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ABSTRACT Diffusion‐weighted imaging (DWI) has been frequently used to examine age‐related deterioration of white matter microstructure and its relationship to cognitive decline. However, typical tensor‐based analytical approaches are often difficult to interpret due to the challenge of decomposing and (mis)interpreting the impact of crossing fibers within a voxel. We hypothesized that a novel analytical approach capable of resolving fiber‐specific changes within each voxel (i.e., fixel‐based analysis [FBA])—would show greater sensitivity relative to the traditional tensor‐based approach for assessing relationships between white matter microstructure, age, and cognitive performance. To test our hypothesis, we studied 636 cognitively normal adults aged 65–80 years (mean age = 69.8 years; 71% female) using diffusion‐weighted MRI. We analyzed fixels (i.e., fiber‐bundle elements) to test our hypotheses. A fixel provides insight into the structural integrity of individual fiber populations in each voxel in the presence of multiple crossing fiber pathways, allowing for potentially increased specificity over other diffusion measures. Linear regression was used to investigate associations between each of three fixel metrics (fiber density, cross‐section, and density × cross‐section) with age and cognitive performance. We then compared and contrasted the FBA results to a traditional tensor‐based approach examining voxel‐wise fractional anisotropy. In a whole‐brain analysis, significant associations were found between fixel‐based metrics and age after adjustments for sex, education, total brain volume, site, and race. We found that increasing age was associated with decreased fiber density and cross‐section, namely in the fornix, striatal, and thalamic pathways. Further analysis revealed that lower fiber density and cross‐section were associated with poorer performance in measuring processing speed and attentional control. In contrast, the tensor‐based analysis failed to detect any white matter tracts significantly associated with age or cognition. Taken together, these results suggest that FBAs of DWI data may be more sensitive for detecting age‐related white matter changes in an older adult population and can uncover potentially clinically important associations with cognitive performance. We assessed the sensitivity and utility of a fixel‐based white matter analysis to detect age‐related white matter degeneration. Results revealed that fixel‐based analyses were more sensitive than tensor‐based analyses and that age‐related white matter decline was related to cognitive decline.

ABSTRACT Recent studies indicate that air pollutants not only increase the risk of cardiovascular and respiratory diseases but also have a negative impact on the developing brain. Exposure to airborne particulate matter (PM) and nitrogen dioxide (NO2) may lead to disruption of neural development by interfering with critical maturation processes. In this study, we assessed the impact of prenatal and early life PM10 and NO2 exposure on diffusion Magnetic Resonance Imaging (dMRI) structural measures: fractional anisotropy (FA), mean diffusivity (MD), and fixel‐based analysis (FBA) on a population of 425 10‐ to 13‐year‐old children with attention deficit hyperactivity disorder (ADHD, n = 116), a sensitive, at‐risk population, and typically developing children (TD, n = 309) from the NeuroSmog study. Unlike traditional voxel‐based methods, FBA allows identification of distinct fiber bundles within voxels. We show that early life exposure to NO2 was associated with lower global FA and higher MD measures. However, despite having a large sample size and using state‐of‐the‐art techniques, we found no significant fixel‐level associations. Notably, we found no evidence that individuals with ADHD are more susceptible to the effects of air pollution. Combined with other studies, our results suggest that dMRI measures are the brain outcomes most consistently affected by air pollution. We explored the association between air pollution and global brain measures and fixel‐specific white matter measures in Polish 10–13‐year‐s old children, with and without ADHD. Global measures were associated with NO2 and PM10 but an insignificant interaction between ADHD and pollutants. No associations between air pollution and fixel‐specific measures. Children and air pollution icons are created by Freepik—Flaticon. Brain icon was downloaded from Pixabay.

