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Background: Sex differences in human brain anatomy have been well-documented, though remain significantly underexplored during early development. The neonatal period is a critical stage for brain development and can provide key insights into the role that prenatal and early postnatal factors play in shaping sex differences in the brain. Methods: Here, we assessed on-average sex differences in global and regional brain volumes in 514 newborns aged 0–28 days (236 birth-assigned females and 278 birth-assigned males) using data from the developing Human Connectome Project. We also assessed sex-by-age interactions to investigate sex differences in early postnatal brain development. Results: On average, males had significantly larger intracranial and total brain volumes, even after controlling for birth weight. After controlling for total brain volume, females showed significantly greater total cortical gray matter volumes, whilst males showed greater total white matter volumes. After controlling for total brain volume in regional comparisons, females had significantly increased white matter volumes in the corpus callosum and increased gray matter volumes in the bilateral parahippocampal gyri (posterior parts), left anterior cingulate gyrus, bilateral parietal lobes, and left caudate nucleus. Males had significantly increased gray matter volumes in the right medial and inferior temporal gyrus (posterior part) and right subthalamic nucleus. Effect sizes ranged from small for regional comparisons to large for global comparisons. Significant sex-by-age interactions were noted in the left anterior cingulate gyrus and left superior temporal gyrus (posterior parts). Conclusions: Our findings demonstrate that sex differences in brain structure are already present at birth and remain comparatively stable during early postnatal development, highlighting an important role of prenatal factors in shaping sex differences in the brain. Plain Language Summary: Sex differences in the human brain have attracted substantial scientific and societal interest, but less is known about whether the brain shows sex differences at birth. Studying sex differences at birth can help to understand how prenatal factors (e.g., hormone levels before birth) and early postnatal factors (e.g., exposure to the sensory environment and caregiver interactions) contribute to shaping sex differences in the brain. In this study, we investigated on-average sex differences in brain structure in a large sample of newborn infants shortly after birth. Our findings show that several on-average differences are present at birth, suggesting that factors before birth play an important role in initiating sex differences in the brain. Highlights: At birth, males on average show significantly increased total brain volumes compared to females even after accounting for sex differences in birth weight. After controlling for total brain volume, females on average show significantly increased total cortical gray matter volumes, while males show increased total white matter volumes. After controlling for total brain volume, significant on-average sex differences are observed in regions such as the corpus callosum (F > M), bilateral parietal lobes (F > M), left anterior cingulate gyrus (F > M), left caudate nucleus (F > M), and right medial and inferior temporal gyri (M > F). Fewer global and regional volumes showed significant sex-by-age interactions, except for the left anterior cingulate gyrus (F > M) and left superior temporal gyrus (M > F). Several sex differences that have previously been observed later in development are present from birth, emphasising the key role that prenatal factors play in initiating sex differences in the brain. [ABSTRACT FROM AUTHOR]

Objective Methods Results Significance Deep brain stimulation, particularly low‐frequency stimulation (LFS) targeting fiber tracts, has emerged as a potential therapy for drug‐resistant epilepsy (DRE) and for generalized epilepsy, both of which pose significant treatment challenges. LFS diffusely suppresses seizures in the cortex when applied to fiber tracts like the corpus callosum (CC). Nevertheless, the specific processes responsible for suppressing epileptic activity in the cortex induced by LFS remain unclear. This study investigates the mechanisms underlying the antiepileptic effect in the cortex of LFS of the CC in coronal rodent brain slices.An in vitro 4‐aminopyridine (4‐AP) seizure model of cortical seizures was generated. LFS stimulation parameters were optimized to provide the largest antiepileptic effect in the cortex when applied to the CC. Changes to tissue excitability and percent time spent seizing were measured due to LFS in artificial cerebrospinal fluid, 4‐AP, and in the presence of various specific and nonspecific γ‐aminobutyric acid type B (GABAB) and slow afterhyperpolarization (sAHP) antagonists.LFS significantly suppressed seizure activity in the cortex, with an optimal frequency of 5 Hz (76.5%). Tissue excitability during LFS reduces across a wide range of interstimulus intervals, with a maximum reduction at 200 ms. Notably, the tissue excitability remains depressed at 1000 ms. LFS, in the presence of GABAB antagonists, had diminished seizure reduction (<15%) and failed to reduce tissue excitability in the 50–400‐ms range. Tissue excitability measured with paired pulses in the 600–1000‐ms range was depressed in the presence of GABAB antagonists, suggesting a different antiepileptic mechanism was active. Upon administering sAHP antagonists, seizure reduction was once again diminished (<15%). Upon administration of both sAHP and GABAB antagonists, LFS failed to provide any meaningful seizure reduction (<5%).LFS of the CC provides an antiepileptic effect in the cortex with well‐understood mechanisms and could be an alternative to surgical intervention for patients suffering from DRE. [ABSTRACT FROM AUTHOR]

We determined the intersubject association between the rhythmic entrainment abilities of human subjects during a synchronization-continuation tapping task (SCT) and the macro- and microstructural properties of their superficial (SWM) and deep (DWM) white matter. Diffusion-weighted images were obtained from 32 subjects who performed the SCT with auditory or visual metronomes and five tempos ranging from 550 to 950 ms. We developed a method to determine the density of short-range fibers that run underneath the cortical mantle, interconnecting nearby cortical regions (U-fibers). Notably, individual differences in the density of U-fibers in the right audiomotor system were correlated with the degree of phase accuracy between the stimuli and taps across subjects. These correlations were specific to the synchronization epoch with auditory metronomes and tempos around 1.5 Hz. In addition, a significant association was found between phase accuracy and the density and bundle diameter of the corpus callosum (CC), forming an interval-selective map where short and long intervals were behaviorally correlated with the anterior and posterior portions of the CC. These findings suggest that the structural properties of the SWM and DWM in the audiomotor system support the tapping synchronization abilities of subjects, as cortical U-fiber density is linked to the preferred tapping tempo and the bundle properties of the CC define an interval-selective topography. [ABSTRACT FROM AUTHOR]

Background: Marchiafava-Bignami disease (MBD) is an exceptionally rare condition, a fact that should pique the professional curiosity of medical practitioners. In recent years, case reports of this disease have been infrequent, and no comprehensive analysis or summary of the characteristics of the published cases has been conducted. Methods: We collected the medical records of three patients treated at our hospital from March 2022 to March 2023. Furthermore, we searched PubMed for "case reports" from January 2017 to March 2023 and included 30 cases. By retrospectively analyzing these 33 cases, we summarized the characteristics of the disease. Results: Based on our analysis, we found that MBD primarily affects middle-aged men and typically has an acute or subacute onset, with the primary clinical manifestations being disturbances of consciousness, speech disorders, cognitive impairment, and psychiatric or behavioral abnormalities, often leading to misdiagnosis of psychiatric disorders. Most patients have a history of alcohol consumption or malnutrition. Head CT or MRI revealed symmetric lesions in the corpus callosum, with the splenium being the most commonly affected area. Lesions might also involve white matter outside the corpus callosum, and a wider range of lesions suggested a poor prognosis. However, the prognosis is generally favorable with timely and adequate administration of B vitamins, providing reassurance to medical professionals and patients alike. Conclusion: The early recognition and treatment of Marchiafava-Bignami disease are paramount, as they can significantly improve the prognosis. This underscores the critical need for prompt clinical intervention in the early stages of the disease, instilling a sense of urgency and significance in the work of medical professionals. [ABSTRACT FROM AUTHOR]

