Impaired White Matter Research Articles

Gait decline while dual-tasking is an early sign of white matter deterioration in middle-aged and older adults.

Loss of white matter integrity (WMI) is associated with gait deficits in middle-aged and older adults. However, these deficits are often only apparent under cognitively demanding situations, such as walking and simultaneously performing a secondary cognitive task. Moreover, evidence suggests that declining executive functions (EF) are linked to gait decline, and their co-occurrence may point to a common underlying pathology, i.e., degeneration of shared brain regions. In this study, we applied diffusion tensor imaging (DTI) and a standardized gait assessment under single- and dual-tasking (DT) conditions (walking and subtracting) in 74 middle-aged and older adults without any significant gait or cognitive impairments to detect subtle WM alterations associated with gait decline under DT conditions. Additionally, the Trail Making Test (TMT) was used to assess EF, classify participants into three groups based on their performance, and examine a possible interaction between gait, EF, and WMI. Gait speed and subtracting speed while dual-tasking correlated significantly with the fractional anisotropy (FA) in the bilateral anterior corona radiata (highest r = 0.51/p < 0.0125 FWE-corrected). Dual-task costs (DTC) of gait speed correlated significantly with FA in widespread pathways, including the corpus callosum, bilateral anterior and superior corona radiata, as well as the left superior longitudinal fasciculus (highest r = −0.47/p < 0.0125 FWE-corrected). EF performance was associated with FA in the left anterior corona radiata (p < 0.05); however, EF did not significantly mediate the effects of WMI on DTC of gait speed. There were no significant correlations between TMT and DTC of gait and subtracting speed, respectively. Our findings indicate that gait decline under DT conditions is associated with widespread WM deterioration even in middle-aged and older adults without any significant gait or cognitive impairments. However, this relationship was not mediated by EF.

WITHDRAWN: Structural impairment in superficial and deep white matter and its association with clinical symptoms in schizophrenia: A harmonized, multisite diffusion MRI study

While the disconnectivity among brain regions has been one of the main hypotheses for schizophrenia, superficial white matter (SWM) has drawn less attention in schizophrenia research than deep white matter (DWM). Using the structural equation model (SEM), we aimed to investigate the structural abnormalities of SWM and DWM in schizophrenia and their association with clinical symptoms. We obtained the diffusion magnetic resonance imaging (dMRI) data of 223 healthy controls and 143 schizophrenia patients. After harmonizing the raw dMRIs from three different studies, we performed whole-brain two-tensor tractography and fiber clustering of the tractography data, resulting in 8 SWM and 33 DWM tracts. In the patient group, we adopted an SEM for the association with clinical symptoms, using the fractional anisotropy (FA) deviation and the Positive and Negative Syndrome Scale scores. Among the 18 tracts with a lower FA in the patient group, the following structures were included in the SEM: the cingulum bundle, genu, rostral body, and isthmus of the corpus callosum; and striato-frontal, superficial frontal, and superficial temporal tracts. The latent variable white matter impairment , consisting of the FA deviations of the seven white matter tracts, was negatively correlated with the latent variable clinical symptom severity (B=-0.23, p=0.047). The negative symptoms (B=1.12) contributed more to the latent variable clinical symptom severity than did the positive symptoms (B=0.74). The SWM and DWM tract structural abnormalities were identified in schizophrenia patients. The association with clinical symptoms was more prominent in the negative symptoms. • The harmonized diffusion MRI data was analyzed using the whole-brain tractography and fiber clustering. • The patients with schizophrenia had a significantly lower FA in 14 DWM and 4 SWM tracts. • The association of white matter impairments with clinical symptoms was more prominent in the negative symptoms.

Characteristics of White Matter Integrity During Different Phases of Abstinence in Heroin Use Disorders: A Diffusion Tensor Imaging Study.

