Tract-specific Fractional Anisotropy Research Articles

Pathways explaining racial/ethnic and socio-economic disparities in brain white matter integrity outcomes in the UK Biobank study

Pathways explaining racial/ethnic and socio-economic status (SES) disparities in white matter integrity (WMI) reflecting brain health, remain underexplored, particularly in the UK population. We examined racial/ethnic and SES disparities in diffusion tensor brain magnetic resonance imaging (dMRI) markers, namely global and tract-specific mean fractional anisotropy (FA), and tested total, direct and indirect effects through lifestyle, health-related and cognition factors using a structural equations modeling approach among 36,184 UK Biobank participants aged 40–70 y at baseline assessment (47% men). Multiple linear regression models were conducted, testing independent associations of race/ethnicity, socio-economic and other downstream factors in relation to global mean FA, while stratifying by Alzheimer’s Disease polygenic Risk Score (AD PRS) tertiles. Race (Non-White vs. White) and lower SES predicted poorer WMI (i.e. lower global mean FA) at follow-up, with racial/ethnic disparities in FAmean involving multiple pathways and SES playing a central role in those pathways. Mediational patterns differed across tract-specific FA outcomes, with SES-FAmean total effect being partially mediated (41% of total effect = indirect effect). Furthermore, the association of poor cognition with FAmean was markedly stronger in the two uppermost AD PRS tertiles compared to the lower tertile (T2 and T3: β±SE: −0.0009 ± 0.0001 vs. T1: β±SE: −0.0005 ± 0.0001, P < 0.001), independently of potentially confounding factors. Race and lower SES were generally important determinants of adverse WMI outcomes, with partial mediation of socio-economic disparities in global mean FA through lifestyle, health-related and cognition factors. The association of poor cognition with lower global mean FA was stronger at higher AD polygenic risk.

The effects of physical activity on white matter microstructure in children with overweight or obesity: The ActiveBrains randomized clinical trial

BackgroundEmerging research supports the idea that physical activity benefits brain development. However, the body of evidence focused on understanding the effects of physical activity on white matter microstructure during childhood is still in its infancy, and further well-designed randomized clinical trials are needed. AimThis study aimed: (i) to investigate the effects of a 20-week physical activity intervention on global white matter microstructure in children with overweight or obesity, and (ii) to explore whether the effect of physical activity on white matter microstructure is global or restricted to a particular set of white matter bundles. MethodsIn total, 109 children aged 8 to 11 years with overweight or obesity were randomized and allocated to either the physical activity program or the control group. Data were collected from November 2014 to June 2016, with diffusion tensor imaging (DTI) data processing and analyses conducted between June 2017 and November 2021. Images were pre-processed using the Functional Magnetic Resonance Imaging (MRI) of the Brain´s Software Library (FSL) and white matter properties were explored by probabilistic fiber tractography and tract-based spatial statistics (TBSS). ResultsIntention-to-treat analyses were performed for all children who completed the pre-test and post-test DTI assessment, with good quality DTI data (N = 89). Of them, 83 children (10.06±1.11 years, 39 % girls, intervention group=44) met the per-protocol criteria (attended at least 70 % of the recommended sessions). Our probabilistic fiber tractography analysis did not show any effects in terms of global and tract-specific fractional anisotropy (FA) and mean diffusivity (MD) in the per-protocol or intention-to-treat analyses. Additionally, we did not observe any effects on the voxel-wise DTI parameters (i.e., FA and MD) using the most restricted TBSS approach (i.e., per protocol analyses and p-corrected image with a statistical threshold of p < 0.05). In the intention-to-treat analysis, we found that our physical activity program had a borderline effect (p-corrected image with a statistical threshold of p < 0.1) on 7 different clusters, including a cluster in the corpus callosum. ConclusionWe conclude that a 20-week physical activity intervention was not enough to induce changes in global and tract-specific white matter during childhood. The effects of physical activity on white matter microstructure could be restricted to local changes in several white matter tracts (e.g., the body of the corpus callosum). However, our results were not significant, and more interventions are needed to determine whether and how physical activity affects white matter microstructure during childhood.

