Dinesh K Shukla’s research while affiliated with San Diego State University and other places

The thalamus plays crucial roles in the development and mature functioning of numerous sensorimotor, cognitive and attentional circuits. Currently limited evidence suggests that autism spectrum disorder may be associated with thalamic abnormalities, potentially related to sociocommunicative and other impairments in this disorder. We used functional connectivity magnetic resonance imaging and diffusion tensor imaging probabilistic tractography to study the functional and anatomical integrity of thalamo-cortical connectivity in children and adolescents with autism spectrum disorder and matched typically developing children. For connectivity with five cortical seeds (prefontal, parieto-occipital, motor, somatosensory and temporal), we found evidence of both anatomical and functional underconnectivity. The only exception was functional connectivity with the temporal lobe, which was increased in the autism spectrum disorders group, especially in the right hemisphere. However, this effect was robust only in partial correlation analyses (partialling out time series from other cortical seeds), whereas findings from total correlation analyses suggest that temporo-thalamic overconnectivity in the autism group was only relative to the underconnectivity found for other cortical seeds. We also found evidence of microstructural compromise within the thalamic motor parcel, associated with compromise in tracts between thalamus and motor cortex, suggesting that the thalamus may play a role in motor abnormalities reported in previous autism studies. More generally, a number of correlations of diffusion tensor imaging and functional connectivity magnetic resonance imaging measures with diagnostic and neuropsychological scores indicate involvement of abnormal thalamocortical connectivity in sociocommunicative and cognitive impairments in autism spectrum disorder.

Autism Spectrum Disorder (ASD) is a pervasive neurodevelopmental disorder characterized by atypical behavioral profiles including deficits in social reciprocity and communication. While many studies have reported abnormal long-distance functional connectivity in ASD, much less is known about local connectivity. We used the regional homogeneity (ReHo) approach to measure the homogeneity of blood oxygen level dependent (BOLD) time series in high-resolution fMRI data as a measure of local excitatory connectivity. Two previous ReHo studies (Shukla et al., 2010; Paakki et al., 2010) detected regional anomalies in ASD, but were limited by conventional spatial resolution. High-resolution (1.4*1.4*2.3mm3) fMRI data from 10 children with ASD and 10 typically developing (TD) children were acquired, using an event-related letter detection task paradigm. The task-related components were removed from time series using linear least squares and motion-corrected for each participant. No significant group differences for motion were detected between ASD and TD groups. Each participant’s four-dimensional preprocessed volume was regressed on eight predictors modeling nuisance signals (white matter, cerebrospinal fluid and six motion parameters). Data were temporally band-pass filtered (0.01<f<0.1 Hz) to reduce low-frequency drift and high-frequency respiratory and cardiac noise. Kendall’s coefficient of concordance (KCC) was used to measure correlation between the time series of each voxel and those of its 6 nearest neighbors. ReHo results showed reduced KCC in the ASD group compared to the TD group in left insula, left superior temporal lobe, left fusiform gyrus, head of the caudate bilaterally, premotor cortex bilaterally and right cingulate gyrus. Increased KCC in the ASD group was found in left anterior cingulate, medial frontal gyrus bilaterally, superior frontal gyrus bilaterally and right inferior parietal lobule. Our results suggest atypical regional homogeneity of the BOLD signal in ASD, potentially reflecting regional abnormalities of local functional connectivity and cortical functional differentiation. The findings suggest that high-resolution ReHo may provide valuable in vivo data complementing the currently limited postmortem evidence of abnormal cortical architecture, such as minicolumnar anomalies, in ASD.