Major depressive disorder (MDD) is a prevalent and disabling mood disorder, thought to be linked with brain white matter (WM) alterations. Prior diffusion tensor imaging (DTI) studies have reported inconsistent changes in fractional anisotropy (FA) across different brain regions in MDD patients. However, none of these studies utilized raw t-map data for WM meta-analysis in MDD. Our study aims to address this gap by conducting a whole-brain-based meta-analysis of FA in MDD using Seed-based d mapping via permutation of subject images (SDM-PSI), combining reported peak coordinates and raw statistical parametric maps. Following PRISMA guidelines, we performed a systematic search and meta-analysis to compare FA in MDD patients with healthy controls (HC). Our goal was to identify WM abnormalities in MDD, using SDM, which could shed light on the disorder's pathogenesis. The meta-analysis included 39 studies with 3696 participants (2094 with MDD, 1602HC). It revealed that MDD patients, in comparison to HC, have lower FA in the corpus callosum (CC) and anterior thalamic projections (ATP). Subgroup analyses indicated that the CC is a more stable pathogenic factor in MDD. Meta-regression analyses showed no linear correlation between the mean age, percentage of female patients, duration of depression, and FA abnormalities. This suggests that WM impairments in interhemispheric connections and anterior thalamocortical circuits are significant in the pathogenesis of MDD. • A whole-brain meta-analysis was performed using SDM-PSI, combining peak coordinates and raw t-map. • Patients with MDD relative to healthy controls have lower FA in the CC and anterior ATP. • The VBA method may be more sensitive than the TBSS method for white matter meta-analysis of MDD. • Subgroup analyses indicated that the CC is a more stable pathogenic factor in MDD. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegia (HSP) with thin corpus callosum can be due to a variety of genetic causes, the most common of which are biallelic variants in SPG11 (HSP11). Only six cases of neuropathologic examination of HSP11 have been reported. Here we present neuropathological findings in another case of HSP11 with novel mutation (homozygous c.6439_6442del) and clinical features of three additional cases of HSP11. These four cases of HSP11 had similar disease courses with prominent lower extremity weakness and spasticity but varied cognitive symptoms and brain magnetic resonance imaging (MRI) findings. Neuropathological examination of one case included ex vivo MRI of the cerebrum, histologic and immunohistochemical evaluation, and Western blot for SPG11. The case was notable for a small cerebrum with decreased volume of cortex, white matter, and deep gray nuclei. The corpus callosum was thin, and the substantia nigra showed marked pallor. Microscopically, the cortex had normal lamination and mild loss of neurons with mild gliosis, the corpus callosum was thin with limited gliosis, and the substantia nigra had marked decrease in neurons and pigment, with minimal gliosis. In contrast, the basal ganglia, thalamus, and spinal cord (anterior horns, corticospinal, and spinocerebellar tracts) had prominent neuron loss and gliosis. Myelin‐laden macrophages were found in multiple sites but were most common in the corpus callosum. No hyperphosphorylated tau or TDP‐43 aggregates, Lewy bodies, or amyloid β plaques were found. Compared to control, SPG11 was absent in HSP11 brain and markers of autophagy were elevated by Western blot. Comparison with prior reports of HSP with thin corpus callosum and HSP11 demonstrates a disease with a broad range of structural changes of the brain, including features of abnormal development and degeneration. [ABSTRACT FROM AUTHOR]

Background: CSF1R-related leukoencephalopathy is a type of autosomal dominant leukodystrophy caused by mutations in the colony stimulating factor 1 receptor (CSF1R) gene. Subcortical ischemic vascular dementia (SIVaD), which is caused by cerebral small vessel disease, is similar to CSF1R-related leukoencephalopathy in that it mainly affects subcortical white matter. In this study, we compared the patterns of white matter hyperintensity (WMH) and cortical thickness in CSF1R-related leukoencephalopathy with those in SIVaD. Methods: Fourteen patients with CSF1R-related leukoencephalopathy and 129 with SIVaD were retrospectively recruited from three tertiary medical centers. We extracted and visualized WMH data using voxel-based morphometry to compare the WMH distributions between the two groups. Cortical thickness was measured using a surface-based method. Statistical maps of differences in cortical thickness between the two groups were generated using a surface model, with age, sex, education, and intracranial volume as covariates. Results: Predominant distribution of WMH in the CSF1R-related leukoencephalopathy group was in the bilateral frontal and parietal areas, whereas the SIVaD group showed diffuse WMH involvement in the bilateral frontal, parietal, and temporal areas. Compared with the SIVaD group, the CSF1R-related leukoencephalopathy group showed more severe corpus callosum atrophy (CCA) and widespread cortical thinning. Conclusions: To our knowledge, this is the first study using the automated MR measurement to capture WMH, cortical thinning, and CCA with signal changes in CSF1R-related leukoencephalopathy. It provides new evidence regarding differences in the patterns of WMH distribution and cortical thinning between CSF1R-related leukoencephalopathy and SIVaD. [ABSTRACT FROM AUTHOR]

Aim Methods Results Conclusion The studies have shown that infants with prenatal OMT exposure had smaller brain volumes than non‐exposed controls, but long‐term outcome data are lacking. We examined 5–13‐year‐old OMT‐exposed children with brain MRI and tested motor and visual‐motor functions and possible associations between brain morphology and outcome.To this retrospective cohort study, we recruited 55 children with prenatal OMT exposure and 59 age‐ and gender‐matched controls. They were examined with brain MRI, Movement‐ABC and Beery‐VMI. MRI images were processed with the Free Surfer® software to obtain volumetrics and estimates of cortical surface area and thickness. We used a general linear regression model (GLM) to calculate group differences.The children in the OMT group had smaller mean total intracranial volume (ICV), 1407 cm3 (CI 95% 1379–1434) versus 1450 cm3 (CI 95% 1423–1476) in the control group (p = 0.026). After adjusting for ICV, significant group differences persisted for volumes of amygdala, basal ganglia and mid‐posterior part of corpus callosum. Cortical surface area was smaller in the left caudal middle frontal gyrus and the right inferior parietal lobule in the OMT‐group. Visual‐motor function was significantly correlated with ICV.Prenatal OMT exposure may alter early brain development with possible negative long‐term functional consequences. [ABSTRACT FROM AUTHOR]

