Citrullinated myelin induces microglial TNFα and inhibits endogenous repair in the cuprizone model of demyelination

Background Microglia are the primary phagocytes of the central nervous system and are responsible for removing damaged myelin following demyelination. Previous investigations exploring the consequences of myelin phagocytosis on microglial activation overlooked the biochemical modifications present on myelin debris. Such modifications, including citrullination, are increased within the inflammatory environment of multiple sclerosis lesions. Methods Mouse cortical myelin isolated by ultracentrifugation was citrullinated ex vivo by incubation with the calcium-dependent peptidyl arginine deiminase PAD2. Demyelination was induced by 6 weeks of cuprizone (0.3%) treatment and spontaneous repair was initiated by reversion to normal chow. Citrullinated or unmodified myelin was injected into the primary motor cortex above the cingulum bundle at the time of reversion to normal chow and the consequent impact on remyelination was assessed by measuring the surface area of myelin basic protein-positive fibers in the cortex 3 weeks later. Microglial responses to myelin were characterized by measuring cytokine release, assessing flow cytometric markers of microglial activation, and RNAseq profiling of transcriptional changes. Results Citrullinated myelin induced a unique microglial response marked by increased tumor necrosis factor α (TNFα) production both in vitro and in vivo. This response was not induced by unmodified myelin. Injection of citrullinated myelin but not unmodified myelin into the cortex of cuprizone-demyelinated mice significantly inhibited spontaneous remyelination. Antibody-mediated neutralization of TNFα blocked this effect and restored remyelination to normal levels. Conclusions These findings highlight the role of post-translation modifications such as citrullination in the determination of microglial activation in response to myelin during demyelination. The inhibition of endogenous repair induced by citrullinated myelin and the reversal of this effect by neutralization of TNFα may have implications for therapeutic approaches to patients with inflammatory demyelinating disorders.

Diffusion MRI data, sulcal anatomy, and tractography for eight species from the Primate Brain Bank

Large-scale comparative neuroscience requires data from many species and, ideally, at multiple levels of description. Here, we contribute to this endeavor by presenting diffusion and structural MRI data from eight primate species that have not or rarely been described in the literature. The selected samples from the Primate Brain Bank cover a prosimian, New and Old World monkeys, and a great ape. We present preliminary labelling of the cortical sulci and tractography of the optic radiation, dorsal part of the cingulum bundle, and dorsal parietal–frontal and ventral temporal-frontal longitudinal white matter tracts. Both dorsal and ventral association fiber systems could be observed in all samples, with the dorsal tracts occupying much less relative volume in the prosimian than in other species. We discuss the results in the context of known primate specializations and present hypotheses for further research. All data and results presented here are available online as a resource for the scientific community.

Lesion location and outcome following cingulotomy for obsessive-compulsive disorder

OBJECTIVE Obsessive-compulsive disorder (OCD) is among the most debilitating and medically refractory psychiatric disorders. While cingulotomy is an anatomically targeted neurosurgical treatment that has shown significant promise in treating OCD-related symptoms, the precise underlying neuroanatomical basis for its beneficial effects has remained poorly understood. Therefore, the authors sought to determine whether lesion location is related to responder status following cingulotomy. METHODS The authors reviewed the records of 18 patients who had undergone cingulotomy. Responders were defined as patients who had at least a 35% improvement in the Yale-Brown Obsessive Compulsive Scale (YBOCS) score. The authors traced the lesion sites on T1-weighted MRI scans and used an anatomical registration matrix generated by the imaging software FreeSurfer to superimpose these lesions onto a template brain. Lesion placement was compared between responders and nonresponders. The placement of lesions relative to various anatomical regions was also compared. RESULTS A decrease in postoperative YBOCS score was significantly correlated with more superiorly placed lesions (decrease −0.52, p = 0.0012). While all lesions were centered within 6 mm of the cingulate sulcus, responder lesions were placed more superiorly and posteriorly along the cingulate sulcus (1-way ANOVA, p = 0.003). The proportions of the cingulum bundle, cingulate gyrus, and paracingulate cortex affected by the lesions were the same between responders and nonresponders. However, all responders had lesions covering a larger subregion of Brodmann area (BA) 32. In particular, responder lesions covered a significantly greater proportion of the posterior BA32 (1-way ANOVA, p = 0.0064). CONCLUSIONS Lesions in patients responsive to cingulotomy tended to be located more superiorly and posteriorly and share greater coverage of a posterior subregion of BA32 than lesions in patients not responsive to this treatment.