It is well documented that attention‐deficit hyperactivity disorder (ADHD) often presents with co‐occurring motor difficulties. However, little is known about the biological mechanisms that explain compromised motor skills in approximately half of those with ADHD. To provide insight into the neurobiological basis of poor motor outcomes in ADHD, this study profiled the development of white matter organization within the cortico‐spinal tract (CST) in adolescents with ADHD with and without co‐occurring motor problems, as well as non‐ADHD control children with and without motor problems. Participants were 60 children aged 9–14 years, 27 with a history of ADHD and 33 controls. All underwent high‐angular resolution diffusion MRI data at up to three time points (115 in scans total). We screened for motor impairment in all participants at the third time point (≈14 years) using the Developmental Coordination Disorder Questionnaire (DCD‐Q). Following pre‐processing of diffusion MRI scans, fixel‐based analysis was performed, and the bilateral CST was delineated using TractSeg. Mean fiber density (FD) and fiber cross‐section (FC) were extracted for each tract at each time‐point. To investigate longitudinal trajectories of fiber development, linear mixed models were performed separately for the left and right CST, controlling for nuisance variables. To examine possible variations in fiber development between groups, we tested whether the inclusion of group and the interaction between age and group improved model fit. At ≈10 years, those with ADHD presented with lower FD within the bilateral CST relative to controls, irrespective of their prospective motor status. While these microstructural abnormalities persisted into adolescence for individuals with ADHD and co‐occurring motor problems, they resolved for those with ADHD alone. Divergent maturational pathways of motor networks (i.e., the CST) may, at least partly, explain motor problems individuals with ADHD. Children with ADHD showed atypical microstructure within the cortico‐spinal tract (CST) at 10 years, regardless of motor ability later in life. These CST abnormalities persisted into adolescence when ADHD co‐occurred with motor problems, yet resolved for those with ADHD alone. Maturation within motor networks may explain motor difficulties in ADHD.

This study investigated changes in white matter (WM) morphology following complex motor learning, that is, the learning to walk a slackline. A sample of young adults from the general population underwent brain imaging before the slackline intervention, after successful learning, and after a subsequent follow‐up period by applying state‐of‐the‐art measures for the assessment of micro‐ and macrostructural characteristics of WM fiber tracts (voxel‐based and fixel‐based). A randomly assigned control group (CG) was scanned at the same time points of assessment but received no intervention over the study period. Learning to walk a slackline resulted in manifold changes in WM morphology: (1) Whole brain fixel‐based analyses revealed robust increases in the fiber cross‐section in bundles closely associated with sensorimotor functions (e.g., superior longitudinal fasciculi, corticospinal tract); (2) The neurite orientation dispersion and density imaging (NODDI) parameters showed widespread decreases in overlapping fiber bundles. In the CG, no time‐related WM changes were apparent at all. This well‐controlled longitudinal intervention study provides substantial new evidence that learning a complex motor skill modulates fiber organization and fiber density in sensorimotor tracts. This randomized longitudinal study investigates training‐induced changes in white matter morphology after a highly challenging motor learning task (slackline). Changes were found solely in the intervention group, demonstrated in NODDI (green box) and Fixel‐related metrics (yellow box).

