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1.  White matter microstructure correlates with autism trait severity in a combined clinical–control sample of high-functioning adults☆ 
NeuroImage : Clinical  2013;3:106-114.
Diffusion tensor imaging (DTI) studies have demonstrated white matter (WM) abnormalities in tracts involved in emotion processing in autism spectrum disorder (ASD), but little is known regarding the nature and distribution of WM anomalies in relation to ASD trait severity in adults. Increasing evidence suggests that ASD occurs at the extreme of a distribution of social abilities. We aimed to examine WM microstructure as a potential marker for ASD symptom severity in a combined clinical–neurotypical population. SIENAX was used to estimate whole brain volume. Tract-based spatial statistics (TBSS) was used to provide a voxel-wise comparison of WM microstructure in 50 high-functioning young adults: 25 ASD and 25 neurotypical. The severity of ASD traits was measured by autism quotient (AQ); we examined regressions between DTI markers of WM microstructure and ASD trait severity. Cognitive abilities, measured by intelligence quotient, were well-matched between the groups and were controlled in all analyses. There were no significant group differences in whole brain volume. TBSS showed widespread regions of significantly reduced fractional anisotropy (FA) and increased mean diffusivity (MD) and radial diffusivity (RD) in ASD compared with controls. Linear regression analyses in the combined sample showed that average whole WM skeleton FA was negatively influenced by AQ (p = 0.004), whilst MD and RD were positively related to AQ (p = 0.002; p = 0.001). Regression slopes were similar within both groups and strongest for AQ social, communication and attention switching scores. In conclusion, similar regression characteristics were found between WM microstructure and ASD trait severity in a combined sample of ASD and neurotypical adults. WM anomalies were relatively more severe in the clinically diagnosed sample. Both findings suggest that there is a dimensional relationship between WM microstructure and severity of ASD traits from neurotypical subjects through to clinical ASD, with reduced coherence of WM associated with greater ASD symptoms. General cognitive abilities were independent of the relationship between WM indices and ASD traits.
Highlights
•Novel comparison of white matter microstructure in neurotypical and autistic adults•White matter coherence related to autistic trait severity in combined sample•The relationship between social intelligence and white matter is independent of IQ.•White matter anomalies are significantly more pronounced in the autistic subjects.
doi:10.1016/j.nicl.2013.07.007
PMCID: PMC3791280  PMID: 24179854
Autism spectrum disorder; Autism quotient; Diffusion tensor imaging; Tract-based spatial statistics; White matter
2.  Autism and Sensory Processing Disorders: Shared White Matter Disruption in Sensory Pathways but Divergent Connectivity in Social-Emotional Pathways 
PLoS ONE  2014;9(7):e103038.
Over 90% of children with Autism Spectrum Disorders (ASD) demonstrate atypical sensory behaviors. In fact, hyper- or hyporeactivity to sensory input or unusual interest in sensory aspects of the environment is now included in the DSM-5 diagnostic criteria. However, there are children with sensory processing differences who do not meet an ASD diagnosis but do show atypical sensory behaviors to the same or greater degree as ASD children. We previously demonstrated that children with Sensory Processing Disorders (SPD) have impaired white matter microstructure, and that this white matter microstructural pathology correlates with atypical sensory behavior. In this study, we use diffusion tensor imaging (DTI) fiber tractography to evaluate the structural connectivity of specific white matter tracts in boys with ASD (n = 15) and boys with SPD (n = 16), relative to typically developing children (n = 23). We define white matter tracts using probabilistic streamline tractography and assess the strength of tract connectivity using mean fractional anisotropy. Both the SPD and ASD cohorts demonstrate decreased connectivity relative to controls in parieto-occipital tracts involved in sensory perception and multisensory integration. However, the ASD group alone shows impaired connectivity, relative to controls, in temporal tracts thought to subserve social-emotional processing. In addition to these group difference analyses, we take a dimensional approach to assessing the relationship between white matter connectivity and participant function. These correlational analyses reveal significant associations of white matter connectivity with auditory processing, working memory, social skills, and inattention across our three study groups. These findings help elucidate the roles of specific neural circuits in neurodevelopmental disorders, and begin to explore the dimensional relationship between critical cognitive functions and structural connectivity across affected and unaffected children.
doi:10.1371/journal.pone.0103038
PMCID: PMC4116166  PMID: 25075609
3.  Diffusion Tensor Imaging in Autism Spectrum Disorder: A Review 
Lay Abstract
White matter tracts are like the “highways” of the brain, allowing for fast and efficient communication among diverse brain regions. The purpose of this paper is to review the results of autism studies that have used Diffusion Tensor Imaging (DTI), which is a neuroimaging method that allows us to examine the structure and integrity of these white matter tracts. From the 48 studies we reviewed, persons with ASD tended to have decreased white matter integrity spanning across many regions of the brain but most consistently in regions such as the corpus callosum (connecting the left and right hemispheres and associated with motor skill and complex information processing), the cingulum bundles (connecting regions along the middle-line of the brain with important frontal projections and associated with executive function), and white matter tracts that pass through the temporal lobe (connecting temporal lobe regions with other brain regions and associated with social functioning). The pattern of results in these studies suggests that the white matter tracts may be atypical in persons with ASD. Additionally, the review suggests that people with ASD may not exhibit the typical left-greater-than-right-brain asymmetry in white matter integrity compared to people with typical development. White matter alterations in persons with ASD are a target of emerging interventions and may help identify the brain basis of individual differences in this population.
