Multiple White Matter Research Articles

White Matter Deficits Underlying the Impaired Consciousness Level in Patients with Disorders of Consciousness.

In this study, we aimed to (1) identify white matter (WM) deficits underlying the consciousness level in patients with disorders of consciousness (DOCs) using diffusion tensor imaging (DTI), and (2) evaluate the relationship between DTI metrics and clinical measures of the consciousness level in DOC patients. With a cohort of 8 comatose, 8 unresponsive wakefulness syndrome/vegetative state, and 14 minimally conscious state patients and 25 patient controls, we performed group comparisons of the DTI metrics in 48 core WM regions of interest (ROIs), and examined the clinical relevance using correlation analysis. We identified multiple abnormal WM ROIs in DOC patients compared with normal controls, and the DTI metrics in these ROIs were significantly correlated with clinical measures of the consciousness level. Therefore, our findings suggested that multiple WM tracts are involved in the impaired consciousness levels in DOC patients and demonstrated the clinical relevance of DTI for DOC patients.

Altered White Matter Microstructure Correlates with IQ and Processing Speed in Children and Adolescents Post-Fontan

To compare white matter microstructure in children and adolescents with single ventricle who underwent the Fontan procedure with healthy controls, and to explore the association of white matter injury with cognitive performance as well as patient and medical factors. Fontan (n = 102) and control subjects (n = 47) underwent diffusion tensor imaging (DTI) at ages 10-19 years. Mean DTI measures (fractional anisotropy, radial diffusivity, axial diffusivity, and mean diffusivity) were calculated for 33 fiber tracts from standard white matter atlases. Voxel-wise group differences in DTI measures were assessed using Tract-Based Spatial Statistics. Associations of regional fractional anisotropy with IQ and processing speed as well as medical characteristics were examined. Subjects with Fontan, compared with controls, had reduced bilateral regional and voxel-wise fractional anisotropy in multiple white matter tracts along with increased regional radial diffusivity in several overlapping tracts; regional mean diffusivity differed in 2 tracts. The groups did not differ in voxel-wise radial diffusivity or mean diffusivity. Among subjects with Fontan, fractional anisotropy in many tracts correlated positively with Full-Scale Intelligence Quotient and processing speed, although similar findings were absent in controls. Lower mean fractional anisotropy in various tracts was associated with more complications in the first operation, a greater number of total operations, and history of neurologic event. Children and adolescents who have undergone the Fontan procedure have widespread abnormalities in white matter microstructure. Furthermore, white matter microstructure in several tracts is associated with cognitive performance and operative and medical history characteristics.

Axonal chronic injury in treatment-na\xefve HIV+ adults with asymptomatic neurocognitive impairment and its relationship with clinical variables and cognitive status

BackgroundHIV is a neurotropic virus, and it can bring about neurodegeneration and may even result in cognitive impairments. The precise mechanism of HIV-associated white matter (WM) injury is unknown. The effects of multiple clinical contributors on WM impairments and the relationship between the WM alterations and cognitive performance merit further investigation.MethodsDiffusion tensor imaging (DTI) was performed in 20 antiretroviral-naïve HIV-positive asymptomatic neurocognitive impairment (ANI) adults and 20 healthy volunteers. Whole-brain analysis of DTI metrics between groups was conducted by employing tract-based spatial statistics (TBSS), including fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). DTI parameters were correlated with clinical variables (age, CD4+ cell count, CD4+/CD8+ ratio, plasma viral load and duration of HIV infection) and multiple cognitive tests by using multilinear regression analyses.ResultsDTI quantified diffusion alterations in the corpus callosum and corona radiata (MD increased significantly, P < 0.05) and chronic axonal injury in the corpus callosum, corona radiata, internal capsule, external capsule, posterior thalamic radiation, sagittal stratum, and superior longitudinal fasciculus (AD increased significantly, P < 0.05). The impairments in the corona radiata had significant correlations with the current CD4+/CD8+ ratios. Increased MD or AD values in multiple white matter structures showed significant associations with many cognitive domain tests.ConclusionsWM impairments are present in neurologically asymptomatic HIV+ adults, periventricular WM (corpus callosum and corona radiata) are preferential occult injuries, which is associated with axonal chronic damage rather than demyelination. Axonopathy may exist before myelin injury. DTI-TBSS is helpful to explore the WM microstructure abnormalities and provide a new perspective for the investigation of the pathomechanism of HIV-associated WM injury.

