Fixel Based Analysis Reveals Atypical White Matter Micro- and Macrostructure in Adults With Autism Spectrum Disorder: An Investigation of the Role of Biological Sex.
ABSTRACT: Atypical white matter (WM) microstructure is commonly implicated in the neuropathophysiology of autism spectrum disorder (ASD). Fixel based analysis (FBA), at the cutting-edge of diffusion-weighted imaging, can account for crossing WM fibers and can provide indices of both WM micro- and macrostructure. We applied FBA to investigate WM structure between 25 (12 males, 13 females) adults with ASD and 24 (12 males, 12 females) matched controls. As the role of biological sex on the neuropathophysiology of ASD is of increasing interest, this was also explored. There were no significant differences in WM micro- or macrostructure between adults with ASD and matched healthy controls. When data were stratified by sex, females with ASD had reduced fiber density and cross-section (FDC), a combined metric comprised of micro- and macrostructural measures, in the corpus callosum, a finding not detected between the male sub-groups. We conclude that micro- and macrostructural WM aberrations are present in ASD, and may be influenced by biological sex.
Project description:Diffusion tensor imaging is often used to assess white matter (WM) changes following traumatic brain injury (TBI), but is limited in voxels that contain multiple fibre tracts. Fixel-based analysis (FBA) addresses this limitation by using a novel method of analysing high angular resolution diffusion-weighted imaging (HARDI) data. FBA examines three aspects of each fibre tract within a voxel: tissue micro-structure (fibre density [FD]), tissue macro-structure (fibre-bundle cross section [FC]) and a combined measure of both (FD and fibre-bundle cross section [FDC]). This study used FBA to identify the location and extent of micro- and macro-structural changes in WM following TBI. A large TBI sample (Nmild =?133, Nmoderate-severe =?29) and control group (healthy and orthopaedic; N =?107) underwent magnetic resonance imaging with HARDI and completed reaction time tasks approximately 7?months after their injury (range: 98-338?days). The TBI group showed micro-structural differences (lower FD) in the corpus callosum and forceps minor, compared to controls. Subgroup analyses revealed that the mild TBI group did not differ from controls on any fixel metric, but the moderate to severe TBI group had significantly lower FD, FC and FDC in multiple WM tracts, including the corpus callosum, cerebral peduncle, internal and external capsule. The moderate to severe TBI group also had significantly slower reaction times than controls, but the mild TBI group did not. Reaction time was not related to fixel findings. Thus, the WM damage caused by moderate to severe TBI manifested as fewer axons and a reduction in the cross-sectional area of key WM tracts.
Project description:Diffusion MRI (dMRI) studies using the tensor model have identified abnormal white matter development associated with perinatal risk factors in preterm infants studied at term equivalent age (TEA). However, this model is an oversimplification of the underlying neuroanatomy. Fixel-based analysis (FBA) is a novel quantitative framework, which identifies microstructural and macrostructural changes in individual fibre populations within voxels containing crossing fibres. The aim of this study was to apply FBA to investigate the relationship between fixel-based measures of apparent fibre density (FD), fibre bundle cross-section (FC), and fibre density and cross-section (FDC) and perinatal risk factors in preterm infants at TEA. We studied 50 infants (28 male) born at 24.0-32.9 (median 30.4) weeks gestational age (GA) and imaged at 38.6-47.1 (median 42.1) weeks postmenstrual age (PMA). dMRI data were acquired in non-collinear directions with b-value 2500 s/mm2 on a 3 Tesla system sited on the neonatal intensive care unit. FBA was performed to assess the relationship between FD, FC, FDC and PMA at scan, GA at birth, days on mechanical ventilation, days on total parenteral nutrition (TPN), birthweight z-score, and sex. FBA reveals fibre population-specific alterations in FD, FC and FDC associated with clinical risk factors. FD was positively correlated with GA at birth and was negatively correlated with number of days requiring ventilation. FC was positively correlated with GA at birth, birthweight z-scores and was higher in males. FC was negatively correlated with number of days on ventilation and days on TPN. FDC was positively correlated with GA at birth and birthweight z-scores, negatively correlated with days on ventilation and days on TPN and higher in males. We demonstrate that these relationships are fibre-specific even within regions of crossing fibres. These results show that aberrant white matter development involves both microstructural changes and macrostructural alterations.