Scientific Abstract
White matter tracts of the brain allow neurons and neuronal networks to communicate and function with high efficiency. The aim of this review is to briefly introduce Diffusion Tensor Imaging (DTI) methods that examine white matter tracts and then to give an overview of the studies that have investigated white matter integrity in the brains of individuals with Autism Spectrum Disorder (ASD). From the 48 studies we reviewed, persons with ASD tended to have decreased fractional anisotropy and increased mean diffusivity in white matter tracts spanning many regions of the brain but most consistently in regions such as the corpus callosum, cingulum, and aspects of the temporal lobe. This decrease in fractional anisotropy was often accompanied by increased radial diffusivity. Additionally, the review suggests possible atypical lateralization in some white matter tracts of the brain and a possible atypical developmental trajectory of white matter microstructure in persons with ASD. Clinical implications and future research directions are discussed.
doi:10.1002/aur.1243
PMCID: PMC3474893  PMID: 22786754
Diffusion Tensor Imaging; Neuroimaging; Autism; White Matter
4.  Microstructural abnormalities of short-distance white matter fiber tracts in autism spectrum disorder 
Neuropsychologia  2011;49(5):1378-1382.
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 fiber 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.
doi:10.1016/j.neuropsychologia.2011.02.022
PMCID: PMC3482113  PMID: 21333661
Autism spectrum disorder; Diffusion tensor imaging; Brain connectivity; Local connectivity
5.  White matter compromise of callosal and subcortical fiber tracts in children with autism spectrum disorder: a diffusion tensor imaging study 
Objective
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.
Method
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, genu, body and splenium of the corpus callosum, genu, anterior and posterior limbs of the internal capsule, and middle cerebellar peduncle.
Results
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 to TD children. Increased MD was found for the whole brain and 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 middle cerebellar peduncle.
Conclusions
Our findings suggest widespread white matter compromise in children with ASD. Abnormalities in the corpus callosum indicate impaired interhemispheric transfer. Results for 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.
doi:10.1016/j.jaac.2010.08.018
PMCID: PMC3346956  PMID: 21093776
Autism; diffusion tensor imaging; corpus callosum; internal Capsule; middle cerebellar peduncle
6.  Decreased frontal gyrification correlates with altered connectivity in children with autism 
The structural correlates of functional dysconnectivity in autism spectrum disorders (ASD) have been seldom explored, despite the fact that altered functional connectivity is one of the most frequent neuropathological observations in the disorder. We analyzed cerebral morphometry and structural connectivity using multi-modal imaging for 11 children/adolescents with ASD and 11 matched controls. We estimated regional cortical and white matter volumes, as well as vertex-wise measures of cortical thickness and local Gyrification Index (lGI). Diffusion Tensor Images (DTI) were used to measure Fractional Anisotropy (FA) and tractography estimates of short- and long-range connectivity. We observed four clusters of lGI reduction in patients with ASD, three were located in the right inferior frontal region extending to the inferior parietal lobe, and one was in the right medial parieto-occipital region. Reduced volume was found in the anterior corpus callosum, along with fewer inter-hemispheric frontal streamlines. Despite the spatial correspondence of decreased gyrification and reduced long connectivity, we did not observe any significant relationship between the two. However, a positive correlation between lGI and local connectivity was present in all four clusters in patients with ASD. Reduced gyrification in the inferior fronto-parietal and posterior medial cortical regions lends support for early-disrupted cortical growth in both the mirror neuron system and midline structures responsible for social cognition. Early impaired neurodevelopment in these regions may represent an initial substrate for altered maturation in the cerebral networks that support complex social skills. We also demonstrate that gyrification changes are related to connectivity. This supports the idea that an imbalance between short- and long-range white matter tracts not only impairs the integration of information from multiple neural systems, but also alters the shape of the brain early on in autism.
doi:10.3389/fnhum.2013.00750
PMCID: PMC3820980  PMID: 24265612
cortical folding; cerebral morphometry; tractography; neuroimaging; autism spectrum disorder
7.  White matter correlates of sensory processing in autism spectrum disorders 
NeuroImage : Clinical  2014;6:379-387.
Autism spectrum disorder (ASD) has been characterized by atypical socio-communicative behavior, sensorimotor impairment and abnormal neurodevelopmental trajectories. DTI has been used to determine the presence and nature of abnormality in white matter integrity that may contribute to the behavioral phenomena that characterize ASD. Although atypical patterns of sensory responding in ASD are well documented in the behavioral literature, much less is known about the neural networks associated with aberrant sensory processing. To address the roles of basic sensory, sensory association and early attentional processes in sensory responsiveness in ASD, our investigation focused on five white matter fiber tracts known to be involved in these various stages of sensory processing: superior corona radiata, centrum semiovale, inferior longitudinal fasciculus, posterior limb of the internal capsule, and splenium. We acquired high angular resolution diffusion images from 32 children with ASD and 26 typically developing children between the ages of 5 and 8. We also administered sensory assessments to examine brain-behavior relationships between white matter integrity and sensory variables. Our findings suggest a modulatory role of the inferior longitudinal fasciculus and splenium in atypical sensorimotor and early attention processes in ASD. Increased tactile defensiveness was found to be related to reduced fractional anisotropy in the inferior longitudinal fasciculus, which may reflect an aberrant connection between limbic structures in the temporal lobe and the inferior parietal cortex. Our findings also corroborate the modulatory role of the splenium in attentional orienting, but suggest the possibility of a more diffuse or separable network for social orienting in ASD. Future investigation should consider the use of whole brain analyses for a more robust assessment of white matter microstructure.
Highlights
•First study of ASD to link observed sensory behaviors to white matter integrity•Findings suggest that aberrant limbic connectivity is related to tactile defensiveness.•Findings corroborate modulatory role of splenium in orienting.•Findings suggest a more diffuse or separable network for social orienting in ASD.
doi:10.1016/j.nicl.2014.09.018
PMCID: PMC4218938  PMID: 25379451
8.  White matter connectivity in children with autism spectrum disorders: a tract-based spatial statistics study 
BMC Neurology  2012;12:148.
