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One of the most fundamental questions in cognitive neuroscience is to understand how the brain constructs our three-dimensional visual world from two-dimensional retinal signals of light and dark intensity. At the time this paper was written, the seminal work of Sperry and his colleagues studying patients who had undergone sections of the corpus callosum was most influential (Gazzaniga et al 1962; Sperry et al 1969). They reported that visual object recognition up to the level of functional significance or meaning was intact in the disconnected right hemisphere, merely the verbal label could not be retrieved. Consequently, at that time current theorising tended to conflate perceptual processing and semantic processing to a single post-sensory categorical stage such that object recognition was achieved by a single system (eg Sutherland 1968, 1973; Tenenbaum and Barrow 1976).

Reference EPFL-ARTICLE-208133doi:10.1007/s00429-014-0974-7View record in Web of Science Record created on 2015-05-29, modified on 2017-05-12

Large deformation diffeomorphic metric mapping for curve (LDDMM‐curve) has been widely used in deformation based statistical shape analysis of the mid‐sagittal corpus callosum. A main limitation of LDDMM‐curve is that it is time‐consuming and computationally complex. In this study, down‐sampling strategies for accelerating LDDMM‐curve are investigated and tested on two large datasets, one on Alzheimer's disease (155 Alzheimer's disease, 325 mild cognitive impairment and 185 healthy controls) and the other on first‐episode schizophrenia (92 first‐episode schizophrenia and 106 healthy controls). For both datasets a variety of down‐sampling factors are tested in terms of registration accuracy, registration speed, and most importantly disease‐related patterns. Experimental results revealed that down‐sampling template curve by a factor of 2 can significantly reduce the running time of LDDMM‐curve without sacrificing the registration accuracy. Also, the disease‐induced patterns, or more specifically the group comparison results, were almost identical before and after down‐sampling. It is also shown that there was no need to down‐sample the target population curves but only the single template curve of the study of interest. Comprehensive analyses were conducted.

Normal brain aging is characterized by declining neuronal integrity, yet it remains unclear how microstructural injury influences cognitive aging and whether such mechanisms differ between sexes. Using restriction spectrum imaging (RSI), we examined sex differences in associations between brain microstructure and cognitive function in 147 community-dwelling older men and women (56-99 years). Gray and white matter microstructure correlated with global cognition, executive function, visuospatial memory, episodic memory, and logical memory, with the strongest associations for restricted, hindered and free isotropic diffusion. Associations were stronger for women than for men, a difference likely due to greater age-related variability in cognitive scores and microstructure in women. Isotropic diffusion mediated effects of age on cognition for both sexes, though distinct mediation patterns were present for women and men. For women, hippocampal and corpus callosum microstructure mediated age effects on verbal and visuospatial memory, respectively, whereas for men fiber microstructure (mainly fornix and corpus callosum) mediated age effects on executive function and visuospatial memory. These findings implicate sex-specific pathways by which changing brain cytoarchitecture contributes to cognitive aging, and suggest that RSI may be useful for evaluating risk for cognitive decline or monitoring efficacy of interventions to preserve brain health in later life.

Growth differentiation factor (GDF) 11 levels decline with aging. The age-related loss of GDF 11 has been implicated in the pathogenesis of a variety of age-related diseases. GDF11 supplementation reversed cardiac hypertrophy, bone loss, and pulmonary dysfunction in old mice, suggesting that GDF11 has a rejuvenating effect. Less is known about the potential of GDF11 to improve recovery after an acute injury, such as stroke, in aged mice. GDF11/8 levels were assessed in young and aged male mice and in postmortem human brain samples. Aged mice were subjected to a transient middle cerebral artery occlusion (MCAo). Five days after MCAo, mice received and bromodeoxyuridine / 5-Bromo-2'-deoxyuridine (BrdU) and either recombinant GDF11 or vehicle for five days and were assessed for recovery for one month following stroke. MRI was used to determine cerebrospinal fluid (CSF) volume, corpus callosum (CC) area, and brain atrophy at 30 days post-stroke. Immunohistochemistry was used to assess gliosis, neurogenesis, angiogenesis and synaptic density. Lower GDF11/8 levels were found with age in both mice and humans (p

Objectives Corpus callosal agenesis (CCA) is one of the most common brain malformations and is generally associated with a good outcome when isolated. However, up to 25% of patients are at risk of neurodevelopmental delay, which currently available clinical and imaging parameters are inadequate to predict. The objectives of this study were to apply and validate a fetal magnetic resonance imaging (MRI) anatomical scoring system in a cohort of fetuses with isolated CCA and to evaluate the correlation with postnatal neurodevelopmental outcome. Methods This was a retrospective cohort study of cases of prenatally diagnosed isolated CCA (as determined on ultrasound and MRI), with normal karyotype and with known postnatal neurodevelopmental outcome assessed by standardized testing. A fetal brain MRI anatomical scoring system based on seven categories (gyration, opercularization, temporal lobe symmetry, lamination, hippocampal position, basal ganglia and ventricular size) was developed and applied to the cohort; a total score of 0–11 points could be given, with a score of 0 representing normal anatomy. Images were scored independently by two neuroradiologists blinded to the outcome. For the purpose of assessing the correlation between fetal MRI score and neurodevelopmental outcome, neurodevelopmental test results were scored as follows: 0, ‘below average’ (poor outcome); 1, ‘average’; and 2, ‘above average’ (good outcome). Spearman's rank coefficient was used to assess correlation, and inter‐rater agreement in the assessment of fetal MRI score was calculated. Results Twenty‐one children (nine females (42.9%)) fulfilled the inclusion criteria. Thirty‐seven fetal MRI examinations were evaluated. Mean gestational age was 28.3 ± 4.7 weeks (range, 20–38 weeks). All fetuses were delivered after 35 weeks' gestation with no perinatal complications. Fetal MRI scores ranged from 0 to 6 points, with a median of 3 points. Inter‐rater agreement in fetal MRI score assessment was excellent (intraclass correlation coefficient, 0.959 (95% CI, 0.921–0.979)). Neurodevelopmental evaluation was performed on average at 2.6 ± 1.46 years (range, 0.5–5.8 years). There was a significant negative correlation between fetal MRI score and neurodevelopmental outcome score in the three areas tested: cognitive (ρ = –0.559, P