High‐fat diet (HFD)‐induced obesity induces peripheral inflammation and hypothalamic pathogenesis linking the activation of astrocytes and microglia. Clinical evidence indicates a positive correlation between obesity and psychiatric disorders, such as depression. The connectivity of the frontal‐striatal (FS) circuit, involving the caudate putamen (CPu) and anterior cingulate cortex (ACC) within the prefrontal cortex (PFC), is known for its role in stress‐induced depression. Thus, there is a need for a thorough investigation into whether chronic obesity‐induced gliosis, characterized by the activation of astrocytes and microglia, in these brain regions of individuals with chronic obesity. The results revealed increased S100β+ astrocytes and Iba1+ microglia in the CPu and ACC of male obese mice, along with immune cell accumulation in meningeal lymphatic drainage. Activated GFAP+ astrocytes and Iba1+ microglia were observed in the corpus callosum of obese mice. Gliosis in the CPu and ACC was linked to elevated cleaved caspase‐3 levels, indicating potential neural cell death by chronic HFD feeding. There was a loss of myelin and adenomatous polyposis coli (APC)+ oligodendrocytes (OLs) in the corpus callosum, an area known to be linked with injury to the CPu. Additionally, reduced levels of aquaporin‐4 (AQP4), a protein associated within the glymphatic systems, were noted in the CPu and ACC, while ciliary neurotrophic factor (CNTF) gene expression was upregulated in these brain regions of obese mice. The in vitro study revealed that high‐dose CNTF causing a trend of reduced astrocytic AQP4 expression, but it significantly impaired OL maturation. This pathological evidence highlights that prolonged HFD consumption induces persistent FS gliosis and demyelination in the corpus callosum. An elevated level of CNTF appears to act as a potential regulator, leading to AQP4 downregulation in the FS areas and demyelination in the corpus callosum. This cascade of events might contribute to neural cell damage within these regions and disrupt the glymphatic flow. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation To delineate the characteristics of stroke‐like episodes (SLEs) in patients with adult‐onset neuronal intranuclear inclusion disease (NIID) and to compare these characteristics with those of patients with MELAS.Twenty‐three adult‐onset NIID patients who presented with acute or subacute brain disorders and 13 late‐onset MELAS patients were enrolled in the study. Patients with NIID were categorized into the SLEs group and the encephalopathy‐like episodes (ELEs) group according to the associated stroke‐like lesions (SLLs) findings. Clinical characteristics were compared between the SLEs group and the ELEs group among NIID patients and between NIID patients with SLEs and MELAS patients.Eleven (47.8%) NIID patients who manifested acute or subacute brain disorders had detectable associated SLLs and were categorized into SLEs group. SLEs patients were more likely to report fever, headache, and seizures instead of sleep disorders than ELEs patients. Four (36.4%) NIID patients with SLEs absence of diagnostic or suggestive NIID imaging features. The clinical manifestations, laboratory test results, and neuroimaging and muscle biopsy histological features of NIID patients with SLEs majorly overlapped with those of late‐onset MELAS patients. Older age at the first SLE (OR [95% CI], 1.203 [1.045–1.384]), symptoms of movement disorders on admission (OR [95% CI], 9.625 [1.378–67.246]), and white matter hyperintensity in corpus callosum (OR [95% CI], 16.00 [1.542–166.46]) associated with the NIID diagnosis in patients with SLEs.NIID patients with SLEs exhibit evident features of mitochondrial disorders. Interventions aimed at mitochondrial dysfunction might be a promising therapeutic approach for treating this disease. [ABSTRACT FROM AUTHOR]

Studies have demonstrated associations between cumulative concussion and repetitive head impact exposure (RHI) through contact sports with white matter (WM) alterations later in life. The course of WM changes associated with exposure earlier in the lifespan is unclear. This study investigated alterations in white matter (WM hyperintensity [WMH] volume and microstructural changes) associated with concussion and RHI exposure from adolescence to early midlife, as well as the interaction between exposure and age cohort (i.e., adolescent/young adult compared with early midlife athlete cohorts) on WM outcomes. Participating football players included an adolescent/young adulthood cohort (n = 82; Mage = 18.4 ± 1.7) and an early midlife cohort (37 former collegiate players approximately 15 years removed from sport; Mage = 37.7 ± 1.4). Years of football participation and number of prior concussions were exposures of interest. White matter outcomes included log-transformed manually segmented total WMH volume and neurite orientation dispersion and density imaging metrics of microstructure/organization (isotropic volume fraction [Viso], intracellular volume fraction [Vic], and orientation dispersion [OD]). Regression models were fit to test the effects of concussion history, years of football participation, and age cohort by years of football participation with WM outcomes. Spearman's correlations assessed associations between significant WM metrics and measures of cognitive and psychological function. A significant age cohort by years of participation effect was observed for whole brain white matter OD, B = −0.002, SE = 0.001, p = 0.001. The interaction was driven by a negative association between years of participation and OD within the younger cohort, B = −0.001, SE = 0.0004, p = 0.008, whereas a positive association between participation and OD in the early midlife cohort, B = 0.001, SE = 0.0003, p = 0.039, was observed. Follow-up ROI analyses showed significant interaction effects for OD in the body of the corpus callosum, genu of the corpus callosum, cingulum, inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and posterior thalamic radiation (p values <0.05). Greater concussion history was significantly associated with greater Viso in the early midlife cohort, B = 0.001, SE = 0.0002, p = 0.010. Years of participation and concussion history were not associated with WMH volume, p values >0.05. Performance on a measure of executive function was significantly associated with years of participation, ρ = 0.34, p = 0.04, and a trend was observed for OD, ρ = 0.28, p = 0.09 in the early midlife cohort only. The global characterization of white matter changes associated with years of football participation were broadly similar and stable from adolescence through early midlife (i.e., microstructural alterations, but not macroscopic lesions). An inverse association between years of participation and orientation dispersion across age cohorts may represent a process of initial recovery/reorganization proximal to sport, followed by later reduction of white matter coherence. [ABSTRACT FROM AUTHOR]

How maximal safe resection of glioblastoma (GBM) is implemented in the clinical setting remains understudied. Here, we utilized a survey-based approach to understand physician perspectives on this matter. Scenarios involving GBMs were presented to physicians who were asked to select from planned subtotal resection, gross total resection (GTR), medical therapy only, or palliative care. Demographic, experience, and Likert scales of value assessment were collected. In the scenario involving a corpus callosum GBM, 2.33% opted for GTR. For a right frontal GBM, 91.7% opted for GTR. In contrast, only 30.8% chose GTR of a right motor strip GBM (P < 0.001). When presented with a left motor strip GBM, fewer respondents (12.7%, P < 0.001) opted for GTR. Physicians who placed a high value on preserving physical independence were more likely to forgo GTR for right motor GBMs (hazard ratio = 0.068, 95% confidence interval: 0.47–0.97, P = 0.035), and physicians who placed a high value on their faith were more likely to opt for surgical treatments that differ from the general consensus, for instance opting for GTR of the corpus callosum GBM (hazard ratio = 4.18, 95% confidence interval: 1.63–10.74, P = 0.003). No other associations were found between the choice for GTR and other variables collected. Our results suggest that while maximal safe resection remains a guiding principle for GBM resection, physician preference in terms of the extent of resection varies significantly as a function of tumor location and personal values. [ABSTRACT FROM AUTHOR]

This study reports two cases of Global Rostral Midbrain Syndrome (GRMS) and corpus callosum infarction in the context of shunt overdrainage caused by obstructive hydrocephalus due to aqueductal stenosis. We detail how thorough clinical evaluation and appropriate investigation helped avoid a coma misdiagnosis and describe the excellent response to pharmacological treatment and successful neurorehabilitation in both cases. We analyze the cognitive profile of patients with GRMS, a rare condition that mimics disorders such as coma and progressive supranuclear palsy at various stages. In conscious cases, GRMS typically presents with parkinsonian syndrome, Parinaud syndrome, and cognitive issues. The awareness of this rare complication of shunt overdrainage facilitates more accurate diagnosis and better management. [ABSTRACT FROM AUTHOR]