The recovery of heroin-induced white matter impairment during abstinence has been reported, determining the characteristics of this recovery can help to improve the therapeutic strategies. In this study, we explored white matter characteristics in heroin use disorders during different phases of abstinence by using a quantitative diffusion tensor imaging method. Seventeen and 22 male patients with long- and short-term abstinence (LA and SA, respectively) from heroin use and 20 male healthy controls participated in this study. Voxel-wise diffusion tensor imaging method was used for the comparison of fractional anisotropy (FA). Radial diffusivity (RD) and axial diffusivity (AD) were induced to explore the pathological characteristics of FA. The correlation between diffusion tensor indices and duration of abstinence was further analyzed. Compared to the healthy controls, patients with SA had significantly reduced FA in extensive white matter regions, while those with LA had only 2 clusters that showed reduced FA, which were located mainly in the genu of the corpus callosum, forceps minor, uncinate fasciculus, left inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and posterior thalamic radiation. Significantly increased RD with unchanged axial diffusivity were detected. FA in the regions with the significant intergroup difference between SA and LA correlated positively with the duration of abstinence. The RD in these regions correlated negatively with the duration of abstinence. The findings suggested that the time-dependent recovery of white matter, especially the restoration of the myelin sheath, occurred in patients with LA. Longer-abstinent duration with strategies of enhancing myelination may improve treatment effectiveness.

Individual differences in slow wave sleep architecture relate to variation in white matter microstructure across adulthood.

Sleep plays a key role in supporting brain function and resilience to brain decline. It is well known that sleep changes substantially with aging and that aging is associated with deterioration of brain structure. In this study, we sought to characterize the relationship between slow wave slope (SWslope)—a key marker of sleep architecture and an indirect proxy of sleep quality—and microstructure of white matter pathways in healthy adults with no sleep complaints. Participants were 12 young (24–27 years) and 12 older (50–79 years) adults. Sleep was assessed with nocturnal electroencephalography (EEG) and the Pittsburgh Sleep Quality Index (PSQI). White matter integrity was assessed using tract-based spatial statistics (TBSS) on tensor-based metrics such as Fractional Anisotropy (FA) and Mean Diffusivity (MD). Global PSQI score did not differ between younger (n = 11) and older (n = 11) adults (U = 50, p = 0.505), but EEG revealed that younger adults had a steeper SWslope at both frontal electrode sites (F3: U = 2, p < 0.001, F4: U = 4, p < 0.001, n = 12 younger, 10 older). There were widespread correlations between various diffusion tensor-based metrics of white matter integrity and sleep SWslope, over and above effects of age (n = 11 younger, 9 older). This was particularly evident for the corpus callosum, corona radiata, superior longitudinal fasciculus, internal and external capsule. This indicates that reduced sleep slow waves may be associated with widespread white matter deterioration. Future studies should investigate whether interventions targeted at improving sleep architecture also impact on decline in white matter microstructure in older adults.

Combined functional and structural imaging of brain white matter reveals stage-dependent impairment in multiple system atrophy of cerebellar type

Advances in fMRI of brain white matter (WM) have established the feasibility of understanding how functional signals of WM evolve with brain diseases. By combining functional signals with structural features of WM, the current study characterizes functional and structural impairments of WM in cerebelar type multiple system atrophy, with the goal to derive new mechanistic insights into the pathological progression of this disease. Our analysis of 30 well-diagnosed patients revealed pronounced decreases in functional connectivity in WM bundles of the cerebellum and brainstem, and concomitant local structural alterations that depended on the disease stage. The novel findings implicate a critical time point in the pathological evolution of the disease, which could guide optimal therapeutic interventions. Furthermore, fMRI signals of impaired WM bundles exhibited superior sensitivity in differentiating initial disease development, which demonstrates great potential of using these signals to inform disease management.