Background
Autism spectrum disorders (ASD) are associated with widespread alterations in white matter (WM) integrity. However, while a growing body of studies is shedding light on microstructural WM alterations in high-functioning adolescents and adults with ASD, literature is still lacking in information about whole brain structural connectivity in children and low-functioning patients with ASD. This research aims to investigate WM connectivity in ASD children with and without mental retardation compared to typically developing controls (TD).
Methods
Diffusion tensor imaging (DTI) was performed in 22 young children with ASD (mean age: 5.54 years) and 10 controls (mean age: 5.25 years). Data were analysed both using the tract-based spatial statistics (TBSS) and the tractography. Correlations were investigated between the WM microstructure in the identified altered regions and the productive language level.
Results
The TBSS analysis revealed widespread increase of fractional anisotropy (FA) in major WM pathways. The tractographic approach showed an increased fiber length and FA in the cingulum and in the corpus callosum and an increased mean diffusivity in the indirect segments of the right arcuate and the left cingulum. Mean diffusivity was also correlated with expressive language functioning in the left indirect segments of the arcuate fasciculus.
Conclusions
Our study confirmed the presence of several structural connectivity abnormalities in young ASD children. In particular, the TBSS profile of increased FA that characterized the ASD patients extends to children a finding previously detected in ASD toddlers only. The WM integrity abnormalities detected may be relevant to the pathophysiology of ASD, since the structures involved participate in some core atypical characteristics of the disorder.
doi:10.1186/1471-2377-12-148
PMCID: PMC3607981  PMID: 23194030
ASD; TBSS; Tractography; Arcuate fasciculs; Language
9.  Age-related abnormalities in white matter microstructure in autism spectrum disorders 
Brain research  2012;1479:1-16.
Abnormalities in structural and functional connectivity have been reported in autism spectrum disorders (ASD) across a wide age range. However, developmental changes in white matter microstructure are poorly understood. We used a cross-sectional design to determine whether white matter abnormalities measured using diffusion tensor imaging (DTI) were present in adolescents and adults with ASD and whether age-related changes in white matter microstructure differed between ASD and typically developing (TD) individuals. Participants included 28 individuals with ASD and 33 TD controls matched on age and IQ and assessed at one time point. Widespread decreased fractional anisotropy (FA), and increased radial diffusivity (RaD) and mean diffusivity (MD) were observed in the ASD group compared to the TD group. In addition, significant group-by-age interactions were also observed in FA, RaD, and MD in all major tracts except the brain stem, indicating that age-related changes in white matter microstructure differed between the groups. We propose that white matter microstructural changes in ASD may reflect myelination and/or other structural differences including differences in axonal density/arborization. In addition, we suggest that white matter microstuctural impairments may be normalizing during young adulthood in ASD. Future longitudinal studies that include a wider range of ages and more extensive clinical characterization will be critical for further uncovering the neurodevelopmental processes unfolding during this dynamic time in development.
doi:10.1016/j.brainres.2012.07.056
PMCID: PMC3513400  PMID: 22902768
autism; white matter; DTI; age; interaction
10.  Linked alterations in gray and white matter morphology in adults with high-functioning autism spectrum disorder: A multimodal brain imaging study 
NeuroImage : Clinical  2014;7:155-169.
Growing evidence suggests that a broad range of behavioral anomalies in people with autism spectrum disorder (ASD) can be linked with morphological and functional alterations in the brain. However, the neuroanatomical underpinnings of ASD have been investigated using either structural magnetic resonance imaging (MRI) or diffusion tensor imaging (DTI), and the relationships between abnormalities revealed by these two modalities remain unclear. This study applied a multimodal data-fusion method, known as linked independent component analysis (ICA), to a set of structural MRI and DTI data acquired from 46 adult males with ASD and 46 matched controls in order to elucidate associations between different aspects of atypical neuroanatomy of ASD. Linked ICA identified two composite components that showed significant between-group differences, one of which was significantly correlated with age. In the other component, participants with ASD showed decreased gray matter (GM) volumes in multiple regions, including the bilateral fusiform gyri, bilateral orbitofrontal cortices, and bilateral pre- and post-central gyri. These GM changes were linked with a pattern of decreased fractional anisotropy (FA) in several white matter tracts, such as the bilateral inferior longitudinal fasciculi, bilateral inferior fronto-occipital fasciculi, and bilateral corticospinal tracts. Furthermore, unimodal analysis for DTI data revealed significant reductions of FA along with increased mean diffusivity in those tracts for ASD, providing further evidence of disrupted anatomical connectivity. Taken together, our findings suggest that, in ASD, alterations in different aspects of brain morphology may co-occur in specific brain networks, providing a comprehensive view for understanding the neuroanatomy of this disorder.