Intrauterine Exposure to Antidepressants or Maternal Depressive Symptoms and Offspring Brain White Matter Trajectories From Late Childhood to Adolescence

BackgroundDuring pregnancy, both selective serotonin reuptake inhibitor (SSRI) exposure and maternal depression have been associated with poor offspring neurodevelopmental outcomes. In a population-based cohort, we investigated the association between intrauterine exposure to SSRIs and depressive symptoms and offspring white matter development from childhood to adolescence. MethodsSelf-reported SSRI use was verified by pharmacy records. In midpregnancy, women reported on depressive symptoms using the Brief Symptom Inventory. Using diffusion tensor imaging, offspring white matter microstructure, including whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity, was measured at 3 assessments between ages 7 to 15 years. The participants were divided into 4 groups: prenatal SSRI exposure (n = 37 with 60 scans), prenatal depression exposure (n = 229 with 367 scans), SSRI use before pregnancy (n = 72 with 95 scans), and reference (n = 2640 with 4030 scans). ResultsIntrauterine exposure to SSRIs and depressive symptoms were associated with lower FA in the whole-brain and the forceps minor at 7 years. Exposure to higher prenatal depressive symptom scores was associated with lower FA in the uncinate fasciculus, cingulum bundle, superior and inferior longitudinal fasciculi, and corticospinal tracts. From ages 7 to 15 years, children exposed to prenatal depressive symptoms showed a faster increase in FA in these white matter tracts. Prenatal SSRI exposure was not related to white matter microstructure growth over and above exposure to depressive symptoms. ConclusionsThese results suggest that prenatal exposure to maternal depressive symptoms was negatively associated with white matter microstructure in childhood, but these differences attenuated during development, suggesting catch-up growth.

Cardiovascular health, infection burden and their interactive association with brain volumetric and white matter integrity outcomes in the UK Biobank

BackgroundCardiovascular health is associated with brain magnetic resonance imaging (MRI) markers of pathology and infections may modulate this association. MethodsUsing data from 38,803 adults (aged 40–70 years) and followed-up for 5–15 years, we tested associations of prevalent total (47.5%) and hospital-treated infection burden (9.7%) with brain structural and diffusion-weighted MRI (i.e., sMRI and dMRI, respectively) common in dementia phenome. Poor white matter tissue integrity was operationalized with lower global and tract-specific fractional anisotropy (FA) and higher mean diffusivity (MD). Volumetric sMRI outcomes included total, gray matter (GM), white matter (WM), frontal bilateral GM, white matter hyperintensity (WMH), and selected based on previous associations with dementia. Cardiovascular health was measured with Life’s Essential 8 score (LE8) converted to tertiles. Multiple linear regression models were used, adjusting for intracranial volumes (ICV) for subcortical structures, and for demographic, socio-economic, and the Alzheimer’s Disease polygenic risk score for all outcomes, among potential confounders. ResultsIn fully adjusted models, hospital-treated infections were inversely related to GM (β ± SE: −1042 ± 379, p = 0.006) and directly related to WMH as percent of ICV (Loge transformed) (β ± SE:+0.026 ± 0.007, p < 0.001). Both total and hospital-treated infections were associated with poor WMI, while the latter was inversely related to FA within the lowest LE8 tertile (β ± SE:-0.0011 ± 0.0003, p < 0.001, PLE8×IB < 0.05), a pattern detected for GM, Right Frontal GM, left accumbens and left hippocampus volumes. Within the uppermost LE8 tertile, total infection burden was linked to smaller right amygdala while being associated with larger left frontal GM and right putamen volumes, in the overall sample. Within that uppermost tertile of LE8, caudate volumes were also positively associated with hospital-treated infections. ConclusionsHospital-treated infections had more consistent deleterious effects on volumetric and white matter integrity brain neuroimaging outcomes compared with total infectious burden, particularly in poorer cardiovascular health groups. Further studies are needed in comparable populations, including longitudinal studies with multiple repeats on neuroimaging markers.