Project description:BACKGROUND:The core symptoms of autism spectrum disorder (ASD) are widely theorized to result from altered brain connectivity. Diffusion-weighted magnetic resonance imaging (DWI) has been a versatile method for investigating underlying microstructural properties of white matter (WM) in ASD. Despite phenotypic and etiological heterogeneity, DWI studies in majority male samples of older children, adolescents, and adults with ASD have largely reported findings of decreased fractional anisotropy (FA) across several commissural, projection, and association fiber tracts. However, studies in preschool-aged children (i.e., <?30-40?months) suggest individuals with ASD have increased measures of WM FA earlier in development. METHODS:We analyzed 127 individuals with ASD (85?, 42?) and 54 typically developing (TD) controls (42?, 26?), aged 25.1-49.6?months. Voxel-wise effects of ASD diagnosis, sex, age, and their interaction on DWI measures of FA, mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity (AD) were investigated using tract-based spatial statistics (TBSS) while controlling mean absolute and relative motion. RESULTS:Compared to TD controls, males and females with ASD had significantly increased measures of FA in eight clusters (threshold-free cluster enhancement p < 0.05) that incorporated several WM tracts including regions of the genu, body, and splenium of the corpus callosum, inferior frontal-occipital fasciculi, inferior and superior longitudinal fasciculi, middle and superior cerebellar peduncles, and corticospinal tract. A diagnosis by sex interaction was observed in measures of AD across six significant clusters incorporating areas of the body, genu, and splenium of the corpus collosum. In these tracts, females with ASD showed increased AD compared to TD females, while males with ASD showed decreased AD compared to TD males. CONCLUSIONS:The current findings support growing evidence that preschool-aged children with ASD have atypical measures of WM microstructure that appear to differ in directionality from alterations observed in older individuals with the condition. To our knowledge, this study represents the largest sample of preschool-aged females with ASD to be evaluated using DWI. Microstructural differences associated with ASD largely overlapped between sexes. However, differential relationships of AD measures indicate that sex likely modulates ASD neuroanatomical phenotypes. Further longitudinal study is needed to confirm and quantify the developmental relationship of WM structure in ASD.
Project description:Although language impairment is commonly associated with the autism spectrum disorder (ASD), the Diagnostic Statistical Manual no longer includes language impairment as a necessary component of an ASD diagnosis (American Psychiatric Association, 2013). However, children with ASD and no comorbid intellectual disability struggle with some aspects of language whose precise nature is still outstanding. Narratives have been extensively used as a tool to examine lexical and syntactic abilities, as well as pragmatic skills in children with ASD. This study contributes to this literature by investigating the narrative skills of 30 Greek-speaking children with ASD and normal non-verbal IQ, 16 with language skills in the upper end of the normal range (ASD-HL), and 14 in the lower end of the normal range (ASD-LL). The control group consisted of 15 age-matched typically-developing (TD) children. Narrative performance was measured in terms of both microstructural and macrostructural properties. Microstructural properties included lexical and syntactic measures of complexity such as subordinate vs. coordinate clauses and types of subordinate clauses. Macrostructure was measured in terms of the diversity in the use of internal state terms (ISTs) and story structure complexity, i.e., children's ability to produce important units of information that involve the setting, characters, events, and outcomes of the story, as well as the characters' thoughts and feelings. The findings demonstrate that high language ability and syntactic complexity pattern together in ASD children's narrative performance and that language ability compensates for autistic children's pragmatic deficit associated with the production of Theory of Mind-related ISTs. Nevertheless, both groups of children with ASD (high and low language ability) scored lower than the TD controls in the production of Theory of Mind-unrelated ISTs, modifier clauses and story structure complexity.