Catalytic Antibodies in Bipolar Disorder: Serum IgGs Hydrolyze Myelin Basic Protein

The pathogenesis of bipolar affective disorder is associated with immunological imbalances, a general pro-inflammatory status, neuroinflammation, and impaired white matter integrity. Myelin basic protein (MBP) is one of the major proteins in the myelin sheath of brain oligodendrocytes. For the first time, we have shown that IgGs isolated from sera of bipolar patients can effectively hydrolyze human myelin basic protein (MBP), unlike other test proteins. Several stringent criteria were applied to assign the studied activity to serum IgG. The level of MBP-hydrolyzing activity of IgG from patients with bipolar disorder was statistically significantly 1.6-folds higher than that of healthy individuals. This article presents a detailed characterization of the catalytic properties of MBP-hydrolyzing antibodies in bipolar disorder, including the substrate specificity, inhibitory analysis, pH dependence of hydrolysis, and kinetic parameters of IgG-dependent MBP hydrolysis, providing the heterogeneity of polyclonal MBP-hydrolyzing IgGs and their difference from canonical proteases. The ability of serum IgG to hydrolyze MBP in bipolar disorder may become an additional link between the processes of myelin damage and inflammation.

Association between peripheral inflammation and free-water imaging in Major Depressive Disorder before and after ketamine treatment – A pilot study

BackgroundAlterations in the peripheral inflammatory profile and white matter (WM) deterioration are frequent in Major Depressive Disorder (MDD). The present study applies free-water imaging to investigate the relationship between altered peripheral inflammation and WM microstructure and their predictive value in determining response to ketamine treatment in MDD. MethodsTen individuals with MDD underwent diffusion-weighted magnetic resonance imaging and a blood-draw before and 24 h after ketamine infusion. We utilized MANCOVAs and ANCOVAs to compare tissue-specific fractional anisotropy (FAT) and free-water (FW) of the forceps and cingulum, and the ratio of pro-inflammatory interleukin(IL)-8/anti-inflammatory IL-10 between individuals with MDD and 15 healthy controls at baseline. Next, we compared all baseline measures between ketamine responders (6) and non-responders (4) and analyzed changes in imaging and blood data after ketamine infusion. ResultsThe MDD group exhibited an increased IL-8/IL-10 ratio compared to controls at baseline (p = .040), which positively correlated with average FW across regions of interest (p = .013). Ketamine responders demonstrated higher baseline FAT in the left cingulum than non-responders (p = .023). Ketamine infusion did not influence WM microstructure but decreased the IL-8/IL-10 ratio (p = .043). LimitationsThe small sample size and short follow-up period limit the conclusion regarding the longer-term effects of ketamine in MDD. ConclusionsThis pilot study provides evidence for the role of inflammation in MDD by illustrating an association between peripheral inflammation and WM microstructure. Additionally, we demonstrate that free-water diffusion-weighted imaging might be a valuable tool to determine which individuals with MDD benefit from the anti-inflammatory mediated effects of ketamine treatment.

Blood-Brain Barrier Dysfunction and the Potential Mechanisms in Chronic Cerebral Hypoperfusion Induced Cognitive Impairment.

Chronic cerebral hypoperfusion (CCH) is a major cause of vascular cognitive impairment and dementia (VCID). Although the underlying mechanisms have not been fully elucidated, the emerging data suggest that blood–brain barrier (BBB) dysfunction is one of the pivotal pathological changes in CCH. BBB dysfunction appears early in CCH, contributing to the deterioration of white matter and the development of cognitive impairment. In this review, we summarize the latest experimental and clinical evidence implicating BBB disruption as a major cause of VCID. We discuss the mechanisms of BBB dysfunction in CCH, focusing on the cell interactions within the BBB, as well as the potential role of APOE genotype. In summary, we provide novel insights into the pathophysiological mechanisms underlying BBB dysfunction and the potential clinical benefits of therapeutic interventions targeting BBB in CCH.

Altered white matter microstructure and neurocognitive function of HIV-infected patients with low nadir CD4.