Highlights
•Structural alterations of gray (GM) and white matter (WM) in ASD were investigated.•Linked independent component analysis was used for multimodal data analysis.•Alterations of GM and WM in ASD co-occurred in cognitive and affective networks.•Results reveal an integrative view of multiple aspects of structural changes in ASD.
doi:10.1016/j.nicl.2014.11.019
PMCID: PMC4299973  PMID: 25610777
Autism spectrum disorder; Multimodal brain imaging; Linked independent component analysis; Voxel-based morphometry; Tract-based spatial statistics
11.  Autism Spectrum Disorder as Early Neurodevelopmental Disorder: Evidence from the Brain Imaging Abnormalities in 2–3 Years Old Toddlers 
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that occurs within the first 3 years of life, which is marked by social skills and communication deficits along with stereotyped repetitive behavior. Although great efforts have been made to clarify the underlying neuroanatomical abnormalities and brain-behavior relationships in adolescents and adults with ASD, literature is still limited in information about the neurobiology of ASD in the early age of life. Brain images of 50 toddlers with ASD and 28 age, gender, and developmental quotient matched toddlers with developmental delay (DD) (control group) between ages 2 and 3 years were captured using combined magnetic resonance-based structural imaging and diffusion tensor imaging (DTI). Structural magnetic resonance imaging was applied to assess overall gray matter (GM) and white matter (WM) volumes, and regional alterations were assessed by voxel-based morphometry. DTI was used to investigate the white matter tract integrity. Compared with DD, significant increases were observed in ASD, primarily in global GM and WM volumes and in right superior temporal gyrus regional GM and WM volumes. Higher fractional anisotropy value was also observed in the corpus callosum, posterior cingulate cortex, and limbic lobes of ASD. The converging findings of structural and white matter abnormalities in ASD suggest that alterations in neural-anatomy of different brain regions may be involved in behavioral and cognitive deficits associated with ASD, especially in an early age of 2–3 years old toddlers.
doi:10.1007/s10803-014-2033-x
PMCID: PMC4057630  PMID: 24419870
Autism spectrum disorder; Toddler; Magnetic resonance imaging; Voxel based morphometry; Diffusion tensor imaging
12.  Longitudinal Processing Speed Impairments in Males with Autism and the Effects of White Matter Microstructure 
Neuropsychologia  2013;53:137-145.
The present study used an accelerated longitudinal design to examine group differences and age-related changes in processing speed in 81 individuals with Autism Spectrum Disorder (ASD) compared to 56 age-matched individuals with typical development (ages 6–39 years). Processing speed was assessed using the Wechsler Intelligence Scale for Children-3rd edition (WISC-III) and the Wechsler Adult Intelligence Scale-3rd edition (WAIS-III). Follow-up analyses examined processing speed subtest performance and relations between processing speed and white matter microstructure (as measured with diffusion tensor imaging [DTI] in a subset of these participants). After controlling for full scale IQ, the present results show that processing speed index standard scores were on average 12 points lower in the group with ASD compared to the group with typical development. There were, however, no significant group differences in standard score age-related changes within this age range. For subtest raw scores, the group with ASD demonstrated robustly slower processing speeds in the adult versions of the IQ test (i.e., WAIS-III) but not in the child versions (WISC-III), even though age-related changes were similar in both the ASD and typically developing groups. This pattern of results may reflect difficulties that become increasingly evident in ASD on more complex measures of processing speed. Finally, DTI measures of whole-brain white matter microstructure suggested that fractional anisotropy (but not mean diffusivity, radial diffusivity, or axial diffusivity) made significant but small-sized contributions to processing speed standard scores across our entire sample. Taken together, the present findings suggest that robust decreases in processing speed may be present in ASD, more pronounced in adulthood, and partially attributable to white matter microstructural integrity.
doi:10.1016/j.neuropsychologia.2013.11.008
PMCID: PMC3946881  PMID: 24269298
autism; processing speed; diffusion tensor imaging; white matter; executive function
13.  Brain white matter integrity and association with age at onset in pediatric obsessive-compulsive disorder 
Background
Obsessive-compulsive disorder (OCD) is a common and debilitating neuropsychiatric illness thought to involve abnormal connectivity of widespread brain networks, including frontal-striatal-thalamic circuits. At least half of OCD cases arise in childhood and their underlying neuropathology may differ at least in part from that of adult-onset OCD. Yet, only a few studies have examined brain white matter (WM) integrity in childhood-onset OCD using diffusion tensor imaging (DTI), and none have examined potential associations with age at onset.
Results
In this study, 17 youth with OCD and 19 healthy control subjects, ages 10 to 19 years, underwent DTI on a 3T Siemens scanner. DSM-IV diagnoses were established with standardized interviews, and OCD symptom severity was evaluated using the Children’s Yale-Brown Obsessive-Compulsive Scale (CY-BOCS). Voxel-wise analyses were conducted on data processed with tract-based spatial statistics (TBSS) to derive measures of fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and mean diffusivity (MD). OCD patients had significantly lower FA in seven WM clusters, with over 80% of significant voxels in bilateral frontal cortex and corpus callosum (CC). There were no regions of significantly higher FA in patients compared with controls. Patients also had significantly higher RD in right frontal cortex and right body of the CC. Earlier age at onset of OCD correlated significantly with lower FA in the right thalamus and with higher RD in the right CC. FA and RD were not significantly associated with symptom severity.
Conclusions
These findings point to compromised WM integrity and reduced myelination in some brain regions of children with OCD, particularly the CC and fiber tracts that connect the frontal lobes to widespread cortical and subcortical targets. They also suggest that age at onset may be a moderator of some of the WM changes in pediatric OCD.
doi:10.1186/s13587-014-0013-6
PMCID: PMC4275938  PMID: 25540681
Obsessive-compulsive disorder; Childhood; Diffusion tensor imaging; Corpus callosum; Thalamus; Age at onset
14.  Abnormal White Matter Integrity in Adolescents with Internet Addiction Disorder: A Tract-Based Spatial Statistics Study 
PLoS ONE  2012;7(1):e30253.
Background
Internet addiction disorder (IAD) is currently becoming a serious mental health issue around the globe. Previous studies regarding IAD were mainly focused on associated psychological examinations. However, there are few studies on brain structure and function about IAD. In this study, we used diffusion tensor imaging (DTI) to investigate white matter integrity in adolescents with IAD.