Glial cell dysfunction results in myelin loss and leads to subsequent motor and cognitive deficits throughout the demyelinating disease course.Therefore, in various therapeutic approaches, significant attention has been directed toward glial-restricted progenitor (GRP) transplantation for myelin repair and remyelination, and numerous studies using exogenous GRP injection in rodent models of hypomyelinating diseases have been performed. Previously, we proposed the transplantation of canine glial-restricted progenitors (cGRPs) into the double-mutant immunodeficient, demyelinated neonatal shiverer mice (shiverer/Rag2−/−). The results of our previous study revealed the myelination of axons within the corpus callosum of transplanted animals; however, the extent of myelination and lifespan prolongation depended on the transplantation site (anterior vs. posterior). The goal of our present study was to optimize the therapeutic effect of cGRP transplantation by using a multisite injection protocol to achieve a broader dispersal of donor cells in the host and obtain better therapeutic results. Experimental analysis of cGRP graft recipients revealed a marked elevation in myelin basic protein (MBP) expression and prominent axonal myelination across the brains of shiverer mice. Interestingly, the proportion of galactosyl ceramidase (GalC) positive cells was similar between the brains of cGRP recipients and control mice, implying a natural propensity of exogenous cGRPs to generate mature, myelinating oligodendrocytes. Moreover, multisite injection of cGRPs improved mice survival as compared to non-transplanted animals. [ABSTRACT FROM AUTHOR]

Subtle motor signs are a common feature in children with attention‐deficit/hyperactivity disorder (ADHD). It has long been suggested that white matter abnormalities may be involved in their presentation, though no study has directly probed this question. The aim of this study was to investigate the relationship between white matter organization and the severity of subtle motor signs in children with and without ADHD. Participants were 92 children with ADHD aged between 8 and 12 years, and 185 typically developing controls. Subtle motor signs were examined using the Physical and Neurological Examination for Soft Signs (PANESS). Children completed diffusion MRI, and fixel‐based analysis was performed after preprocessing. Tracts of interest were delineated using TractSeg including the corpus callosum (CC), the bilateral corticospinal tracts (CST), superior longitudinal fasciculus, and fronto‐pontine tracts (FPT). Fiber cross‐section (FC) was calculated for each tract. Across all participants, lower FC in the CST was associated with higher PANESS Total score (greater motor deficits). Within the PANESS, similar effects were observed for Timed Left and Right maneuvers of the hands and feet, with lower FC of the CST, CC, and FPT associated with poorer performance. No significant group differences were observed in FC in white matter regions associated with PANESS performance. Our data are consistent with theoretical accounts implicating white matter organization in the expression of motor signs in childhood. However, rather than contributing uniquely to the increased severity of soft motor signs in those with ADHD, white matter appears to contribute to these symptoms in childhood in general. [ABSTRACT FROM AUTHOR]

Leukodystrophies are rare genetic white matter disorders that have been regarded as mainly occurring in childhood. This perception has been altered in recent years, as a growing number of leukodystrophies have been described as having an onset in adulthood. Still, many adult patients presenting with white matter changes remain without a specific molecular diagnosis. We describe a novel adult onset leukodystrophy in 16 patients from eight families carrying one of four different stop-gain or frameshift dominant variants in the CST3 gene. Clinical and radiological features differ markedly from the previously described Icelandic cerebral amyloid angiopathy found in patients carrying p.Leu68Asn substitution in CST3. The clinical phenotype consists of recurrent episodes of hemiplegic migraine associated with transient unilateral focal deficits and slowly progressing motor symptoms and cognitive decline in mid to older adult ages. In addition, in some cases acute onset clinical deterioration led to a prolonged episode with reduced consciousness and even early death. Radiologically, pathognomonic changes are found at typical predilection sites involving the deep cerebral white matter sparing a periventricular and directly subcortical rim, the middle blade of corpus callosum, posterior limb of the internal capsule, middle cerebellar peduncles, cerebral peduncles and specifically the globus pallidus. Histopathologic characterization in two autopsy cases did not reveal angiopathy, but instead micro- to macrocystic degeneration of the white matter. Astrocytes were activated at early stages and later displayed severe degeneration and loss. In addition, despite the loss of myelin, elevated numbers of partly apoptotic oligodendrocytes were observed. A structural comparison of the variants in CST3 suggests that specific truncations of cystatin C result in an abnormal function, possibly by rendering the protein more prone to aggregation. Future studies are required to confirm the assumed effect on the protein and to determine pathophysiologic downstream events at the cellular level. [ABSTRACT FROM AUTHOR]

Introduction: LMNB1-related autosomal dominant leukodystrophy (ADLD) is a slowly progressive neurodegenerative disorder caused by overexpression of LMNB1. We retrospectively reviewed charts of all ADLD patients seen at Mayo Clinic. Methods: All available data from molecularly confirmed ADLD patients was reviewed. Results: Of eight patients identified, three were male. Age at symptom onset ranged from 33 to 64 years. In males, the first symptom was erectile dysfunction (2/3) or neurogenic bladder (1/3) and, in females, weakness (3/5), bladder dysfunction (2/5), or depression (1/5). Diagnostic delay from symptom onset was a median of 6 (IQR 2.3–10) years. Other reported symptoms included cognitive difficulties (8/8), fatigue (7/8), sleep issues (4/8), mood disturbances (5/8), tremor (4/8), and migraine (4/8). Family history was positive in 6. All eight patients had LMNB1 duplication. Eighteen brain MRIs were reviewed from 7 patients. All showed symmetric confluent T2W deep cerebral and periventricular white matter hyperintensities with involvement of the posterior limb of the internal capsule, corpus callosum, corticospinal tract in brain stem, and superior and middle cerebellar peduncles. Seven spine MRIs from six patients showed moderate diffuse atrophy of the spinal cord. Conclusion: Typical clinical symptoms and characteristic MRI changes should prompt genetic testing for ADLD. [ABSTRACT FROM AUTHOR]

This article explores the neurobiological aspects of schizophrenia, with a focus on the reduced functioning of the dorsolateral prefrontal cortex (DLPFC) and the loss of spines and dendrites on pyramidal cells in deep layer III of the DLPFC in individuals with schizophrenia. The study examines the transcriptional changes in macaque DLPFC during different stages of development and identifies the callosal projection (CP) cells as particularly vulnerable to genetic or environmental factors that cause dendritic spine loss during adolescence. The article also discusses the impact of stress on DLPFC function and its potential implications for understanding the causes of schizophrenia. Additionally, the study explores the expression of potassium channels in layer III spines and their potential role in dendritic spine loss, suggesting that high expression of SK3 channels in CUX2B pyramidal cells may contribute to overpruning of dendritic spines. The authors also speculate on the involvement of PACAP in driving spine loss through its effects on signaling pathways. Overall, these findings provide valuable insights into the molecular and connectional properties of cells affected in schizophrenia. [Extracted from the article]

Hereditary spastic paraplegias (HSPs) are a genetically heterogeneous group of neurodegenerative disorders clinically characterized by progressive lower limb spasticity with pyramidal weakness. Around a dozen potential molecular mechanisms are recognized. Childhood HSP is a significant diagnostic challenge in clinical practice. Mutations in AP5Z1 , which are associated with spastic paraplegia type 48 (SPG48), are extremely rare and seldom described in children. We report the clinical, radiologic, and molecular studies performed in a child harboring novel biallelic mutations in AP5Z1. The child presented a neurodevelopmental disorder with slight lower limb pyramidal signs. Brain magnetic resonance imaging (MRI) showed minimal white matter changes in the frontal horns of the lateral ventricles and a normally shaped corpus callosum. Western blotting in cultured skin fibroblasts indicated reduced protein expression, which confirmed the genetic diagnosis and framed this as a case of protein reduction in a context of impaired autophagy. Our findings expand the spectrum of phenotypes associated with mutations in AP5Z1 , highlighting their clinical and pathophysiologic overlap with lysosomal storage disorders. SPG48 should be considered in the differential diagnosis of neurodevelopmental disorders even when pyramidal signs are minimal and brain MRI not fully informative. [ABSTRACT FROM AUTHOR]