The specific role of the corpus callosum (CC) in language network organization remains unclear, two contrasting models have been proposed: inhibition of homotopic areas allowing for independent functioning of the hemispheres versus integration of information from both hemispheres. This study aimed to add to this discussion with the first investigation of language network connectivity in combination with CC volume measures. In 38 healthy children aged 6–12, we performed task‐based functional magnetic resonance imaging to measure language network connectivity, used structural magnetic resonance imaging to quantify CC subsection volumes, and administered various language tests to examine language abilities. We found an increase in left intrahemispheric and bilateral language network connectivity and a decrease in right intrahemispheric connectivity associated with larger volumes of the posterior, mid‐posterior, and central subsections of the CC. Consistent with that, larger volumes of the posterior parts of the CC were significantly associated with better verbal fluency and vocabulary, the anterior CC volume was positively correlated with verbal span. Thus, children with larger volumes of CC subsections showed increased interhemispheric language network connectivity and were better in different language domains. This study presents the first evidence that the CC is directly linked to language network connectivity and underlines the excitatory role of the CC in the integration of information from both hemispheres., In 38 healthy children aged 6–12, the present study measured language network connectivity, corpus callosum subsection volumes, and language abilities. Children with larger volumes of CC subsections showed increased interhemispheric language network connectivity and were better in different language domains. The present study suggests that the corpus callosum is directly linked to language network connectivity and underlines the excitatory role of the corpus callosum in the integration of information from both hemispheres. .

Purpose: To investigate whether the genu of the corpus callosum is involved in patients with clinically mild encephalitis/encephalopathy with a reversible splenial lesion (MERS) type I. Methods: Twenty-three cases of clinically confirmed MERS I were analyzed retrospectively, and MRI features of the lesion were observed. The apparent diffusion coefficient (ADC) values of the same region of interests in lesions at the splenium and genu of the corpus callosum were measured before and after treatment (i.e., four groups), and the average ADC values were calculated. Paired t-tests were used to compare the ADC values of lesions in the splenium and genu before and after treatment. Independent sample t-tests were used to compare the values in the splenium and genu after treatment. Results: The mean ADC values of the splenium before and after treatment were 0.448 ± 0.124 and 0.790 ± 0.070 × 10−3 mm2/s, respectively, showing significant difference (P < 0.01). The mean ADC values in the genu before and after treatment were 0.783 ± 0.067 and 0.829 ± 0.070 × 10−3 mm2/s, respectively, also showing significant difference (P < 0.01). There was no significant difference in the ADC values between the splenium and genu after treatment (P > 0.05). Conclusion: The genu showed a slight restriction in diffusion in the acute stage of type I MERS. After treatment, this diffusion restriction diminished as it typically does in the splenium. Our results indicate that the pathology in MERS extends well beyond the visible lesions.

Background: The underlying white matter impairment in patients with early and late-onset Alzheimer’s disease (EOAD and LOAD) is still unclear, and this might due to the complex AD pathology. Methods: We included 31 EOAD, 45 LOAD, and 64 younger, 46 elder controls in our study to undergo MRI examinations. Fiber density (FD) and fiber bundle cross-section (FC) were measured using fixel-based analysis based on diffusion weighted images. On whole brain and tract-based level, we compared these parameters among different groups (p

Brain laterality refers to the asymmetric location of functional elements within the bilateral brain of animals and humans. Thus far, five lateralized functions have been recognized in humans: handedness, language ability, spatial skills, facial recognition, and emotion recognition. Recently, a sixth asymmetric functional element bearing on personality has been discovered. It is the larger side of the split bilateral anterior cingulate cortex (ACC). This appears to be the final output element of the executive system of which, by logic, there can be only one. Which side is somewhat larger varies among the general population in a seemingly idiosyncratic manner, yet with a genetic basis because true-breeding lineages exist. Here, hemisity is binary measure where a person is inherently born either right brain or left brain oriented. This is determined by nine statistically robust sets of four biophysical tests, none of which depend upon personality, and five behavioral questionnaires. Crucially these hemisity methods have been validated by the Magnetic Resonance Imaging (MRI)-based discovery that the larger side of the ACC is on the same side as one’s hemisity, making MRI the primary standard for hemisity determination (r = 0.96). There are at least 30 measurable differences in individual characteristics and behaviors between those persons whose hemsity is on the right compared to those with it on the left. The hemisity of 2929 individuals was determined by these methods. Large groups included 1428 junior and senior high schools students both in Hawaii and Utah. There were somewhat comparable numbers present for both types of hemisity. Hemisity of individuals was found stable from infancy to old age. There was no relation between hemisity and handedness. Larger corpus callosum (CC) size of male or female subjects was larger in right brainer that in left brainers. Twin studies demonstrate that CC size is inherited. Thirty-eight percent of individuals of both sexes were right brain oriented, while 62% of individuals of both sexes were left brain oriented. In pairings, there were more than twice as many couples with opposite hemisity. Of these couples, the right brain male and females were dominant. Reproductive outcomes of these were “Like father like son, Like mother like daughter.”