There is robust evidence implicating inhibitory deficits as a fundamental behavioural phenotype in children with attention‐deficit/hyperactivity disorder (ADHD). However, prior studies have not directly investigated the role in which white matter properties within the fronto‐basal‐ganglia circuit may play in the development of inhibitory control deficits in this group. Combining recent advancements in brain‐behavioural modelling, we mapped the development of stop‐signal task (SST) performance and fronto‐basal‐ganglia maturation in a longitudinal sample of children aged 9–14 with and without ADHD. In a large sample of 135 ADHD and 138 non‐ADHD children, we found that the ADHD group had poorer inhibitory control (i.e., longer stop‐signal reaction times) across age compared to non‐ADHD controls. When applying the novel parametric race model, this group effect was driven by higher within‐subject variability (sigma) and higher number of extreme responses (tau) on stop trials. The ADHD group also displayed higher within‐subject variability on correct responses to go stimuli. Moreover, we observed the ADHD group committing more task‐based failures such as responding on stop trials (trigger failures) and omissions on go trials (go failures) compared to non‐ADHD controls, suggesting the contribution of attentional lapses to poorer response inhibition performance. In contrast, longitudinal modelling of fixel‐based analysis measures revealed no significant group differences in the maturation of fronto‐basal‐ganglia fibre cross‐section in a subsample (74 ADHD and 73 non‐ADHD children). Finally, brain‐behavioural models revealed that age‐related changes in fronto‐basal‐ganglia morphology (fibre cross‐section) were significantly associated with reductions in the variability of the correct go‐trial responses (sigma.true) and skew of the stop‐trial distribution (tauS). However, this effect did not differ between ADHD and typically developing children. Overall, our findings support the growing consensus suggesting that attentional deficits subserve ADHD‐related inhibitory dysfunction. Furthermore, we show novel evidence suggesting that while children with ADHD are consistently performing worse on the SST than their non‐affected peers, they appear to have comparable rates of neurocognitive maturation across this period. The development of response inhibition and fronto‐basal‐ganglia white matter was investigated longitudinally in a sample of ADHD and non‐ADHD children. Using the novel parametric race model, children with ADHD had higher within‐subject variability and extreme responses during the stop‐signal task (SST) across age compared to controls. ADHD children also committed more trigger‐and‐go failures, thus implicating the role of attentional deficits in ADHD‐related disinhibition. Longitudinal fixel‐based analysis models revealed both ADHD and control children had similar age‐related increases in fronto‐basal‐ganglia morphology (fibre cross‐section), which was associated with improved SST performance across childhood.

ABSTRACT Mild traumatic brain injury (mTBI) can result in persistent cognitive deficits (particularly in attention, processing speed, and working memory), even years after the injury. The majority of behavioural studies have focussed on averaged cognitive performance scores, such as average reaction time or accuracy scores after mTBI. However, less is understood about how mTBI affects intraindividual variability (IIV) in cognitive performance across repeated sessions or measurement occasions over time. In this study, we investigate IIV in cognitive performance in chronic mTBI patients (n = 11) relative to healthy controls (n = 22). Participants underwent a single behavioural testing session (incorporating the Rivermead Post‐Concussion Symptom Questionnaire and a computerised processing speed task) and a multi‐shell diffusion MRI scan. This was followed by a 30‐day ecological momentary assessment (EMA) protocol using a smartphone app which measured symptoms and cognitive performance on a daily basis. Our results revealed that mTBI patients exhibited higher IIV than controls in both single‐session trial‐by‐trial and daily EMA measures. Higher daily IIV in cognitive performance coincided with higher daily fluctuations in post‐concussive symptoms. Additionally, mTBI patients showed reduced white matter organization, as indexed by fixel‐wise fibre density and fibre density cross‐section, in the left superior longitudinal fasciculus‐II compared to controls. Finally, trial‐by‐trial IIV was positively associated with white matter alterations in the SLF‐II in mTBI. Our findings suggest that mTBI results in dynamic performance deficits that persist into the chronic phase of injury. In addition, the white matter organization of a major fronto‐parietal tract seems to play an important role in supporting the consistency of cognitive performance over time, highlighting its potential as a biomarker for understanding cognitive dynamics in healthy adults and clinical populations. This study combined smartphone‐based ecological momentary assessment (EMA) and fixel‐based analysis (FBA) of diffusion MRI data to examine intraindividual variability (IIV) in cognitive performance and its neural correlates in chronic mild TBI. Our findings revealed persistent cognitive instability linked to daily symptom fluctuations and structural changes in the left superior longitudinal fasciculus‐II in mTBI patients.

