White Matter Bundles Research Articles

In vivo quantification of demyelination and recovery using compartment-specific diffusion MRI metrics validated by electron microscopy

There is a need for accurate quantitative non-invasive biomarkers to monitor myelin pathology in vivo and distinguish myelin changes from other pathological features including inflammation and axonal loss. Conventional MRI metrics such as T2, magnetization transfer ratio and radial diffusivity have proven sensitivity but not specificity. In highly coherent white matter bundles, compartment-specific white matter tract integrity (WMTI) metrics can be directly derived from the diffusion and kurtosis tensors: axonal water fraction, intra-axonal diffusivity, and extra-axonal radial and axial diffusivities. We evaluate the potential of WMTI to quantify demyelination by monitoring the effects of both acute (6weeks) and chronic (12weeks) cuprizone intoxication and subsequent recovery in the mouse corpus callosum, and compare its performance with that of conventional metrics (T2, magnetization transfer, and DTI parameters). The changes observed in vivo correlated with those obtained from quantitative electron microscopy image analysis. A 6-week intoxication produced a significant decrease in axonal water fraction (p<0.001), with only mild changes in extra-axonal radial diffusivity, consistent with patchy demyelination, while a 12-week intoxication caused a more marked decrease in extra-axonal radial diffusivity (p=0.0135), consistent with more severe demyelination and clearance of the extra-axonal space. Results thus revealed increased specificity of the axonal water fraction and extra-axonal radial diffusivity parameters to different degrees and patterns of demyelination. The specificities of these parameters were corroborated by their respective correlations with microstructural features: the axonal water fraction correlated significantly with the electron microscopy derived total axonal water fraction (ρ=0.66; p=0.0014) but not with the g-ratio, while the extra-axonal radial diffusivity correlated with the g-ratio (ρ=0.48; p=0.0342) but not with the electron microscopy derived axonal water fraction. These parameters represent promising candidates as clinically feasible biomarkers of demyelination and remyelination in the white matter.

Measuring Cortical Connectivity in Alzheimer's Disease as a Brain Neural Network Pathology: Toward Clinical Applications.

The objective was to review the literature on diffusion tensor imaging as well as resting-state functional magnetic resonance imaging and electroencephalography (EEG) to unveil neuroanatomical and neurophysiological substrates of Alzheimer's disease (AD) as a brain neural network pathology affecting structural and functional cortical connectivity underlying human cognition. We reviewed papers registered in PubMed and other scientific repositories on the use of these techniques in amnesic mild cognitive impairment (MCI) and clinically mild AD dementia patients compared to cognitively intact elderly individuals (Controls). Hundreds of peer-reviewed (cross-sectional and longitudinal) papers have shown in patients with MCI and mild AD compared to Controls (1) impairment of callosal (splenium), thalamic, and anterior-posterior white matter bundles; (2) reduced correlation of resting state blood oxygen level-dependent activity across several intrinsic brain circuits including default mode and attention-related networks; and (3) abnormal power and functional coupling of resting state cortical EEG rhythms. Clinical applications of these measures are still limited. Structural and functional (in vivo) cortical connectivity measures represent a reliable marker of cerebral reserve capacity and should be used to predict and monitor the evolution of AD and its relative impact on cognitive domains in pre-clinical, prodromal, and dementia stages of AD.

After Intracerebral Hemorrhage, Oligodendrocyte Precursors Proliferate and Differentiate Inside White-Matter Tracts in the Rat Striatum.