In the field of autism spectrum disorder (ASD), research on functional connectivity between gray matter and white matter remains under-researched. To address this gap, this study innovatively introduced a nested cross-validation method that integrates gray-white matter functional connectivity with an F-Score algorithm. This method calculates the correlation based on signals extracted from functional magnetic resonance imaging data using gray matter and white matter brain region templates. After applying the method to a New York University Langone Medical Center dataset consisting of 55 individuals with high-functioning ASD and 52 healthy subjects, we achieved a classification accuracy of 72.94%. This study found abnormal functional connectivity, primarily involving the left anterior prefrontal cortex and right superior corona radiata, left retrosplenial cortex and left superior corona radiata, as well as the left ventral anterior cingulate cortex and body of corpus callosum. Besides, we discovered that these abnormal connections are closely related to social impairment and restrictive and repetitive behaviors in ASD. In conclusion, this study provides a gray-white matter functional connectivity perspective for the diagnosis and understanding of ASD. • Using functional connectivity between the white matter and gray matter of the brain as features. • Using F-Score and nested cross-validation method for feature extraction. • A total of 38 Gy-white matter FC features were extracted, with some of these features showing correlation with the severity of social impairments and restricted and repetitive behaviors in ASD. [ABSTRACT FROM AUTHOR]

Objective: Many patients with long COVID experience neurological and psychological symptoms. Signal abnormalities on MR images in the corpus callosum have been reported. Knowledge about the metabolic profile in the splenium of the corpus callosum (CCS) may contribute to a better understanding of the pathophysiology of long COVID. Materials and methods: Eighty-one subjects underwent proton MR spectroscopy examination. The metabolic concentrations of total N-acetylaspartate (NAA), choline-containing compounds (Cho), total creatine (Cr), myo-inositol (mI), and NAA/Cho in the CCS were statistically compared in the group of patients containing 58 subjects with positive IgG COVID-19 antibodies or positive SARS-CoV-2 qPCR test at least two months before the MR and the group of healthy controls containing 23 subjects with negative IgG antibodies. Results: An age-dependent effect of SARS-CoV-2 on Cho concentrations in the CCS has been observed. Considering the subjective threshold of age = 40 years, older patients showed significantly increased Cho concentrations in the CCS than older healthy controls (p = 0.02). NAA, Cr, and mI were unchanged. All metabolite concentrations in the CCS of younger post-COVID-19 patients remained unaffected by SARS-CoV-2. Cho did not show any difference between symptomatic and asymptomatic patients (p = 0.91). Discussion: Our results suggest that SARS-CoV-2 disproportionately increases Cho concentration in the CCS among older post-COVID-19 patients compared to younger ones. The observed changes in Cho may be related to the microstructural reorganization in the CCS also reported in diffusion measurements rather than increased membrane turnover. These changes do not seem to be related to neuropsychological problems of the post-COVID-19 patients. Further metabolic studies are recommended to confirm these observations. [ABSTRACT FROM AUTHOR]

The corpus callosum, a major white matter tract in the brain, undergoes age-related functional changes. To extend our investigation of age-related gene expression dynamics in the mouse corpus callosum, we compared RNA-seq data from 2 week-old and 12 week-old wild-type C57BL/6 J mice and identified the differentially expressed genes (e.g., Marcksl1, Chst3, C4b, Neat1, Ndrg1, Emid1, etc.) between these ages. Interestingly, we found that genes highly expressed in myelinating oligodendrocytes were upregulated in 12 week-old mice compared to 2 week-old mice, while genes highly expressed in oligodendrocyte precursor cells (OPCs) and newly formed oligodendrocytes were downregulated. Furthermore, by comparing these genes with the datasets from 20 week-old and 96 week-old mice, we identified novel sets of genes with age-dependent variations in the corpus callosum. These gene expression changes potentially affect key biological pathways and may be closely linked to age-related neurological disorders, including dementia and stroke. Therefore, our results provide an additional dataset to explore age-dependent gene expression dynamics of oligodendrocyte lineage cells in the corpus callosum. [ABSTRACT FROM AUTHOR]

Demyelination occurs widely in the central nervous system (CNS) neurodegenerative diseases, especially the multiple sclerosis (MS), which with a complex and inflammatory lesion microenvironment inhibiting remyelination. Sirtuin6 (SIRT6), a histone/protein deacetylase is of interest for its promising effect in transcriptional regulation, cell cycling, inflammation, metabolism and longevity. Here we show that SIRT6 participates in the remyelination process in mice subjected to LPC-induced demyelination. Using pharmacological SIRT6 inhibitor or activator, we found that SIRT6 modulated LPC-induced damage in motor or cognitive function. Inhibition of SIRT6 impaired myelin regeneration, exacerbated neurological deficits, and decreased oligodendrocyte precursor cells (OPCs) proliferation and differentiation, whereas activation of SIRT6 reversed behavioral performance in mice, demonstrating a beneficial effect of SIRT6. Importantly, based on RNA sequencing analysis of the corpus callosum tissues, it was further revealed that SIRT6 took charge in regulation of glial activation during remyelination, and significant alterations in CHI3L1 were obtained, a glycoprotein specifically secreted by astrocytes. Impaired proliferation and differentiation of OPCs could be induced in vitro using supernatants from reactive astrocyte, especially when SIRT6 was inhibited. Mechanistically, SIRT6 regulates the secretion of CHI3L1 from reactive astrocytes by histone-H3-lysine-9 acetylation (H3K9Ac). Adeno-associated virus-overexpression of SIRT6 (AAV-SIRT6-OE) in astrocytes improved remyelination and functional recovery after LPC-induced demyelination, whereas together with AAV-CHI3L1-OE inhibits this therapeutic effect. Collectively, our data elucidate the role of SIRT6 in remyelination and further reveal astrocytic SIRT6/CHI3L1 as the key regulator for improving the remyelination environment, which may be a potential target for MS therapy. [ABSTRACT FROM AUTHOR]

Purpose: GM1-gangliosidosis (GM1) leads to extensive neurodegenerative changes and atrophy that precludes the use of automated MRI segmentation techniques for generating brain volumetrics. We developed a standardized segmentation protocol for brain MRIs of patients with type II GM1 and then assessed the inter- and intra-rater reliability of thismethodology. The volumetric data may be used as a biomarker of disease burden and progression, and standardized methodology may support research into the natural history of the disease which is currently lacking in the literature. Approach: Twenty-five brain MRIs were included in this study from 22 type II GM1 patients of which 8 were late-infantile subtype and 14 were juvenile subtype. The following structures were segmented by two rating teams on a slice-by-slice basis: whole brain, ventricles, cerebellum, lentiform nucleus, thalamus, corpus callosum, and caudate nucleus. The inter- and intra-rater reliability of the segmentationmethod was assessed with an intraclass correlation coeffcient as well as Sorensen-Dice and Jaccard coeffcients. Results: Based on the Sorensen-Dice and Jaccard coeffcients, the inter- and intra-rater reliability of the segmentation method was significantly better for the juvenile patients compared to late-infantile (p < 0.01). In addition, the agreement between the two rater teams and within themselves can be considered good with all p-values < 0.05. Conclusions: The standardized segmentation approach described here has good inter- and intra-rater reliability and may provide greater accuracy and reproducibility for neuromorphological studies in this group of patients and help to further expand our understanding of the natural history of this disease. [ABSTRACT FROM AUTHOR]