Methodology/Principal Findings
Seventeen IAD subjects and sixteen healthy controls without IAD participated in this study. Whole brain voxel-wise analysis of fractional anisotropy (FA) was performed by tract-based spatial statistics (TBSS) to localize abnormal white matter regions between groups. TBSS demonstrated that IAD had significantly lower FA than controls throughout the brain, including the orbito-frontal white matter, corpus callosum, cingulum, inferior fronto-occipital fasciculus, and corona radiation, internal and external capsules, while exhibiting no areas of higher FA. Volume-of-interest (VOI) analysis was used to detect changes of diffusivity indices in the regions showing FA abnormalities. In most VOIs, FA reductions were caused by an increase in radial diffusivity while no changes in axial diffusivity. Correlation analysis was performed to assess the relationship between FA and behavioral measures within the IAD group. Significantly negative correlations were found between FA values in the left genu of the corpus callosum and the Screen for Child Anxiety Related Emotional Disorders, and between FA values in the left external capsule and the Young's Internet addiction scale.
Conclusions
Our findings suggest that IAD demonstrated widespread reductions of FA in major white matter pathways and such abnormal white matter structure may be linked to some behavioral impairments. In addition, white matter integrity may serve as a potential new treatment target and FA may be as a qualified biomarker to understand the underlying neural mechanisms of injury or to assess the effectiveness of specific early interventions in IAD.
doi:10.1371/journal.pone.0030253
PMCID: PMC3256221  PMID: 22253926
15.  Abnormal Anatomical Connectivity between the Amygdala and Orbitofrontal Cortex in Conduct Disorder 
PLoS ONE  2012;7(11):e48789.
Objective
Previous research suggested that structural and functional abnormalities within the amygdala and orbitofrontal cortex contribute to the pathophysiology of Conduct Disorder (CD). Here, we investigated whether the integrity of the white-matter pathways connecting these regions is abnormal and thus may represent a putative neurobiological marker for CD.
Methods
Diffusion Tensor Imaging (DTI) was used to investigate white-matter microstructural integrity in male adolescents with childhood-onset CD, compared with healthy controls matched in age, sex, intelligence, and socioeconomic status. Two approaches were employed to analyze DTI data: voxel-based morphometry of fractional anisotropy (FA), an index of white-matter integrity, and virtual dissection of white-matter pathways using tractography.
Results
Adolescents with CD displayed higher FA within the right external capsule relative to controls (T = 6.08, P<0.05, Family-Wise Error, whole-brain correction). Tractography analyses showed that FA values within the uncinate fascicle (connecting the amygdala and orbitofrontal cortex) were abnormally increased in individuals with CD relative to controls. This was in contrast with the inferior frontal-occipital fascicle, which showed no significant group differences in FA. The finding of increased FA in the uncinate fascicle remained significant when factoring out the contribution of attention-deficit/hyperactivity disorder symptoms. There were no group differences in the number of streamlines in either of these anatomical tracts.
Conclusions
These results provide evidence that CD is associated with white-matter microstructural abnormalities in the anatomical tract that connects the amygdala and orbitofrontal cortex, the uncinate fascicle. These results implicate abnormal maturation of white-matter pathways which are fundamental in the regulation of emotional behavior in CD.
doi:10.1371/journal.pone.0048789
PMCID: PMC3492256  PMID: 23144970
16.  Altered functional and structural brain network organization in autism☆ 
NeuroImage : Clinical  2012;2:79-94.
Structural and functional underconnectivity have been reported for multiple brain regions, functional systems, and white matter tracts in individuals with autism spectrum disorders (ASD). Although recent developments in complex network analysis have established that the brain is a modular network exhibiting small-world properties, network level organization has not been carefully examined in ASD. Here we used resting-state functional MRI (n = 42 ASD, n = 37 typically developing; TD) to show that children and adolescents with ASD display reduced short and long-range connectivity within functional systems (i.e., reduced functional integration) and stronger connectivity between functional systems (i.e., reduced functional segregation), particularly in default and higher-order visual regions. Using graph theoretical methods, we show that pairwise group differences in functional connectivity are reflected in network level reductions in modularity and clustering (local efficiency), but shorter characteristic path lengths (higher global efficiency). Structural networks, generated from diffusion tensor MRI derived fiber tracts (n = 51 ASD, n = 43 TD), displayed lower levels of white matter integrity yet higher numbers of fibers. TD and ASD individuals exhibited similar levels of correlation between raw measures of structural and functional connectivity (n = 35 ASD, n = 35 TD). However, a principal component analysis combining structural and functional network properties revealed that the balance of local and global efficiency between structural and functional networks was reduced in ASD, positively correlated with age, and inversely correlated with ASD symptom severity. Overall, our findings suggest that modeling the brain as a complex network will be highly informative in unraveling the biological basis of ASD and other neuropsychiatric disorders.
Highlights
► Complex network analysis of resting-state fMRI and DTI tractography in autism ► Local and long-range functional connectivity is reduced in ASD. ► Reduced local efficiency and modularity of functional networks in ASD ► Altered age-related trajectory of global efficiency for structural networks in ASD
doi:10.1016/j.nicl.2012.11.006
PMCID: PMC3777708  PMID: 24179761
Resting-state functional connectivity; Diffusion tensor imaging; Graph theory; Brain networks; Autism spectrum disorders
17.  Abnormal white matter microstructure in children with sensory processing disorders☆ 
NeuroImage : Clinical  2013;2:844-853.