Altered white matter microstructure has been reported repeatedly using diffusion tensor imaging (DTI) in HIV-associated neurocognitive disorders. However, the associations between neurocognitive deficits and impaired white matter remains obscure due to frequent physical and psychiatric comorbidities in the patients. Severe immune suppression, reflected by low nadir CD4 T-cell counts, is reported to be associated with the neurocognitive deficits in the patients. In the present study, we examined white matter integrity using DTI and tract-based spatial statistics (TBSS), and neurocognitive functions using a battery of tests, in 15 HIV-infected patients with low nadir CD4, 16 HIV-infected patients with high nadir CD4, and 33 age- and sex-matched healthy controls. As DTI measures, we analyzed fractional anisotropy (FA) and mean diffusivity (MD). In addition, we investigated the correlation between white matter impairments and neurocognitive deficits. Among the three participant groups, the patients with low nadir CD4 showed significantly lower performance in processing speed and motor skills, and had significantly increased MD in widespread regions of white matter in both hemispheres. In the patients with low nadir CD4, there was a significant negative correlation between motor skills and MD in the right motor tracts, as well as in the corpus callosum. In summary, this study may provide white matter correlates of neurocognitive deficits in HIV-infected patients with past severe immune suppression as legacy effects.

Unraveling the mystery of white matter in depression: A translational perspective on recent advances.

BackgroundNumerous cortical and subcortical structures have been studied extensively concerning alterations of their integrity as well as their neurotransmitters in depression. However, connections between these structures have received considerably less attention.ObjectiveThis systematic review presents results from recent neuroimaging as well as neuropathologic studies conducted on humans and other mammals. It aims to provide evidence for impaired white matter integrity in individuals expressing a depressive phenotype.MethodsA systematic database search in accordance with the PRISMA guidelines was conducted to identify imaging and postmortem studies conducted on humans with a diagnosis of major depressive disorder, as well as on rodents and primates subjected to an animal model of depression.ResultsAlterations are especially apparent in frontal gyri, as well as in structures establishing interhemispheric connectivity between frontal regions. Translational neuropathological findings point to alterations in oligodendrocyte density and morphology, as well as to alterations in the expression of genes related to myelin synthesis. An important role of early life adversities in the development of depressive symptoms and white matter alterations across species is thereby revealed. Data indicating that stress can interfere with physiological myelination patterns is presented. Altered myelination is most notably present in regions that are subject to maturation during the developmental stage of exposure to adversities.ConclusionTranslational studies point to replicable alterations in white matter integrity in subjects suffering from depression across multiple species. Impaired white matter integrity is apparent in imaging as well as neuropathological studies. Future studies should focus on determining to what extent influencing white matter integrity is able to improve symptoms of depression in animals as well as humans.

Association of balance control mechanisms with brain structural integrity in older adults with mild cognitive impairment

BackgroundOlder adults with mild cognitive impairment (OAwMCI) exhibit subtle balance control and gait deficits which are predominantly associated with structural brain pathologies such as impaired white matter integrity and reduced gray matter volume. However, the relationship between balance recovery mechanisms and neural substrates in OAwMCI remains unknown. This study thus aimed to explore the associations of volitional (self-initiated) and reactive balance (in response to an external perturbation) control with structural brain integrity. MethodsTen OAwMCI (MoCA 18-25/30; greater than 55 years) were examined on the limits of stability test (volitional balance via Equitest), stance perturbation test (reactive balance via ActiveStep treadmill) and underwent magnetic resonance imaging. Forward movement (frequently performed functional activity of daily living) was quantified by maximum excursion (maximum ability to shift one’s center of gravity toward the theoretical limit [MXE-%])and directional control (amount of movement exhibited towards the target proportional to the movement away from the target [DCL-%]) on the limits of stability test. Slip-like (prevalent type of accidental falls) perturbations were quantified by postural stability (shortest distance of the COM motion state, i.e., its position and velocity, to the theoretical boundary) on the ActiveStep treadmill. White matter integrity was quantified by fractional anisotropy (FA, movement of water molecules directionality) and gray matter volume measured in mm3. ResultsFor volitional balance control, reduced forward MXE was significantly (p < 0.05) associated with lower FA in left (R2 = 0.56) and right (R2 = 0.60) corticospinal tract, left (R2 = 0.49) and right (R2 = 0.51) corticothalamic tract, left (R2 = 0.70) and right (R2 = 0.57) frontopontine tract, right (R2 = 0.67) cingulum, anterior commissure (R2 = 0.82), and corpus callosum (R2 = 0.62). Reduced forward DCL was significantly (p < 0.05) associated with reduced gray matter volume in the left (R2 = 0.75) and right (R2 = 0.81) cerebellum, brainstem (R2 = 0.64), right (R2 = 0.49) thalamus. For reactive balance control, reduced postural stability (p < 0.05) was significantly associated with reduced FA in the left (R2 = 0.75) and right (R2 = 0.64) corticospinal tract, left (R2 = 0.67) and right (R2 = 0.65) frontopontine tract. Reduced postural stability was significantly (p < 0.05) associated with reduced gray matter volume in the brainstem (R2 = 0.72) and right cerebellum (R2 = 0.70). ConclusionOur results indicate that structural brain integrity influences stability control in OAwMCI for both volitional and reactive balance tasks, which may share some common cortico-subcortical motor pathways and relay centers. Results also show that the integrity of descending pathways from cortical attentional centers could influence stability control for both tasks.