Correlation of diffusion tensor imaging findings and episodic memory impairment in temporal lobe epilepsy

PurposeOur aim was to evaluate the utility of diffusion tensor imaging (DTI) in exploration of white matter tracts microstructure changes and clarify their relation to episodic memory in temporal lobe epilepsy (TLE). Materials and methodsDTI was performed on 30 (18 left, 12 right) TLE patients and 20 healthy controls. Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated for six fiber tracts; the parahippocampal cingulum (PHC), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), fornix (FORX), uncinate fasciculus (UF) and corpus callosum (CC). Assessment for episodic memory (visual and verbal) was performed at least 48 h after the last seizure. ResultsAll TLE patients had episodic memory impairment. Left TLE patients demonstrated more verbal memory affection, whereas right TLE patients demonstrated more visual memory affection (p < 0.05). Abnormal DTI parameters (decreased FA and increased ADC) were detected in most of the white matter tracts (p < 0.001) compared to control group. In left TLE patients, there was significant correlation between DTI parameters of left (PHC, SLF, UF, FORX) and verbal memory. Whereas, in right TLE patient, we found significant correlation between DTI parameters of right ILF and visual memory. ConclusionsTLE patients had multiple micro-structural white matter tracts abnormalities and episodic memory impairment. Both are structurally and functionally related.

Multifocal alterations of white matter accompany the transition from normal cognition to dementia in Parkinson's disease patients.

The purpose of the present study was to investigate the pattern of white matter (WM) changes associated with Parkinson's disease (PD)-related cognitive impairment by using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) measures. Diffusion Tensor Imaging (DTI) was performed in 21 PD-patients with dementia (PDD) and in an age-matched control group including 40 PD-patients without dementia (PD-CTRL). The Parkinson's disease-Cognitive Rating Scale (PD-CRS) was used for patients' neuropsychological assessment. Local microstructural WM differences associated with the presence of cognitive impairment were tested using tract-based spatial statistics analysis. Multiple regression models investigated the association of DTI indices with total PD-CRS score, PD-CRS raw items and other clinical measures across the whole study sample. Significant FA decreases were found in PDD compared to PD-CTRL patients mainly in the body of corpus callosum, corona radiata and cingulum. Lower PD-CRS score was significantly associated with decreased FA, MD and AD values in multiple WM tracts primarily located in prefrontal and limbic areas as well as across the corpus callosum. Lower performance in specific PD-CRS raw items was also associated with FA decreases in major WM tracts. The results suggest that multifocal microstructural changes of WM accompany the transition from normal to demented cognitive state in PD-patients. The corpus callosum, the corona radiata and the cingulum are among the regions mostly affected during this course. A progressive axonal degeneration is proposed as a key underlying mechanism.

Epstein-Barr virus-associated immune reconstitution inflammatory syndrome as possible cause of fulminant multiple sclerosis relapse after natalizumab interruption

Studying rebound mechanisms in MS patients after interruption of natalizumab may advance our understanding of MS pathogenesis. To verify the role of Epstein-Barr virus (EBV) infection and anti-EBV immunity in post-natalizumab rebound, we analyzed postmortem brain tissue of a case of fatal MS relapse. Using immunohistochemistry, EBV latent, early and late lytic proteins and CD8+ T cells sticking to EBV lytically-infected cells were detected in multiple inflammatory white matter lesions. Using the pentamer technology on brain sections, EBV-specific CD8+ T cells were observed perivascularly. Cell-free EBV DNA was detected in cerebrospinal fluid. These findings confirm and extend the results obtained in another case of post-natalizumab fatal MS relapse, suggesting that this condition represents an EBV-associated immune reconstitution inflammatory syndrome.