Early morning physical activity is associated with healthier white matter microstructure and happier children: the ActiveBrains project

The background of this study is to examine the associations of individual and combined early morning patterns (i.e., active commuting to school, physical activity before school, having breakfast and good sleep) with white matter microstructure (WMM) and, whether the associated white mater microstructure outcomes were related to mental health outcomes in children with overweight or obesity. 103 children with overweight or obesity (10.0 ± 1.1 years old, 42 girls) from the ActiveBrains project participated in this cross-sectional study. Early morning patterns and mental health indicators (i.e., self-esteem, optimism, positive and negative affect, stress, depression and anxiety) were self-reported by the children using validated questionnaires. WMM was assessed by magnetic resonance imaging using diffusion tensor imaging. When examined independently, early morning patterns were not related with WMM (all P > 0.05). However, the combination of early morning patterns was related with WMM (P < 0.05). Specifically, physically active early morning patterns (i.e., active commuting to school and physical activity before school) were associated with global fractional anisotropy (FA) (β = 0.298, P = 0.013) and global radial diffusivity (RD) (β = − 0.272, P = 0.021), as well as with tract-specific FA (β = 0.314, P = 0.004) and RD (β = − 0.234, P = 0.032) in the superior longitudinal fasciculus (SLF). Furthermore, combined physically active early morning pattern-associated global (i.e., FA and RD) and tract-specific (i.e., FA and RD in the SLF) WMM indicators were positively associated with happiness (β absolute value range from 0.252 to 0.298, all P < 0.05). A combination of physically active early morning patterns may positively relate to white matter microstructure in children with overweight or obesity, and, in turn, happiness.

Serum inflammation markers associated with altered brain white matter microstructure in people with HIV on antiretroviral treatment.

Many studies have reported reduced brain white matter fractional anisotropy (FA) and increased mean diffusivity (MD) on diffusion tensor imaging (DTI) of people with HIV (PWH). Few, however, have linked individual blood inflammatory markers with white matter tract-specific FA and MD. PWH 50years old or older from New York, NY, USA, were invited to a cross-sectional study. Demographic data, blood samples, and brain DTI were obtained. Least absolute shrinkage and selection operator (LASSO) regression was used to examine associations between biomarkers and white matter tract-specific FA and MD. All models included age, sex, race, ethnicity, diabetes, hypertension, smoking, and viral load as control variables. Seventy-two cases were analyzed. Mean age was 60 ± 6years, 47% were women, 21% were Hispanic, and 78% were black. All had asymptomatic HIV infection and were on antiretroviral therapy. Eighty-nine percent had CD4 count >200 cell/mm3 and 78% were virally suppressed. Vascular endothelial growth factor (VEGF) and macrophage inflammatory proteins (MIP) 1β and 1α were consistently associated with lower FA and higher MD across white matter tracts. Elevated serum VEGF, MIP-1α, and MIP-1β were associated with altered white matter microstructure. These blood biomarkers may help predict HIV-associated white matter damage.

A Diffusion Tensor Imaging Analysis of Frontal Lobe White Matter Microstructure in Trigonocephaly Patients

BackgroundChildren with trigonocephaly are at risk for neurodevelopmental disorders. The aim of this study is to investigate white matter properties of the frontal lobes in young, unoperated patients with metopic synostosis as compared to healthy controls using diffusion tension imaging (DTI). MethodsPreoperative DTI data sets of 46 patients with trigonocephaly with a median age of 0.49 (interquartile range: 0.38) years were compared with 21 controls with a median age of 1.44 (0.98) years. White matter metrics of the tracts in the frontal lobe were calculated using FMRIB Software Library (FSL). The mean value of tract-specific fractional anisotropy (FA) and mean diffusivity (MD) were estimated for each subject and compared to healthy controls. By linear regression, FA and MD values per tract were assessed by trigonocephaly, sex, and age. ResultsThe mean FA and MD values in the frontal lobe tracts of untreated trigonocephaly patients, younger than 3 years, were not significantly different in comparison to controls, where age showed to be a significant associated factor. ConclusionsMicrostructural parameters of white matter tracts of the frontal lobe of patients with trigonocephaly are comparable to those of controls aged 0-3 years.