Evaluation of a connectivity-based imaging metric that reflects functional decline in Multiple Sclerosis

Cognitive impairment is a common symptom in individuals with Multiple Sclerosis (MS), but meaningful, reliable biomarkers relating to cognitive decline have been elusive, making evaluation of the impact of therapeutics on cognitive function difficult. Here, we combine pathway-based MRI measures of structural and functional connectivity to construct a metric of functional decline in MS. The Structural and Functional Connectivity Index (SFCI) is proposed as a simple, z-scored metric of structural and functional connectivity, where changes in the metric have a simple statistical interpretation and may be suitable for use in clinical trials. Using data collected at six time points from a 2-year longitudinal study of 20 participants with MS and 9 age- and sex-matched healthy controls, we probe two common symptomatic domains, motor and cognitive function, by measuring structural and functional connectivity in the transcallosal motor pathway and posterior cingulum bundle. The SFCI is significantly lower in participants with MS compared to controls (p = 0.009) and shows a significant decrease over time in MS (p = 0.012). The change in SFCI over two years performed favorably compared to measures of brain parenchymal fraction and lesion volume, relating to follow-up measures of processing speed (r = 0.60, p = 0.005), verbal fluency (r = 0.57, p = 0.009), and score on the Multiple Sclerosis Functional Composite (r = 0.67, p = 0.003). These initial results show that the SFCI is a suitable metric for longitudinal evaluation of functional decline in MS.

Age-related differences in negative cognitive empathy but similarities in positive affective empathy

Empathy, among other social-cognitive processes, changes across adulthood. More specifically, cognitive components of empathy (understanding another’s perspective) appear to decline with age, while findings for affective empathy (sharing another’s emotional state) are rather mixed. Structural and functional correlates underlying cognitive and affective empathy in aging and the extent to which valence affects empathic response in brain and behavior are not well understood yet. To fill these research gaps, younger and older adults completed a modified version of the Multifaceted Empathy Test, which measures both cognitive and affective empathy as well as empathic responding to both positive and negative stimuli (i.e., positive vs. negative empathy). Adopting a multimodal imaging approach and applying multivariate analysis, the study found that for cognitive empathy to negative emotions, regions of the salience network including the anterior insula and anterior cingulate were more involved in older than younger adults. For affective empathy to positive emotions, in contrast, younger and older adults recruited a similar brain network including main nodes of the default mode network. Additionally, increased structural microstructure (fractional anisotropy values) of the posterior cingulum bundle (right henisphere) was related to activation of default mode regions during affective empathy for positive emotions in both age groups. These findings provide novel insights into the functional networks subserving cognitive and affective empathy in younger and older adults and highlight the importance of considering valence in empathic response in aging research. Further this study, for the first time, underscores the role of the posterior cingulum bundle in higher-order social-cognitive processes such as empathy, specifically for positive emotions, in aging.

Behavioral and Histopathological Impairments Caused by Topical Exposure of the Rat Brain to Mild-Impulse Laser-Induced Shock Waves: Impulse Dependency