In 1969 Joseph Bogen, a colleague of Roger Sperry and the neurosurgeon who performed commissurotomy on Sperry's "split-brain" study participants, wrote an article subtitled "The Corpus Callosum and Creativity." The article argued for the critical role of the corpus callosum and hemispheric specialization in creativity. Building on a four-stage model of creativity (learning, incubation, illumination, refinement) and Sperry's innovative studies, the Bogens posited that in the intact brain, creativity relies on two opposing functions of the corpus callosum: (a) interhemispheric inhibition to facilitate simultaneous and independent activity of uniquely-specialized processing centers during learning and incubation and (b) interhemispheric facilitation to support the increased bi-hemispheric integration and coordination which produces illumination. This article revisits the Bogens' theory considering scientific discoveries over the past 50 years. We begin by reviewing relevant findings from split-brain studies, and then briefly consider findings from studies that examine the association of creativity with callosal structure and function in neurotypical participants. Finally, we provide an in-depth discussion of creativity in persons with agenesis of the corpus callosum (ACC)--the congenital absence of the corpus callosum. These three lines of inquiry strongly support the theory suggested by Bogen and Bogen in 1969 and provide further clarification regarding the critical and unique role of the corpus callosum in creative cognition. [ABSTRACT FROM AUTHOR]

Resection of a glioma from the dorsomedial frontal lobe, including the supplementary motor area (SMA), can result in postoperative SMA syndrome. SMA syndrome may occur during awake craniotomies. However, it is often difficult to intraoperatively distinguish between motor dysfunction due to pyramidal tract damage from that due to SMA syndrome. Patients with suspected intraoperative SMA syndrome are indifferent to their surroundings, have stiff facial muscles, and maintain a fixed gaze. We defined this condition as "apathetic look." The present study aimed to investigate whether intraoperative "apathetic look" is useful for identifying intraoperative SMA syndrome in patients with glioma close to motor-related areas, including the SMA, during awake craniotomy. This study included 33 consecutive patients with glioma included in the SMA. We excluded patients whose tumors extended to motor-related areas. We also assessed whether intraoperative SMA syndrome occurred in each patient. We evaluated the correlation between the occurrence of intraoperative SMA syndrome and various clinical factors, including intraoperative "apathetic look." Of the 33 patients, 12 had intraoperative SMA syndrome. Intraoperative "apathetic look" showed strong correlation with intraoperative SMA syndrome (p < 0.0001). Additionally, higher extent of resection (EOR) and resection of the corpus callosum showed a significantly higher incidence of intraoperative "apathetic look." All 12 patients with intraoperative SMA syndrome showed intraoperative "apathetic look" and recovered from SMA syndrome with high EOR. In conclusion, intraoperative "apathetic look" shows strong correlation with intraoperative SMA syndrome. Therefore, "apathetic look" may be a valuable indicator of intraoperative SMA syndrome during awake craniotomy. [ABSTRACT FROM AUTHOR]

Background: Reversible splenial lesion syndrome (RESLES) is known as a neuro-imaging syndrome with recurrent but reversible lesion of the corpus callosum, characterized by nonspecific but usually mild encephalopathies and specific imaging manifestations.There are few published reports in the field of oncology. Case presentation: A 33-year-old female with right breast cancer and with no particular family history was admitted to hospital with high fever and severe headache, after receiving adjuvant radiotherapy. Blood routine test upon admission suggested neutropenia, considering myelosuppression associated with radiotherapy. There were no definite findings of common pathogenic microorganism, and no imaging indication of certain infectious sites other than a likely reversible corpus callosum syndrome suggested by brain MRI, which was relieved after systemic antibiotic therapy and granulocyte colony-stimulating factor injection. Conclusions: Reversible splenial lesion syndrome is a kind of clinical-imaging syndrome with multiple clinical manifestations and etiologies. This breast cancer patient after postoperative adjuvant radiotherapy develops a complication of RESLES that rings an alarm bell to the oncologists not to easily recognize the corpus callosum lesion as infarction or metastasis. Meanwhile, the potential pathogenic mechanisms need to be explored further. [ABSTRACT FROM AUTHOR]

A-kinase anchor protein 12 (AKAP12), a scaffold protein, has been implicated in the central nervous system, including blood-brain barrier (BBB) function. Although its expression level in the corpus callosum is higher than in other brain regions, such as the cerebral cortex, the role of AKAP12 in the corpus callosum remains unclear. In this study, we investigate the impact of AKAP12 deficiency by transcriptome analysis using RNA-sequencing (RNA-seq) on the corpus callosum of AKAP12 knockout (KO) mice. We observed minimal changes, with only 13 genes showing differential expression, including Akap12 itself. Notably, Klf2 and Sgk1, genes potentially involved in BBB function, were downregulated in AKAP12 KO mice and expressed in vascular cells similar to Akap12. These changes in gene expression may affect important biological pathways that may be associated with neurological disorders. Our findings provide an additional data set for future research on the role of AKAP12 in the central nervous system. [ABSTRACT FROM AUTHOR]

The largest white matter structure in the brain, the corpus callosum (CC), is involved in many disorders of the central nervous system. The extent and/or severity of neurodegenerative illnesses are correlated with its size. Though numerous approaches and procedures for CC fragmentation have been offered, and the role of CC has been scrutinized more and more over the past few centuries. Nevertheless, the segmentation accuracy of the current models is not very good. This research offers a thorough analysis of various segmentation methods for CC fragmentation. Additionally, it investigates the different deep learning models focused on CC segmentation obtained from brain magnetic resonance imaging. The results show that not all of the issues with the computational methods for segmenting CC on magnetic resonance imaging have been resolved. [ABSTRACT FROM AUTHOR]

• Higher free-water index in bipolar group suggests neuroinflammation links. • ALPS index and disease duration are inversely related suggesting glymphatic issues. • FW-corrected measures linked with DRS indicate severe bipolar impacts myelin. The glymphatic system, an expansive cerebral waste-disposal network, harbors myriad enigmatic facets necessitating elucidation of their nexus with diverse pathologies. Murine investigations have revealed a relationship between the glymphatic system and affective disorders. This study aimed to illuminate the interplay between bipolar disorder and the glymphatic system. Fifty-eight individuals afflicted with bipolar disorder were identified through meticulous psychiatric assessment. These individuals were juxtaposed with a cohort of 66 comparably aged and sex-matched, mentally stable subjects. Subsequent analysis entailed the application of covariance analysis to evaluate along with the perivascular space (ALPS) index, a novel magnetic resonance imaging method for assessing brain interstitial fluid dynamics via diffusion tensor imaging within the bipolar and control cohorts. We also evaluated the correlation between the ALPS index and clinical parameters, which included the Hamilton Depression scale scores, disease duration, and other clinical assessments. Moreover, partial correlation analyses, incorporating age and sex as covariates, were performed to investigate the relationships between the ALPS index and clinical measures within the two cohorts. A noteworthy adverse correlation was observed between the ALPS index and illness duration. A free-water imaging analysis revealed a substantial elevation in the free-water index within the white-matter tracts, prominently centered on the corpus callosum, within the bipolar cohort relative to that in the control group. In analogous cerebral regions, a conspicuous affirmative correlation was observed between the free-water–corrected radial diffusivity and depression rating scales. Our results showed that the protracted course of bipolar disorder concomitantly exacerbated glymphatic system dysregulation. [ABSTRACT FROM AUTHOR]