White matter tract-specific microstructural disruption is associated with depressive symptoms in isolated RBD

ObjectiveWhite matter (WM) tract-specific changes may precede gray matter loss in isolated rapid eye movement sleep behavior disorder (iRBD). We aimed to evaluate tract-specific WM changes using tract-specific statistical analysis (TSSA) and their correlation with clinical variables in iRBD patients. MethodsThis was a cross-sectional single-center study of 50 polysomnography-confirmed iRBD patients and 20 age- and sex-matched controls. We used TSSA to identify tract-specific fractional anisotropy (FA) and mean diffusivity (MD) in fourteen major fiber tracts and analyzed between-group differences in these values. Correlations between FA or MD values and clinical variables, including RBD symptom severity, depression and cognition, were evaluated. ResultsPatients with iRBD showed lower FA in the right anterior thalamic radiation (ATR) and higher MD in the bilateral ATR and right inferior fronto-occipital fasciculus (IF-OF) than controls after adjusting for age, sex, and years of education. MD values in the IF-OF positively correlated with scores on the Korean version of the Rapid Eye Movement Sleep Behavior Disorder Questionnaire-Hong Kong (RBDQ-KR, p = 0.042) and the Korean version of the geriatric depression scale (GDS-K, p = 0.002) in iRBD patients. Only GDS-K scores independently correlated with IF-OF MD values after adjusting for RBDQ-KR scores (adjusted p = 0.026). ConclusionThis study suggests WM microstructural disruption in the bilateral ATR and right IF-OF in patients with iRBD and that alterations in the IF-OF may contribute to depressive symptoms.

Edge Density Imaging Identifies White Matter Biomarkers of Late-Life Obesity and Cognition.

Alzheimer disease (AD) and obesity are related to disruptions in the white matter (WM) connectome. We examined the link between the WM connectome and obesity and AD through edge-density imaging/index (EDI), a tractography-based method that characterizes the anatomical embedding of tractography connections. A total of 60 participants, 30 known to convert from normal cognition or mild-cognitive impairment to AD within a minimum of 24 months of follow up, were selected from the Alzheimer disease Neuroimaging Initiative (ADNI). Diffusion-weighted MR images from the baseline scans were used to extract fractional anisotropy (FA) and EDI maps that were subsequently averaged using deterministic WM tractography based on the Desikan-Killiany atlas. Multiple linear and logistic regression analysis were used to identify the weighted sum of tract-specific FA or EDI indices that maximized correlation to body-mass-index (BMI) or conversion to AD. Participants from the Open Access Series of Imaging Studies (OASIS) were used as an independent validation for the BMI findings. The edge-density rich, periventricular, commissural and projection fibers were among the most important WM tracts linking BMI to FA as well as to EDI. WM fibers that contributed significantly to the regression model related to BMI overlapped with those that predicted conversion; specifically in the frontopontine, corticostriatal, and optic radiation pathways. These results were replicated by testing the tract-specific coefficients found using ADNI in the OASIS-4 dataset. WM mapping with EDI enables identification of an abnormal connectome implicated in both obesity and conversion to AD.

Early life factors and white matter microstructure in children with overweight and obesity: The ActiveBrains project

Exposure to a suboptimal environment during the fetal and early infancy period's results in long-term consequences for brain morphology and function. We investigated the associations of early life factors such as anthropometric neonatal data (i.e., birth length, birth weight and birth head circumference) and breastfeeding practices (i.e., exclusive and any breastfeeding) with white matter (WM) microstructure, and ii) we tested whether WM tracts related to early life factors are associated with academic performance in children with overweight/obesity. 96 overweight/obese children (10.03±1.16 years; 38.7% girls) were included from the ActiveBrains Project. WM microstructure indicators used were fractional anisotropy (FA) and mean diffusivity (MD), derived from Diffusion Tensor Imaging. Academic performance was evaluated with the Battery III Woodcock-Muñoz Tests of Achievement. Regression models were used to examine the associations of the early life factors with tract-specific FA and MD, as well as its association with academic performance. Head circumference at birth was positively associated with FA of the inferior fronto-occipital fasciculus tract (0.441; p=0.005), as well as negatively associated with MD of the cingulate gyrus part of cingulum (-0.470; p=0.006), corticospinal (-0.457; p=0.005) and superior thalamic radiation tract (-0.476; p=0.001). Association of birth weight, birth length and exclusive breastfeeding with WM microstructure did not remain significant after false discovery rate correction. None tract related to birth head circumference was associated with academic performance (all p>0.05). Our results highlighted the importance of the perinatal growth in WM microstructure later in life, although its possible academic implications remain inconclusive.