Damage to myelinated axons contributes to neurological deficits after acute CNS injury, including ischemic and hemorrhagic stroke. Potential treatments to promote re-myelination will require fully differentiated oligodendrocytes, but almost nothing is known about their fate following intracerebral hemorrhage (ICH). Using a rat model of ICH in the striatum, we quantified survival, proliferation, and differentiation of oligodendrocyte precursor cells (OPCs) (at 1, 3, 7, 14, and 28 days) in the peri-hematoma region, surrounding striatum, and contralateral striatum. In the peri-hematoma, the density of Olig2+ cells increased dramatically over the first 7 days, and this coincided with disorganization and fragmentation of myelinated axon bundles. Very little proliferation (Ki67+) of Olig2+ cells was seen in the anterior subventricular zone from 1 to 28 days. However, by 3 days, many were proliferating in the peri-hematoma region, suggesting that local proliferation expands their population. By 14 days, the density of Olig2+ cells declined in the peri-hematoma region, and, by 28 days, it reached the low level seen in the contralateral striatum. At these later times, many surviving axons were aligned into white-matter bundles, which appeared less swollen or fragmented. Oligodendrocyte cell maturation was prevalent over the 28-day period. Densities of immature OPCs (NG2+Olig2+) and mature (CC-1+Olig2+) oligodendrocytes in the peri-hematoma increased dramatically over the first week. Regardless of the maturation state, they increased preferentially inside the white-matter bundles. These results provide evidence that endogenous oligodendrocyte precursors proliferate and differentiate in the peri-hematoma region and have the potential to re-myelinate axon tracts after hemorrhagic stroke.

Limbic-motor areas interactions as revealed by Constrained Spherical Deconvolution tractography: a mechanism to shape complex motor behaviors?

Although there are several evidences in animal research on the emotional motor-limbic subcortical system including amygdala, hyppocampus, parahyppocampal cortex and nucleus accumbens, little is known about its connections to cortical motor-related areas. All these structures are in a position to influence behavior via cortical motor-related areas, which in turn have access, both directly and indirectly, to descending motor pathways. If on the one hand, many animal studies have investigated the neural connectivity of the motor-limbic system using electrophysiological and tracing techniques, on the other hand the use of these methods in the live human brain is limited and elusive due to their invasive nature [1]. By contrast, recent developments in diffusion magnetic resonance imaging and tractography have allowed for non-invasive and in vivo investigation of the human brain. Diffusion-based tractography is a method analyzing the preferential water diffusivity directionality along white matter bundles, thus calculating the highest mathematical probability that water diffuses in a given direction [2]. Using diffusion-weighted magnetic resonance imaging and Constrained Spherical Deconvolution tractography on a population of 15 healthy subjects, we provided tractographic evidence of a structural connection between the amygdala and motor-related areas in humans. These direct limbic-motor pathways may allow for the regulation and modulation of complex motor behaviors and subtle behaviors such as social interactions. The demonstration of these interactions might be fundamental for the comprehension of the pathophysiology of several limbic-sensorimotor diseases, such autism spectrum disorders and motor conversion disorders.

A study of brain white matter plasticity in early blinds using tract-based spatial statistics and tract statistical analysis.

Early blind individuals are known to exhibit structural brain reorganization. Particularly, early-onset blindness may trigger profound brain alterations that affect not only the visual system but also the remaining sensory systems. Diffusion tensor imaging (DTI) allows in-vivo visualization of brain white matter connectivity, and has been extensively used to study brain white matter structure. Among statistical approaches based on DTI, tract-based spatial statistics (TBSS) is widely used because of its ability to automatically perform whole brain white matter studies. Tract specific analysis (TSA) is a more recent method that localizes changes in specific white matter bundles. In the present study, we compare TBSS and TSA results of DTI scans from 12 early blind individuals and 13 age-matched sighted controls, with two aims: (a) to investigate white matter alterations associated with early visual deprivation; (b) to examine the relative sensitivity of TSA when compared with TBSS, for both deficit and hypertrophy of white matter microstructures. Both methods give consistent results for broad white matter regions of deficits. However, TBSS does not detect hypertrophy of white matter, whereas TSA shows a higher sensitivity in detecting subtle differences in white matter colocalized to the posterior parietal lobe.

Mapping the "Depression Switch" During Intraoperative Testing of Subcallosal Cingulate Deep Brain Stimulation.