[Display omitted] • In the cuprizone-induced demyelination model, the absence of Olig2 was significantly linked to the failure of remyelination. • Exosomes specifically enriched with Olig2 protein were constructed by XPack technology. • Exosomes loaded with Olig2 can engulfed by OPCs and efficient promote cell differentiation. • Exosomes loaded with Olig2 alleviate the demyelination process and enhance remyelination. The research aims to study the therapeutic impact of HEK293-XPack-Olig2 cell-derived exosomes on remyelination of the corpus callosum in a cuprizone-induced demyelinating disease model. A lentiviral vector expressing Olig2 was constructed using XPack technology. The highly abundant Olig2 exosomes (ExoOs) were isolated by centrifugation for subsequent experiments. Western blot, nanoparticle tracking analysis (NTA), and electron microscopy showed no significant difference in particle size and morphology between Exos and ExoOs, and a high level of Olig2 expression could be detected in ExoOs, indicating that exosome modification by XPack technology was successful. The Black Gold/Fluromyelin staining analysis showed that the ExoOs group significantly reduced the demyelination area in the corpus callosum compared to the PBS and Exos groups. Additionally, the PDGFRα/APC staining of the demyelinating region revealed an increase in APC+ oligodendrocytes and a decrease in PDGFRα+ oligodendrocyte progenitor cells (OPCs) in the ExoOs group. Furthermore, there was evident myelin regeneration in the demyelinated areas after ExoOs treatment, with better g-ratio and a higher number of intact myelin compared to the other treatment groups. The level of Sox10 expression in the brain tissue of the ExoOs group were higher compared to those of the PBS and Exos groups. The demyelination process can be significantly slowed down by the XPack-modified exosomes, the differentiation of OPCs promoted, and myelin regeneration accelerated under pathological conditions. This process is presumed to be achieved by changing the expression level of intracellular differentiation-related genes after exosomes transport Olig2 enriched into oligodendrocyte progenitors. [ABSTRACT FROM AUTHOR]

Multiple embryonic origins give rise to forebrain oligodendrocytes (OLs), yet controversies and uncertainty exist regarding their differential contributions. We established intersectional and subtractional strategies to genetically fate map OLs produced by medial ganglionic eminence/ preoptic area (MGE/POA), lateral/caudal ganglionic eminences (LGE/CGE), and dorsal pallium in the mouse brain. We found that, contrary to the canonical view, LGE/CGE-derived OLs make minimum contributions to the neocortex and corpus callosum, but dominate piriform cortex and anterior commissure. Additionally, MGE/POA-derived OLs, instead of being entirely eliminated, make small but sustained contribution to cortex with a distribution pattern distinctive from those derived from the dorsal origin. Our study provides a revised and more comprehensive view of cortical and white matter OL origins, and established valuable new tools and strategies for future OL studies. [ABSTRACT FROM AUTHOR]

Proprioceptive impairments occur in approximately 50–64% of people following stroke. While much is known about the grey matter structures underlying proprioception, our understanding of the white matter correlates of proprioceptive impairments is less well developed. It is recognised that behavioural impairments post-stroke are often the result of disconnection between wide-scale brain networks, however the disconnectome associated with proprioception post-stroke is unknown. In the current study, white matter disconnection was assessed in relation to performance on a robotic arm position matching (APM) task. Neuroimaging and robotic assessments of proprioception were collected for 203 stroke survivors, approximately 2-weeks post-stroke. The robotic assessment was performed in a KINARM Exoskeleton robotic device and consisted of a nine-target APM task. First, the relationship between white matter tract lesion load and performance on the APM task was assessed. Next, differences in the disconnectome between participants with and without impairments on the APM task were examined. Greater lesion load to the superior longitudinal fasciculus (SLF II and III), arcuate fasciculus (all segments) and fronto-insular tracts were associated with worse APM task performance. In those with APM task impairments, there was, additionally, disconnection of the posterior corpus callosum, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus and optic radiations. This study highlights an important perisylvian white matter network supporting proprioceptive processing in the human brain. It also identifies white matter tracts, important for relaying proprioceptive information from parietal and frontal brain regions, that are not traditionally considered proprioceptive in nature. [ABSTRACT FROM AUTHOR]

During infancy and adolescence, language develops from a predominantly interhemispheric control--through the corpus callosum (CC)--to a predominantly intrahemispheric control, mainly subserved by the left arcuate fasciculus (AF). Using multimodal neuroimaging, we demonstrate that human left-handers (both male and female) with an atypical language lateralization show a rightward participation of language areas from the auditory cortex to the inferior frontal cortex when contrasting speech to tone perception and an enhanced interhemispheric anatomical and functional connectivity. Crucially, musicianship determines two different structural pathways to this outcome. Nonmusicians present a relation between atypical lateralization and intrahemispheric underdevelopment across the anterior AF, hinting at a dysregulation of the ontogenetic shift from an interhemispheric to an intrahemispheric brain. Musicians reveal an alternative pathway related to interhemispheric overdevelopment across the posterior CC and the auditory cortex. We discuss the heterogeneity in reaching atypical language lateralization and the relevance of early musical training in altering the normal development of language cognitive functions. [ABSTRACT FROM AUTHOR]

The joint analysis of imaging‐genetics data facilitates the systematic investigation of genetic effects on brain structures and functions with spatial specificity. We focus on voxel‐wise genome‐wide association analysis, which may involve trillions of single nucleotide polymorphism (SNP)‐voxel pairs. We attempt to identify underlying organized association patterns of SNP‐voxel pairs and understand the polygenic and pleiotropic networks on brain imaging traits. We propose a bi‐clique graph structure (ie, a set of SNPs highly correlated with a cluster of voxels) for the systematic association pattern. Next, we develop computational strategies to detect latent SNP‐voxel bi‐cliques and an inference model for statistical testing. We further provide theoretical results to guarantee the accuracy of our computational algorithms and statistical inference. We validate our method by extensive simulation studies, and then apply it to the whole genome genetic and voxel‐level white matter integrity data collected from 1052 participants of the human connectome project. The results demonstrate multiple genetic loci influencing white matter integrity measures on splenium and genu of the corpus callosum. [ABSTRACT FROM AUTHOR]

Intravital 2P-microscopy enables the longitudinal study of brain tumor biology in superficial mouse cortex layers. Intravital microscopy of the white matter, an important route of glioblastoma invasion and recurrence, has not been feasible, due to low signal-to-noise ratios and insufficient spatiotemporal resolution. Here, we present an intravital microscopy and artificial intelligence-based analysis workflow (Deep3P) that enables longitudinal deep imaging of glioblastoma up to a depth of 1.2 mm. We find that perivascular invasion is the preferred invasion route into the corpus callosum and uncover two vascular mechanisms of glioblastoma migration in the white matter. Furthermore, we observe morphological changes after white matter infiltration, a potential basis of an imaging biomarker during early glioblastoma colonization. Taken together, Deep3P allows for a non-invasive intravital investigation of brain tumor biology and its tumor microenvironment at subcortical depths explored, opening up opportunities for studying the neuroscience of brain tumors and other model systems. Observation of glioblastoma invasion in subcortical brain regions is challenging. Here the authors develop a Deep3P workflow to enable longitudinal deep imaging of glioblastoma and its microenvironment by combining three-photon microscopy and deep learning-based analysis, unraveling the invasion routes of these tumor cells into and within the white matter. [ABSTRACT FROM AUTHOR]