Background: Individuals with autism spectrum disorder (ASD) exhibit early and lifelong abnormalities in adaptive allocation of visual attention. Previous studies have shown white matter compromise in children and adults with ASD, which may relate to impaired function in distributed networks. Objectives: The goals of the present study were to 1) investigate whether white matter integrity in regions-of-interest (ROIs) associated with attention networks differ between children with ASD and typically developing (TD) children, and 2) to examine the relationship between attention network efficiency and white matter integrity in ASD and TD children. Methods: Diffusion tensor imaging (DTI) data of 17 children with ASD and 14 TD children were acquired from a 3T MRI scanner. Six ROIs were placed on white matter tracts based on previous literature associating these areas with attention. These ROIs were derived from Johns Hopkins University atlas for uncinate fasciculus, inferior longitudinal fasciculus, genu of the corpus callosum, anterior corona radiata, cingulum bundle, and superior longitudinal fasciculus. Fractional anisotropy (FA) was calculated for each ROI and was averaged over all ROIs for a global measure of white matter integrity of attentional networks. Participants also completed three 96-trial blocks of the Attention Network Test. Alerting, orienting, and executive attention network scores for each participant were calculated. Results: FA of white matter associated with the attentional networks was significantly reduced in the ASD group compared to the TD group (0.32 ± 0.04 for ASD versus 0.35 ± 0.02 for TD (p=0.04)). FA was positively correlated with orienting scores in the TD group (r=0.51, p=0.05); however, this correlation was absent in the ASD group (r=0.11, p=0.67). Conclusions: Our findings suggest that white matter compromise may contribute to attentional inefficiency in ASD. Absence of typical relationships between integrity of crucial white matter tracts and attention scores may indicate atypical network organization for attention. This was specifically observed for orienting, which was also found to be the attentional network of primary impairment in ASD in a behavioral study (Keehn et al., J Child Psychol Psychiatry, 2010).

Background: A number of studies have shown abnormal volume, neuronal integrity, perfusion, and metabolism of the thalamus in autism spectrum disorder (ASD). However, evidence on thalamocortical connectivity remains scant, except for a few functional studies. This lack of evidence is surprising, given the important role of thalamocortical connectivity in cortical functional specialization and differentiation, which are generally thought to be affected in ASD. Objectives: We assessed the integrity of connections between thalamus and cortex in children and adolescents with ASD, using probabilistic diffusion tensor imaging (DTI) tractography. Methods: DTI data from 17 children with ASD and 17 typically developing (TD)children were acquired from a 3T MRI scanner using single-shot diffusion-weighted EPI pulse sequence with two degrees of diffusion weighting (b=0 and 2000 s/mm2, 15 non-linear directions, four repetitions). Geometric distortions due to local magnetic field inhomogeneities were corrected using field maps. The PickAtlas SPM toolbox was used to obtain white matter masks for thalamus, and fronto-temporal and parieto-occipital cortices from the standard MNI brain template. Tracts were derived for pairs between thalamus and frontal/temporal and parietal/occipital white matter regions-of-interest (ROIs). Bayesian estimation of diffusion parameters using Markov Chain Monte Carlo sampling techniques and trilinear interpolation of the probability density functions were employed to determine the streamline between given ROI pairs using probabilistic tractography toolbox in FSL software. Fractional anisotropy (FA) values of identified tracts were determined. Results: FA of thalamocortical projections to and from the fronto-temporal cortex was significantly reduced in the ASD group compared to the TD group in both hemispheres (left hemisphere: 0.25±0.05 for ASD group versus 0.36±.04 for TD group, p=0.03; right hemisphere: 0.26±0.05 for ASD group versus 0.34±0.03 for TD group, p=0.04). For connections between thalamus and parieto-occipital cortex, the difference in FA was marginally significant (p=.08) in both hemispheres. No significant group differences in hemispheric asymmetry were found. Conclusions: These results suggest that abnormalities in thalamocortical fiber tracts are present in children and adolescents with ASD. They add anatomical support for a few previous findings of impaired functional thalamocortical connectivity. Findings of white matter compromise were significant for thalamic connections with fronto-temporal cortex, but less robust for parieto-occipital cortex, consistent with evidence of severe white matter growth anomalies in frontal lobe, but relative sparing of occipital lobe. A follow-up study examining thalamocortical connectivity at higher resolution is underway. Funding: R01-MH081023