The clinical utility of monitoring behavioral changes during intraoperative testing of subcallosal cingulate deep brain stimulation is unknown. To characterize the structural connectivity correlates of deep brain stimulation-evoked behavioral effects using probabilistic tractography in depression. Categorization of acute behavioral effects was conducted in 9 adults undergoing deep brain stimulation implantation surgery for chronic treatment-resistant depression in a randomized and blinded testing session at Emory University. Patients were studied from September 1, 2011, through June 30, 2013. Post hoc analyses of the structural tractography patterns mediating distinct categories of evoked behavioral effects were defined, including the best response overall. Data analyses were performed from May 1 through July 1, 2015. Categorization of stimulation-induced transient behavioral effects and delineation of the shared white matter tracts mediating response subtypes. Among the 9 patients, 72 active and 36 sham trials were recorded. The following stereotypical behavior patterns were identified: changes in interoceptive (noted changes in body state in 30 of 72 active and 4 of 36 sham trials) and in exteroceptive (shift in attention from patient to others in 9 of 72 active and 0 sham trials) awareness. The best response was a combination of exteroceptive and interoceptive changes at a single left contact for all 9 patients. Structural connectivity showed that the best response contacts had a pattern of connections to the bilateral ventromedial frontal cortex (via forceps minor and left uncinate fasciculus) and to the cingulate cortex (via left cingulum bundle), whereas behaviorally salient but nonbest contacts had only cingulate involvement. The involvement of the 3 white matter bundles during stimulation of the best contacts suggests a mechanism for the observed transient "depression switch." This analysis of transient behavior changes during intraoperative deep brain stimulation of the subcallosal cingulate and the subsequent identification of unique connectivity patterns may provide a biomarker of a rapid-onset depression switch to guide surgical implantation and to refine and optimize algorithms for the selection of contacts in long-term stimulation for treatment-resistant depression.

A joint compressed-sensing and super-resolution approach for very high-resolution diffusion imaging

Diffusion MRI (dMRI) can provide invaluable information about the structure of different tissue types in the brain. Standard dMRI acquisitions facilitate a proper analysis (e.g. tracing) of medium-to-large white matter bundles. However, smaller fiber bundles connecting very small cortical or sub-cortical regions cannot be traced accurately in images with large voxel sizes. Yet, the ability to trace such fiber bundles is critical for several applications such as deep brain stimulation and neurosurgery. In this work, we propose a novel acquisition and reconstruction scheme for obtaining high spatial resolution dMRI images using multiple low resolution (LR) images, which is effective in reducing acquisition time while improving the signal-to-noise ratio (SNR). The proposed method called compressed-sensing super resolution reconstruction (CS-SRR), uses multiple overlapping thick-slice dMRI volumes that are under-sampled in q-space to reconstruct diffusion signal with complex orientations. The proposed method combines the twin concepts of compressed sensing and super-resolution to model the diffusion signal (at a given b-value) in a basis of spherical ridgelets with total-variation (TV) regularization to account for signal correlation in neighboring voxels. A computationally efficient algorithm based on the alternating direction method of multipliers (ADMM) is introduced for solving the CS-SRR problem. The performance of the proposed method is quantitatively evaluated on several in-vivo human data sets including a true SRR scenario. Our experimental results demonstrate that the proposed method can be used for reconstructing sub-millimeter super resolution dMRI data with very good data fidelity in clinically feasible acquisition time.

Somatotopic organization of the white matter tracts underpinning motor control in humans: an electrical stimulation study.

The somatotopic organization of the primary motor cortex is well documented. However, a possible somatotopy of the network involved in motor control, i.e., eliciting negative motor phenomena during electrostimulation, is unknown in humans, particularly at the subcortical level. Here, we performed electrical stimulation mapping in awake patients operated for gliomas, to study the distribution of the white matter tracts subserving movement control of the lower limb, upper limb(s), and speech. Eighteen patients underwent awake surgery for frontal low-grade gliomas, by using intraoperative subcortical electrostimulation mapping to search interference with movement of the leg, arm(s), and face. We assessed the negative motor responses and their distribution throughout the tracts located under premotor areas. The corresponding stimulation sites were reported on a standard brain template for visual analysis and between-subjects comparisons. During stimulation of the white matter underneath the dorsal premotor cortex and supplementary motor area, rostral to the corticospinal tracts, all patients experienced cessation of the movement of lower and upper limbs, of bimanual coordination, and/or speech. These subcortical sites were somatotopically distributed. Indeed, stimulation of the fibers from mesial to lateral directions and from posterior to anterior directions evoked arrest of movement of the lower limb (mesially and posteriorly), upper limb(s), and face/speech (laterally and anteriorly). There were no postoperative permanent deficits. This is the first evidence of a somatotopic organization of the white matter bundles underpinning movement control in humans. A better knowledge of the distribution of this motor control network may be helpful in neurosciences and neurosurgery.