Project description:<h4>Background</h4>Macro- and micro-structural neuroimaging measures provide valuable information on the pathophysiology of Huntington's disease (HD) and are proposed as biomarkers. Despite theoretical advantages of microstructural measures in terms of sensitivity to pathology, there is little evidence directly comparing the two.<h4>Methods</h4>40 controls and 61 early HD subjects underwent 3 T MRI (T1- and diffusion-weighted), as part of the PADDINGTON study. Macrostructural volumetrics were obtained for the whole brain, caudate, putamen, corpus callosum (CC) and ventricles. Microstructural diffusion metrics of fractional anisotropy (FA), mean-, radial- and axial-diffusivity (MD, RD, AD) were computed for white matter (WM), CC, caudate and putamen. Group differences were examined adjusting for age, gender and site. A formal comparison of effect sizes determined which modality and metrics provided a statistically significant advantage over others.<h4>Results</h4>Macrostructural measures showed decreased regional and global volume in HD (p < 0.001); except the ventricles which were enlarged (p < 0.01). In HD, FA was increased in the deep grey-matter structures (p < 0.001), and decreased in the WM (CC, p = 0.035; WM, p = 0.053); diffusivity metrics (MD, RD, AD) were increased for all brain regions (p < 0.001). The largest effect sizes were for putamen volume, caudate volume and putamen diffusivity (AD, RD and MD); each was significantly larger than those for all other metrics (p < 0.05).<h4>Conclusion</h4>The highest performing macro- and micro-structural metrics had similar sensitivity to HD pathology quantified via effect sizes. Region-of-interest may be more important than imaging modality, with deep grey-matter regions outperforming the CC and global measures, for both volume and diffusivity. FA appears to be relatively insensitive to disease effects.
Project description:BACKGROUND:Autism spectrum disorder (ASD) is more prevalent in male than female individuals. Very few studies have examined sex modulations of brain anatomical differences between individuals with ASD and typically developing (TD) individuals, especially in children. The current study aimed to identify sex-dependent and/or sex-independent neuroanatomical mechanisms underlying ASD. METHODS:Magnetic resonance imaging data were acquired from the Autism Brain Imaging Data Exchange. A 2 (diagnosis) × 2 (sex) design was used. Subjects whose ages were between 6 and 20 years were included for analysis, with matched full-scale IQ between groups for each dataset. The resulting effective numbers of subjects were 36 female subjects with ASD, 54 TD female subjects, 182 male subjects with ASD, and 172 TD male subjects. Twenty independent gray matter (GM) and 20 white matter (WM) volume sources were estimated using source-based morphometry. RESULTS:Among all the independent GM and WM sources, none of them showed a significant diagnosis by sex interaction. One GM source of the bilateral inferior and middle temporal lobe showed a significantly larger volume in ASD than TD individuals and in male than in female subjects. This diagnosis effect was age sensitive and was present only in participants between 8 and 14 years of age. CONCLUSIONS:Only sex-independent, large-scale neuroanatomical alterations could be observed in children with ASD. The directionality of bilateral temporal GM alterations was in line with the prediction of the extreme male brain hypothesis, supporting the view that similar neurobiological mechanisms may drive sexual dimorphism and the onset of ASD.
