Differential Development of Human Brain White Matter Tracts

Neuroscience is increasingly focusing on developmental factors related to human structural and functional connectivity. Unfortunately, to date, diffusion-based imaging approaches have only contributed modestly to these broad objectives, despite the promise of diffusion-based tractography. Here, we report a novel data-driven approach to detect similarities and differences among white matter tracts with respect to their developmental trajectories, using 64-direction diffusion tensor imaging. Specifically, using a cross-sectional sample comprising 144 healthy individuals (7 to 48 years old), we applied k-means cluster analysis to separate white matter voxels based on their age-related trajectories of fractional anisotropy. Optimal solutions included 5-, 9- and 14-clusters. Our results recapitulate well-established tracts (e.g., internal and external capsule, optic radiations, corpus callosum, cingulum bundle, cerebral peduncles) and subdivisions within tracts (e.g., corpus callosum, internal capsule). For all but one tract identified, age-related trajectories were curvilinear (i.e., inverted ‘U-shape’), with age-related increases during childhood and adolescence followed by decreases in middle adulthood. Identification of peaks in the trajectories suggests that age-related losses in fractional anisotropy occur as early as 23 years of age, with mean onset at 30 years of age. Our findings demonstrate that data-driven analytic techniques may be fruitfully applied to extant diffusion tensor imaging datasets in normative and neuropsychiatric samples

Connectivity-enhanced diffusion analysis reveals white matter density disruptions in first episode and chronic schizophrenia.

Reduced fractional anisotropy (FA) is a well-established correlate of schizophrenia, but it remains unclear whether these tensor-based differences are the result of axon damage and/or organizational changes and whether the changes are progressive in the adult course of illness. Diffusion MRI data were collected in 81 schizophrenia patients (54 first episode and 27 chronic) and 64 controls. Analysis of FA was combined with "fixel-based" analysis, the latter of which leverages connectivity and crossing-fiber information to assess both fiber bundle density and organizational complexity (i.e., presence and magnitude of off-axis diffusion signal). Compared with controls, patients with schizophrenia displayed clusters of significantly lower FA in the bilateral frontal lobes, right dorsal centrum semiovale, and the left anterior limb of the internal capsule. All FA-based group differences overlapped substantially with regions containing complex fiber architecture. FA within these clusters was positively correlated with principal axis fiber density, but inversely correlated with both secondary/tertiary axis fiber density and voxel-wise fiber complexity. Crossing fiber complexity had the strongest (inverse) association with FA (r = -0.82). When crossing fiber structure was modeled in the MRtrix fixel-based analysis pipeline, patients exhibited significantly lower fiber density compared to controls in the dorsal and posterior corpus callosum (central, postcentral, and forceps major). Findings of lower FA in patients with schizophrenia likely reflect two inversely related signals: reduced density of principal axis fiber tracts and increased off-axis diffusion sources. Whereas the former confirms at least some regions where myelin and or/axon count are lower in schizophrenia, the latter indicates that the FA signal from principal axis fiber coherence is broadly contaminated by macrostructural complexity, and therefore does not necessarily reflect microstructural group differences. These results underline the need to move beyond tensor-based models in favor of acquisition and analysis techniques that can help disambiguate different sources of white matter disruptions associated with schizophrenia

Genetics of brain fiber architecture and intellectual performance

The study is the first to analyze genetic and environmental factors that affect brain fiber architecture and its genetic linkage with cognitive function. We assessed white matter integrity voxelwise using diffusion tensor imaging at high magnetic field (4 Tesla), in 92 identical and fraternal twins. White matter integrity, quantified using fractional anisotropy (FA), was used to fit structural equation models (SEM) at each point in the brain, generating three-dimensional maps of heritability. We visualized the anatomical profile of correlations between white matter integrity and full-scale, verbal, and performance intelligence quotients (FIQ, VIQ, and PIQ). White matter integrity (FA) was under strong genetic control and was highly heritable in bilateral frontal (a2 = 0.55, p = 0.04, left; a2 = 0.74, p = 0.006, right), bilateral parietal (a2 = 0.85, p < 0.001, left; a2 = 0.84, p < 0.001, right), and left occipital (a2 = 0.76, p = 0.003) lobes, and was correlated with FIQ and PIQ in the cingulum, optic radiations, superior fronto-occipital fasciculus, internal capsule, callosal isthmus, and the corona radiata (p = 0.04 for FIQ and p = 0.01 for PIQ, corrected for multiple comparisons). In a cross-trait mapping approach, common genetic factors mediated the correlation between IQ and white matter integrity, suggesting a common physiological mechanism for both, and common genetic determination. These genetic brain maps reveal heritable aspects of white matter integrity and should expedite the discovery of single-nucleotide polymorphisms affecting fiber connectivity and cognition