Location of brain tumor intersecting white matter tracts predicts patient prognosis.

Brain tumor cells invade adjacent normal brain along white matter (WM) bundles of axons. We therefore hypothesized that the location of tumor intersecting WM tracts would be associated with differing survival. This study introduces a method, voxel-wise survival analysis (VSA), to determine the relationship between the location of brain tumor intersecting WM tracts and patient prognosis. 113 primary glioblastoma (GBM) patients were retrospectively analyzed for this study. Patient specific tumor location, defined by contrast-enhancement, was combined with diffusion tensor imaging derived tractography to determine the location of axons intersecting tumor enhancement (AXITEs). VSA was then used to determine the relationship between the AXITE location and patient survival. Tumors intersecting the right anterior thalamic radiation (ATR), right inferior fronto-occipital fasciculus (IFOF), right and left cortico-spinal tract (CST), and corpus callosum (CC) were associated with decreased overall survival. Tumors intersecting the CST, body of the CC, right ATR, posterior IFOF, and inferior longitudinal fasciculus are associated with decreased progression-free survival (PFS), while tumors intersecting the right genu of the CC and anterior IFOF are associated with increased PFS. Patients with tumors intersecting the ATR, IFOF, CST, or CC had significantly improved survival prognosis if they were additionally treated with bevacizumab. This study demonstrates the usefulness of VSA by locating AXITEs associated with poor prognosis in GBM patients. This information should be included in patient-physician conversations, therapeutic strategy, and clinical trial design.

Two different immunostaining patterns of beta-amyloid precursor protein (APP) may distinguish traumatic from nontraumatic axonal injury.

Immunostaining for beta-amyloid precursor protein (APP) is recognized as an effective tool for detecting traumatic axonal injury, but it also detects axonal injury due to ischemic or other metabolic causes. Previously, we reported two different patterns of APP staining: labeled axons oriented along with white matter bundles (pattern 1) and labeled axons scattered irregularly (pattern 2) (Hayashi et al. (Leg Med (Tokyo) 11:S171-173, 2009). In this study, we investigated whether these two patterns are consistent with patterns of trauma and hypoxic brain damage, respectively. Sections of the corpus callosum from 44 cases of blunt head injury and equivalent control tissue were immunostained for APP. APP was detected in injured axons such as axonal bulbs and varicose axons in 24 of the 44 cases of head injuries that also survived for three or more hours after injury. In 21 of the 24 APP-positive cases, pattern 1 alone was observed in 14 cases, pattern 2 alone was not observed in any cases, and both patterns 1 and 2 were detected in 7 cases. APP-labeled injured axons were detected in 3 of the 44 control cases, all of which were pattern 2. These results suggest that pattern 1 indicates traumatic axonal injury, while pattern 2 results from hypoxic insult. These patterns may be useful to differentiate between traumatic and nontraumatic axonal injuries.

DTI measurements of non-decussating fibers in defective axon guidance disorders (Horizontal gaze palsy and progressive scoliosis and Joubert syndrome)

Diffusion tensor imaging has been useful in demonstrating non-decussating corticospinal tract (CST) and superior cerebellar peduncles (SCP) in Joubert syndrome (JS) related disorder and in horizontal gaze palsy with progressive scoliosis (HGPPS). However, measurements of fractional anisotropy (FA) and mean diffusivity (MD) have never been performed in these diseases. The aim of our work was to investigate if FA and MD values in uncrossed white matter bundles due to defective axon guidance are different from normal decussating fibers. Two patients with HGPPS and four with JS were included. FA and MD were measured by region of interest manually placed on the CST, the SCP and the posterior rows (PR) of the pons. The same measurements were performed in 59 control patients. Comparison of these values between patients and controls was performed by graphical inspection. MD values were normal in all cases. In all patients with HGPPS and JS, FA measurements in SCP were not different from normal controls. FA values in PR and in CST were not different in JS patients but higher than in controls in HGPPS patients. This difference was statistically significant. Normal MD values seem to indicate that MD and FA values likely represent two very different processes in the developing brain. High FA values in PRs and CST in HGPPS, implicating micro- scopic deficits of axonal structures, is a unique finding in this disease. Abnormal measurements on PR confirm a role of these fibers in the pathogenesis and clinical presentation of HGPPS.