ABSTRACT Fixel‐based analysis (FBA) is an advanced diffusion MRI analysis technique that facilitates the evaluation of white matter microstructure within ‘fixels’ (specific fibre populations within a voxel). In recent years, FBA has gained prominence for its ability to better characterise fibre tract‐specific changes than the more conventional diffusion MRI approaches and has shown promise in elucidating the pathophysiology of psychiatric and neurological diseases. However, FBA has been predominantly limited to single‐centre studies, minimising the generalisability of the technique. In this study, the popular ComBat harmonisation technique was adapted for whole‐brain FBA of diffusion MRI data. The study evaluates the effectiveness of ComBat in harmonising FBA metrics of fibre density, fibre cross‐section and the combined metric of fibre density and cross‐section in a large travelling subject dataset (n = 49, scan = 162). Participants were scanned across multiple centres, using different scanner models and imaging protocols, and FBA metrics were compared under these varying conditions before and after harmonisation. In addition, the impact of ComBat harmonisation on disease‐related findings was evaluated in an independent multi‐centre Alzheimer's disease (AD) dataset, by comparing the same fixel‐based measures in patients with AD (n = 27) to those in cognitively normal control participants (n = 29) before and after ComBat harmonisation. We demonstrated that ComBat harmonisation effectively mitigated variability across scanner sites, scanner models, and protocols, in the travelling subject dataset, thus enhancing the comparability of FBA metrics. Notably, ComBat harmonisation improved the detection of AD‐related changes in the fornix, a critical white matter tract associated with cognitive function, and strengthened the correlations between FBA metrics and cognitive scores. These results underscore the potential of ComBat harmonisation in enhancing the reliability of multi‐centre neuroimaging studies, supporting the use of harmonisation techniques for accurate detection of disease‐specific changes in neurodegenerative conditions. The ability to perform ComBat harmonisation within the whole‐brain FBA pipeline may help further this fibre‐specific technique into large‐scale multi‐centre studies. ComBat harmonisation effectively reduces measurement bias in fixel‐based diffusion MRI metrics across multiple sites, scanner models, and imaging protocols. This enables improved detection of Alzheimer's disease‐related changes in white matter microstructure. The approach enhances both the reliability and scalability of multi‐centre neuroimaging studies.

ABSTRACT Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by a range of motor and nonmotor symptoms, often with the motor dysfunction initiated unilaterally. Knowledge regarding disease‐related alterations in white matter pathways can effectively help improve the understanding of the disease and propose targeted treatment strategies. Microstructural imaging techniques, including diffusion tensor imaging (DTI), allows inspection of white matter integrity to study the pathogenesis of various neurological conditions. Previous voxel‐based analyses with DTI measures, such as fractional anisotropy and mean diffusivity have uncovered changes in brain regions that are associated with PD, but the conclusions were inconsistent, partially due to small patient cohorts and the lack of consideration for clinical laterality onset, particularly in early PD. Fixel‐based analysis (FBA) is a recent framework that offers tract‐specific insights regarding white matter health, but very few FBA studies on PD exist. We present a study that reveals strengthened and weakened white matter integrity that is subject to symptom laterality in a large drug‐naïve de novo PD cohort using complementary DTI and FBA measures. The findings suggest that the disease gives rise to tissue degeneration and potential re‐organization in the early stage. Parkinson's disease (PD) is a progressive neurodegenerative disorder that is characterized by a range of motor and nonmotor symptoms, often with the motor dysfunction initiated unilaterally. We present a study that reveals strengthened and weakened white matter integrity that is subject to symptom laterality in a large drug‐naïve de novo Parkinson's disease cohort using complementary DTI and FBA measures. The findings suggest that the disease gives rise to tissue degeneration and potential re‐organization in the early stage.