Although an enormous number of animal studies on blast-induced traumatic brain injury (bTBI) have been conducted, there still remain many uncertain issues in its neuropathology and mechanisms. This is partially due to the complex and hence difficult experimental environment settings, e.g., to minimize the effects of blast winds (tertiary mechanism) and to separate the effects of brain exposure and torso exposure. Since a laser-induced shock wave (LISW) is free from dynamic pressure and its energy is spatially well confined, the effects of pure shock wave exposure (primary mechanism) solely on the brain can be examined by using an LISW. In this study, we applied a set of four LISWs in the impulse range of 15–71 Pa·s to the rat brain through the intact scalp and skull; the interval between each exposure was ~5 s. For the rats, we conducted locomotor activity, elevated plus maze and forced swimming tests. Axonal injury in the brain was also examined by histological analysis using Bodian silver staining. Only the rats with exposure at higher impulses of 54 and 71 Pa·s showed significantly lower spontaneous movements at 1 and 2 days post-exposure by the locomotor activity test, but after 3 days post-exposure, they had recovered. At 7 days post-exposure, however, these rats (54 and 71 Pa·s) showed significantly higher levels of anxiety-related and depression-like behaviors by the elevated plus maze test and forced swimming test, respectively. To the best of the authors' knowledge, there have been few studies in which a rat model showed both anxiety-related and depression-like behaviors caused by blast or shock wave exposure. At that time point (7 days post-exposure), histological analysis showed significant decreases in axonal density in the cingulum bundle and corpus callosum in impulse-dependent manners; axons in the cingulum bundle were found to be more affected by a shock wave. Correlation analysis showed a statistically significant correlation between the depression like-behavior and axonal density reduction in the cingulum bundle. The results demonstrated the dependence of behavior deficits and axonal injury on the shock wave impulse loaded on the brain.

Correlation between DTI effect and white matter structural integrity, working memory in leukoaraiosis patients

Our objective was to study the correlation between Diffusion tensor MR imaging (DTI) effect and white matter structural integrity, working memory in leukoaraiosis patients. 100 leukoaraiosis patients referring to the First Affiliated Hospital of Beijing Medical University from December 2018 to December 2019, were selected as study subjects and divided into four groups according to disease severity: lesion-free group, mild lesion group, moderate lesion group, and severe lesion group. All patients underwent magnetic resonance diffusion tensor imaging to collect DWI images and analyze Fractional anisotropy (FA), mean diffusivity (MD), ReHo values of white matter area under different grading. The patients’ working memory was tested via auditory verb learning test and Stroop color word test, so that correlation between white matter structural integrity and working memory can be analyzed. Results: There are statistically significant differences in FA values of the right posterior thalamic radiation, the right sagittal layer and the right superior longitudinal fasciculus, MD values of the right sagittal layer, the right cingulum bundle, the left cingulum bundle, the right inferior fasciculus fronto-occipitalis and the left inferior fasciculus frontooccipitalis, as well as instant recall, delayed recall, delayed recognition, card A (dot), card B (character), card C (color word) and SIE value (P<0.01). Correlation is shown between white matter structural integrity and working memory, gender, age, grading, disease course, recurrence interval, white matter area, and testing methods. There was a correlation between DTI effect and white matter structural integrity, working memory in leukoaraiosis patients, and leukoaraiosis patients have memory impairment.

Age-Related Differences in White Matter: Understanding Tensor-Based Results Using Fixel-Based Analysis

Aging is associated with widespread alterations in cerebral white matter (WM). Most prior studies of age differences in WM have used diffusion tensor imaging (DTI), but typical DTI metrics (e.g., fractional anisotropy; FA) can reflect multiple neurobiological features, making interpretation challenging. Here, we used fixel-based analysis (FBA) to investigate age-related WM differences observed using DTI in a sample of 45 older and 25 younger healthy adults. Age-related FA differences were widespread but were strongly associated with differences in multi-fiber complexity (CX), suggesting that they reflected differences in crossing fibers in addition to structural differences in individual fiber segments. FBA also revealed a frontolimbic locus of age-related effects and provided insights into distinct microstructural changes underlying them. Specifically, age differences in fiber density were prominent in fornix, bilateral anterior internal capsule, forceps minor, body of the corpus callosum, and corticospinal tract, while age differences in fiber cross section were largest in cingulum bundle and forceps minor. These results provide novel insights into specific structural differences underlying major WM differences associated with aging.