synchronization of spontaneous fMRI signals and has been successfully utilized in detecting alterations in subjects with attention-deficit hyperactivity disorder (ADHD), depression, schizophrenia, Parkinson's disease and Alzheimer's dementia. Resting-state brain activity was investigated in 28 adolescents with autism spectrum disorders (ASD) and 27 typically developing controls being imaged with BOLD fMRI and analyzed with the ReHo method. The hypothesis was that ReHo of resting-state brain activity would be different between ASD subjects and controls in brain areas previously shown to display functional alterations in stimulus or task based fMRI studies. Compared with the controls, the subjects with ASD had significantly decreased ReHo in right superior temporal sulcus region, right inferior and middle frontal gyri, bilateral cerebellar crus I, right insula and right postcentral gyrus. Significantly increased ReHo was discovered in right thalamus, left inferior frontal and anterior subcallosal gyrus and bilateral cerebellar lobule VIII. We conclude that subjects with ASD have right dominant ReHo alterations of resting-state brain activity, i.e., areas known to exhibit abnormal stimulus or task related functionality. Our results demonstrate that there is potential in utilizing the ReHo method in fMRI analyses of ASD.

Soluble adhesion molecules in Finnish schoolchildren with signs of preclinical type 1 diabetes.

BACKGROUND: We measured the circulating concentrations of the soluble forms of intercellular adhesion molecule-1, ICAM-1 (sCD54) and L-selectin (sCD62L) in 104 non-diabetic Finnish schoolchildren testing positive for one or more diabetes-associated autoantibodies and in 104 autoantibody-negative children to elucidate the relationship between soluble adhesion molecules and humoral, genetic and metabolic markers of preclinical type 1 diabetes. METHODS: Specific enzyme-linked immunosorbent assays were used to analyse serum sICAM-1 and sL-selectin concentrations. RESULTS: The sICAM-1 and sL-selectin levels were comparable in the autoantibody-positive and control children, even when comparing children with multiple autoantibodies with those having one or no autoantibodies. The IA-2A titres in children testing positive for this autoantibody correlated with the sICAM-1 concentrations (rs=0.62, P=0.05), but otherwise no significant associations were seen between the autoantibody specificities and the concentrations of soluble adhesion molecules. Control children with HLA DQB1 genotypes conferring a low or decreased risk of type 1 diabetes had higher levels of sL-selectin than those with high or moderate risk genotypes (P=0.04). sL-selectin concentrations were significantly increased in the autoantibody-positive children with a first-phase insulin response (FPIR) below the 5th (n=11;P=0.026) or 10th percentiles (n=17;P=0.009) relative to the children with a normal FPIR. No associations were observed between sICAM-1 concentrations and DQB1 genotypes or FPIR. CONCLUSIONS: The data indicate that there are a few conspicuous signs of endothelial/leukocyte activation reflected in increased circulating levels of soluble adhesion molecules in schoolchildren who are positive for markers of preclinical type 1 diabetes. The correlation between sICAM-1 concentrations and IA-2A levels in the IA-2A-positive children suggests that the former may increase in late preclinical type 1 diabetes, as IA-2A are the last autoantibodies to appear in the prediabetic process. Increased sL-selectin concentrations in subjects with impaired beta-cell function may reflect an active destructive insulitis process.