Brain white matter microstructural alterations in children of type I Gaucher disease characterized with diffusion tensor MR imaging

ObjectivesTo investigate white matter (WM) microstructural alterations in type I Gaucher disease (type I GD) pediatric patients and explore the correlation between the disease duration and WM changes. MethodsTwenty-two GD patients and twenty-two sex- and age-matched typical development (TD) children were recruited. Changes in WM were investigated using diffusion tensor imaging (DTI) and applying atlas-based tract analysis. For all DTI measurements, independent-samples t-test was applied to report significant differences between type I GD and TD. Partial correlation was applied to determine whether the disease duration was correlated with DTI measurements. ResultsBidirectional fractional anisotropy (FA) changes were found in the bilateral superior cerebellar peduncle, right posterior limb of the internal capsule, right posterior corona radiata, and right posterior thalamic radiation (p < 0.05). Higher mean diffusivity (MD)was found in the right superior corona radiata, middle cerebellar peduncle, right posterior thalamic radiation and right superior longitudinal fasciculus (p < 0.05) in type I GD. And higher radial diffusivity (RD) was also found in the left superior cerebellar peduncle (p < 0.05) in type I GD. The disease duration of type I GD patients is positively correlated with axial diffusivity and MD in multiple major WM tracts. ConclusionDTI findings supported the microstructural alterations of multiple WM tracts in type I GD patients.

Alterations in the inferior longitudinal fasciculus in autism and associations with visual processing: a diffusion-weighted MRI study

BackgroundOne of the most reported neural features of autism spectrum disorder (ASD) is the alteration of multiple long-range white matter fiber tracts, as assessed by diffusion-weighted imaging and indexed by reduced fractional anisotropy (FA). Recent methodological advances, however, have shown that this same pattern of reduced FA may be an artifact resulting from excessive head motion and poorer data quality and that aberrant structural connectivity in children with ASD is confined to the right inferior longitudinal fasciculus (ILF). This study aimed at replicating the observation of reduced FA along the right ILF in ASD, while controlling for group differences in head motion and data quality. In addition, we explored associations between reduced FA in the right ILF and quantitative ASD characteristics, and the involvement of the right ILF in visual processing, which is known to be altered in ASD.MethodGlobal probabilistic tractography was performed on diffusion-weighted imaging data of 17 adolescent boys with ASD and 17 typically developing boys, matched for age, performance IQ, handedness, and data quality. Four tasks were administered to measure various aspects of visual information processing, together with questionnaires assessing ASD characteristics. Group differences were examined and the neural data were integrated with previously published findings using Bayesian statistics to quantify evidence for replication and to pool data and thus increase statistical power. (Partial) correlations were calculated to investigate associations between measures.ResultsThe ASD group showed consistently reduced FA only in the right ILF and slower performance on the visual search task. Bayesian statistics pooling data across studies confirmed that group differences in FA were confined to the right ILF only, with the evidence for altered FA in the left ILF being indecisive. Lower FA in the right ILF tended to covary with slower visual search and a more fragmented part-oriented processing style. Individual differences in FA of the right ILF were not reliably associated with the severity of ASD traits after controlling for clinical status.ConclusionOur findings support the growing evidence for reduced FA along a specific fiber tract in ASD, the right ILF.

