Convergent Findings of Altered Functional and Structural Brain Connectivity in Individuals with High Functioning Autism: A Multimodal MRI Study

<div><p>Brain tissue changes in autism spectrum disorders seem to be rather subtle and widespread than anatomically distinct. Therefore a multimodal, whole brain imaging technique appears to be an appropriate approach to investigate whether alterations in white and gray matter integrity relate to consistent changes in functional resting state connectivity in individuals with high functioning autism (HFA). We applied diffusion tensor imaging (DTI), voxel-based morphometry (VBM) and resting state functional connectivity magnetic resonance imaging (fcMRI) to assess differences in brain structure and function between 12 individuals with HFA (mean age 35.5, SD 11.4, 9 male) and 12 healthy controls (mean age 33.3, SD 9.0, 8 male). Psychological measures of empathy and emotionality were obtained and correlated with the most significant DTI, VBM and fcMRI findings. We found three regions of convergent structural and functional differences between HFA participants and controls. The right temporo-parietal junction area and the left frontal lobe showed decreased fractional anisotropy (FA) values along with decreased functional connectivity and a trend towards decreased gray matter volume. The bilateral superior temporal gyrus displayed significantly decreased functional connectivity that was accompanied by the strongest trend of gray matter volume decrease in the temporal lobe of HFA individuals. FA decrease in the right temporo-parietal region was correlated with psychological measurements of decreased emotionality. In conclusion, our results indicate common sites of structural and functional alterations in higher order association cortex areas and may therefore provide multimodal imaging support to the long-standing hypothesis of autism as a disorder of impaired higher-order multisensory integration.</p></div

Correlation between DTI results and psychological test data.

<p>This plot shows the correlation between test results of the FPI (Freiburger Personality Inventory) test, subscale emotionality, and DTI results. Individual FA values within the white matter skeleton were averaged across the right temporo-parietal region.</p

Localization of common sites of structural and functional alterations in high functioning autism.

<p>(I) indicates the right temporo-parietal cluster and (II) indicates the left medial frontal cluster of convergent DTI, VBM and fcMRI findings in Asperger’s syndrome; (III) indicates a bilateral temporal cluster of concomitant fcMRI and VBM alterations in HFA participants. For visualization purposes VBM and fMRI group differences are displayed at p_uncorr≤0.001, corrected significance levels can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067329#pone-0067329-t002" target="_blank">Table 2</a> and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067329#pone-0067329-t003" target="_blank">3</a> respectively. All DTI, VBM and fMRI results that survived multiple comparison correction are marked with an asterisk (*). Brains are displayed in radiologic convention (the right side of the brain Figure corresponds to the left hemisphere and vice versa).</p

Functional connectivity between group differences.

<p>(A) Resting state networks (RSN) of interest, identified by group-ICA of resting state fMRI data and subjected to analysis of functional connectivity differences between high functioning autism (HFA) participants and healthy controls (HC). Three RSNs, namely the DAN (dorsal attention network), the DMN (default mode network) and the LFPN (left-lateralized fronto-parietal network) exhibited clusters of decreased functional connectivity in HFA as compared to HC (B). Indices 1–3 correspond to cluster indices in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067329#pone-0067329-t002" target="_blank">Table 2</a>. For visualization purposes group differences are displayed at p_uncorr≤0.001, corrected significance levels can be found in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067329#pone-0067329-t003" target="_blank">Table 3</a>. Brains are displayed in radiologic convention (the right side of the brain Figure corresponds to the left hemisphere and vice versa).</p

Brain regions showing clusters of significant differences in RSN connectivity between HFA probands and controls (HC>HFA).

<p>Abbreviations: ACC = anterior cingulated gyrus, IPL = inferior parietal lobe, MPFC = medial prefrontal cortex, PCC = posterior cingulated gyrus, PCU = precuneus, PoCG = postcentral gyrus, PreCG = precental gyrus, RSN = resting state network, SMG = supramarginal gyrus, SPL = superior parietal lobe, STG = superior temporal gyrus;</p>a<p>Coordinates are given in MNI152 standard space.</p

Structural between group differences.

<p>(A) The top row shows clusters of decreased FA values in high functioning autism (HFA) participants compared to healthy controls (HC) (p_corr≤0.01). (B) The bottom row shows clusters of decreased gray matter volume in HFA compared to HC (p_uncorr≤0.001). Clusters d-h are not displayed in the Figure but shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067329#pone-0067329-t002" target="_blank">Table 2</a>. Indices A–E and a–c correspond to cluster indices in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067329#pone-0067329-t002" target="_blank">Table 2</a>. Brains are displayed in radiologic convention (the right side of the brain Figure corresponds to the left hemisphere and vice versa).</p

Results of a single patient with true neurofeedback: A) Neuronal response in the ROI during the fourth neurofeedback session compared to the first session [alcohol-related pictures > neutral pictures].

<p>B) Time course of activity within the specific ROI during the fourth neurofeedback session [green: presentation of alcohol-related pictures; grey: presentation of neutral pictures; p(Bonf)<0.002; x = 3; y = 57; z = 15].</p

Structural differences between HFA individuals and healthy controls (HC>HFA), group differences in FA values derived from DTI analysis (clusters A–E, also see Figure 1) and group differences (HC>HFA) in gray matter volume (clusters a–j, also see Figure 1) derived from VBM analysis.

<p>Abbreviations: ACC = anterior cingulated cortex, AG = angular gyrus, CG = cingulated gyrus, FP = frontal pole, IFG = inferior frontal gyrus, ITG = inferior temporal gyrus, LOL = lateral occipital lobe, MFG = middle frontal gyrus, MPFC = medial prefrontal cortex, MTG = medial temporal gyrus, OFC = orbito-frontal cortex, SMG = supramarginal gyrus, SPL = superior parietal lobe, STG = superior temporal gyrus, TL = temporal lobe, TPJ = temporo-parietal junction;</p>a<p>Coordinates are given in MNI152 standard space.</p

Regions defined for the seed-based functional connectivity analysis in areas are known to be relevant for addictive behaviour, including the left insula, the right insula, the left DLPFC (BA 9, 46) and the right DLPFC (BA 9, 46).

<p>Regions defined for the seed-based functional connectivity analysis in areas are known to be relevant for addictive behaviour, including the left insula, the right insula, the left DLPFC (BA 9, 46) and the right DLPFC (BA 9, 46).</p

Results of the default mode network in patients and controls: increased medial frontal and dorsolateral prefrontal responses after rtfMRI in patients; in healthy controls, the activity was comparable before and after rtfMRI (p < 0.05, FWE corrected).

<p>Results of the default mode network in patients and controls: increased medial frontal and dorsolateral prefrontal responses after rtfMRI in patients; in healthy controls, the activity was comparable before and after rtfMRI (p < 0.05, FWE corrected).</p