ABSTRACT A fundamental issue in neuroscience is a lack of understanding regarding the relationship between brain function and the white matter architecture that supports it. Individuals with chronic neuropathic pain (NP) exhibit functional abnormalities throughout brain networks collectively termed the “dynamic pain connectome” (DPC), including the default mode network (DMN), salience network, and ascending nociceptive and descending pain modulation systems. These functional abnormalities are often observed in a sex‐dependent fashion. However, the enigmatic white matter structural features underpinning these functional networks and the relationship between structure and function/dysfunction in NP remain poorly understood. Here we used fixel‐based analysis of diffusion weighted imaging data in 80 individuals (40 with NP [21 female, 19 male] and 40 sex‐ and age‐matched healthy controls [HCs]) to evaluate white matter microstructure (fiber density [FD]), macrostructure (fiber bundle cross section) and combined microstructure and macrostructure (fiber density and cross section) within anatomical connections that support the DPC. We additionally examined whether there are sex‐specific abnormalities in NP white matter structure. We performed fixel‐wise and connection‐specific mean analyses and found three main ways in which individuals with NP differed from HCs: (1) people with NP exhibited abnormally low FD and FDC within the corona radiata consistent with the ascending nociceptive pathway between the sensory thalamus and primary somatosensory cortex (S1). Furthermore, the entire sensory thalamus—S1 pathway exhibited abnormally low FD and FDC in people with NP, and this effect was driven by the females with NP; (2) females, but not males, with NP had abnormally low FD within the cingulum consistent with the right medial prefrontal cortex—posterior cingulate cortex DMN pathway; and (3) individuals with NP had higher connection‐specific mean FDC than HCs in the anterior insula—temporoparietal junction and sensory thalamus—posterior insula pathways. However, sex‐specific analyses did not corroborate these connection‐specific findings in either females or males with NP. Our findings suggest that females with NP exhibit microstructural and macrostructural white matter abnormalities within the DPC networks including the ascending nociceptive system and DMN. We propose that aberrant white matter structure contributes to or is driven by functional abnormalities associated with NP. Our sex‐specific findings highlight the utility and importance of using sex‐disaggregated analyses to identify white matter abnormalities in clinical conditions such as chronic pain. We used diffusion weighted imaging (DWI) to examine whether individuals with neuropathic pain (NP) show white matter abnormalities in structural connections between regions of the dynamic pain connectome. We identified microstructural and macrostructural abnormalities within the ascending nociceptive pathway and default mode network (DMN) in females with NP.

INTRODUCTION Typical Alzheimer's disease (AD) and limbic‐predominant age‐related TAR DNA‐binding protein 43 (TDP‐43) encephalopathy (LATE) are two neurodegenerative diseases that present with a similar initial amnestic clinical phenotype but are associated with distinct proteinopathies. METHODS We investigated white matter (WM) fiber bundle alterations, using fixel‐based analysis, a state‐of‐the‐art diffusion magnetic resonance imaging model, in early AD, presumed LATE, and controls. We also investigated regional cortical atrophy. RESULTS Both amnestic AD and presumed LATE patients exhibited WM alterations in tracts of the temporal and limbic lobes and in callosal fibers connecting superior frontal gyri. In addition, presumed LATE patients showed alterations in callosal fibers connecting the middle frontal gyri and in the cerebello–thalamo–cortical tract. Cortical thickness was reduced in regions connected by the most altered tracts. DISCUSSION These findings, the first to describe WM fiber bundle alterations in presumed LATE, are consistent with results on cortical atrophy and with the staging system of tau or TDP‐43 accumulation. Highlights Fixel‐based analysis revealed white matter (WM) fiber bundle alterations in presumed limbic‐predominant age‐related TAR DNA‐binding protein 43 encephalopathy (LATE) patients identified by isolated episodic/limbic amnesia, the absence of positive Alzheimer's disease (AD) biomarkers, and no other neurological diagnosis after 2 years of follow‐up. Presumed LATE and amnestic AD shared similar patterns of WM alterations in fiber bundles of the limbic and temporal lobes, in congruence with their similar limbic cognitive phenotype. Presumed LATE differed from AD by the alteration of the callosal fibers connecting the middle frontal gyri and of the cerebello–thalamo–cortical tract. WM fiber bundle alterations were consistent with results on regional cortical atrophy. The different anatomical patterns of WM degeneration could provide information on the propagation pathways of distinct proteinopathies.