Background Nuclear Factor One X (NFIX) haploinsufficiency in humans results in Malan syndrome, a disorder characterized by overgrowth, macrocephaly and intellectual disability. Although clinical assessments have determined the underlying symptomology of Malan syndrome, the fundamental mechanisms contributing to the enlarged head circumference and intellectual disability in these patients remains undefined. Methods Here, we used Nfix heterozygous mice as a model to investigate these aspects of Malan syndrome. Volumetric magnetic resonance imaging (MRI) was used to calculate the volumes of 20 brain sub regions. Diffusion tensor MRI was used to perform tractography-based analyses of the corpus callosum, hippocampal commissure, and anterior commissure, as well as structural connectome mapping of the whole brain. Immunohistochemistry examined the neocortical cellular populations. Two behavioral assays were performed, including the active place avoidance task to assess spatial navigation and learning and memory function, and the 3-chambered sociability task to examine social behaviour. Findings Adult Nfix+/− mice exhibit significantly increased brain volume (megalencephaly) compared to wildtypes, with the cerebral cortex showing the highest increase. Moreover, all three forebrain commissures, in particular the anterior commissure, revealed significantly reduced fractional anisotropy, axial and radial diffusivity, and tract density intensity. Structural connectome analyses revealed aberrant connectivity between many crucial brain regions. Finally, Nfix+/− mice exhibit behavioral deficits that model intellectual disability. Interpretation Collectively, these data provide a significant conceptual advance in our understanding of Malan syndrome by suggesting that megalencephaly underlies the enlarged head size of these patients, and that disrupted cortical connectivity may contribute to the intellectual disability these patients exhibit. Fund Australian Research Council (ARC) Discovery Project Grants, ARC Fellowship, NYSTEM and Australian Postgraduate Fellowships.

Background: The infant brain grows quickly with elaborate microstructural development during the neonatal period. The white matter, during critical periods of development, is selectively vulnerable to altered maturation and impaired growth in very-low-birth-weight (VLBW) infants. Objective: To evaluate whether abnormal white matter maturation in VLBW infants is associated with poor neurodevelopmental outcomes at 18 months of corrected age. Methods: Between 2015 and 2017, we recruited 60 VLBW infants at 24–32 weeks of gestational age and 15 full-term controls. All participants underwent magnetic resonance imaging at near-term age and were assessed at 18 months of corrected age with the Bayley Scales of Infant and Toddler Development, Third Edition. The associations between regional white matter fractional anisotropy (FA) and mean diffusivity on diffusion tensor imaging (DTI) and developmental outcomes were explored using multivariable linear regression after correcting for gestational age, postmenstrual age at DTI scan, and maternal education level. Results: The FA values of the splenium of the corpus callosum (p = 0.032), corticospinal tract (p = 0.025), middle cerebellar peduncle (MCP) (p < 0.001), and cingulum (p = 0.043) were significantly related to cognitive scores; however, only the association corresponding to the MCP remained significant after correcting for multiple comparisons. The MCP FA (p = 0.008) was associated with motor scores after correction for multiple comparisons (p = 0.008). Cognitive impairment (area under the curve [AUC] = 0.823, 95% confidence interval [CI] = 0.722–0.911) and motor impairment (AUC = 0.776, 95% CI = 0.656–0.899) were predicted by MCP FA. Conclusions: The FA of MCP at near-term age may predict developmental outcomes of VLBW infants at 18 months of corrected age.

The corpus callosum has become a key area of interest for researchers in severe mental illness. Disruptions in fractional anisotropy in the callosum have been reported in schizophrenia and major depressive disorder. No change has been reported in oligodendrocyte density and overall size of the callosum in either illness, suggesting that gross morphology is unchanged, but subtler organisational disruption may exist within this structure. Using high-resolution oil immersion microscopy, we examined the cross-sectional area of the nerve fibre and the axonal myelin sheath; and using standard high-resolution light microscopy, we measured the density of myelinated axons. These measurements were made in the splenium of the corpus callosum. Measures were taken in the sagittal plane in the callosal splenium to contrast with the previous similar examination of the callosal genu. Cases of major depressive disorder had significantly decreased mean myelin cross-sectional area (p = 0.014) per axon in the splenium than in controls or schizophrenia groups. There was no significant change in the density of myelinated axons. The results suggest a clear decrease of myelin in the axons of the callosal splenium in MDD, although this type of neuropathological study is unable to clarify whether this is caused by changes during life or has a developmental origin. In contrast with increased myelin in the callosal genu, this result suggests a longitudinal change in callosal myelination in major depressive disorder not present in normal or schizophrenic brains.

Conditional knockout mice for Atg9a, specifically in brain tissue, were generated to understand the roles of ATG9A in the neural tissue cells. The mice were born normally, but half of them died within one wk, and none lived beyond 4 wk of age. SQSTM1/p62 and NBR1, receptor proteins for selective autophagy, together with ubiquitin, accumulated in Atg9a-deficient neurosoma at postnatal d 15 (P15), indicating an inhibition of autophagy, whereas these proteins were significantly decreased at P28, as evidenced by immunohistochemistry, electron microscopy and western blot. Conversely, degenerative changes such as spongiosis of nerve fiber tracts proceeded in axons and their terminals that were occupied with aberrant membrane structures and amorphous materials at P28, although no clear-cut degenerative change was detected in neuronal cell bodies. Different from autophagy, diffusion tensor magnetic resonance imaging and histological observations revealed Atg9a-deficiency-induced dysgenesis of the corpus callosum and anterior commissure. As for the neurite extensions of primary cultured neurons, the neurite outgrowth after 3 d culturing was significantly impaired in primary neurons from atg9a-KO mouse brains, but not in those from atg7-KO and atg16l1-KO brains. Moreover, this tendency was also confirmed in Atg9a-knockdown neurons under an atg7-KO background, indicating the role of ATG9A in the regulation of neurite outgrowth that is independent of autophagy. These results suggest that Atg9a deficiency causes progressive degeneration in the axons and their terminals, but not in neuronal cell bodies, where the degradations of SQSTM1/p62 and NBR1 were insufficiently suppressed. Moreover, the deletion of Atg9a impaired nerve fiber tract formation.