White matter microstructural variability mediates the relation between obesity and cognition in healthy adults

Obesity has been linked with structural and functional brain changes. However, the impact of obesity on brain and cognition in aging remains debatable, especially for white matter. We therefore aimed to determine the effects of obesity on white matter microstructure and potential implications for cognition in a well-characterized large cohort of healthy adults. In total, 1255 participants (50% females, 19–80 years, BMI 16.8–50.2 kg/m2) with diffusion-weighted magnetic resonance imaging at 3T were analysed. Tract-based spatial statistics (TBSS) probed whether body mass index (BMI) and waist-to-hip ratio (WHR) were related to fractional anisotropy (FA). We conducted partial correlations and mediation analyses to explore whether obesity or regional FA were related to cognitive performance. Analyses were adjusted for demographic, genetic, and obesity-associated confounders. Results showed that higher BMI and higher WHR were associated with lower FA in multiple white matter tracts (p < 0.05, FWE-corrected). Mediation analyses provided evidence for indirect negative effects of higher BMI and higher WHR on executive functions and processing speed through lower FA in fiber tracts connecting (pre)frontal, visual, and associative areas (indirect paths, |ß| ≥ 0.01; 99% |CI| > 0). This large cross-sectional study showed that obesity is correlated with lower FA in multiple white matter tracts in otherwise healthy adults, independent of confounders. Moreover, although effect sizes were small, mediation results indicated that visceral obesity was linked to poorer executive functions and lower processing speed through lower FA in callosal and associative fiber tracts. Longitudinal studies are needed to support this hypothesis.

Reduced white matter connectivity associated with auditory verbal hallucinations in first-episode and chronic schizophrenia: A diffusion tensor imaging study

This study aims to explore whether auditory verbal hallucinations (AVH) in schizophrenia are associated with the white matter abnormalities in tracts connecting language, auditory and memory/limbic networks in first-episode and chronic schizophrenia patients. 21 first-episode (FE-AVH) and 12 chronic (chronic-AVH group) patients who suffered from auditory verbal hallucinations and 26 healthy controls (HC group) were enrolled. Diffusion tensor imaging with tract-based spatial statistics was performed to assess the white matter changes between the two patient groups and HC group. Decreased fractional anisotropy and increased radial diffusivity were found in the patient groups compared to the HC group in multiple white matter tracts including the corpus callosum, superior longitudinal fasciculus, inferior fronto-occipital fasciculus, uncinate fasciculus, cingulum, external capsule and anterior limb of the internal capsule. The chronic-AVH group showed more widespread white matter impairment than the FE-AVH group. Furthermore, increased axial diffusivity was also observed in some discrete regions of the chronic-AVH group. Auditory verbal hallucinations in schizophrenia are accompanied by white matter abnormalities in tracts connecting the language, auditory and memory/limbic networks. Chronic-AVH schizophrenia patients may present with more severe neurodegeneration relative to first-episode patients.

Lipid biochemical changes detected in normal appearing white matter of chronic multiple sclerosis by spectral coherent Raman imaging.

Multiple sclerosis (MS) exhibits demyelination, inflammatory infiltration, axonal degeneration, and gliosis, affecting widespread regions of the central nervous system (CNS). While white matter MS lesions have been well characterized pathologically, evidence indicates that the MS brain may be globally altered, with subtle abnormalities found in grossly normal appearing white matter (NAWM). These subtle changes are difficult to investigate by common methods such as histochemical stains and conventional magnetic resonance imaging. Thus, the prototypical inflammatory lesion likely represents the most obvious manifestation of a more widespread involvement of the CNS. We describe the application of spectral coherent anti-Stokes Raman Scattering (sCARS) microscopy to study such changes in chronic MS tissue particularly in NAWM. Subtle changes in myelin lipid biochemical signatures and intra-molecular disorder of fatty acid acyl chains of otherwise normal-appearing myelin were detected, supporting the notion that the biochemical involvement of the MS brain is far more extensive than conventional methods would suggest.