White Matter Fractional Anisotropy Is a Superior Predictor for Cognitive Impairment Than Brain Volumes in Older Adults With Confluent White Matter Hyperintensities.

Older patients with confluent white matter hyperintensities (WMHs) on magnetic resonance imaging have an increased risk for the onset of vascular cognitive impairment (VCI). This study investigates the predictive effects of the white matter (WM) fractional anisotropy (FA) and brain volumes on cognitive impairment for those with confluent WMHs. This study enrolled 77 participants with confluent WMHs (Fazekas grade 2 or 3), including 44 with VCI-no dementia (VCIND) and 33 with normal cognition (NC). The mean FA of 20 WM tracts was calculated to evaluate the global WM microstructural integrity, and major WM tracts were reconstructed using probabilistic tractography. Voxel-based morphometry was used to calculate brain volumes for the total gray matter (GM), the hippocampus, and the nucleus basalis of Meynert (NbM). All volumetric assays were corrected for total intracranial volume. All regression analyses were adjusted for age, gender, education, and apolipoprotein E (ApoE) gene ε4 status. Logistic regression analysis revealed that the mean FA value for global WM was the only independent risk factor for VCI (z score of FA: OR = 4.649, 95%CI 1.576–13.712, p = 0.005). The tract-specific FAs were not associated with the risk of cognitive impairment after controlling the mean FA for global WM. The mean FA value was significantly associated with scores of Mini-Mental State Examination (MMSE) and Auditory Verbal Learning Test. A lower FA was also associated with smaller volumes of total GM, hippocampus, and NbM. However, brain volumes were not found to be directly related to cognitive performances, except for an association between the hippocampal volume and MMSE. In conclusion, the mean FA for global WM microstructural integrity is a superior predictor for cognitive impairment than tract-specific FA and brain volumes in people with confluent WMHs.

White Matter Microstructure in Attention-Deficit/Hyperactivity Disorder: A Systematic Tractography Study in 654 Individuals

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by age-inappropriate levels of inattention and/or hyperactivity-impulsivity. ADHD has been related to differences in white matter (WM) microstructure. However, much remains unclear regarding the nature of these WM differences and which clinical aspects of ADHD they reflect. We systematically investigated whether fractional anisotropy (FA) is associated with current and/or lifetime categorical diagnosis, impairment in daily life, and continuous ADHD symptom measures. MethodsDiffusion-weighted imaging data were obtained from 654 participants (322 unaffected, 258 affected, 74 subthreshold; 7–29 years of age). We applied automated global probabilistic tractography on 18 major WM pathways. Linear mixed-effects regression models were used to examine associations of clinical measures with overall brain and tract-specific FA. ResultsThere were significant interactions of tract with all ADHD variables on FA. There were no significant associations of FA with current or lifetime diagnosis, nor with impairment. Lower FA in the right cingulum angular bundle was associated with higher hyperactivity-impulsivity symptom severity (pfamilywise error = .045). There were no significant effects for other tracts. ConclusionsThis is the first time global probabilistic tractography has been applied to an ADHD dataset of this size. We found no evidence for altered FA in association with ADHD diagnosis. Our findings indicate that associations of FA with ADHD are not uniformly distributed across WM tracts. Continuous symptom measures of ADHD may be more sensitive to FA than diagnostic categories. The right cingulum angular bundle in particular may play a role in symptoms of hyperactivity and impulsivity.

Structural disconnectivity and the risk of dementia in the general population.