Purpose Frequency difference mapping (FDM) is a phase processing technique which characterizes the nonlinear temporal evolution of the phase of gradient echo (GE) signals. Here, a novel FDM‐processing algorithm is introduced, which is shown to reveal information about white matter microstructure. Unlike some other phase‐processing techniques, the FDM algorithm presented here does not require the use of phase unwrapping or sophisticated image processing. It uses a series of scaled complex divisions to unwrap phase and remove background fields. Methods Ten healthy subjects underwent a series of single‐slice, sagittal multi‐echo GE scans at 7T with the slice positioned at the midline. Phase data were processed with the novel FDM algorithm, and the temporal evolution of the magnitude signal and frequency difference was examined in 5 regions of the corpus callosum (CC; genu, anterior body, middle body, posterior body, and splenium). Results Consistent frequency difference contrast relative to surrounding tissue was observed in all subjects in the CC and in other white matter regions where the nerve fibers run perpendicular to B0 , such as the superior cerebellar peduncle. Examination of the frequency difference curves shows distinct variations over the CC, with the genu and splenium displaying larger frequency differences than the other regions (in addition to a faster decay of signal magnitude). Conclusion The novel FDM algorithm presented here yields images sensitive to tissue microstructure and microstructural differences over the CC in a simple manner, without the requirement for phase unwrapping or sophisticated image processing.

We report here on the ultrastructure of amyloid plaques in chronic wasting disease (CWD) transmitted to Tg20 transgenic mice overexpressing prion protein (PrPc). We identified three main types of amyloid deposits in mCWD: large amyloid deposits, unicentric plaques similar to kuru plaques in human prion diseases and multicentric plaques reminiscent of plaques typical of GSS. The most unique type of plaques were large subpial amyloid deposits. They were composed of large areas of amyloid fibrils but did not form „star-like” appearances of unicentric plaques. All types of plaques were totally devoid of dystrophic neuritic elements. However, numerous microglial cells invaded them. The plaques observed by confocal laser microscope were of the same types as those analyzed by electron microscopy. Neuronal processes surrounding the plaques did not show typical features of neuroaxonal dystrophy.

Background: Multiple meta-analyses of diffusion tensor imaging (DTI) studies have reported impaired white matter integrity in patients with major depressive disorder (MDD). However, owing to inclusion of medicated patients in these studies, it is difficult to conclude whether these reported alterations are associated with MDD or confounded by medication effects. A meta-analysis of DTI studies on medication-free (medication-naive and medication washout) patients with MDD would therefore be necessary to disentangle MDD-specific effects. Methods: We analyzed white matter alterations between medication-free patients with MDD and healthy controls using anisotropic effect size–signed differential mapping (AES-SDM). We used DTI query software for fibre tracking. Results: Both pooled and subgroup meta-analyses in medication washout patients showed robust fractional anisotropy (FA) reductions in white matter of the right cerebellum hemispheric lobule, body of the corpus callosum (CC) and bilateral superior longitudinal fasciculus III (SLF III), whereas FA reductions in the genu of the CC and right anterior thalamic projections were seen in only medication-naive patients. Fibre tracking showed that the main tracts with observed FA reductions included the right cerebellar tracts, body of the CC, bilateral SLF III and arcuate fascicle. Limitations: The analytic techniques, patient characteristics and clinical variables of the included studies were heterogeneous; we could not exclude the effects of nondrug therapies owing to a lack of data. Conclusion: By excluding the confounding influences of current medication status, findings from the present study may provide a better understanding of the underlying neuropathology of MDD.

Background: This study applies multimodal MRI to investigate neurodevelopment in nine-year-old children born to cancer-complicated pregnancies. Methods: In this cohort study, children born after cancer-complicated pregnancies were recruited alongside 1:1 matched controls regarding age, sex and gestational age at birth (GA). Multimodal MRI was used to investigate whole-brain and subcortical volume, cortical structure (using surface-based morphometry), white matter microstructure (using fixel-based analysis) and functional connectivity (using resting-state bloodoxygen-level-dependant signal correlations). Graph theory probed whole-brain structural and functional organization. For each imaging outcome we conducted two group comparisons: 1) children born after cancer-complicated pregnancies versus matched controls, and 2) the subgroup of children with prenatal chemotherapy exposure versus matched controls. In both models, we used the covariate of GA and the group-byGA interaction, using false-discovery-rate (FDR) or family-wise-error (FWE) correction for multiple comparisons. Exploratory post-hoc analyses investigated the relation between brain structure/function, neuropsychological outcome and maternal oncological/obstetrical history. Findings: Forty-two children born after cancer-complicated pregnancies were included in this study, with 30 prenatally exposed to chemotherapy. Brain organization and functional connectivity were not significantly different between groups. Both cancer and chemotherapy in pregnancy, as compared to matched controls, were associated with a lower travel depth, indicating less pronounced gyrification, in the left superior temporal gyrus (pFDR 006), with post-hoc analysis indicating platinum derivatives during pregnancy as a potential risk factor (p = .028). Both cancer and chemotherapy in pregnancy were related to a lower fibre cross-section (FCS) and lower fibre density and cross-section (FDC) in the posterior corpus callosum and its tapetal fibres, compared to controls. Higher FDC in the chemotherapy subgroup and higher FCS in the whole study group were observed in the anterior thalamic radiations. None of the psycho-behavioural parameters correlated significantly with any of the brain differences in the study group or chemotherapy subgroup. Interpretation: Prenatal exposure to maternal cancer and its treatment might affect local grey and white matter structure, but not functional connectivity or global organization. While platinum-based therapy was identified as a potential risk factor, this was not the case for chemotherapy in general. Funding: This project has received funding from the European Union’s Horizon 2020 research and innovation program (European Research council, grant no 647,047), the Foundation against cancer (Stichting tegen kanker, grant no. 2014 152) and the Research Foundation Flanders (FWO, grants no. 11B9919N, 12ZV420N) ispartof: EClinicalMedicine vol:28 ispartof: location:England status: Published online