Cognitive disorders in the middle-aged population and cerebrovascular risk factors

To study the frequency of subjective and objective cognitive disorders in the middle-aged population and their associations with main and additional cerebrovascular risk factors. The authors examined 169 men and 239 women aged 40-59 years. Medical history study, blood tests, electrocardiography, brachiocephalic and common femoral arteries scan, echocardiography, magnetic resonance imaging of the brain (MRI) were performed. Luria and Munsterberg tests were done to assess cognitive dysfunction. Affective disorders were assessed by the Hospital scale of anxiety and depression. Absence of subjective (SCI) and/or objective (OCI) cognitive impairments was found in 26,5%; 10% had purely SCI, more than 35,7% of complaints were accompanied by deviations in neuropsychological test results (OCI+), over 25% had only OCI-. The average age of patients with OCI+ was higher than in the control group. In women, the frequency of SCI was twice as high and OCI less frequent as in men. Absence of cognitive impairment and SCI were observed more frequently in individuals with higher education. The prevalence of multiple white matter lesions (WML) in MRI was 36%. Multiple WML and atherosclerosis of major arteries were more common in OCI+ group (47%). Mild affective disorders were more frequent in the studied groups. Anxiety disorders were more common than depressive ones. The amount of patients with affective disorders was highest in OCI+. Therefore, SCI is a common phenomenon among people aged 40-60 years. The use of simple neuropsychological tests in screening examination allows to identify individuals who are most appropriate for active search for vascular risk factors. Anxiety and depressive disorders cause a significant proportion of SCI among middle-aged people and are an important additional target for therapeutic measures.

Multimodality Neuroimaging in Mild Cognitive Impairment: A Cross-sectional Comparison Study.

Background and Purpose:Mild cognitive impairment (MCI) is a focus of considerable research. The present study aimed to test the utility of a logistic regression-derived classifier, combining specific quantitative multimodal magnetic resonance imaging (MRI) data for the early objective phenotyping of MCI in the clinic, over structural MRI data.Methods:Thirty-three participants with cognitively stable amnestic MCI; 15 MCI converters to early Alzheimer's disease (AD; diseased controls) and 20 healthy controls underwent high-resolution T1-weighted volumetric MRI, diffusion tensor imaging (DTI), and proton magnetic resonance spectroscopy (1H MR spectroscopy). The regional volumes were obtained from T1-weighted MRI. The fractional anisotropy and mean diffusivity maps were derived from DTI over multiple white matter regions. The 1H MRS voxels were placed over posterior cingulate gyri, and N-acetyl aspartate (NAA)/creatine (Cr), choline (Cho)/Cr, myoinositol (mI/Cr), and NAA/mI ratios were obtained. A multimodal classifier comprising MR volumetry, DTI, and MRS was prepared. A cutoff point was arrived based on receiver operator characteristics analysis. Results were considered significant, if P < 0.05.Results:The most sensitive individual marker to discriminate MCI from controls was DTI (90.9%), with a specificity of 50%. For classifying MCI from AD, the best individual modality was DTI (72.7%), with a high specificity of 87.9%. The multimodal classifier approach for MCI control classification achieved an area under curve (AUC) (AUC = 0.89; P < 0.001), with 93.9% sensitivity and 70% specificity. The combined classifier for MCI-AD achieved a highest AUC (AUC = 0.93; P < 0.001), with 93% sensitivity and 85.6% specificity.Conclusions:The combined method of gray matter atrophy, white matter tract changes, and metabolite variation achieved a better performance at classifying MCI compared to the application of individual MRI biomarkers.

Grey and White Matter Alterations in Juvenile Myoclonic Epilepsy: A Comprehensive Review.