Aberrant White Matter Organization Correlated With Neurodevelopment Outcomes in Tetralogy of Fallot: An Atlas-Based Diffusion Tensor Imaging Study

BackgroundWhite matter injury (WMI) and impaired neurodevelopment are common in children with congenital heart disease. However, the effect of WMI on neurodevelopmental outcomes is still rarely reported. In this study, we aimed to investigate microstructural changes in white matter (WM) and its relationship with neurodevelopmental outcomes and further explore the underlying neurophysiological mechanisms of neurocognitive impairments in the tetralogy of Fallot (ToF). MethodDiffusion tensor imaging (DTI) data were acquired in preschool-aged children with ToF (n = 29) and normal controls (NC, n = 19), and neurodevelopmental assessments were performed with the Wechsler Preschool and Primary Scale of Intelligence in ToF. The differences in DTI metrics including fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity were evaluated between ToF and NC. Correlations between WM microstructural changes and neurodevelopmental outcomes were further analyzed. ResultsSignificant WM differences were found in the uncinate fasciculus, cingulum hippocampus, superior longitudinal fasciculus, and corticospinal tract between children with ToF and NC. Impaired WM integrity was correlated with the verbal comprehension index and working memory index in ToF. ConclusionsThis study demonstrated WM microstructure injury, and this injury is related to worse language and working memory performance in preschool-aged children with ToF. These findings suggested that DTI metrics may be a potential biomarker of neurocognitive impairments in ToF and can be used to predict future neurodevelopmental outcomes, which also provide new insights into the underlying neurophysiological mechanisms of neurocognitive impairments in ToF.

Free water diffusion MRI and executive function with a speed component in healthy aging

Extracellular free water (FW) increases are suggested to better provide pathophysiological information in brain aging than conventional biomarkers such as fractional anisotropy. The aim of the present study was to determine the relationship between conventional biomarkers, FW in white matter hyperintensities (WMH), FW in normal appearing white matter (NAWM) and in white matter tracts and executive functions (EF) with a speed component in elderly persons.We examined 226 healthy elderly participants (median age 69.83 years, IQR: 56.99–74.42) who underwent brain MRI and neuropsychological examination. FW in WMH and in NAWM as well as FW corrected diffusion metrics and measures derived from conventional MRI (white matter hyperintensities, brain volume, lacunes) were used in partial correlation (adjusted for age) to assess their correlation with EF with a speed component. Random forest analysis was used to assess the relative importance of these variables as determinants. Lastly, linear regression analyses of FW in white matter tracts corrected for risk factors of cognitive and white matter deterioration, were used to examine the role of specific tracts on EF with a speed component, which were then ranked with random forest regression.Partial correlation analyses revealed that almost all imaging metrics showed a significant association with EF with a speed component (r = -0.213 – 0.266). Random forest regression highlighted FW in WMH and in NAWM as most important among all diffusion and structural MRI metrics. The fornix (R2=0.421, p = 0.018) and the corpus callosum (genu (R2 = 0.418, p = 0.021), prefrontal (R2 = 0.416, p = 0.026), premotor (R2 = 0.418, p = 0.021)) were associated with EF with a speed component in tract based regression analyses and had highest variables importance.In a normal aging population FW in WMH and NAWM is more closely related to EF with a speed component than standard DTI and brain structural measures. Higher amounts of FW in the fornix and the frontal part of the corpus callosum leads to deteriorating EF with a speed component.