White matter integrity in physically fit older adults

Background: White matter (WM) integrity declines with normal aging. Physical activity may attenuate age-related WM integrity changes and improve cognitive function. This study examined brain WM integrity in Masters athletes who have engaged in life-long aerobic exercise training. We tested the hypothesis that life-long aerobic training is associated with improved brain WM integrity in older adults. Methods: Ten Masters athletes (3 females, age = 72.2 ± 5.3 years, endurance training \u3e15 years) and 10 sedentary older adults similar in age and educational level (2 females, age = 74.5 ± 4.3 years) participated. MRI fluid-attenuated-inversion-recovery (FLAIR) images were acquired to assess white matter hyperintensities (WMH) volume. Diffusion tensor imaging (DTI) was performed to evaluate the WM microstructural integrity with a DTI-derived metric, fractional anisotropy (FA) and mean diffusivity (MD). Results: After normalization to whole-brain volume, Masters athletes showed an 83% reduction in deep WMH volume relative to their sedentary counterparts (0.05 ± 0.05% vs. 0.29 ± 0.29%, p b 0.05). In addition, we found an inverse relationship between aerobic fitness (VO2max) and deep WMH volume (r = −0.78, p \u3c 0.001). Using TBSS, Masters athletes showed higher FA values in the right superior corona radiata (SCR), both sides of superior longitudinal fasciculus (SLF), right inferior fronto-occipital fasciculus (IFO), and left inferior longitudinal fasciculus (ILF). In addition, Masters athletes also showed lower MD values in the left posterior thalamic radiation (PTR) and left cingulum hippocampus. Conclusions: These findings suggest that life-long exercise is associated with reducedWMH and may preserveWM fiber microstructural integrity related to motor control and coordination in older adults

Complex regional pain syndrome : The matter of white matter?

Introduction: Many central pathophysiological aspects of complex regional pain syndrome (CRPS) are still unknown. Although brain-imaging studies are increasingly supporting the contribution of the central nervous system to the generation and maintenance of the CRPS pain, the brain's white-matter alterations are seldom investigated. Methods: In this study, we used diffusion tensor imaging to explore white-matter changes in twelve CRPS-type-1 female patients suffering from chronic right upper-limb pain compared with twelve healthy control subjects. Results: Tract-based spatial-statistics analysis revealed significantly higher mean diffusivity, axial diffusivity, and radial diffusivity in the CRPS patients, suggesting that the structural connectivity is altered in CRPS. All these measures were altered in the genu, body, and splenium of corpus callosum, as well as in the left anterior and posterior and the right superior parts of the corona radiata. Axial diffusivity was significantly correlated with clinical motor symptoms at whole-brain level, supporting the physiological significance of the observed white-matter abnormalities. Conclusions: Altogether, our findings further corroborate the involvement of the central nervous system in CRPS.Peer reviewe

White matter integrity in physically fit older adults

Background: White matter (WM) integrity declines with normal aging. Physical activity may attenuate age-related WM integrity changes and improve cognitive function. This study examined brain WM integrity in Masters athletes who have engaged in life-long aerobic exercise training. We tested the hypothesis that life-long aerobic training is associated with improved brain WM integrity in older adults. Methods: Ten Masters athletes (3 females, age = 72.2 ± 5.3 years, endurance training \u3e15 years) and 10 sedentary older adults similar in age and educational level (2 females, age = 74.5 ± 4.3 years) participated. MRI fluid-attenuated-inversion-recovery (FLAIR) images were acquired to assess white matter hyperintensities (WMH) volume. Diffusion tensor imaging (DTI) was performed to evaluate the WM microstructural integrity with a DTI-derived metric, fractional anisotropy (FA) and mean diffusivity (MD). Results: After normalization to whole-brain volume, Masters athletes showed an 83% reduction in deep WMH volume relative to their sedentary counterparts (0.05 ± 0.05% vs. 0.29 ± 0.29%, p b 0.05). In addition, we found an inverse relationship between aerobic fitness (VO2max) and deep WMH volume (r = −0.78, p \u3c 0.001). Using TBSS, Masters athletes showed higher FA values in the right superior corona radiata (SCR), both sides of superior longitudinal fasciculus (SLF), right inferior fronto-occipital fasciculus (IFO), and left inferior longitudinal fasciculus (ILF). In addition, Masters athletes also showed lower MD values in the left posterior thalamic radiation (PTR) and left cingulum hippocampus. Conclusions: These findings suggest that life-long exercise is associated with reducedWMH and may preserveWM fiber microstructural integrity related to motor control and coordination in older adults