Juvenile myoclonic epilepsy (JME) has been classified as a syndrome of idiopathic generalized epilepsy and is characterized by a strong genetic basis, age-specific onset of seizures, specific types of seizures, generalized spike-wave discharges on electroencephalography, and a lack of focal abnormality on magnetic resonance imaging (MRI). Recently, a wide range of advanced neuroimaging techniques have been utilized to elucidate the neuroanatomical substrates and pathophysiological mechanisms underlying JME. Specifically, a number of quantitative MRI studies have reported focal or regional abnormalities of the subcortical and cortical grey matter, particularly the thalamus and frontal cortex, in JME patients. In addition, diffusion tensor imaging studies have pointed to disrupted microstructural integrity of the corpus callosum and multiple frontal white matter tracts as well as thalamofrontal dysconnectivity in JME patients. Converging evidence from neuroimaging studies strongly suggests that JME is a predominantly thalamofrontal network epilepsy, challenging the traditional concept of JME as a generalized epilepsy. There is also limited evidence indicating extrafrontal and extrathalamic involvement in JME. This systematic review outlines the main findings from currently available MRI studies focusing on grey and white matter alterations, and discusses their contributions to the etiology and pathophysiology of JME. The clinical utility, advantages, and drawbacks of each imaging modality are briefly described as well.

White matter changes and gait decline in cerebral small vessel disease.

The relation between progression of cerebral small vessel disease (SVD) and gait decline is uncertain, and diffusion tensor imaging (DTI) studies on gait decline are lacking. We therefore investigated the longitudinal associations between (micro) structural brain changes and gait decline in SVD using DTI. 275 participants were included from the Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort (RUN DMC), a prospective cohort of participants with cerebral small vessel disease aged 50–85 years. Gait (using GAITRite) and magnetic resonance imaging measures were assessed during baseline (2006–2007) and follow-up (2011 − 2012). Linear regression analysis was used to investigate the association between changes in conventional magnetic resonance and diffusion tensor imaging measures and gait decline. Tract-based spatial statistics analysis was used to investigate region-specific associations between changes in white matter integrity and gait decline. 56.2% were male, mean age was 62.9 years (SD8.2), mean follow-up duration was 5.4 years (SD0.2) and mean gait speed decline was 0.2 m/s (SD0.2). Stride length decline was associated with white matter atrophy (β = 0.16, p = 0.007), and increase in mean white matter radial diffusivity and mean diffusivity, and decrease in mean fractional anisotropy (respectively, β = − 0.14, p = 0.009; β = − 0.12, p = 0.018; β = 0.10, p = 0.049), independent of age, sex, height, follow-up duration and baseline stride length. Tract-based spatial statistics analysis showed significant associations between stride length decline and fractional anisotropy decrease and mean diffusivity increase (primarily explained by radial diffusivity increase) in multiple white matter tracts, with the strongest associations found in the corpus callosum and corona radiata, independent of traditional small vessel disease markers. White matter atrophy and loss of white matter integrity are associated with gait decline in older adults with small vessel disease after 5 years of follow-up. These findings suggest that progression of SVD might play an important role in gait decline.

Age Stratification and Impact of Eicosapentaenoic Acid and Docosahexaenoic Acid to Arachidonic Acid Ratios in Ischemic Stroke Patients.

Aim: We focused on the ratios of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to arachidonic acid (AA) and explored the significance of these ratios relative to clinical characteristics by age in ischemic stroke patients.Methods: We enrolled patients with acute ischemic stroke who underwent radiological investigations and laboratory examinations, including measurement of serum EPA, DHA, and AA levels, and controls. Patients were classified according to age (< 65, 65–74, and ≥ 75 years) and the tertile of EPA/AA and DHA/AA ratios, and clinical aspects were compared with these factors.Results: We analyzed 373 patients (age 70.2 ± 13.4 years; 245 males) and 105 controls. Among stroke patients, patients aged < 65 years had the lowest EPA/AA (0.35 ± 0.23, p = 0.006) and DHA/AA (0.73 ± 0.27, p < 0.001) ratios. Compared with controls, patients aged < 65 years showed lower EPA/AA (vs. 0.49 ± 0.25, p < 0.001) and DHA/AA (vs. 0.82 ± 0.26, p = 0.009) ratios. From logistic regression analysis, the EPA/AA (odds ratio 0.18, 95% confidence interval 0.04–0.81, p = 0.026) and DHA/AA (odds ratio 0.09, 95% confidence interval 0.02–0.33, p < 0.001) ratios were inversely related to patients aged < 65 years. According to age-stratified analyses, we found an association of aortic arch calcification with a lower EPA/AA ratio for patients aged ≥ 75 years and an association of multiple infarctions and cerebral white matter lesions with a lower EPA/AA ratio for patients aged 65–74 years (p < 0.05).Conclusions: The ratios of EPA/AA and DHA/AA could be specific markers for younger stroke patients. The EPA/AA ratio may be related to aortic arch calcification for elderly stroke patients and to multiple infarctions and cerebral white matter disease for middle-aged stroke patients.