Editorial: The Claustrum: charting a way forward for the brain's most mysterious nucleus.

Editorial: The Claustrum: charting a way forward for the brain's most mysterious nucleus.

Microstructure of the superior longitudinal fasciculus predicts stimulation-induced interference with on-line motor control

A cortical visuomotor network, comprising the medial intraparietal sulcus (mIPS) and the dorsal premotor area (PMd), encodes the sensorimotor transformations required for the on-line control of reaching movements. How information is transmitted between these two regions and which pathways are involved, are less clear. Here, we use a multimodal approach combining repetitive transcranial magnetic stimulation (rTMS) and diffusion tensor imaging (DTI) to investigate whether structural connectivity in the ‘reaching’ circuit is associated to variations in the ability to control and update a movement. We induced a transient disruption of the neural processes underlying on-line motor adjustments by applying 1Hz rTMS over the mIPS. After the stimulation protocol, participants globally showed a reduction of the number of corrective trajectories during a reaching task that included unexpected visual perturbations. A voxel-based analysis revealed that participants exhibiting higher fractional anisotropy (FA) in the second branch of the superior longitudinal fasciculus (SLF II) suffered less rTMS-induced behavioral impact. These results indicate that the microstructural features of the white matter bundles within the parieto-frontal ‘reaching’ circuit play a prominent role when action reprogramming is interfered. Moreover, our study suggests that the structural alignment and cohesion of the white matter tracts might be used as a predictor to characterize the extent of motor impairments.

Functional networks and structural connectivity of visuospatial and visuoperceptual working memory.

Neural correlates of working memory (WM) in healthy subjects have been extensively investigated using functional MRI (fMRI). However it still remains unclear how cortical areas forming part of functional WM networks are also connected by white matter fiber bundles, and whether DTI measures, used as indices of microstructural properties and directionality of these connections, can predict individual differences in task performance. fMRI data were obtained from 23 healthy young subjects while performing one visuospatial (square location) and one visuoperceptual (face identification) 2-back task. Diffusion tensor imaging (DTI) data were also acquired. We used independent component analysis (ICA) of fMRI data to identify the main functional networks involved in WM tasks. Voxel-wise DTI analyses were performed to find correlations between structural white matter and task performance measures, and probabilistic tracking of DTI data was used to identify the white matter bundles connecting the nodes of the functional networks. We found that functional recruitment of the fusiform and the inferior frontal cortex was specific for the visuoperceptual working memory task, while there was a high overlap in brain activity maps in parietal and middle frontal areas for both tasks. Axial diffusivity and fractional anisotropy, of the tracts connecting the fusiform with the inferior frontal areas correlated with processing speed in the visuoperceptual working memory task. Although our findings need to be considered as exploratory, we conclude that both tasks share a highly-overlapping pattern of activity in areas of frontal and parietal lobes with the only differences in activation between tasks located in the fusiform and inferior frontal regions for the visuoperceptual task. Moreover, we have found that the DTI measures are predictive of the processing speed.

SU-E-I-68: The Relationship Between White Matter Tract Abnormalities and Brain Atrophy Correlation Analysis in Neurodegenerative Disease

Purpose: We evaluated the relationship between white matter (WM) tract disintegration and gray matter (GM) atrophy in patients with Alzheimer's disease (AD), mild cognitive impairment (MCI) and controls, using diffusion tensor imaging (DTI) and an optimized voxel-based analy Methods: Two hundred individuals (60 controls, 100 MCI and 40 AD) were included. Voxel-based WM tract statistics was used to obtain wholebrain maps of WM bundles for FA. Voxel-based morphometry (VBM) was conducted to detect regions of gray matter (GM) atrophy in the AD, MCI group relative to the control group. FA maps were processed to make voxelwise comparison of tract based analysis in whole brain between each the two groups. The relationship between locations of abnormalities in the WM and GM were examined Results: Patients with AD showed significant GM atrophy in posterior cingulate gyrus (BA31, 32) to the precuneus, the middle temporal lobe (BA19), the superior frontal (BA9) to the anterior cingulate (BA 32), the medial frontal lobe (BA 11, BA25), the hippocampus, the parahippocampal gyrus (BA30/34) and the insula, and WM tract disintegrity of the uncinate fasciculus, posterior cingulate fasciculus and fornix compared with the control and MCI groups. These abnormalities in the AD group were caused by either structural changes in GM atrophy or neural dysfunction due to functional disconnections in the WM tract Conclusion: The GM atrophy resulting from WM tract disintegration or GM atrophy itself may be the first step in the AD process, resulting in anatomically congruent correlations between WM disintegration and regional GM atrophy. Using tract based spatial statistics and voxel based analysis, both of which are useful in investigating GM and WM changes in individuals with neurodegenerative disorders

