Person:

Pasternak, Ofer

Background: Activity-induced structural remodeling of dendritic spines and glial cells was recently proposed as an important factor in neuroplasticity and suggested to accompany the induction of long-term potentiation (LTP). Although T1 and diffusion MRI have been used to study structural changes resulting from long-term training, the cellular basis of the findings obtained and their relationship to neuroplasticity are poorly understood. Methodology/Principal Finding: Here we used diffusion tensor imaging (DTI) to examine the microstructural manifestations of neuroplasticity in rats that performed a spatial navigation task. We found that DTI can be used to define the selective localization of neuroplasticity induced by different tasks and that this process is age-dependent in cingulate cortex and corpus callosum and age-independent in the dentate gyrus. Conclusion/Significance: We relate the observed DTI changes to the structural plasticity that occurs in astrocytes and discuss the potential of MRI for probing structural neuroplasticity and hence indirectly localizing LTP.

The ability to perform complex as well as simple cognitive tasks engages a network of brain regions that is mediated by the white matter fiber bundles connecting them. Different cognitive tasks employ distinctive white matter fiber bundles. The temporal lobe and its projections subserve a variety of key functions known to deteriorate during aging. In a cohort of 52 healthy subjects (ages 25–82 years), we performed voxel-wise regression analysis correlating performance in higher-order cognitive domains (executive function, information processing speed, and memory) with white matter integrity, as measured by diffusion tensor imaging (DTI) fiber tracking in the temporal lobe projections [uncinate fasciculus (UF), fornix, cingulum, inferior longitudinal fasciculus (ILF), and superior longitudinal fasciculus (SLF)]. The fiber tracts were spatially registered and statistical parametric maps were produced to spatially localize the significant correlations. Results showed that performance in the executive function domain is correlated with DTI parameters in the left SLF and right UF; performance in the information processing speed domain is correlated with fractional anisotropy (FA) in the left cingulum, left fornix, right and left ILF and SLF; and the memory domain shows significant correlations with DTI parameters in the right fornix, right cingulum, left ILF, left SLF and right UF. These findings suggest that DTI tractography enables anatomical definition of region of interest (ROI) for correlation of behavioral parameters with diffusion indices, and functionality can be correlated with white matter integrity.

In a cohort of community-recruited elderly subjects with normal cognition at initial evaluation, we found that baseline fornix white matter (WM) microstructure was significantly correlated with early volumetric longitudinal tissue change across a region of interest (called fornix significant ROI, fSROI), which overlaps circuits known to be selectively vulnerable to Alzheimer’s dementia pathology. Other WM and gray matter regions had much weaker or non-existent associations with longitudinal tissue change. Tissue loss in fSROI was in turn a significant factor in a survival model of cognitive decline, as was baseline fornix microstructure. These findings suggest that WM deterioration in the fornix and tissue loss in fSROI may be the early beginnings of posterior limbic circuit and default mode network degeneration. We also found that gray matter baseline volumes in the entorhinal cortex and hippocampus predicted cognitive decline in survival models. But since GM regions did not also significantly predict brain-tissue loss, our results may imply a view in which early, prodromal deterioration appears as two quasi independent processes in white and gray matter regions of the limbic circuit crucial to memory.

A significant percentage of individuals diagnosed with mild traumatic brain injury (mTBI) experience persistent post-concussive symptoms (PPCS). Little is known about the pathology of these symptoms and there is often no radiological evidence based on conventional clinical imaging. We aimed to utilize methods to evaluate microstructural tissue changes and to determine whether or not a link with PPCS was present. A novel analysis method was developed to identify abnormalities in high-resolution diffusion tensor imaging (DTI) when the location of brain injury is heterogeneous across subjects. A normative atlas with 145 brain regions of interest (ROI) was built from 47 normal controls. Comparing each subject’s diffusion measures to the atlas generated subject-specific profiles of injury. Abnormal ROIs were defined by absolute z-score values above a given threshold. The method was applied to 11 PPCS patients following mTBI and 11 matched controls. Z-score information for each individual was summarized with two location-independent measures: “load” (number of abnormal regions) and “severity” (largest absolute z-score). Group differences were then computed using Wilcoxon rank sum tests. Results showed statistically significantly higher load (p = 0.018) and severity (p = 0.006) for fractional anisotropy (FA) in patients compared with controls. Subject-specific profiles of injury evinced abnormally high FA regions in gray matter (30 occurrences over 11 patients), and abnormally low FA in white matter (3 occurrences over 11 subjects). Subject-specific profiles provide important information regarding the pathology associated with PPCS. Increased gray matter (GM) anisotropy is a novel in-vivo finding, which is consistent with an animal model of brain trauma that associates increased FA in GM with pathologies such as gliosis. In addition, the individualized analysis shows promise for enhancing the clinical care of PPCS patients as it could play a role in the diagnosis of brain injury not revealed using conventional imaging.