Minocycline plus N-Acetylcysteine Reduce Behavioral Deficits and Improve Histology with a Clinically Useful Time Window.

There are no drugs to manage traumatic brain injury (TBI) presently. A major problem in developing therapeutics is that drugs to manage TBI lack sufficient potency when dosed within a clinically relevant time window. Previous studies have shown that minocycline (MINO, 45 mg/kg) plus N-acetylcysteine (NAC, 150 mg/kg) synergistically improved cognition and memory, modulated inflammation, and prevented loss of oligodendrocytes that remyelinated damaged white matter when first dosed 1 h after controlled cortical impact (CCI) in rats. We show that MINO (45 mg/kg) plus NAC (150 mg/kg) also prevent brain injury in a mouse closed head injury (CHI) TBI model. Using the CHI model, the concentrations of MINO and NAC were titrated to determine that MINO (22.5 mg/kg) plus NAC (75 mg/kg) was more potent than the original formulation. MINO (22.5 mg/kg) plus NAC (75 mg/kg) also limited injury in the rat CCI model. The therapeutic time window of MINO plus NAC was then tested in the CHI and CCI models. Mice and rats could acquire an active place avoidance task when MINO plus NAC was first dosed at 12 h post-injury. A first dose at 12 h also limited gray matter injury in the hippocampus and preserved myelin in multiple white matter tracts. Mice and rats acquired Barnes maze when MINO plus NAC was first dosed at 24 h post-injury. These data suggest that MINO (22.5 mg/kg) plus NAC (75 mg/kg) remain potent when dosed at clinically useful time windows. Both MINO and NAC are drugs approved by the Food and Drug Administration and have been administered safely to patients in clinical trials at the doses in the new formulation. This suggests that the drug combination of MINO plus NAC may be effective in treating patients with TBI.

White Matter Structure in Older Adults Moderates the Benefit of Sleep Spindles on Motor Memory Consolidation.

Sleep spindles promote the consolidation of motor skill memory in young adults. Older adults, however, exhibit impoverished sleep-dependent motor memory consolidation. The underlying pathophysiological mechanism(s) explaining why motor memory consolidation in older adults fails to benefit from sleep remains unclear. Here, we demonstrate that male and female older adults show impoverished overnight motor skill memory consolidation relative to young adults, with the extent of impairment being associated with the degree of reduced frontal fast sleep spindle density. The magnitude of the loss of frontal fast sleep spindles in older adults was predicted by the degree of reduced white matter integrity throughout multiple white matter tracts known to connect subcortical and cortical brain regions. We further demonstrate that the structural integrity of selective white matter fiber tracts, specifically within right posterior corona radiata, right tapetum, and bilateral corpus callosum, statistically moderates whether sleep spindles promoted overnight consolidation of motor skill memory. Therefore, white matter integrity within tracts known to connect cortical sensorimotor control regions dictates the functional influence of sleep spindles on motor skill memory consolidation in the elderly. The deterioration of white matter fiber tracts associated with human brain aging thus appears to be one pathophysiological mechanism influencing subcortical-cortical propagation of sleep spindles and their related memory benefits.SIGNIFICANCE STATEMENT Numerous studies have shown that sleep spindle expression is reduced and sleep-dependent motor memory is impaired in older adults. However, the mechanisms underlying these alterations have remained unknown. The present study reveals that age-related degeneration of white matter within select fiber tracts is associated with reduced sleep spindles in older adults. We further demonstrate that, within these same fiber tracts, the degree of degeneration determines whether sleep spindles can promote motor memory consolidation. Therefore, white matter integrity in the human brain, more than age per se, determines the magnitude of decline in sleep spindles in later life and, with it, the success (or lack thereof) of sleep-dependent motor memory consolidation in older adults.