Sensory processing disorders (SPD) affect 5–16% of school-aged children and can cause long-term deficits in intellectual and social development. Current theories of SPD implicate primary sensory cortical areas and higher-order multisensory integration (MSI) cortical regions. We investigate the role of white matter microstructural abnormalities in SPD using diffusion tensor imaging (DTI). DTI was acquired in 16 boys, 8–11 years old, with SPD and 24 age-, gender-, handedness- and IQ-matched neurotypical controls. Behavior was characterized using a parent report sensory behavior measure, the Sensory Profile. Fractional anisotropy (FA), mean diffusivity (MD) and radial diffusivity (RD) were calculated. Tract-based spatial statistics were used to detect significant group differences in white matter integrity and to determine if microstructural parameters were significantly correlated with behavioral measures. Significant decreases in FA and increases in MD and RD were found in the SPD cohort compared to controls, primarily involving posterior white matter including the posterior corpus callosum, posterior corona radiata and posterior thalamic radiations. Strong positive correlations were observed between FA of these posterior tracts and auditory, multisensory, and inattention scores (r = 0.51–0.78; p < 0.001) with strong negative correlations between RD and multisensory and inattention scores (r = − 0.61–0.71; p < 0.001). To our knowledge, this is the first study to demonstrate reduced white matter microstructural integrity in children with SPD. We find that the disrupted white matter microstructure predominantly involves posterior cerebral tracts and correlates strongly with atypical unimodal and multisensory integration behavior. These findings suggest abnormal white matter as a biological basis for SPD and may also distinguish SPD from overlapping clinical conditions such as autism and attention deficit hyperactivity disorder.
Highlights
•Abnormal posterior white matter microstructure in sensory processing disorders (SPD)•Posterior cerebral white matter microstructure correlates with sensory behavior.•DTI may help distinguish SPD from autism spectrum disorder and ADHD.•DTI may yield prognostic and predictive biomarkers of SPD for clinical use.
doi:10.1016/j.nicl.2013.06.009
PMCID: PMC3778265  PMID: 24179836
Attention deficit hyperactivity disorder (ADHD); Autism; Brain development; Connectivity; Diffusion tensor imaging (DTI); Pediatrics
18.  Gray and white matter water diffusion in the syndromic variants of frontotemporal dementia 
Neurology  2010;74(16):1279-1287.
Objective:
To use diffusion tensor imaging (DTI) to assess gray matter and white matter tract diffusion in behavioral variant frontotemporal dementia (bvFTD), semantic dementia (SMD), and progressive nonfluent aphasia (PNFA).
Methods:
This was a case-control study where 16 subjects with bvFTD, 7 with PNFA, and 4 with SMD were identified and matched by age and gender to 19 controls. All subjects had 3-T head MRI with a DTI sequence with diffusion encoding in 21 directions. Gray matter mean diffusivity (MD) was assessed using a region-of-interest (ROI) and voxel-level approach, and voxel-based morphometry was used to assess patterns of gray matter loss. White matter tract diffusivity (fractional anisotropy and radial diffusivity) was assessed by placing ROIs on tracts of interest.
Results:
In bvFTD, increased gray matter MD and gray matter loss were identified bilaterally throughout frontal and temporal lobes, with abnormal diffusivity observed in white matter tracts that connect to these regions. In SMD, gray matter loss and increased MD were identified predominantly in the left temporal lobe, with tract abnormalities observed in the inferior longitudinal fasciculus and uncinate fasciculus. In PNFA, gray matter loss and increased MD were observed in left inferior frontal lobe, insula, and supplemental motor area, with tract abnormalities observed in the superior longitudinal fasciculus.
Conclusions:
The diffusivity of gray matter is increased in regions that are atrophic in frontotemporal dementia, suggesting disruption of the cytoarchitecture of remaining tissue. Furthermore, damage was identified in white matter tracts that interconnect these regions, supporting the hypothesis that these diseases involve different and specific brain networks.
GLOSSARY
= automated anatomic labeling;
= anterior cingulate;
= Alzheimer's Disease Research Center;
= Alzheimer's Disease Patient Registry;
= apraxia of speech;
= behavioral variant frontotemporal dementia;
= coefficient of variation;
= axial diffusivity;
= radial diffusivity;
= diffusion tensor imaging;
= fractional anisotropy;
= false discovery rate;
= field of view;
= frontotemporal dementia;
= full-width at half-maximum;
= genu of the corpus callosum;
= high-dimensional warping;
= inferior longitudinal fasciculus;
= mean diffusivity;
= magnetization prepared rapid acquisition gradient echo;
= posterior cingulate;
= progressive nonfluent aphasia;
= partial volume correction;
= region of interest;
= superior longitudinal fasciculus;
= semantic dementia;
= uncinate fasciculus.
doi:10.1212/WNL.0b013e3181d9edde
PMCID: PMC2860485  PMID: 20404309
19.  Diffusion Tensor Imaging of Frontal Lobe in Autism Spectrum Disorder 
Cerebral Cortex (New York, NY)  2008;18(11):2659-2665.
To investigate frontal lobe white matter in children with autism spectrum disorder (ASD), we performed diffusion tensor imaging (DTI) in 50 ASD children (mean age: 57.5 ± 29.2 months, 43 males) and 16 typically developing children (mean age: 82.1 ± 41.4 months, 11 males). The apparent diffusion coefficient (ADC) was significantly higher for whole frontal lobe (P = 0.011), long (P < 0.001) and short range (P = 0.0126) association fibers in ASD group. There was a trend toward statistical significance in the fractional anisotropy (FA) of whole frontal lobe fibers (P = 0.11). FA was significantly lower in ASD group for short range fibers (P = 0.0031) but not for long range fibers (P = not significant [NS]). There was no between-group difference in the number of frontal lobe fibers (short and long) (P = NS). The fiber length distribution was significantly more positively skewed in the normal population than in the ASD group (P < 0.001). The long range association fibers of frontal lobe were significantly longer in ASD group (P = 0.026 for both left and right hemispheres). Abnormal frontal FA and ADC may be due to white matter organization abnormalities in ASD. Lack of evidence for excessive short range connectivity in ASD in this study may need to be re-examined with future advances in DTI technology.
doi:10.1093/cercor/bhn031
PMCID: PMC2567426  PMID: 18359780
apparent diffusion coefficient; fractional anisotropy; magnetic resonance imaging; short range connectivity; tractography
20.  White matter impairment in the speech network of individuals with autism spectrum disorder☆ 
NeuroImage : Clinical  2013;3:234-241.