Patients with hypoglycemic coma show abnormal signals in the white matter on magnetic resonance imaging. However, the precise pathological changes in the white matter caused by hypoglycemic coma remain unclear in humans and experimental animals. This study aimed to reveal the distribution and time course of histopathological and immunohistochemical changes occurring in the white matter during the early stages of hypoglycemic coma in rats. Insulin-induced hypoglycemic coma of 15-30-min duration was induced in rats, followed by recovery using a glucose solution. Rat brains were collected after 6 and 24 hr and after 3, 5, 7, and 14 days. The brains were submitted for histological and immunohistochemical analysis for neurofilament 200 kDa (NF), myelin basic protein, olig-2, Iba-1, and glial fibrillary acidic protein (GFAP). Vacuolation was observed in the fiber bundles of the globus pallidus on days 1-14. Most of the vacuoles were located in GFAP-positive astrocytic processes or the extracellular space and appeared to be edematous. Additionally, myelin pallor and a decrease in NF-positive signals were observed on day 14. Microgliosis and astrogliosis were also detected. Observations similar to the globus pallidus, except for edema, were noted in the internal capsule. In the corpus callosum, a mild decrease in NF-positive signals, microgliosis, and astrogliosis were observed. These results suggest that after transient hypoglycemic coma, edema and/or degeneration occurred in the white matter, especially in the globus pallidus, internal capsule, and corpus callosum in the early stages.

Purpose Poorly characterized macromolecular (MM) and baseline artefacts are known to reduce metabolite quantitation accuracy in 1H MR spectroscopic imaging (MRSI). Increasing echo time (TE) and improvements in MM analysis schemes have both been proposed as strategies to improve metabolite measurement reliability. In this study, the influence of TE and two MM analysis schemes on MRSI reproducibility are investigated. Methods An experimentally acquired baseline was collected using an inversion recovery sequence (TI = 750 ms) and incorporated into the analysis method. Intrasubject reproducibility of MRSI scans, acquired at 3 Tesla, was assessed using metabolite coefficients of variance (COVs) for both experimentally acquired and simulated MM analysis schemes. In addition, the reproducibility of TE = 35 ms, 80 ms, and 144 ms was evaluated. Results TE = 80 ms was the most reproducible for singlet metabolites with COVs

This study aims to investigate the effect and mechanism of type 2 voltage-gated chloride channel (ClC-2) on myelin development of newborn rats' cerebral white matter with gestational diabetes mellitus (GDM). In this study, GDM model was induced in late pregnant rat model. The alteration of ClC-2 expression in various developmental stages of cerebral white matter with/without being exposed to high glucose was analyzed using RT-PCR, active oxygen detection, TUNEL staining, Western Blot as well as immuno-histochemical staining. Our results showed that ClC-2 mRNA and protein expressions in GDM group were significantly increased in white matter of fetal rats after E18 stage, and elevated the level of TNF-α and iNOS in white matter at P0 and P3 stage of newborn rats. Meanwhile, In GDM group, reactive oxygen species (ROS) levels of the white matter at E18, P0, and P3 stage were significantly higher than control group. Furthermore, the expression level of myelin transcription factor Olig2 at P0 stage and CNPase at P3 stage were strikingly lower than that of the control group. In GDM group, ClC-2 expression in the corpus callosum (CC) and cingulate gyrus (CG) regains, and TUNEL positive cell number were increased at P0 and P3 stage. However, PDGFα positive cell number at P0 stage and CNPase expression at P3 stage were significantly decreased. Caspase-3 was also increased in those white matter regions in GDM group, but p-Akt expression was inhibited. While DIDS (a chloride channel blocker) can reverse these changes. In conclusion, ClC-2 and caspase-3 were induced by GDM, which resulted in apoptosis and myelination inhibition. The effect was caused by repressing PI3K-Akt signaling pathway. Application of ClC-2 inhibitor DIDS showed protective effects on cerebral white matter damage stimulated by high glucose concentration.

Working memory (WM) skills are closely associated with learning progress in key areas such as reading and mathematics across childhood. As yet, however, little is known about how the brain systems underpinning WM develop over this critical developmental period. The current study investigated whether and how structural brain correlates of components of the working memory system change over development. Verbal and visuospatial short‐term and working memory were assessed in 153 children between 5.58 and 15.92 years, and latent components of the working memory system were derived. Fractional anisotropy and cortical thickness maps were derived from T1‐weighted and diffusion‐weighted MRI and processed using eigenanatomy decomposition. There was a greater involvement of the corpus callosum and posterior temporal white matter in younger children for performance associated with the executive part of the working memory system. For older children, this was more closely linked with the thickness of the occipitotemporal cortex. These findings suggest that increasing specialization leads to shifts in the contribution of neural substrates over childhood, moving from an early dependence on a distributed system supported by long‐range connections to later reliance on specialized local circuitry. Our findings demonstrate that despite the component factor structure being stable across childhood, the underlying brain systems supporting working memory change. Taking the age of the child into account, and not just their overall score, is likely to be critical for understanding the nature of the limitations on their working memory capacity.