Fiber-Flux Diffusion Density for White Matter Tracts Analysis: Application to Mild Anomalies Localization in Contact Sports Players

We present the concept of fiber-flux density for locally quantifying white matter (WM) fiber bundles. By combining scalar diffusivity measures (e.g., fractional anisotropy) with fiber-flux measurements, we define new local descriptors called Fiber-Flux Diffusion Density (FFDD) vectors. Applying each descriptor throughout fiber bundles allows along-tract coupling of a specific diffusion measure with geometrical properties, such as fiber orientation and coherence. A key step in the proposed framework is the construction of an FFDD dissimilarity measure for sub-voxel alignment of fiber bundles, based on the fast marching method (FMM). The obtained aligned WM tract-profiles enable meaningful inter-subject comparisons and group-wise statistical analysis. We demonstrate our method using two different datasets of contact sports players. Along-tract pairwise comparison as well as group-wise analysis, with respect to non-player healthy controls, reveal significant and spatially-consistent FFDD anomalies. Comparing our method with along-tract FA analysis shows improved sensitivity to subtle structural anomalies in football players over standard FA measurements

Structural Alterations in the Corpus Callosum Are Associated with Suicidal Behavior in Women with Borderline Personality Disorder

Structural alterations in the corpus callosum (CC), the major white matter tract connecting functionally related brain regions in the two hemispheres, have been shown to be associated with emotional instability, impulsivity and suicidality in various mental disorders. To explore whether structural alterations of the CC would be similarly associated with emotional instability, impulsivity and suicidality in borderline personality disorder (BPD), we used diffusion tensor imaging (DTI) to assess the structural integrity of the CC in 21 BPD and 20 healthy control (HC) participants. Our hypothesis-driven analyses revealed a positive correlation between BPD participants’ suicidal behavior and fractional anisotropy (FA) in the splenium and genu of the CC and a negative correlation between BPD participants’ suicidal behavior and mean diffusivity (MD) in the splenium of CC. Our exploratory analyses suggested that suicidal BPD participants showed less FA and more MD in these regions than HC participants but that non-suicidal BPD participants showed similar FA and MD in these regions as HC participants. Taken together, our findings suggest an association between BPD participants’ suicidal behavior and structural alterations in regions of the CC that are connected with brain regions implicated in emotion regulation and impulse control. Structural alterations of the CC may, thus, account for deficits in emotion regulation and impulse control that lead to suicidal behavior in BPD. However, these findings should be considered as preliminary until replicated and extended in future studies that comprise larger samples of suicidal and non-suicidal BPD participants

Investigating brain connectivity heritability in a twin study using diffusion imaging data

Heritability of brain anatomical connectivity has been studied with diffusion-weighted imaging (DWI) mainly by modeling each voxel's diffusion pattern as a tensor (e.g., to compute fractional anisotropy), but this method cannot accurately represent the many crossing connections present in the brain. We hypothesized that different brain networks (i.e., their component fibers) might have different heritability and we investigated brain connectivity using High Angular Resolution Diffusion Imaging (HARDI) in a cohort of twins comprising 328 subjects that included 70 pairs of monozygotic and 91 pairs of dizygotic twins. Water diffusion was modeled in each voxel with a Fiber Orientation Distribution (FOD) function to study heritability for multiple fiber orientations in each voxel. Precision was estimated in a test-retest experiment on a sub-cohort of 39 subjects. This was taken into account when computing heritability of FOD peaks using an ACE model on the monozygotic and dizygotic twins. Our results confirmed the overall heritability of the major white matter tracts but also identified differences in heritability between connectivity networks. Inter-hemispheric connections tended to be more heritable than intra-hemispheric and cortico-spinal connections. The highly heritable tracts were found to connect particular cortical regions, such as medial frontal cortices, postcentral, paracentral gyri, and the right hippocampus

Development of Advanced, Clinically Feasible Neuroimaging Methodology with Diffusional Kurtosis Imaging

Diffusion MRI (dMRI) is a powerful, non-invasive tool for probing the structural organization of the human brain. Quantitative dMRI analyses provide unique capabilities for the characterization of tissue microstructure as well as imaging contrast that is not available to other modalities. White matter tractography relies on dMRI and is currently the only non-invasive technique for mapping structural connections in the human brain. In this chapter, we will describe diffusional kurtosis imaging, an effective and versatile dMRI technique, and discuss a clinical problem in temporal lobe epilepsy (TLE) which is insurmountable with current diagnostic approaches. Subsequent chapters will further develop the capabilities of DKI and demonstrate how it may be particularly well suited to overcome current barriers to care in the clinical management of TLE