Impairments in language and communication are core features of Autism Spectrum Disorder (ASD), and a substantial percentage of children with ASD do not develop speech. ASD is often characterized as a disorder of brain connectivity, and a number of studies have identified white matter impairments in affected individuals. The current study investigated white matter integrity in the speech network of high-functioning adults with ASD. Diffusion tensor imaging (DTI) scans were collected from 18 participants with ASD and 18 neurotypical participants. Probabilistic tractography was used to estimate the connection strength between ventral premotor cortex (vPMC), a cortical region responsible for speech motor planning, and five other cortical regions in the network of areas involved in speech production. We found a weaker connection between the left vPMC and the supplementary motor area in the ASD group. This pathway has been hypothesized to underlie the initiation of speech motor programs. Our results indicate that a key pathway in the speech production network is impaired in ASD, and that this impairment can occur even in the presence of normal language abilities. Therapies that result in normalization of this pathway may hold particular promise for improving speech output in ASD.
Highlights
•We used diffusion tensor imaging to measure white matter (WM) tracts in autism.•Autistic participants were high-functioning individuals with normal language skills.•WM between left supplementary motor and premotor areas is impaired in autism.•This tract is believed to be involved in the initiation of speech articulation.•Speech production may be impaired in the absence of language deficits in autism.
doi:10.1016/j.nicl.2013.08.011
PMCID: PMC3815014  PMID: 24273708
Autism; ASD; Speech; Diffusion tensor imaging; Tractography; Communication
21.  Sharp Curvature of Frontal Lobe White Matter Pathways in Children with Autism Spectrum Disorder: Tract-Based Morphometry Analysis 
AJNR. American journal of neuroradiology  2011;32(9):10.3174/ajnr.A2557.
Background and Purpose
As we had previously observed geometrical changes of frontal lobe association pathways in children with autism spectrum disorder (ASD), in the present study we analyzed the curvature of these white matter pathways using an objective tract based morphometry (TBM) analysis.
Materials and Methods
Diffusion tensor imaging (DTI) was performed in 32 children with ASD and 14 children with typical development. Curvature, fractional anisotropy (FA), axial diffusivity (AD), and radial diffusivity (RD) of bilateral arcuate fasciculus (AF), uncinate fasciculus (UF), and genu of corpus callosum (gCC) were investigated using the TBM group analysis assessed by False Discovery Rate p-value (PFDR) for multiple comparisons.
Results
Significantly higher curvatures were found in children with ASD especially at the parieto-temporal junction for AF (left: PFDR < 0.001; right: PFDR < 0.01), at the fronto-temporal junction for UF (left: PFDR < 0.005; right: PFDR < 0.03), and at the midline of the gCC (PFDR < 0.0001). RD was significantly higher in children with ASD at the same bending regions of AF (left: PFDR < 0.03, right: PFDR < 0.02), UF (left: PFDR < 0.04), and gCC (PFDR < 0.01).
Conclusion
Higher curvature and curvature dependent RD changes in children with ASD may be the result of higher density of thinner axons in these frontal lobe tracts.
doi:10.3174/ajnr.A2557
PMCID: PMC3868442  PMID: 21757519
Autisim spectrum disorders; Diffusion tensor MRI; Frontal lobe white matter pathways; Curvature; Diffusivity
22.  Functional Brain Networks and White Matter Underlying Theory-of-Mind in Autism 
Human beings constantly engage in attributing causal explanations to one’s own and to others’ actions, and theory-of-mind (ToM) is critical in making such inferences. Although children learn causal attribution early in development, children with autism spectrum disorders (ASDs) are known to have impairments in the development of intentional causality. This functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) study investigated the neural correlates of physical and intentional causal attribution in people with ASDs. In the fMRI scanner, 15 adolescents and adults with ASDs and 15 age- and IQ-matched typically developing peers made causal judgments about comic strips presented randomly in an event-related design. All participants showed robust activation in bilateral posterior superior temporal sulcus at the temporo-parietal junction (TPJ) in response to intentional causality. Participants with ASDs showed lower activation in TPJ, right inferior frontal gyrus and left premotor cortex. Significantly weaker functional connectivity was also found in the ASD group between TPJ and motor areas during intentional causality. DTI data revealed significantly reduced fractional anisotropy in ASD participants in white matter underlying the temporal lobe. In addition to underscoring the role of TPJ in ToM, this study found an interaction between motor simulation and mentalizing systems in intentional causal attribution and its possible discord in autism.
doi:10.1093/scan/nss106
PMCID: PMC3871731  PMID: 22977198
functional MRI; theory-of-mind; intentional causality; physical causality; causal attribution; diffusion tensor imaging; fractional anisotropy; functional connectivity; autism
23.  Diffusion tensor imaging in autism spectrum disorders: Preliminary evidence of abnormal neural connectivity 
Objective
This study indirectly tested the hypothesis that individuals with autism spectrum disorders (ASDs) have impaired neural connections between the amygdala, fusiform face area, and superior temporal sulcus, key processing nodes of the “social brain.” This would be evidenced by abnormalities in the major fibre tracts known to connect these structures, including the inferior longitudinal fasciculus and inferior fronto-occipital fasciculus.