Tract-based analysis of white matter degeneration in Alzheimer’s disease

Although much prior work has focused on the known cortical pathology that defines Alzheimer’s disease (AD) histologically, recent work has additionally demonstrated substantial damage to the cerebral white matter in this condition. While there is large evidence of diffuse damage to the white matter in AD, it is unclear whether specific white matter tracts exhibit a more accelerated pattern of damage and whether the damage is associated with the classical neurodegenerative changes of AD. In this study, we investigated microstructural differences in the large fascicular bundles of the cerebral white matter of individuals with AD and mild cognitive impairment (MCI), using recently developed automated diffusion tractography procedures in the Alzheimer’s disease Neuroimaging Initiative (ADNI) dataset. Eighteen major fiber bundles in a total of 36 individuals with AD, 81 MCI and 60 control participants were examined with the TRActs Constrained by UnderLying Anatomy (TRACULA) procedure available as part of the FreeSurfer image processing software package. For each fiber bundle, the mean fractional anisotropy (FA), and mean, radial and axial diffusivities were calculated. Individuals with AD had increased diffusivities in both left and right cingulum-angular bundles compared to control participants (p<0.001). Individuals with MCI also had increased axial and mean diffusivities and increased FA in both cingulum-angular bundles compared to control participants (p<0.05) and decreased radial diffusivity compared to individuals with AD (p<0.05). We additionally examined how white matter deterioration relates to hippocampal volume, a traditional imaging measure of AD pathology, and found the strongest negative correlations in AD patients between hippocampal volume and the diffusivities of the cingulum-angular and cingulum-cingulate gyrus bundles and of the corticospinal tracts (p<0.05). However, statistically controlling for hippocampal volume did not remove all group differences in white matter measures, suggesting a unique contribution of white matter damage to AD unexplained by this disease biomarker. These results suggest that (1) AD-associated deterioration of white matter fibers is greatest in tracts known to be connected to areas of pathology in AD and (2) lower white matter tract integrity is more diffusely associated with lower hippocampal volume indicating that the pathology in the white matter follows to some degree the neurodegenerative staging and progression of this condition.

Neuroimaging evidence of gray and white matter damage and clinical correlates in progressive supranuclear palsy.

To evaluate gray matter (GM) and white matter (WM) abnormalities and their clinical correlates in patients with progressive supranuclear palsy (PSP). Sixteen PSP patients and sixteen age-matched healthy subjects underwent a clinical evaluation and multimodal magnetic resonance imaging, including three-dimensional T1-weighted imaging and diffusion tensor imaging (DTI). Volumetric and DTI analyses were computed using SPM and FSL tools. PSP patients showed GM volume decrease, involving the frontal cortex, putamen, pallidum, thalamus and accumbens nucleus, cerebellum, and brainstem. Additionally, they had widespread changes in WM bundles, mainly affecting cerebellar peduncles, thalamic radiations, corticospinal tracts, corpus callosum, and longitudinal fasciculi. GM volumes did not correlate with WM abnormalities. DTI indices of WM damage, but not GM volumes, correlated with clinical scores of disease severity and cognitive impairment. The neurodegenerative changes that occur in PSP involve both GM and WM structures and develop concurrently though independently. WM damage in PSP correlates with clinical scores of disease severity and cognitive impairment, thus providing further insight into the pathophysiology of the disease.

