White Matter Fiber Density Research Articles

Adrenarcheal hormone-related development of white matter during late childhood

The aim of the current study was to longitudinally examine how adrenarcheal hormones influence the development of white matter structure from age 8.5 to 10 years. Participants were 120 children (66 female; mean age 8.45 years at Time 1 and 9.97 years at Time 2) who completed two diffusion-weighted imaging scans 1.5 years apart. Morning saliva samples were taken at both assessment time points to measure levels of dehydroepiandrosterone (DHEA), its sulphate (DHEAS), and testosterone. Fixel-based analysis was performed to examine how changes in white matter fibre density (FD) and cross-section (FC) over time were associated with initial levels of hormones, and changes in hormone levels over time. Both FD and FC increased over time in a wide range of white matter tracts. Increases in testosterone over time were related to relatively weaker increases in FC in the inferior fronto-occipital fasciculus. Levels and change in DHEA and DHEAS were not related to FD or FC changes. The results demonstrated development of white matter fibre density and cross-section from age 8.5 to 10 years. Changes in adrenarcheal hormone levels showed limited, localized associations with development of white matter FC. Future research should examine the relevance of adrenarcheal hormone-related white matter development for cognitive functioning; as well as directly compare analysis techniques of white matter structure.

Longitudinal patterns of white matter fibre density and morphology in children are associated with age and pubertal stage

The pubertal period involves dynamic white matter development. This period also corresponds with rapid gains in higher cognitive functions including attention, as well as increased risk of developing mental health difficulties. This longitudinal study comprised children aged 9–13 years (n = 130). Diffusion magnetic resonance imaging (dMRI) data were acquired (b = 2800s/mm2, 60 directions) at two time-points. We derived measures of fibre density and morphology using the fixel-based analysis framework and performed a tract-based mixed-effects modelling analysis to understand patterns of white matter development with respect to age, sex, pubertal stage, and the change in pubertal stage. We observed significant increases in apparent fibre density across a large number of white matter pathways, including major association and commissural pathways. We observed a linear relationship between pubertal stage and fibre density and morphology in the right superior longitudinal fasciculus, and fibre morphology in the right inferior longitudinal fasciculus. Finally, we report a significant interaction between the change in pubertal stage and age in the development of fibre density, for left-lateralised association tracts. Overall, white matter development across ages 9–13 years involves the expansion of major white matter fibre pathways, with key association pathways linked with pubertal stage.

Long-term development of white matter fibre density and morphology up to 13 years after preterm birth: A fixel-based analysis

BackgroundIt is well documented that infants born very preterm (VP) are at risk of brain injury and altered brain development in the neonatal period, however there is a lack of long-term, longitudinal studies on the effects of VP birth on white matter development over childhood. Most previous studies were based on voxel-averaged, non-fibre-specific diffusion magnetic resonance imaging (MRI) measures, such as fractional anisotropy. In contrast, the novel diffusion MRI analysis framework, fixel-based analysis (FBA), enables whole-brain analysis of microstructural and macrostructural properties of individual fibre populations at a sub-voxel level. We applied FBA to investigate the long-term implications of VP birth and associated perinatal risk factors on fibre development in childhood and adolescence. MethodsDiffusion images were acquired for a cohort of VP (born <30 weeks’ gestation) and full-term (FT, ≥37 weeks’ gestation) children at two timepoints: mean (SD) 7.6 (0.2) years (n ​= ​138 VP and 32 FT children) and 13.3 (0.4) years (n ​= ​130 VP and 45 FT children). 103 VP and 21 FT children had images at both ages for longitudinal analysis. At every fixel (individual fibre population within an image voxel) across the white matter, we compared FBA metrics (fibre density (FD), cross-section (FC) and a combination of these properties (FDC)) between VP and FT groups cross-sectionally at each timepoint, and longitudinally between timepoints. We also examined associations between known perinatal risk factors and FBA metrics in the VP group. ResultsCompared with FT children, VP children had lower FD, FC and FDC throughout the white matter, particularly in the corpus callosum, tapetum, inferior fronto-occipital fasciculus, fornix and cingulum at ages 7 and 13 years, as well as the corticospinal tract and anterior limb of the internal capsule at age 13 years. VP children also had slower FDC development in the corpus callosum and corticospinal tract between ages 7 and 13 years compared with FT children. Within VP children, earlier gestational age at birth, lower birth weight z-score, and neonatal brain abnormalities were associated with lower FD, FC and FDC throughout the white matter at both ages. ConclusionsVP birth and concomitant perinatal risk factors are associated with fibre tract-specific alterations to axonal development in childhood and adolescence.