Diffusion MRI measures micron scale displacement of water molecules, providing unique insight into microstructural tissue architecture. However, current practical image resolution is in the millimeter scale, and thus diffusivities from many tissue compartments are averaged in each voxel, reducing the sensitivity and specificity of the measurement to subtle pathologies. Recent studies have pointed out that eliminating the contribution of extracellular water increases the sensitivity of the diffusion measures to tissue architecture. Moreover, in brain imaging, estimation of the extracellular volume appears to indicate pathological processes such as atrophy, edema and neuroinflammation. Here we study the free-water method, which assumes a bi-tensor model. We add low b-value shells to a regular DTI acquisition and present methods to improve the estimation of the model parameters using the extra information. In addition, we define a Laplace-Beltrami regularization operator that further stabilizes the multi-shell estimation.

Diffusion tensor imaging (DTI) holds promise for developing our understanding of white-matter pathology in major depressive disorder (MDD). Variable findings in DTI-based investigations of MDD, however, have thwarted development of this literature. Effects of extra-cellular free-water on the sensitivity of DTI metrics could account for some of this inconsistency. Here we investigated whether applying a free-water correction algorithm to DTI data could improve the sensitivity to detect clinical effects using DTI metrics. Only after applying this correction, we found: a) significantly decreased fractional anisotropy and axial diffusivity (AD) in the left inferior fronto-occipital fasciculus (IFOF) in MDD; and b) increased self-reported stress that significantly correlated with decreased IFOF AD in depression. We estimated and confirmed the robustness of differences observed between free-water corrected and uncorrected approaches using bootstrapping. We conclude that applying a free-water correction to DTI data increases the sensitivity of DTI-based metrics to detect clinical effects in MDD.

Background: There is growing evidence to suggest that delusions associated with schizophrenia arise from altered structural brain connectivity. The present study investigated whether structural changes in three major fasciculi that interconnect the limbic system – the cingulum bundle, uncinate fasciculus and fornix – are associated with delusions in chronic schizophrenia patients. Methods: Free-water corrected Diffusion Tensor Imaging was used to investigate the association between delusions and both microstructural changes within these three fasciculi and extracellular changes in the surrounding free-water. Clinical data and diffusion MRI scans were obtained from 28 healthy controls and 86 schizophrenia patients, of whom 34 had present state delusions, 35 had a lifetime history but currently remitted delusions, and 17 had never experienced delusions. Results: While present state and remitted delusions were found to be associated with reduced free-water corrected fractional anisotropy (FAT) and increased free-water corrected radial diffusivity (RDT) in the cingulum bundle bilaterally, extracellular free-water (FW) in the left cingulum bundle was found to be specifically associated with present state delusions in chronic schizophrenia. No changes were observed in the remaining tracts. Conclusions: These findings suggest that state and trait delusions in chronic schizophrenia are associated with microstructural processes, such as myelin abnormalities (as indicated by decreased FAT and increased RDT) in the cingulum bundle and that state delusions are additionally associated with extracellular processes such as neuroinflammation or atrophy (as indicated by increased FW) in the left cingulum bundle.