The disconnectivity hypothesis postulates that partial loss of connecting white matter fibers between brain regions contributes to the development of dementia. Using diffusion MRI to quantify global and tract-specific white matter microstructural integrity, we tested this hypothesis in a longitudinal population-based study. Global and tract-specific fractional anisotropy (FA) and mean diffusivity (MD) were obtained in 4,415 people without dementia (mean age 63.9 years, 55.0% women) from the prospective population-based Rotterdam Study with brain MRI between 2005 and 2011. We modeled the association of these diffusion measures with risk of dementia (follow-up until 2016) and with changes on repeated cognitive assessment after on average 5.4 years, adjusting for age, sex, education, macrostructural MRI markers, depressive symptoms, cardiovascular risk factors, and APOE genotype. During a median follow-up of 6.8 years, 101 participants had incident dementia, of whom 83 had clinical Alzheimer disease (AD). Lower global values of FA and higher values of MD were associated with an increased risk of dementia (adjusted hazard ratio [95% confidence interval (CI)] per SD increase for MD 1.79 [1.44-2.23] and FA 0.65 [0.52-0.80]). Similarly, lower global values of FA and higher values of MD related to more cognitive decline in people without dementia (difference in global cognition per SD increase in MD [95% CI] was -0.04 [-0.07 to -0.01]). Associations were most profound in the projection, association, and limbic system tracts. Structural disconnectivity is associated with an increased risk of dementia and more pronounced cognitive decline in the general population.

Physical Activity, Sedentary Behavior, and White Matter Microstructure in Children with Overweight or Obesity.

This study aimed to investigate the associations of objectively measured and self-reported physical activity (PA) and sedentary behavior with white matter microstructure in children with overweight or obesity. In a sample of 103 participants (age, 10.02 ± 1.15 yr; 42 girls) from the ActiveBrains project, we assessed PA and sedentary behavior using accelerometers (GT3X+; ActiGraph, Pensacola, FL), and the Youth Activity Profile-Spain questionnaire. Objectively measured PA and sedentary behavior were classified into different intensities following the hip- and wrist-based cutoff points for the Euclidean Norm Minus One metric by Hildebrand et al., wrist-based cutoff points for counts metric by Chandler et al., and hip-based cutoff points for counts metric for Romanzini et al. and Evenson et al. Magnetic resonance imaging of white matter microstructure, fractional anisotropy (FA), and mean diffusivity (MD) were derived from diffusion tensor imaging. Linear regression models were used to examine the associations of objectively measured and self-reported PA and sedentary behavior with global and tract-specific FA and MD. Self-reported total PA was positively associated with global FA (β = 0.236, P = 0.038), whereas watching television was negatively associated with global FA (β = -0.270, P = 0.014). In regard to the objective measures, using single regression models, light PA (β = 0.273, P = 0.016), moderate-to-vigorous PA (β = 0.257, P = 0.035), and total PA (β = 0.294, P = 0.013) were positively associated with global FA only when Hildebrand-Euclidean Norm Minus One hip cut points were used for analyses. Lastly, no association was found between PA and sedentary behavior and FA and MD within individual tracts. Our results suggest that PA and watching television are related to white matter microstructure in children with overweight or obesity. However, longitudinal large-scale studies are needed to confirm and expand these findings.

The prospective association of objectively measured sleep and cerebral white matter microstructure in middle-aged and older persons

Poor sleep may destabilize axonal integrity and deteriorate cerebral white matter. In middle-aged and older adults sleep problems increase alongside structural brain changes, but the temporal relation between these processes is poorly understood. We studied longitudinal associations between sleep and cerebral white matter microstructure. One thousand one persons (59.3 ± 7.9 years, 55% women) were followed across 5.8 years (3.9-10.8). Total sleep time (TST, hours), sleep efficiency (SE, percentage), sleep onset latency (SOL, minutes), and wake after sleep onset (WASO, minutes) were measured at baseline using a wrist-worn actigraph. White matter microstructure (global and tract-specific fractional anisotropy [FA] and mean diffusivity [MD]) was measured twice with diffusion tensor imaging (DTI). Poor sleep was associated with worse white matter microstructure up to 7 years later but did not predict trajectories of DTI over time. Longer TST was associated with higher global FA (β = 0.06, 95% CI: 0.01 to 0.12), but not with MD. Persons with higher SE had higher global FA (β = 0.01, 95% CI: 0.002 to 0.01) and lower MD (β = -0.01, 95% CI: -0.01 to -0.0004). Consistently, those with more WASO had lower global FA (β = -0.003, 95% CI: -0.005 to -0.001) and higher MD (β = 0.002, 95% CI: 0.0004 to 0.004). Global findings seemed to be driven by microstructural alterations in the cingulum, anterior forceps of corpus callosum, projection and association tracts. Middle-aged and older persons with more WASO, lower SE and shorter TST have worse microstructure of cerebral white matter. Microstructural alterations are most pronounced projection and association tracts, in the cingulum, and in the anterior forceps of corpus callosum.