Changes in white matter fiber density and morphology across the adult lifespan: A cross-sectional fixel-based analysis.

White matter (WM) fiber bundles change dynamically with age. These changes could be driven by alterations in axonal diameter, axonal density, and myelin content. In this study, we applied a novel fixel‐based analysis (FBA) framework to examine these changes throughout the adult lifespan. Using diffusion‐weighted images from a cohort of 293 healthy volunteers (89 males/204 females) from ages 21 to 86 years old, we performed FBA to analyze age‐related changes in microscopic fiber density (FD) and macroscopic fiber morphology (fiber cross section [FC]). Our results showed significant and widespread age‐related alterations in FD and FC across the whole brain. Interestingly, some fiber bundles such as the anterior thalamic radiation, corpus callosum, and superior longitudinal fasciculus only showed significant negative relationship with age in FD values, but not in FC. On the other hand, some segments of the cerebello‐thalamo‐cortical pathway only showed significant negative relationship with age in FC, but not in FD. Analysis at the tract‐level also showed that major fiber tract groups predominantly distributed in the frontal lobe (cingulum, forceps minor) exhibited greater vulnerability to the aging process than the others. Differences in FC and the combined measure of FD and cross section values observed between sexes were mostly driven by differences in brain sizes although male participants tended to exhibit steeper negative linear relationship with age in FD as compared to female participants. Overall, these findings provide further insights into the structural changes the brain's WM undergoes due to the aging process.

Differences in brain structure and function in children with the FTO obesity-risk allele.

SummaryObjectiveNoncoding alleles of the fat mass and obesity‐associated (FTO) gene have been associated with obesity risk, yet the underlying mechanisms remain unknown. Risk allele carriers show alterations in brain structure and function, but previous studies have not disassociated the effects of genotype from those of body mass index (BMI).MethodsDifferences in brain structure and function were examined in children without obesity grouped by their number of copies (0,1,2) of the FTO obesity‐risk single‐nucleotide polymorphism (SNP) rs1421085. One hundred five 5‐ to 10‐year‐olds (5th–95th percentile body fat) were eligible to participate. Usable scans were obtained from 93 participants (15 CC [homozygous risk], 31 CT [heterozygous] and 47 TT [homozygous low risk]).ResultsHomozygous C allele carriers (CCs) showed greater grey matter volume in the cerebellum and temporal fusiform gyrus. CCs also demonstrated increased bilateral cerebellar white matter fibre density and increased resting‐state functional connectivity between the bilateral cerebellum and regions in the frontotemporal cortices.ConclusionsThis is the first study to examine brain structure and function related to FTO alleles in young children not yet manifesting obesity. This study lends support to the notion that the cerebellum may be involved in FTO‐related risk for obesity, yet replication and further longitudinal study are required.

Early childhood development of white matter fiber density and morphology

Early childhood is an important period for cognitive and brain development, though white matter changes specific to this period remain understudied. Here we utilize a novel analytic approach to quantify and track developmental changes in white matter micro- and macro-structure, calculated from individually oriented fiber-bundle populations, termed “fixels”. Fixel-based analysis and mixed-effects models were used to assess tract-wise changes in fiber density and bundle morphology in 73 girls scanned at baseline (ages 4.09–7.02, mean ​= ​5.47, SD ​= ​0.81), 6-month (N ​= ​7), and one-year follow-up (N ​= ​42). For comparison, we also assessed changes in commonly utilized diffusion tensor metrics: fractional anisotropy (FA), and mean, radial and axial diffusivity (MD, RD, AD). Maturational increases in fixel-metrics were seen in most major white matter tracts, with the most rapid increases in the corticospinal tract and slowest or non-significant increases in the genu of the corpus callosum and uncinate fasciculi. As expected, we observed developmental increases in FA and decreases in MD, RD and AD, though percent changes were smaller relative to fixel-metrics. The majority of tracts showed more substantial morphological than microstructural changes. These findings highlight early childhood as a period of dynamic white matter maturation, characterized by large increases in macroscopic fiber bundle size, mild changes in axonal density, and parallel, albeit less substantial, changes in diffusion tensor metrics.