Growing consensus suggests that autism spectrum disorders (ASD) are associated with atypical brain networks, thus shifting the focus to the study of connectivity. Many functional connectivity studies have reported underconnectivity in ASD, but results in others have been divergent. We conducted a survey of 32 functional connectivity magnetic resonance imaging studies of ASD for numerous methodological variables to distinguish studies supporting general underconnectivity (GU) from those not consistent with this hypothesis (NGU). Distinguishing patterns were apparent for several data analysis choices. The study types differed significantly with respect to low-pass filtering, task regression, and whole-brain field of view. GU studies were more likely to examine task-driven time series in regions of interest, without the use of low-pass filtering. Conversely, NGU studies mostly applied task regression (for removal of activation effects) and low-pass filtering, testing for correlations across the whole brain. Results thus suggest that underconnectivity findings may be contingent on specific methodological choices. Whereas underconnectivity reflects reduced efficiency of within-network communication in ASD, diffusely increased functional connectivity can be attributed to impaired experience-driven mechanisms (e.g., synaptic pruning). Both GU and NGU findings reflect important aspects of network dysfunction associated with sociocommunicative, cognitive, and sensorimotor impairments in ASD.

Recent functional connectivity magnetic resonance imaging and diffusion tensor imaging (DTI) studies have suggested atypical functional connectivity and reduced integrity of long-distance white matter fibers in autism spectrum disorder (ASD). However, evidence for short-distance white matter fibers is still limited, despite some speculation of potential sparing of local connectivity in ASD. Short-distance U-fibers are an important component of neural networks and are thought to play a crucial role in cognitive function. In the present study, we applied tract-based spatial statistics to derive short- and long-distance white matter tracts in frontal, parietal, and temporal lobes in both hemispheres. DTI data were acquired from 26 children with ASD and 24 typically developing (TD) children. A mean fractional anisotropy (FA) image was created and thinned to represent centers of all common tracts. Evidence of compromised short-distance tracts for the ASD group was found in frontal lobe (reduced FA, increased mean diffusivity [MD] and radial diffusivity) as well as in temporal and parietal lobes (increased MD and radial diffusivity). Significant positive correlations between age and FA and negative correlations between age and MD and radial diffusivity were also found for short-distance tracts in each lobe in the TD, but not the ASD group. These results suggest white matter compromise in short-distance tracts in ASD. Absence of typical age-related correlations with DTI indices may reflect altered maturation of short-distance tracts in ASD. Our results are inconsistent with a notion of selective sparing of short-distance connectivity in ASD.

Autism spectrum disorder (ASD) is increasingly viewed as a disorder of functional networks, highlighting the importance of investigating white matter and interregional connectivity. We used diffusion tensor imaging (DTI) to examine white matter integrity for the whole brain and for corpus callosum, internal capsule, and middle cerebellar peduncle in children with ASD and typically developing (TD) children. DTI data were obtained from 26 children with ASD and 24 matched TD children. Fractional anisotropy (FA), mean diffusivity (MD), and axial and radial diffusion were calculated for the whole brain, the genu, body, and splenium of the corpus callosum, the genu and anterior and posterior limbs of the internal capsule, and the middle cerebellar peduncle. Children with ASD had reduced FA and increased radial diffusion for whole-brain white matter and all three segments of the corpus callosum and internal capsule, compared with those in TD children. Increased MD was found for the whole brain and for anterior and posterior limbs of the internal capsule. Reduced axial diffusion was found for the body of corpus callosum. Reduced FA was also found for the middle cerebellar peduncle. Our findings suggest widespread white matter compromise in children with ASD. Abnormalities in the corpus callosum indicate impaired interhemispheric transfer. Results for the internal capsule and middle cerebellar peduncle add to the currently limited DTI evidence on subcortico-cortical tracts in ASD. The robust impairment found in all three segments of the internal capsule is consistent with studies documenting impairment of elementary sensorimotor function in ASD.