BackgroundA significantly lower fractional anisotropy (FA) value has been shown in anterior parts of the corpus callosum in patients with bipolar disorder.AimsWe investigated the association between abnormal corpus callosum integrity and interhemispheric functional connectivity (IFC) in patients with bipolar disorder.MethodsWe examined the association between FA values in the corpus callosum (CC-FA) and the IFC between homotopic regions in the anterior cortical structures of bipolar disorder (n=16) and major depressive disorder (n=22) patients with depressed or euthymic states.ResultsWe found a positive correlation between the CC-FA and IFC values between homotopic regions of the ventral prefrontal cortex and insula cortex, and significantly lower IFC between these regions in bipolar disorder patients.ConclusionsThe abnormal corpus callosum integrity in bipolar disorder patients is relevant to the IFC between homotopic regions, possibly disturbing the exchange of emotional information between the cerebral hemispheres resulting in emotional dysregulation.

Contains fulltext : 171765.pdf (Publisher’s version ) (Closed access) Myelination, the process by which oligodendrocytes form the myelin sheath around axons, is key to axonal signal transduction and related motor function in the central nervous system (CNS). Aging is characterized by degenerative changes in the myelin sheath, although the molecular underpinnings of normal and aberrant myelination remain incompletely understood. Here we report that axon myelination and related motor function are dependent on BubR1, a mitotic checkpoint protein that has been linked to progeroid phenotypes when expressed at low levels and healthy lifespan when overabundant. We found that oligodendrocyte progenitor cell proliferation and oligodendrocyte density is markedly reduced in mutant mice with low amounts of BubR1 (BubR1H/H mice), causing axonal hypomyelination in both brain and spinal cord. Expression of essential myelin-related genes such as MBP and PLP1 was significantly reduced in these tissues. Consistent with defective myelination, BubR1H/H mice exhibited various motor deficits, including impaired motor strength, coordination, and balance, irregular gait patterns and reduced locomotor activity. Collectively, these data suggest that BubR1 is a key determinant of oligodendrocyte production and function and provide a molecular entry point to understand age-related degenerative changes in axon myelination.

Microglia are highly plastic immune cells which exist in a continuum of activation states. By shaping the function of oligodendrocyte precursor cells (OPCs), the brain cells which differentiate to myelin-forming cells, microglia participate in both myelin injury and remyelination during multiple sclerosis. However, the mode(s) of action of microglia in supporting or inhibiting myelin repair is still largely unclear. Here, we analysed the effects of extracellular vesicles (EVs) produced in vitro by either pro-inflammatory or pro-regenerative microglia on OPCs at demyelinated lesions caused by lysolecithin injection in the mouse corpus callosum. Immunolabelling for myelin proteins and electron microscopy showed that EVs released by pro-inflammatory microglia blocked remyelination, whereas EVs produced by microglia co-cultured with immunosuppressive mesenchymal stem cells promoted OPC recruitment and myelin repair. The molecular mechanisms responsible for the harmful and beneficial EV actions were dissected in primary OPC cultures. By exposing OPCs, cultured either alone or with astrocytes, to inflammatory EVs, we observed a blockade of OPC maturation only in the presence of astrocytes, implicating these cells in remyelination failure. Biochemical fractionation revealed that astrocytes may be converted into harmful cells by the inflammatory EV cargo, as indicated by immunohistochemical and qPCR analyses, whereas surface lipid components of EVs promote OPC migration and/or differentiation, linking EV lipids to myelin repair. Although the mechanisms through which the lipid species enhance OPC maturation still remain to be fully defined, we provide the first demonstration that vesicular sphingosine 1 phosphate stimulates OPC migration, the first fundamental step in myelin repair. From this study, microglial EVs emerge as multimodal and multitarget signalling mediators able to influence both OPCs and astrocytes around myelin lesions, which may be exploited to develop novel approaches for myelin repair not only in multiple sclerosis, but also in neurological and neuropsychiatric diseases characterized by demyelination. Electronic supplementary material The online version of this article (10.1007/s00401-019-02049-1) contains supplementary material, which is available to authorized users.

An increasing number of psychoradiology studies that use tract-based spatial statistics (TBSS) of diffusion tensor imaging have reported abnormalities of white matter in patients with bipolar disorder; however, robust conclusions have proven elusive, especially considering some important clinical and demographic factors. In the present study, we performed a quantitative meta-analysis of TBSS studies to elucidate the most consistent white-matter abnormalities in patients with bipolar disorder.We conducted a systematic search up to May 2017 for all TBSS studies comparing fractional anisotropy (FA) between patients with bipolar disorder and healthy controls. We performed anisotropic effect size-signed differential mapping meta-analysis.We identified a total of 22 data sets including 556 patients with bipolar disorder and 623 healthy controls. We found significant FA reductions in the genu and body of the corpus callosum in patients with bipolar disorder relative to healthy controls. No regions of increased FA were reported. In subgroup analyses, the FA reduction in the genu of the corpus callosum retained significance in patients with bipolar disorder type I, and the FA reduction in the body of the corpus callosum retained significance in euthymic patients with bipolar disorder. Meta-regression analysis revealed that the percentage of female patients was negatively correlated with reduced FA in the body of the corpus callosum.Data acquisition, patient characteristics and clinical variables in the included studies were heterogeneous. The small number of diffusion tensor imaging studies using TBSS in patients with bipolar disorder type II, as well as the lack of other clinical information, hindered the application of subgroup meta-analyses.Our study consistently identified decreased FA in the genu and body of the corpus callosum, suggesting that interhemispheric communication may be the connectivity most affected in patients with bipolar disorder.