White matter alterations over the course of two consecutive high-school football seasons and the effect of a jugular compression collar: A preliminary longitudinal diffusion tensor imaging study.

The cumulative effects of repetitive subclinical head impacts during sports may result in chronic white matter (WM) changes and possibly, neurodegenerative sequelae. In this pilot study, we investigated the longitudinal WM changes over the course of two consecutive high-school football seasons and explored the long-term effects of a jugular vein compression collar on these WM alterations. Diffusion tensor imaging data were prospectively collected both pre- and postseason in the two consecutive seasons. Participants were assigned into either collar or noncollar groups. Tract-based spatial statistics (TBSS) approach and region of interest-based approach were used to quantify changes in WM diffusion properties. Despite comparable exposure to repetitive head impacts, significant reductions in mean, axial, and/or radial diffusivity were identified in Season 1 in multiple WM regions in the noncollar group but not in the collar group. After an 8- to 9-month long off-season, these changes observed in the noncollar group partially and significantly reversed but also remained significantly different from the baseline. In Season 2, trend level WM alterations in the noncollar group were found but located in spatially different regions than Season 1. Last, the WM integrity in the collar group remained unchanged throughout the four time points. In conclusion, we quantitatively assessed the WM structural changes and partial reversal over the course of two consecutive high-school football seasons. In addition, the mitigated WM alterations in athletes in the collar group might indicate potential effect of the collar in ameliorating the changes against repetitive head impacts. Hum Brain Mapp 39:491-508, 2018. © 2017 Wiley Periodicals, Inc.

Multiparametric MRI changes persist beyond recovery in concussed adolescent hockey players.

Objective:To determine whether multiparametric MRI data can provide insight into the acute and long-lasting neuronal sequelae after a concussion in adolescent athletes.Methods:Players were recruited from Bantam hockey leagues in which body checking is first introduced (male, age 11–14 years). Clinical measures, diffusion metrics, resting-state network and region-to-region functional connectivity patterns, and magnetic resonance spectroscopy absolute metabolite concentrations were analyzed from an independent, age-matched control group of hockey players (n = 26) and longitudinally in concussed athletes within 24 to 72 hours (n = 17) and 3 months (n = 14) after a diagnosed concussion.Results:There were diffusion abnormalities within multiple white matter tracts, functional hyperconnectivity, and decreases in choline 3 months after concussion. Tract-specific spatial statistics revealed a large region along the superior longitudinal fasciculus with the largest decreases in diffusivity measures, which significantly correlated with clinical deficits. This region also spatially intersected with probabilistic tracts connecting cortical regions where we found acute functional connectivity changes. Hyperconnectivity patterns at 3 months after concussion were present only in players with relatively less severe clinical outcomes, higher choline concentrations, and diffusivity indicative of relatively less axonal disruption.Conclusions:Changes persisted well after players' clinical scores had returned to normal and they had been cleared to return to play. Ongoing white matter maturation may make adolescent athletes particularly vulnerable to brain injury, and they may require extended recovery periods. The consequences of early brain injury for ongoing brain development and risk of more serious conditions such as second impact syndrome or neural degenerative processes need to be elucidated.