White matter fiber density abnormalities in cognitively normal adults at risk for late-onset Alzheimer's disease

Tau accumulation affecting white matter tracts is an early neuropathological feature of late-onset Alzheimer's disease (LOAD). There is a need to ascertain methods for the detection of early LOAD features to help with disease prevention efforts. The microstructure of these tracts and anatomical brain connectivity can be assessed by analyzing diffusion MRI (dMRI) data. Considering that family history increases the risk of developing LOAD, we explored the microstructure of white matter through dMRI in 23 cognitively normal adults who are offspring of patients with Late-Onset Alzheimer's Disease (O-LOAD) and 22 control subjects (CS) without family history of AD. We also evaluated the relation of white matter microstructure metrics with cortical thickness, volumetry, in vivo amyloid deposition (with the help of PiB positron emission tomography -PiB-PET) and regional brain metabolism (as FDG-PET) measures. Finally we studied the association between cognitive performance and white matter microstructure metrics. O-LOAD exhibited lower fiber density and fractional anisotropy in the posterior portion of the corpus callosum and right fornix when compared to CS. Among O-LOAD, reduced fiber density was associated with lower amyloid deposition in the right hippocampus, and greater cortical thickness in the left precuneus, while higher mean diffusivity was related with greater cortical thickness of the right superior temporal gyrus. Additionally, compromised white matter microstructure was associated with poorer semantic fluency. In conclusion, white matter microstructure metrics may reveal early differences in O-LOAD by virtue of parental history of the disorder, when compared to CS without a family history of LOAD. We demonstrate that these differences are associated with lower fiber density in the posterior portion of the corpus callosum and the right fornix.

Structural connectivity prior to whole-body sensorimotor skill learning associates with changes in resting state functional connectivity

Changes in resting state functional connectivity are induced by sensorimotor training and assumed to be concomitant of motor learning, although a potential relationship between functional and structural connectivity associated with sensorimotor sequence learning remains elusive. To investigate whether initial structural connectivity relates to changes in functional connectivity, we evaluated resting state functional connectivity (rs-FC), white matter fibre density (FD), fibre-bundle cross-section (FC), and gray matter volume (GMV) in healthy human participants before and after two days of performing a complex whole-body serial reaction time task (CWB-SRTT). As CWB-SRTT was implicit, participants were not told about the presence of any sequence. Since the lateral prefrontal cortex (PFC) plays an important role in sequence learning, we hypothesized that structural connectivity within the PFC prior to learning is associated with changes in rs-FC involving the lateral PFC. Sequence specific improvements, as assessed by the time difference between the last random and the last sequence blocks, were observed for reaction times, suggesting that sensorimotor sequence memory was acquired. Rs-FC between the right lateral PFC and bilateral striatum increased significantly in the learning group, when compared to a control group who performed only random blocks. This indicated that rs-FC changes are related to sequence memory but not to exercise itself. In addition, changes in rs-FC between the right lateral PFC and the left striatum were correlated with sequence specific improvements in individual reaction times. Furthermore, changes in rs-FC between right lateral PFC and left striatum were positively correlated with FC in the right anterior corona radiata measured before the task. We did not find any structural changes or significant correlations in FD or GMV. These findings suggest that an early phase of sensorimotor sequence learning in complex whole-body movements is associated with an increase in rs-FC between prefrontal and subcortical regions. Furthermore, we provide novel evidence that CWB-SRTT-induced changes in rs-FC were correlated with FC within the PFC.