Project description:BACKGROUND:Mounting evidence suggests that autism is a network disorder, characterized by atypical brain connectivity, especially in the context of high level cognitive processes such as working memory (WM). Accordingly, atypical WM processes have been related to the social and cognitive deficits observed in children with autism spectrum disorder (ASD). METHODS:We used magnetoencephalography (MEG) to investigate connectivity differences during a high memory load (2-back) WM task between 17 children with ASD and 20 age-, sex-, and IQ-matched controls. RESULTS:We identified reduced inter-regional alpha-band (9-15 Hz) phase synchronization in children with ASD during the WM task. Reduced WM-related brain synchronization encompassed fronto-temporal networks (ps < 0.04 corrected) previously associated with challenging high-level conditions (i.e. the left insula and the anterior cingulate cortex (ACC)) and memory encoding and/or recognition (i.e. the right middle temporal gyrus and the right fusiform gyrus). Additionally, we found that reduced connectivity processes related to the right fusiform were correlated with the severity of symptoms in children with ASD, suggesting that such atypicalities could be directly related to the behavioural deficits observed. DISCUSSION:This study provides new evidence of atypical long-range synchronization in children with ASD in fronto-temporal areas that crucially contribute to challenging WM tasks, but also emotion regulation and social cognition processes. Thus, these results support the network disorder hypothesis of ASD and argue for a specific pathophysiological contribution of brain processes related to working memory and executive functions on the symptomatology of autism.
Project description:Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology.
Project description:Sex differences in cerebral white matter (WM) aging have been debated extensively over the past 2 decades without unequivocal resolution. We aimed to determine if the effects of age and arterial stiffness on WM microstructure differ between sexes. Artery elasticity via carotid artery compliance (CAC) and WM diffusion metrics via diffusion tensor image-derived fractional anisotropy (FA) and mean diffusivity (MD) were measured in 155 (87 females) middle-aged (40-62 years) adults. Males demonstrated poorer water diffusion metrics in WM than women in the corpus callosum body, cingulum, and cingulum (hippocampal). Age and CAC had greater effects on WM water diffusion in males than females in midlife independent of education and cardiovascular risk factors. Sex-moderated age (cingulum FA, cingulum [hippocampal] MD, and uncinate MD, all p < 0.05) and CAC (cingulum FA, p < 0.05) related reductions in regional WM diffusion metrics. CAC mediated age-related associations in regional WM diffusion metrics (cingulum FA, cingulum MD, superior corona radiata MD, and uncinate MD, all p < 0.05) in males but not in females. Age and CAC were associated with WM diffusion metrics independent of cardiovascular risk factors. These associations appear to be stronger in males than in females.
Project description:OBJECTIVES:The aim of this study was to evaluate the morphological changes of the femur in the coronal plane in progressing varus gonarthrosis and to explore the interrelation of each component. PATIENTS AND METHODS:From January to July 2017, radiographic images of 1538 knees of 883 consecutive patients were collected and analyzed. We drew the alignments and measured the orientation angles of the lower extremities and compared the results among age groups for each sex. Correlation and regression tests were used to analyze the measurements. RESULTS:There were significant differences in the neck-shaft angle (NSA), femoral bowing angle (FBA) and anatomic medial distal femoral angle (aMDFA) by age group in females, whereas the differences were not significant in males. In females, a positive correlation was found between age and the FBA and aMDFA (r = 0.253, 0.141, p<0.01), and a negative correlation was found between age and the NSA while the FBA was controlled (r = -0.065, p<0.05). The FBA was positively correlated with the NSA (r = 0.312, p<0.01) and aMDFA (r = 0.233, p<0.01). The NSA, FBA, and aMDFA together affected 72.2% of the mechanical medial distal femoral angle (mMDFA) (? = 0.071, -0.528, 0.803, p<0.01). CONCLUSION:As knee osteoarthritis (KOA) progressed, dynamic deformation of the femur was found in females, while no obvious changes were found in males. Femoral mechanical axis varus (mMDFA decrease) was the result of changes in the NSA, FBA and aMDFA. The deformation was throughout the femur rather than in a local area, as femur bowing can lead to corresponding changes in both ends of the femur. We provided a theoretical basis for TKA and knee-salvage treatment, and more attention should be paid to aging patients, especially females, in the preoperative protocol for orthomorphia.