Background: Diffusion imaging tractography is increasingly used to trace critical fiber tracts in brain tumor patients to reduce the risk of post-operative neurological deficit. However, the effects of peritumoral edema pose a challenge to conventional tractography using the standard diffusion tensor model. The aim of this study was to present a novel technique using a two-tensor unscented Kalman filter (UKF) algorithm to track the arcuate fasciculus (AF) in brain tumor patients with peritumoral edema. Methods: Ten right-handed patients with left-sided brain tumors in the vicinity of language-related cortex and evidence of significant peritumoral edema were retrospectively selected for the study. All patients underwent 3-Tesla magnetic resonance imaging (MRI) including a diffusion-weighted dataset with 31 directions. Fiber tractography was performed using both single-tensor streamline and two-tensor UKF tractography. A two-regions-of-interest approach was applied to perform the delineation of the AF. Results from the two different tractography algorithms were compared visually and quantitatively. Results: Using single-tensor streamline tractography, the AF appeared disrupted in four patients and contained few fibers in the remaining six patients. Two-tensor UKF tractography delineated an AF that traversed edematous brain areas in all patients. The volume of the AF was significantly larger on two-tensor UKF than on single-tensor streamline tractography (p < 0.01). Conclusions: Two-tensor UKF tractography provides the ability to trace a larger volume AF than single-tensor streamline tractography in the setting of peritumoral edema in brain tumor patients.

The neural correlates of spaceflight-induced sensorimotor impairments are unknown. Head down-tilt bed rest (HDBR) serves as a microgravity analog because it mimics the headward fluid shift and axial body unloading of spaceflight. We investigated focal brain white matter (WM) changes and fluid shifts during 70 days of 6° HDBR in 16 subjects who were assessed pre (2x), during (3x), and post-HDBR (2x). Changes over time were compared to those in control subjects (n = 12) assessed four times over 90 days. Diffusion MRI was used to assess WM microstructure and fluid shifts. Free-Water Imaging was used to quantify distribution of intracranial extracellular free water (FW). Additionally, we tested whether WM and FW changes correlated with changes in functional mobility and balance measures. HDBR resulted in FW increases in fronto-temporal regions and decreases in posterior-parietal regions that largely recovered by two weeks post-HDBR. WM microstructure was unaffected by HDBR. FW decreases in the post-central gyrus and precuneus correlated negatively with balance changes. We previously reported that gray matter increases in these regions were associated with less HDBR-induced balance impairment, suggesting adaptive structural neuroplasticity. Future studies are warranted to determine causality and underlying mechanisms.

Object—Concussion, or mild traumatic brain injury (mTBI), is a commonly occurring sports related injury, especially in contact sports such as hockey. Cerebral microbleeds (CMBs), which are small, hypointense lesions on T2*-weighted images, can result from TBI. The authors use susceptibility-weighted imaging (SWI) to automatically detect small hypointensities that may be subtle signs of chronic and acute damage due to both subconcussive and concussive injury. The goal was to investigate how the burden of these hypointensities change over time, over a playing season, and postconcussion, compared with subjects who did not suffer a medically observed and diagnosed concussion. Methods—Images were obtained in 45 university-level adult male and female ice hockey players before and after a single Canadian Interuniversity Sports season. In addition, 11 subjects (5 men and 6 women) underwent imaging at 72 hours, 2 weeks, and 2 months after concussion. To identify subtle changes in brain tissue and potential CMBs, nonvessel clusters of hypointensities on SWI were automatically identified and a hypointensity burden index was calculated for all subjects at the beginning of the season (BOS) and the end of the season (EOS), in addition to postconcussion time points (where applicable). Results—A statistically significant increase in the hypointensity burden, relative to the BOS, was observed for male subjects at the 2-week postconcussion time point. A smaller, nonsignificant rise in the burden for all female subjects was also observed within the same time period. The difference in hypointensity burden was also statistically significant for men with concussions between the 2-week time point and the BOS. There were no significant changes in burden for nonconcussed subjects of either sex between the BOS and EOS time points. However, there was a statistically significant difference in the burden between male and female subjects in the nonconcussed group at both the BOS and EOS time points, with males having a higher burden. Conclusions—This method extends the utility of SWI from the enhancement and detection of larger (> 5 mm) CMBs that are often observed in more severe TBI, to concussion in which visual detection of injury is difficult. The hypointensity burden metric proposed here shows statistically significant changes over time in the male subjects. A smaller, nonsignificant increase in the burden metric was observed in the female subjects.