Post-Stroke Administration of L-4F Promotes Neurovascular and White Matter Remodeling in Type-2 Diabetic Stroke Mice.

Patients with type 2 diabetes mellitus (T2DM) exhibit a distinct and high risk of ischemic stroke with worse post-stroke neurovascular and white matter (WM) prognosis than the non-diabetic population. In the central nervous system, the ATP-binding cassette transporter member A 1 (ABCA1), a reverse cholesterol transporter that efflux cellular cholesterol, plays an important role in high-density lipoprotein (HDL) biogenesis and in maintaining neurovascular stability and WM integrity. Our previous study shows that L-4F, an economical apolipoprotein A member I (ApoA-I) mimetic peptide, has neuroprotective effects via alleviating neurovascular and WM impairments in the brain of db/db-T2DM stroke mice. To further investigate whether L-4F has neurorestorative benefits in the ischemic brain after stroke in T2DM and elucidate the underlying molecular mechanisms, we subjected middle-aged, brain-ABCA1 deficient (ABCA1−B/−B), and ABCA1-floxed (ABCA1fl/fl) T2DM control mice to distal middle cerebral artery occlusion. L-4F (16 mg/kg, subcutaneous) treatment was initiated 24 h after stroke and administered once daily for 21 days. Treatment of T2DM-stroke with L-4F improved neurological functional outcome, and decreased hemorrhage, mortality, and BBB leakage identified by decreased albumin infiltration and increased tight-junction and astrocyte end-feet densities, increased cerebral arteriole diameter and smooth muscle cell number, and increased WM density and oligodendrogenesis in the ischemic brain in both ABCA1−B/−B and ABCA1fl/fl T2DM-stroke mice compared with vehicle-control mice, respectively (p < 0.05, n = 9 or 21/group). The L-4F treatment reduced macrophage infiltration and neuroinflammation identified by decreases in ED-1, monocyte chemoattractant protein-1 (MCP-1), and toll-like receptor 4 (TLR4) expression, and increases in anti-inflammatory factor Insulin-like growth factor 1 (IGF-1) and its receptor IGF-1 receptor β (IGF-1Rβ) in the ischemic brain (p < 0.05, n = 6/group). These results suggest that post-stroke administration of L-4F may provide a restorative strategy for T2DM-stroke by promoting neurovascular and WM remodeling. Reducing neuroinflammation in the injured brain may contribute at least partially to the restorative effects of L-4F independent of the ABCA1 signaling pathway.

Perinatal methadone exposure attenuates myelination and induces oligodendrocyte apoptosis in neonatal rat brain.