Robust and efficient linear registration of white-matter fascicles in the space of streamlines

The neuroscientific community today is very much interested in analyzing specific white matter bundles like the arcuate fasciculus, the corticospinal tract, or the recently discovered Aslant tract to study sex differences, lateralization and many other connectivity applications. For this reason, experts spend time manually segmenting these fascicles and bundles using streamlines obtained from diffusion MRI tractography. However, to date, there are very few computational tools available to register these fascicles directly so that they can be analyzed and their differences quantified across populations. In this paper, we introduce a novel, robust and efficient framework to align bundles of streamlines directly in the space of streamlines. We call this framework Streamline-based Linear Registration. We first show that this method can be used successfully to align individual bundles as well as whole brain streamlines. Additionally, if used as a piecewise linear registration across many bundles, we show that our novel method systematically provides higher overlap (Jaccard indices) than state-of-the-art nonlinear image-based registration in the white matter. We also show how our novel method can be used to create bundle-specific atlases in a straightforward manner and we give an example of a probabilistic atlas construction of the optic radiation. In summary, Streamline-based Linear Registration provides a solid registration framework for creating new methods to study the white matter and perform group-level tractometry analysis.

Cognitive severity-specific neuronal degenerative network in charcoal burning suicide-related carbon monoxide intoxication: a multimodality neuroimaging study in Taiwan.

While carbon monoxide (CO) intoxication often triggers multiple intraneuronal immune- or inflammatory-related cascades, it is not known whether the pathological processes within the affected regions evolve equally in the long term. To understand the neurodegenerative networks, we examined 49 patients with a clinical diagnosis of CO intoxication related to charcoal burning suicide at the chronic stage and compared them with 15 age- and sex-matched controls. Reconstructions of degenerative networks were performed using T1 magnetic resonance imaging, diffusion-tensor imaging, and fluorodeoxyglucose positron emission tomography (PET). Tract-specific fractional anisotropy (FA) quantification of 11 association fibers was performed while the clinical significance of the reconstructed structural or functional networks was determined by correlating them with the cognitive parameters. Compared with the controls, the patients had frontotemporal gray matter (GM) atrophy, diffuse white matter (WM) FA decrement, and axial diffusivity (AD) increment. The patients were further stratified into 3 groups based on the cognitive severities. The spatial extents within the frontal-insular-caudate GM as well as the prefrontal WM AD increment regions determined the cognitive severities among 3 groups. Meanwhile, the prefrontal WM FA values and PET signals also correlated significantly with the patient's Mini-Mental State Examination score. Frontal hypometabolic patterns in PET analysis, even after adjusted for GM volume, were highly coherent to the GM atrophic regions, suggesting structural basis of functional alterations. Among the calculated major association bundles, only the anterior thalamic radiation FA values correlated significantly with all chosen cognitive scores. Our findings suggest that fronto-insular-caudate areas represent target degenerative network in CO intoxication. The topography that occurred at a cognitive severity-specific level at the chronic phase suggested the clinical roles of frontal areas. Although changes in FA are also diffusely distributed, different regional changes in AD suggested unequal long-term compensatory capacities among WM bundles. As such, the affected WM regions showing irreversible changes may exert adverse impacts to the interconnected GM structures.

GENETIC ANALYSIS OF STRUCTURAL BRAIN CONNECTIVITY USING DICCCOL MODELS OF DIFFUSION MRI IN 522 TWINS.

Genetic and environmental factors affect white matter connectivity in the normal brain, and they also influence diseases in which brain connectivity is altered. Little is known about genetic influences on brain connectivity, despite wide variations in the brain's neural pathways. Here we applied the "DICCCOL" framework to analyze structural connectivity, in 261 twin pairs (522 participants, mean age: 21.8 y ± 2.7SD). We encoded connectivity patterns by projecting the white matter (WM) bundles of all "DICCCOLs" as a tracemap (TM). Next we fitted an A/C/E structural equation model to estimate additive genetic (A), common environmental (C), and unique environmental/error (E) components of the observed variations in brain connectivity. We found 44 "heritable DICCCOLs" whose connectivity was genetically influenced (a2>1%); half of them showed significant heritability (a2>20%). Our analysis of genetic influences on WM structural connectivity suggests high heritability for some WM projection patterns, yielding new targets for genome-wide association studies.