BACKGROUND AND PURPOSE: Imaging studies have shown that people with schizophrenia exhibit abnormal connectivity termed “dysconnectivity” in several white matter tracts, including the cingulum bundle (CB), corpus callosum (CC), and arcuate fasciculus (AF). This study aimed to elucidate potential contributors to schizophrenia “dysconnectivity.” EXPERIMENTAL APPROACH: Western blot analysis was used to compare protein levels of myelin basic protein, neurofilament heavy, autophagosome marker LC3, and microtubule marker α‐tubulin in post‐mortem human CB, CC, and AF in schizophrenia subjects (SZ) and matched normal controls (NC). Additionally, SZ cases were subdivided by treatment status: off‐medication (OFF) or on‐medication (ON). KEY RESULTS: In the CC, the combined SZ group exhibited less neurofilament heavy protein than the NCs. In the CB, the combined SZ group had similar levels of α‐tubulin protein versus NC, but OFF subjects had increased α‐tubulin protein versus ON and NCs. There were significant correlations between α‐tubulin and all other proteins but only in the CB. The strong negative relationship between α‐tubulin versus myelin basic protein and α‐tubulin versus LC3 in NCs was absent in SZs; coefficients comparison showed significant differences. Preliminary race analyses revealed that African American SZ had less AF α‐tubulin than Caucasian SZ and African American normal controls. CONCLUSIONS AND IMPLICATIONS: The results show a relationship between tract‐ and protein‐specific abnormalities and diagnosis, treatment, and race. These data suggest there is a dysregulation of the relationship between α‐tubulin and the other markers of white matter integrity observed in the CB in schizophrenia.

Prior research on 3-week hydrocephalic rats showed that behavioral deficits and white matter damage could be reduced by treatment with Ca2+ channel blocker nimodipine. We hypothesized that treatment with nimodipine would be also beneficial to young ferrets with kaolin-induced hydrocephalus. Hydrocephalus was induced at 14 days of age and animals were treated either with vehicle, low dose nimodipine (3.2 mg/kg/day), or high dose nimodipine (16 mg/kg/day) for 2 weeks from 38 to 52 days age. Hydrocephalic ferrets developed progressive ventriculomegaly, behavioral changes, and in some cases cortical blindness. These changes were not ameliorated by nimodipine. Histological examination showed damage in periventricular white matter, corpus callosum thinning, axonal damage, reactive astroglial changes, and suppressed cell proliferation compared to non-hydrocephalic controls. Treatment with nimodipine was not beneficial for any of the pathological changes mentioned above; only low dose nimodipine treatment was associated with normalized content of glial fibrillary acidic protein, despite larger ventricles. We conclude that young hydrocephalic ferrets experience behavioral impairments and structural brain damage that are not consistently improved by intermittent nimodipine treatment. Continuous delivery should be considered in further preclinical studies.

Hypomyelination in developing brain is often accompanied by congenital metabolic disorders. Menkes kinky hair disease is an X-linked neurodegenerative disease of impaired copper transport, resulting from a mutation of the Menkes disease gene, a transmembrane copper-transporting p-type ATPase gene (ATP7A). In a macular mutant mouse model, the murine ortholog of Menkes gene (mottled gene) is mutated, and widespread neurodegeneration and subsequent death are observed. Although some biochemical analysis of myelin protein in macular mouse has been reported, detailed histological study of myelination in this mouse model is currently lacking. Since myelin abnormality is one of the neuropathologic findings of human Menkes disease, in this study early myelination in macular mouse brain was evaluated by immunohistochemistry. Two-week-old macular mice and normal littermates were perfused with 4% paraformaldehyde. Immunohistochemical staining of paraffin embedded and vibratome sections was performed using antibodies against either CNPase, cleaved caspase-3 or O4 (marker of immature oligodendrocytes). This staining showed that cerebral myelination in macular mouse was generally hypoplastic and that hypomyelination was remarkable in internal capsule, corpus callosum, and cingulate cortex. In addition, an increased number of cleaved caspase-3 positive cells were observed in corpus callosum and internal capsule. Copper deficiency induced by low copper diet has been reported to induce oligodendrocyte dysfunction and leads to hypomyelination in this mouse model. Taken together, hypomyelination observed in this study in a mouse model of Menkes disease is assumed to be induced by increased apoptosis of immature oligodendrocytes in developing cerebrum, through deficient intracellular copper metabolism.

Background Previous studies have reported MRI abnormalities of the corpus callosum (CC) in patients with bipolar disorder (BD), although only a few studies have directly compared callosal areas in psychotic versus nonpsychotic patients with this disorder. We sought to compare regional callosal areas in a large international multicentre sample of patients with BD and healthy controls. Methods We analyzed anatomic T-1 MRI data of patients with BD-I and healthy controls recruited from 4 sites (France, Germany, Ireland and the United States). We obtained the mid-sagittal areas of 7 CC subregions using an automatic CC delineation. Differences in regional callosal areas between patients and controls were compared using linear mixed models (adjusting for age, sex, handedness, brain volume, history of alcohol abuse/dependence, lithium or antipsychotic medication status, symptomatic status and site) and multiple comparisons correction. We also compared regional areas of the CC between patients with BD with and without a history of psychotic features. Results We included 172 patients and 146 controls in our study. Patients with BD had smaller adjusted mid-sagittal CC areas than controls along the posterior body, the isthmus and the splenium of the CC. Patients with a positive history of psychotic features had greater adjusted area of the rostral CC region than those without a history of psychotic features. Limitations We found small to medium effect sizes, and there was no calibration technique among the sites. Conclusion Our results suggest that BD with psychosis is associated with a different pattern of interhemispheric connectivity than BD without psychosis and could be considered a relevant neuroimaging subtype of BD.