Methadone (MTD) is a commonly prescribed treatment for opioid use disorder in pregnancy, despite limited information on the effects of passive exposure on fetal brain development. Animal studies suggest a link between perinatal MTD exposure and impaired white matter development. In this study, we characterized the effect of perinatal MTD exposure through the evaluation of oligodendrocyte development and glial cell activation in the neonatal rat brain. Six pregnant Sprague Dawley rat dams were randomized to MTD (0.2 mL/L) or untreated drinking water from embryonic day 7. Pups were terminated at postnatal day 7 and tissue sections were harvested from six randomly selected pups (one male and one female per litter) of each experimental group for immunohistochemistry in areas of corpus callosum (CC), lateral CC, external capsule (EC), and cerebellar white matter. In the MTD-exposed rat pups, myelination was significantly decreased in the CC, lateral CC, EC, and arbor vitae compared with the controls. The increased density and percentage of oligodendrocyte precursor cells (OPCs) were observed in the CC and cerebellar white matter. The highly active proliferation of OPCs as well as decreased density and percentage of differentiated oligodendrocytes were found in the cerebellum but no differences in the cerebrum. Apoptotic activities of both differentiated oligodendrocytes and myelinating oligodendrocytes were significantly increased in all regions of the cerebrum and cerebellum after MTD exposure. There was no quantitative difference in astrocyte, however, cell density and/or morphologic difference consistent with activation were observed in microglia throughout MTD-exposed CC and cerebellum. Taken together, perinatal MTD exposure reveals global attenuation of myelination, accelerated apoptosis of both differentiated and myelinating oligodendrocytes, and microglia activation, supporting an association between antenatal MTD exposure and impaired myelination in the developing brain.

Altered Levels of Plasma Inflammatory Cytokines and White Matter Integrity in Bipolar Disorder Patients With Suicide Attempts.

ObjectiveBipolar disorder (BD) has a higher lifetime rate of suicide attempts (SA) than other psychiatric disorders. Furthermore, BD patients with SA (BD + S) are prone to a worse quality of life. However, the pathophysiology of BD + S is poorly understood. To further reveal the potential mechanisms of BD + S, abnormalities in peripheral plasma inflammatory cytokines and brain white matter (WM) in BD + S, as well as the correlation between them are investigated.MethodsWe tested the levels of TNF-α, IL-1β, and IL-6 in peripheral plasma and collected the diffusion tensor imaging (DTI) data from 14 BD + S, 24 BD patients without SA (BD-S), and 26 healthy controls (HCs). The three groups were matched by age and gender. The levels of TNF-α, IL-1β, and IL-6 were detected by Luminex multifactor detection technology, and the fractional anisotropy (FA) values were employed to depict the alterations of WM. Partial correlation analyses were conducted to detect correlations between levels of TNF-α, IL-1β, and IL-6 and changes of WM, and the relationships between severity of clinical symptoms, including scores of HAMD-17 and YMRS, and cytokine levels or FA values in all groups.ResultsFor plasma inflammatory cytokines, there was no significant difference in their levels except for IL-6 among the three groups. Post-hoc analyses revealed that increased IL-6 level was only detected in BD + S (p < 0.05, Bonferroni correction). For DTI, BD + S showed specifically decreased FA in the bilateral middle cerebellar peduncle and the left superior corona radiata compared to BD-S and HCs (p < 0.05, Bonferroni correction). Additionally, both BD + S and BD-S groups revealed decreased FA in the bilateral body and genu of corpus callosum (CC) compared to HCs (p < 0.05, Bonferroni correction). No significant correlation between plasma inflammatory cytokines and WM integrity was found. In the BD + S group, we found negative correlation between the scores of YMRS and FA values of the left middle cerebellar peduncle (r = −0.74, p = 0.035).ConclusionThe inflammation and impaired WM integrity may provide a scientific basis to understand the potential mechanisms of BD + S.

Reduced structural connectivity in the corpus callosum in patients with anorexia nervosa.

Previous diffusion tensor imaging studies reported a reduced fractional anisotropy in the body of the corpus callosum in patients with anorexia nervosa, which may indicate impaired white matter integrity in interhemispheric connections. The aim of the current study was to investigate whether structural connectivity is affected in patients with anorexia nervosa. To this end, we compared the number of streamlines (a model of the white matter fibre tracts) and the total volume filled by these streamlines in different subsections of the corpus callosum in 33 women with and 33 without anorexia nervosa as well as in 20 recovered individuals. The volume of streamlines in the anterior and mid-anterior subsection of the corpus callosum was reduced in women with, but not in those who had recovered from anorexia nervosa. No differences in number of streamlines was detected in the corpus callosum between patients with anorexia nervosa, healthy controls and recovered patients. Alterations of the corpus callosum have been repeatedly reported in anorexia nervosa. Since the recovered group did not differ from the healthy control group, the reported alterations in acute patients appear to represent a state and not a trait marker.