Childhood sleep disturbances and white matter microstructure in preadolescence.

Sleep problems occur in up to 30% of children and have been associated with adverse developmental outcomes. However, due to a lack of longitudinal neuroimaging studies, the neurobiological changes that may underlie some of these associations have remained unclear. This study explored the association between sleep problems during childhood and white matter (WM) microstructure in preadolescence. Children from the population-based birth cohort, the Generation R Study, who had repeatedly assessed sleep problems between 1.5 and 10years of age and a MRI scan at age 10 (N=2,449), were included. Mothers reported on their child's sleep problems using the Child Behavior Checklist (CBCL 1.5-5) when children were 1.5, 3, and 6years of age. At age 2, mothers completed very similar questions. At age 10, both children and their mothers reported on sleep problems. We used whole-brain and tract-specific fractional anisotropy (FA) and mean diffusivity (MD) values obtained through diffusion tensor imaging as measures of WM microstructure. Childhood sleep problems at 1.5, 2, and 6 years of age were associated with less WM microstructural integrity (approximately 0.05 SD lower global FA score per 1-SD sleep problems). In repeated-measures analyses, children with more sleep problems (per 1-SD) at baseline had lower FA values at age 10 in particular in the corticospinal tract (-0.12 SD, 95% CI:-0.20;-0.05), the uncinate fasciculus (-0.12 SD, 95% CI:-0.19;-0.05), and the forceps major (-0.11 SD, 95% CI:-0.18;-0.03), although effect estimates across the tracts did not differ substantially. Childhood sleep disturbances are associated with less WM microstructural integrity in preadolescence. Our results show that early neurodevelopment may be a period of particular vulnerability to sleep problems. This study cannot demonstrate causality but suggests that preventive interventions addressing sleep problems should be further explored to test whether they impact adverse neurodevelopment.

Cerebral tract integrity relates to white matter hyperintensities, cortex volume, and cognition.

We examined the relationship among white matter (WM) tract integrity, WM hyperintensities (WMH), lobar gray matter (GM) volumes, and cognition in the cross-sectional Framingham Offspring Study. Six hundred eighty participants (71.7 ± 7.7years) completed cognitive testing and magnetic resonance imaging. Diffusion tensor imaging probabilistic tractography was used to reconstruct major WM tracts. We computed tract-specific mean fractional anisotropy (FA) and tract-specific WMH ratio. Linear regressions identified relations between tracts and lobar GM volumes. Partial least squares regression examined associations between integrity of combined tracts, lobar GM volumes and cognition, including scores of memory and processing speed. Five tracts were particularly vulnerable to WMH, and tract-specific WMH volumes were inversely associated with tract-specific FA (p values < 0.05). Tract-specific FA related to lobar GM volumes. Memory was associated with lobar GM, while processing speed related to both tract integrity and lobar GM volumes. We conclude that subtle microstructural WM tract degeneration relates to specific lobar GM atrophy. The integrity of associated WM tracts and GM lobes differentially impacts memory and processing speed.