Reduced White Matter Fiber Density in Autism Spectrum Disorder.

Differences in brain networks and underlying white matter abnormalities have been suggested to underlie symptoms of autism spectrum disorder (ASD). However, robustly characterizing microstructural white matter differences has been challenging. In the present study, we applied an analytic technique that calculates structural metrics specific to differently-oriented fiber bundles within a voxel, termed “fixels”. Fixel-based analyses were used to compare diffusion-weighted magnetic resonance imaging data from 25 individuals with ASD (mean age = 16.8 years) and 27 typically developing age-matched controls (mean age = 16.9 years). Group comparisons of fiber density (FD) and bundle morphology were run on a fixel-wise, tract-wise, and global white matter (GWM) basis. We found that individuals with ASD had reduced FD, suggestive of decreased axonal count, in several major white matter tracts, including the corpus callosum (CC), bilateral inferior frontal-occipital fasciculus, right arcuate fasciculus, and right uncinate fasciculus, as well as a GWM reduction. Secondary analyses assessed associations with social impairment in participants with ASD, and showed that lower FD in the splenium of the CC was associated with greater social impairment. Our findings suggest that reduced FD could be the primary microstructural white matter abnormality in ASD.

Development of white matter fibre density and morphology over childhood: A longitudinal fixel-based analysis

PurposeWhite matter fibre development in childhood involves dynamic changes to microstructural organisation driven by increasing axon diameter, density, and myelination. However, there is a lack of longitudinal studies that have quantified advanced diffusion metrics to identify regions of accelerated fibre maturation, particularly across the early pubertal period. We applied a novel longitudinal fixel-based analysis (FBA) framework, in order to estimate microscopic and macroscopic white matter changes over time. MethodsDiffusion-weighted imaging (DWI) data were acquired for 59 typically developing children (27 female) aged 9–13 years at two time-points approximately 16 months apart (time-point 1: 10.4 ± 0.4 years, time-point 2: 11.7 ± 0.5 years). Whole brain FBA was performed using the connectivity-based fixel enhancement method, to assess longitudinal changes in fibre microscopic density and macroscopic morphological measures, and how these changes are related to sex, pubertal stage, and pubertal progression. Follow-up analyses were performed in sub-regions of the corpus callosum to confirm the main findings using a Bayesian repeated measures approach. ResultsThere was a statistically significant increase in fibre density over time localised to medial and posterior commissural and association fibres, including the forceps major and bilateral superior longitudinal fasciculus. Increases in fibre cross-section were substantially more widespread. The rate of fibre development was not associated with age or sex. In addition, there was no significant relationship between pubertal stage or progression and longitudinal fibre development over time. Follow-up Bayesian analyses were performed to confirm the findings, which supported the null effect of the longitudinal pubertal comparison. ConclusionUsing a novel longitudinal fixel-based analysis framework, we demonstrate that white matter fibre density and fibre cross-section increased within a 16-month scan rescan period in specific regions. The observed increases might reflect increasing axonal diameter or axon count. Pubertal stage or progression did not influence the rate of fibre development in the early stages of puberty. Future work should focus on quantifying these measures across a wider age range to capture the full spectrum of fibre development across the pubertal period.

Investigation of Neurodegenerative Processes in Amyotrophic Lateral Sclerosis Using White Matter Fiber Density

In the current work two novel parameters, fiber density (FD) and mean diffusion signal (MDS) are investigated for evaluating neurodegenerative processes in amyotrophic lateral sclerosis (ALS). The MDS provides a measure of the FD but is derived directly from the diffusion signal. Using tract-based spatial statistics (TBSS), pathological changes across the entire white matter and changes in the parameters over time were evaluated. The results were related to those obtained using the fractional anisotropy (FA) value. A widespread pattern of significantly decreased FD and MDS values was observed. A strong trend towards statistical significance was seen in similar white matter structures using TBSS analysis based on the FA value. Longitudinal analysis of the FD values demonstrated continuing deterioration of the same fiber tracts that were shown to be impaired in the group analysis. The findings suggest that MDS and in particular FD show great promise for evaluating microstructural white matter changes in ALS and may be more sensitive than the more commonly used FA value.