Handedness differentiates patterns of neural asymmetry and interhemispheric connectivity in cortical systems that underpin manual and language functions. Contemporary models of cerebellar function incorporate complex motor behaviour and higher-order cognition, expanding upon earlier, traditional associations between the cerebellum and motor control. Structural MRI defined cerebellar volume asymmetries and correlations with corpus callosum (CC) size were compared in 19 pairs of adult female monozygotic twins strongly discordant for handedness (MZHd). Volume and asymmetry of cerebellar lobules were obtained using automated parcellation.CC area and regional widths were obtained from midsagittal planimetric measurements. Within the cerebellum and CC, neurofunctional distinctions were drawn between motor and higher-order cognitive systems. Relationships amongst regional cerebellar asymmetry and cortical connectivity (as indicated by CC widths) were investigated. Interactions between hemisphere and handedness in the anterior cerebellum were due to a larger right-greater-than-left hemispheric asymmetry in right-handed (RH) compared to left-handed (LH) twins. In LH twins only, anterior cerebellar lobule volumes (IV, V) for motor control were associated with CC size, particularly in callosal regions associated with motor cortex connectivity. Superior posterior cerebellar lobule volumes (VI, Crus I, Crus II, VIIb) showed no correlation with CC size in either handedness group. These novel results reflected distinct patterns of cerebellar-cortical relationships delineated by specific CC regions and an anterior-posterior cerebellar topographical mapping. Hence, anterior cerebellar asymmetry may contribute to the greater degree of bilateral cortical organisation of frontal motor function in LH individuals.

Schizophrenia (SCZ) is a serious neuropsychiatric disorder that manifests through several symptoms from early adulthood. Numerous studies over the last decades have led to significant advances in increasing our understanding of the factors involved in SCZ. For example, mass spectrometry-based proteomic analysis has provided important insights by uncovering protein dysfunctions inherent to SCZ. Here, we present a comprehensive analysis of the nuclear proteome of postmortem brain tissues from corpus callosum (CC) and anterior temporal lobe (ATL). We show an overview of the role of deregulated nuclear proteins in these two main regions of the brain: the first, mostly composed of glial cells and axons of neurons, and the second, represented mainly by neuronal cell bodies. These samples were collected from SCZ patients in an attempt to characterize the role of the nucleus in the disease process. With the ATL nucleus enrichment, we found 224 proteins present at different levels, and 76 of these were nuclear proteins. In the CC analysis, we identified 119 present at different levels, and 24 of these were nuclear proteins. The differentially expressed nuclear proteins of ATL are mainly associated with the spliceosome, whereas those of the CC region are associated with calcium/calmodulin signaling.

Autism spectrum disorder (ASD) is a complex neurodevelopmental condition that occurs within the first 3 years of life, which is marked by social skills and communication deficits along with stereotyped repetitive behavior. Although great efforts have been made to clarify the underlying neuroanatomical abnormalities and brain-behavior relationships in adolescents and adults with ASD, literature is still limited in information about the neurobiology of ASD in the early age of life. Brain images of 50 toddlers with ASD and 28 age, gender, and developmental quotient matched toddlers with developmental delay (DD) (control group) between ages 2 and 3 years were captured using combined magnetic resonance-based structural imaging and diffusion tensor imaging (DTI). Structural magnetic resonance imaging was applied to assess overall gray matter (GM) and white matter (WM) volumes, and regional alterations were assessed by voxel-based morphometry. DTI was used to investigate the white matter tract integrity. Compared with DD, significant increases were observed in ASD, primarily in global GM and WM volumes and in right superior temporal gyrus regional GM and WM volumes. Higher fractional anisotropy value was also observed in the corpus callosum, posterior cingulate cortex, and limbic lobes of ASD. The converging findings of structural and white matter abnormalities in ASD suggest that alterations in neural-anatomy of different brain regions may be involved in behavioral and cognitive deficits associated with ASD, especially in an early age of 2–3 years old toddlers.

Objective: A fine structure of the corpus callosum (CC), consisting of radial lines, is seen in historical anatomical atlases as far back as that of Vicq d'Azyr (1786). This study examines a similar pattern observed in vivo using high-resolution MR images at 7 T. Methods: 8 healthy subjects were examined with 7.0-T MRI. Anatomical images were collected with a gradient echo scan with 0.5-mm isotropic resolution, which were rated for visibility of the radial pattern. In addition, the second eigenvector of the diffusion tensor images was examined. Results: The fine radial lines are detected not only in the sagittal view but also in the axial view of the in vivo MR images. From this, it is likely that these structures are two-dimensional ribbons. Interestingly, and confirming the structural nature of these stripes, the second eigenvector of the diffusion tensor imaging data shows an extremely similar pattern of oriented foliate structure. A similar modular structure involving transient septa has been observed previously in histological sections of human fetal CC. Conclusion: The separate sets of data—the atlas of Klingler, anatomical images and second eigenvector images—all indicate a ribbon-like arrangement of the fibres in the CC. As such, they closely match the structures shown in the drawn atlases of as old as 1786. Advances in knowledge: This ribbon arrangement of fibres in the CC, previously unseen in CT or lower field MRI, can now be observed in vivo. This appears to match over two centuries of ex vivo observations.