Polygenic Scores for Neuropsychiatric Traits and White Matter Microstructure in the Pediatric Population

BackgroundGenome-wide association studies have identified numerous genetic variants that predispose to neuropsychiatric traits. Identification of mechanisms in the brain that underlie these associations is essential for understanding manifestations of genetic predisposition within the general population. Here, we investigated the association between polygenic scores (PGSs) for seven neuropsychiatric traits and white matter microstructure of the brain on diffusion tensor imaging in the pediatric population. MethodsParticipants from the Generation R Study who had genotype and diffusion tensor imaging data available (n = 1138, mean age = 10.2 years, range = 8.7–12.0) were included. PGSs were calculated for five psychiatric disorders (attention-deficit/hyperactivity disorder, bipolar disorder, autism, major depressive disorder, and schizophrenia) and two cognitive traits (intelligence and educational attainment) and were tested for associations with global and tract-specific fractional anisotropy (FA) and mean diffusivity. ResultsSignificant positive associations with global FA were observed for the PGSs of intelligence (β = .109, SE = .029, p < .001, ΔR2 = .012) and educational attainment (β = .118, SE = .029, p < .001, ΔR2 = .014). No significant associations were observed with FA for the PGSs of psychiatric disorders. Tract-specific analysis showed that the PGSs for intelligence and educational attainment were associated with FA of several association and projection fibers of the brain. ConclusionsOur results show that genetic predisposition for cognition-related traits, but not for psychiatric disorders, is associated with microstructural diffusion measures of white matter tracts at an early age. These results suggest a shared genetic etiology among structural connectivity, intelligence, and educational achievement.

Cytokine Response, Tract-Specific Fractional Anisotropy, and Brain Morphometry in Post-Stroke Cognitive Impairment

Post-stroke cognitive impairment is a clinically heterogeneous condition and its types have a different course and prognosis. The aim of the present study is to address the roles of inflammation, white matter pathology, and brain atrophy in different neuropsychological types of cognitive impairment in the acute period of ischemic stroke. In 92 patients, we performed an assessment of the cognitive status and measured concentrations of cytokines (interleukin [IL]-1β, IL-6, tumor necrosis factor-alpha, IL-10) in liquor and serum, as well as a number of magnetic resonance imaging (MRI) morphometric parameters and fractional anisotropy. The control group consisted of 14 individuals without cerebrovascular disease. All patients had a higher level of IL-10 in serum than the control group. Patients with dysexecutive cognitive impairment had a higher concentration of IL-1β and IL-10 in liquor, IL-6 level in serum, and a lower fractional anisotropy of the ipsilateral thalamus than patients with normal cognition. Patients with mixed cognitive impairment were characterized by a lower fractional anisotropy of contralateral fronto-occipital fasciculus, compared with patients with dysexecutive cognitive impairment. Patients with both dysexecutive and mixed cognitive deficit had a wide area of leukoaraiosis and a reduced fractional anisotropy of the contralateral cingulum, compared with patients without cognitive impairment. Also, we found numerous correlations between cognitive status and levels of cytokines, MRI morphometric parameters, and fractional anisotropy of certain regions of the brain. The concentrations of cytokines in serum and cerebrospinal fluid studied in combination with MRI morphometric parameters and fractional anisotropy appear to be informative biomarkers of clinical types of post-stroke cognitive impairment.

White Matter Microstructural Properties are Related to Inter-Individual Differences in Cognitive Instability after Sleep Deprivation

Several diseases are characterized by cognitive instability, which is amplified in the conditions of sleep deprivation (SD). Cognitive instability in SD can be examined by the number of lapses on the psychomotor vigilance test (PVT), which is considered to be a gold standard in the field. However, the number of PVT lapses widely range according to inter-individual differences, from apparent cognitive resistance to severe cognitive impairment. In this study, tract-based spatial statistical analyses with multiple diffusion tensor imaging-derived characteristics (i.e., fractional anisotropy (FA), mean diffusivity, radial diffusivity, and axial diffusivity) were employed to investigate the relationships between the number of PVT lapses and the diffusion characteristics. A hierarchical linear regression model was then used to assess the contributions of tract-specific FA values in predicting PVT lapses. Finally, dichotomized analysis was used to investigate white matter (WM) differences between resilient and vulnerable groups. Our results showed significant negative correlations between numbers of PVT lapses and FA in multiple WM tracts, with the FA variations in the superior longitudinal fasciculus and splenium of the corpus callosum accounting for nearly 37.5% of individual variability in PVT lapses. In addition, dichotomized analyses indicated that the resilient participants exhibited significantly higher FA values compared with the vulnerable participants. Together, these findings suggest that cognitive instability after SD was closely associated with individual differences in WM integrity.