Method
Magnetic resonance diffusion tensor imaging was performed on 20 right-handed males (ASD = 10, controls = 10) with a mean age 13.5 ± 4.0 years. Subjects were group-matched according to age, full-scale IQ, handedness, and ethnicity. Fractional anisotropy was used to assess structural integrity of major fibre tracts. Voxel-wise comparison of white matter fractional anisotropy was conducted between groups using ANCOVA adjusting for age, full-scale IQ, and brain volume. Volumes of interest were identified using predetermined probability and cluster thresholds. Follow-up tractography was performed to confirm the anatomic location of all volumes of interest.
Results
All volumes of interest were regions of lower FA and were observed primarily in pericallosal regions and temporal lobes. As confirmed by tractography, affected white matter structures included the inferior longitudinal fasciculus/inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and corpus callosum/cingulum. Notably, some volumes of interest were adjacent to the fusiform face area, bilaterally, corresponding to involvement of the inferior longitudinal fasciculus. The largest effect sizes were noted for volumes of interest in the right anterior radiation of the corpus callosum/cingulum and right fusiform face area (inferior longitudinal fasciculus).
Conclusions
This study provides preliminary evidence of impaired neural connectivity in the corpus callosum/cingulum and temporal lobes involving the inferior longitudinal fasciculus/inferior fronto-occipital fasciculus and superior longitudinal fasciculus in ASDs. These findings provide preliminary support for aberrant neural connectivity between the amygdala, fusiform face area, and superior temporal sulcus – temporal lobe structures critical for normal social perception and cognition.
doi:10.3109/00048674.2010.534069
PMCID: PMC3123660  PMID: 21128874
autism; connectivity; diffusion tensor imaging; social brain; white matter
24.  Altered white matter microstructure underlies listening difficulties in children suspected of auditory processing disorders: a DTI study 
Brain and Behavior  2014;4(4):531-543.
Introduction
The purpose of the present study was to identify biomarkers of listening difficulties by investigating white matter microstructure in children suspected of auditory processing disorder (APD) using diffusion tensor imaging (DTI). Behavioral studies have suggested that impaired cognitive and/or attention abilities rather than a pure sensory processing deficit underlie listening difficulties and auditory processing disorder (APD) in children. However, the neural signature of listening difficulties has not been investigated.
Methods
Twelve children with listening difficulties and atypical left ear advantage (LEA) in dichotic listening and twelve age- and gender-matched typically developing children with typical right ear advantage (REA) were tested. Using voxel-based analysis, fractional anisotropy (FA), and mean, axial and radial diffusivity (MD, AD, RD) maps were computed and contrasted between the groups.
Results
Listening difficulties were associated with altered white matter microstructure, reflected by decreased FA in frontal multifocal white matter regions centered in prefrontal cortex bilaterally and left anterior cingulate. Increased RD and decreased AD accounted for the decreased FA, suggesting delayed myelination in frontal white matter tracts and disrupted fiber organization in the LEA group. Furthermore, listening difficulties were associated with increased MD (with increase in both RD and AD) in the posterior limb of the internal capsule (sublenticular part) at the auditory radiations where auditory input is transmitted between the thalamus and the auditory cortex.
Conclusions
Our results provide direct evidence that listening difficulties in children are associated with altered white matter microstructure and that both sensory and supramodal deficits underlie the differences between the groups.
doi:10.1002/brb3.237
PMCID: PMC4128035  PMID: 25161820
Attention; auditory processing disorder; dichotic listening; diffusion tensor imaging; listening difficulties
25.  Is depression a disconnection syndrome? Meta-analysis of diffusion tensor imaging studies in patients with MDD 
Background
Many studies using diffusion tensor imaging (DTI) have demonstrated impaired white matter integrity in patients with major depressive disorder (MDD), with significant results found in diverse brain regions. We sought to identify whether there are consistent changes of regional white matter integrity in patients with MDD, as shown by decreased fractional anisotropy in DTI.
Method
A systematic search strategy was used to identify relevant whole brain voxel-based DTI studies of patients with MDD in relation to comparison groups. Relevant databases were searched for studies published between January 1994 and February 2011 using combinations of the terms “DTI” or “diffusion tensor;” “whole brain” or “voxel-based;” and “depress*.” Using the studies that met our inclusion criteria, we performed a meta-analysis of the coordinates of decreased fractional anisotropy using the activation likelihood estimation (ALE) method, which detects 3-dimensional conjunctions of coordinates from multiple studies, weighted by sample size. We then used DTIquery software for fibre tracking to locate the fascicles involved in each region.
Results
We included 11 studies with a combined sample of 231 patients with MDD and 261 comparison participants, providing 50 coordinates of decreased fractional anisotropy. Our meta-analysis identified 4 consistent locations of decreased fractional anisotropy in patients with MDD: white matter in the right frontal lobe, right fusiform gyrus, left frontal lobe and right occipital lobe. Fibre tracking showed that the main fascicles involved were the right inferior longitudinal fasciculus, right inferior fronto-occipital fasciculus, right posterior thalamic radiation and interhemispheric fibres running through the genu and body of the corpus callosum.
Limitations
The number of studies included was relatively small, and the DTI data acquisition and analysis techniques were heterogeneous. The ALE method cannot handle studies with no significant group differences.
Conclusion
Voxel-based analysis of DTI studies of patients with MDD consistently identified decreased fractional anisotropy in the white matter fascicles connecting the prefrontal cortex within cortical (frontal, temporal and occipital lobes) and subcortical areas (amygdala and hippocampus). This is strong evidence for the involvement of these neural circuits in the pathology of MDD.
doi:10.1503/jpn.110180
PMCID: PMC3529219  PMID: 22691300

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