The impact of levamisole and alcohol on white matter microstructure in adult chronic cocaine users.

Previous brain imaging studies with chronic cocaine users (CU) using diffusion tensor imaging (DTI) mostly focused on fractional anisotropy to investigate white matter (WM) integrity. However, a quantitative interpretation of fractional anisotropy (FA) alterations is often impeded by the inherent limitations of the underlying tensor model. A more fine‐grained measure of WM alterations could be achieved by measuring fibre density (FD). This study investigates this novel DTI metric comparing 23 chronic CU and 32 healthy subjects. Quantitative hair analysis was used to determine intensity of cocaine and levamisole exposure—a cocaine adulterant with putative WM neurotoxicity. We first assessed the impact of cocaine use, levamisole exposure and alcohol use on group differences in WM integrity. Compared with healthy controls, all models revealed cortical reductions of FA and FD in CU. At the within‐patient group level, we found that alcohol use and levamisole exposure exhibited regionally different FA and FD alterations than cocaine use. We found mostly negative correlations of tract‐based WM associated with levamisole and weekly alcohol use. Specifically, levamisole exposure was linked with stronger WM reductions in the corpus callosum than alcohol use. Cocaine use duration correlated negatively with FA and FD in some regions. Yet, most of these correlations did not survive a correction for multiple testing. Our results suggest that chronic cocaine use, levamisole exposure and alcohol use were all linked to significant WM impairments in CU. We conclude that FD could be a sensitive marker to detect the impact of the use of multiple substances on WM integrity in cocaine but also other substance use disorders.

Altered transcallosal fiber count and volume in high-functioning adults with autism spectrum disorder

An altered pattern of information processing has been hypothesized in autism spectrum disorder (ASD), characterized by enhanced local network connectivity and reduced long-distance communication. Previous findings of impaired white matter integrity in the genu and the body of the corpus callosum already indicated reduced long-distance connectivity in patients with ASD. However, it remained unclear how this reduced white matter integrity affects the structural connectivity of the corresponding brain areas. To this end, we analyzed magnetic resonance images (MRI) from 30 participants with high-functioning ASD and 30 typically developed individuals using a global tracking approach to estimate the fiber count and volume of the transcallosal fiber tracts of the five corpus callosum subsections. A reduced fiber count and fiber volume in the anterior subsection of the corpus callosum was detected, supporting the hypothesis of reduced long-distance connectivity in ASD.

A novel Lgi1 mutation causes white matter abnormalities and impairs motor coordination in mice.

Leucine-rich glioma-inactivated protein 1 (LGI1) is known to play a key role in autosomal dominant lateral temporal lobe epilepsy (ADLTE). The ADLTE is an inherited disease characterized by focal seizures with distinctive auditory or aphasic symptoms. A large number of mutations on the Lgi1gene have been reported and are believed to be the genetic cause for ADLTE. We identified a novel missense mutation, c.152A>G (p.Asp51Gly), on Lgi1 from a Chinese ADLTE patient who manifests locomotor imbalance and white matter reduction. However, it remains unknown how mutant LGI1 causes white matter abnormalities at molecular and cellular levels. Here, we generated a knock-in mouse bearing this Lgi1mutation. We found that Lgi1D51G/D51G mice exhibited impaired defective white matter and motor coordination. We observed that Lgi1D51G/D51G mice displayed a reduced number of mature oligodendrocytes (OLs) and deficient OL differentiation in the white matter. However, the population of oligodendrocyte precursor cells was not affected in Lgi1D51G/D51G mice. Mechanistically, we showed that the Lgi1D51G mutation resulted in altered mTOR signaling and led to decreased levels of Sox10. Given that Sox10 is a key transcriptional factor to control OL differentiation, our results strongly suggest that the Lgi1D51G mutation may cause white matter abnormalities via inhibiting Sox10-dependent OL differentiation and myelination in the central nervous system.