Investigating white matter fibre density and morphology using fixel-based analysis

Voxel-based analysis of diffusion MRI data is increasingly popular. However, most white matter voxels contain contributions from multiple fibre populations (often referred to as crossing fibres), and therefore voxel-averaged quantitative measures (e.g. fractional anisotropy) are not fibre-specific and have poor interpretability. Using higher-order diffusion models, parameters related to fibre density can be extracted for individual fibre populations within each voxel (‘fixels’), and recent advances in statistics enable the multi-subject analysis of such data. However, investigating within-voxel microscopic fibre density alone does not account for macroscopic differences in the white matter morphology (e.g. the calibre of a fibre bundle). In this work, we introduce a novel method to investigate the latter, which we call fixel-based morphometry (FBM). To obtain a more complete measure related to the total number of white matter axons, information from both within-voxel microscopic fibre density and macroscopic morphology must be combined. We therefore present the FBM method as an integral piece within a comprehensive fixel-based analysis framework to investigate measures of fibre density, fibre-bundle morphology (cross-section), and a combined measure of fibre density and cross-section. We performed simulations to demonstrate the proposed measures using various transformations of a numerical fibre bundle phantom. Finally, we provide an example of such an analysis by comparing a clinical patient group to a healthy control group, which demonstrates that all three measures provide distinct and complementary information. By capturing information from both sources, the combined fibre density and cross-section measure is likely to be more sensitive to certain pathologies and more directly interpretable.

Microstructural Changes of Anterior Corona Radiata in Bipolar Depression.

ObjectiveIn bipolar disorder, dysregulation of mood may result from white matter abnormalities that change fiber tract length and fiber density. There are few studies evaluating the white matter microstructural changes in bipolar I patients (BD) with depressive episodes. The present study aimed to evaluate anterior corona radiata in BD patients with depressive episode using Diffusion Tensor Imaging (DTI).MethodsTwenty-one patients with bipolar depression and 19 healthy controls were investigated and groups were matched for age and gender. Diffusion-weighted echoplanar brain images (DW-EPI) were obtained using a 1.5 T MRI scanner. Regions of interest (ROIs) were manually placed on directional maps based on principal anisotropy. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) values of white matter were measured in the anterior corona radiata (ACR) bilaterally by diffusion tensor imaging.ResultsThere was not a significant difference between groups of age and gender (p>0.05). Significantly lower FA was observed in bilateral ACR in bipolar patients with depression compared with healthy individuals. And there is significantly higher ADC values in the left frontal corona radiate in bipolar patients.ConclusionWhite matter abnormalities can be detected in patients with BD using DTI. The neuropathology of these abnormalities is unclear, but neuronal and axonal loss, myelin abnormalities and reduced white matter fiber density are likely to be relevant.

Mapping Remote Subcortical Ramifications of Injury after Ischemic Strokes

Background. The extent of brain damage in chronic stroke patients is traditionally defined as the necrotic tissue observed on magnetic resonance image (MRI). However, patients often exhibit symptoms suggesting that functional impairment may affect areas beyond the cortical necrotic lesion, for example, when cortical symptoms ensue after subcortical damage. This observation suggests that disconnection or diaschisis can lead to remote cortical dysfunction that can be functionally equivalent to direct cortical lesions. Objective. To directly measure subcortical disconnection after stroke. Methods. We describe a principled approach utilizing the whole brain connectome reconstructed from diffusion MRI to evaluate the reduction of apparent white matter fiber density in the hemisphere affected by the stroke compared with the spared hemisphere. Results. In eight chronic stroke patients, we observed subcortical disconnection extending beyond the location of tissue necrosis and affecting major white matter pathways underlying the necrotic area. Conclusions. We suggest that it is possible to detect and quantify previously unappreciated areas of subcortical and cortical disconnection. Specifically, this method can be used to evaluate the relationship between lesion location and symptoms, with emphasis on a connectivity-based approach.