Previous diffusion tensor imaging (DTI) studies have shown white matter compromise in children and adults with autism spectrum disorder (ASD), which may relate to reduced connectivity and impaired function of distributed networks. However, tract-specific evidence remains limited in ASD. We applied tract-based spatial statistics (TBSS) for an unbiased whole-brain quantitative estimation of the fractional anisotropy (FA), mean diffusion (MD) and axial and radial diffusion of the white matter tracts in children and adolescents with ASD. DTI was performed in 26 ASD and 24 typically developing (TD) participants, aged 9-20 years. Groups were matched for age and IQ. Each participant's aligned FA, MD and axial and radial diffusion data were projected onto the mean FA skeleton representing the centers of all tracts and the resulting data fed into voxelwise group statistics. TBSS revealed decreased FA and increased MD and radial diffusion in the ASD group compared to the TD group in the corpus callosum, anterior and posterior limbs of the internal capsule, inferior longitudinal fasciculus, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, cingulum, anterior thalamic radiation, and corticospinal tract. No single site with inverse effects (increased FA, reduced MD or radial diffusion in the ASD group) was detected. In clusters of significant group difference, age was positively correlated with FA and negatively correlated with MD and radial diffusion in the TD, but not the ASD group. Our findings reveal white matter compromise affecting numerous tracts in children and adolescents with ASD. Slightly varying patterns of diffusion abnormalities detected for some tracts may suggest tract-specific patterns of white matter abnormalities associated with ASD. Age-dependent effects further show that maturational changes (increasing FA, decreasing MD and radial diffusion with age) are diminished in ASD from school-age childhood into young adulthood.

Background: A few previous studies have suggested reduced functional connectivity within default mode network in children and adults with autism spectrum disorder (ASD), possibly related to impaired self-reference and social cognition. However, anatomical connectivity studies of the default mode network are lacking in ASD. Objectives: To examine the white matter integrity within the default mode network in children with ASD using probabilistic white matter fiber tracking. Methods: Diffusion tensor imaging (DTI) data of 19 children with ASD and 17 typically developing (TD) children were acquired from a 3T MRI scanner, using single-shot diffusion-weighted EPI pulse sequence with two degrees of diffusion weighting (b=0 and 2000 s/mm2, 15 non-linear directions, four repetitions). Geometric distortions due to local magnetic field inhomogeneities were corrected using field maps. T1-weighted data were also acquired using spoiled gradient-recalled (SPGR) echo pulse sequence. Diffusion tensor tractography was performed using a probabilistic tracking approach from three regions of interest (ROIs) in both hemispheres, identified using Freesurfer parcellation of T1-weighted images: posterior cingulate gyrus (PCC), medial prefrontal cortex (MFC), middle temporal lobe (MTL), and inferior parietal lobe (IPL). Shared tracts for seed pairs (PCC-MFC, PCC-MTL, MFC-IPL) were obtained from single-seed tractography for each ROI and hemisphere. Fractional anisotropy (FA) was calculated to determine the white matter integrity of shared tracts. Results: Significant group differences were detected for FA of all three region pairs in both hemispheres. No significant group differences in hemispheric asymmetry were found. In the ASD group, FA was significantly lower for the left hemisphere (lh) PCC-MFC (0.27+/-0.008 [mean+/-sem] for ASD vs. 0.29+/-0.005 for TD, p=0.04); lh PCC-MTL (0.28+/-0.007 for ASD vs. 0.30+/-0.005 for TD, p=0.03); lh MFC-IPL (0.27+/-0.007 for ASD vs. 0.29+/-0.005 for TD, p=0.05). Similar results were also found for the right hemisphere (rh): rh PCC-MFC (0.29+/-0.007 for ASD vs. 0.31+/-0.004 for TD, p=0.01); rh PCC-MTL (0.29+/-0.007 for ASD vs. 0.31+/-0.005 for TD, p=0.03); rh MFC-IPL (0.28+/-0.007 for ASD vs. 0.30+/-0.004 for TD, p=0.03). Conclusions: These results suggest impairment of white matter tracts among regions of the default mode network in children with ASD, consistent with atypical functional connectivity of this network, as previously reported. Convergent functional and anatomical connectivity findings indicate that the default mode network may be one of (potentially many) atypically organized brain networks contributing to sociocommunicative impairments in ASD.