Background: Mirror movements (MM) are commonly caused by a defect of interhemispheric pathways also affected in multiple sclerosis (MS), particularly the corpus callosum. We investigated the prevalence of MM in MS in relation to functional and morphological callosal fiber integrity by transcranial magnetic stimulation (TMS), magnetic resonance imaging (MRI), as well as fatigue. Methods: In 21 patients with relapsing–remitting MS and 19 healthy controls, MM were assessed and graded (Woods and Teuber scale: MM 1—4) using a bedside test. Fatigue was evaluated using the Fatigue Scale for Motor and Cognitive Functions (FSMC) questionnaire. TMS measured ipsilateral silent period latency and duration. MRI assessed callosal atrophy by measuring the normalized corpus callosum area (nCCA), corpus callosum index (CCI), and lesion volume. Results: MS patients had significantly more often and pronounced MM compared to healthy controls (p = 0.0002) and nCCA was significantly lower (p = 0.045) in MRI studies. Patients with higher MM scores (MM > 1 vs. MM 0/1) showed significantly more fatigue (higher FSMC sum score, p = 0.04, motor score, p = 0.01). In TMS and MRI studies, no significant differences were found between patients with MM 0/1 and those with MM > 1 (ipsilateral silent period measurements, CCA, CCI and lesion volume). Conclusions: MM are common in MS and can easily be detected through bedside testing. As MM are associated with fatigue, they might indicate fatigue in MS. It is possible that other cerebral structures, in addition to the corpus callosum, may contribute to the origin of MM in MS. [ABSTRACT FROM AUTHOR]

Prenatal alcohol exposure (PAE) refers to the exposure of the developing fetus due to alcohol consumption during pregnancy and can have life-long consequences for learning, behavior, and health. Understanding the impact of PAE on the developing brain manifests challenges due to its complex structural and functional attributes, which can be addressed by leveraging machine learning (ML) and deep learning (DL) approaches. While most ML and DL models have been tailored for adult-centric problems, this work focuses on applying DL to detect PAE in the pediatric population. This study integrates the pre-trained simple fully convolutional network (SFCN) as a transfer learning approach for extracting features and a newly trained classifier to distinguish between unexposed and PAE participants based on Tl-weighted structural brain magnetic resonance (MR) scans of individuals aged 2-8 years. Among several varying dataset sizes and augmentation strategy during training, the classifier secured the highest sensitivity of 88.47% with 85.04% average accuracy on testing data when considering a balanced dataset with augmentation for both classes. Moreover, we also preliminarily performed explainability analysis using the Grad-CAM method, highlighting various brain regions such as corpus callosum, cerebellum, pons, and white matter as the most important features in the model's decision-making process. Despite the challenges of constructing DL models for pediatric populations due to the brain's rapid development, motion artifacts, and insufficient data, this work highlights the potential of transfer learning in situations where data is limited. Furthermore, this study underscores the importance of preserving a balanced dataset for fair classification and clarifying the rationale behind the model's prediction using explainability analysis. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a debilitating demyelinating disease characterized by remyelination failure attributed to inadequate oligodendrocyte precursor cells (OPCs) differentiation and aberrant astrogliosis. A comprehensive cell atlas reanalysis of clinical specimens brings to light heightened clusterin (CLU) expression in a specific astrocyte subtype links to active lesions in MS patients. Our investigation reveals elevated astrocytic CLU levels in both active lesions of patient tissues and female murine MS models. CLU administration stimulates primary astrocyte proliferation while concurrently impeding astrocyte-mediated clearance of myelin debris. Intriguingly, CLU overload directly impedes OPC differentiation and induces OPCs and OLs apoptosis. Mechanistically, CLU suppresses PI3K-AKT signaling in primary OPCs via very low-density lipoprotein receptor. Pharmacological activation of AKT rescues the damage inflicted by excess CLU on OPCs and ameliorates demyelination in the corpus callosum. Furthermore, conditional knockout of CLU emerges as a promising intervention, showcasing improved remyelination processes and reduced severity in murine MS models. Glia abnormalities drive the progression of demyelinating diseases. Here, the authors show that reactivated astrocytes secrete clusterin to impede remyelination by blocking astrocytic removal of myelin debris and oligodendrocyte precursor cell differentiation in mouse models of demyelination. [ABSTRACT FROM AUTHOR]

AbstractBackgroundMethodsResultsConclusionBilateral, biventricular lesions present a challenging scenario in neurosurgery, often requiring complex surgical techniques for management. Gangliogliomas (GG), while typically indolent, can manifest as anaplastic variants (AGG), necessitating comprehensive treatment strategies. This case study explores a unique surgical approach for a patient with bilateral, intra-extraventricular lesions infiltrating the corpus callosum, highlighting the complexities of managing such cases.A 63-year-old female presented with a progressive intraventricular lesion infiltrating the left frontal lobe, diagnosed initially as a ganglioglioma. Following resection and histological examination, the lesion was confirmed as a WHO Grade 1 ganglioglioma. Subsequently, a contralateral lesion emerged, necessitating a novel surgical approach to achieve maximal safe resection while minimising neurological deficits. The technique involved extending the surgical corridor contralaterally along the tumour route, guided by neuronavigation and fluorescence imaging.The surgical approach enabled maximal safe resection of the lesion, with postoperative imaging confirming complete resection in most sites except for a known infiltration in the right posterior lateral ventricle. Histological examination revealed AGG, prompting subsequent adjuvant radiotherapy due to its aggressive nature.The management of bilateral, biventricular lesions such as AGG requires innovative surgical approaches tailored to individual patient characteristics. The case highlights the efficacy of a transtumoral approach in achieving maximal safe resection while minimising neurological sequelae. Moreover, it underscores the importance of comprehensive treatment strategies, including adjuvant therapies, in addressing aggressive histological variants of gangliogliomas. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disorder affecting the central nervous system. Evidence suggests that age‐related neurodegeneration contributes to disability progression during the chronic stages of MS. Aging is characterized by decreased regeneration potential and impaired myelin repair in the brain. It is hypothesized that accelerated cellular aging contributes to the functional decline associated with neurodegenerative diseases. We assessed the impact of aging on myelin content in the corpus callosum (CC) and compared aging with the long‐term demyelination (LTD) consequents induced by 12 weeks of feeding with a cuprizone (CPZ) diet. Initially, evaluating myelin content in 2‐, 6‐, and 18‐month‐old mice revealed a reduction in myelin content, particularly at 18 months. Myelin thickness was decreased and the g‐ratio increased in aged mice. Although a lower myelin content and higher g‐ratio were observed in LTD model mice, compared to the normally aged mice, both aging and LTD exhibited relatively similar myelin ultrastructure. Our findings provide evidence that LTD exhibits the hallmarks of aging such as elevated expression of senescence‐associated genes, mitochondrial dysfunction, and high level of oxidative stress as observed following normal aging. We also investigated the senescence‐associated β‐galactosidase activity in O4+ late oligodendrocyte progenitor cells (OPCs). The senescent O4+/β‐galactosidase+ cells were elevated in the CPZ diet. Our data showed that the myelin degeneration in CC occurs throughout the lifespan, and LTD induced by CPZ accelerates the aging process which may explain the impairment of myelin repair in patients with progressive MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a strong neuroinflammatory component. Current treatments principally target the immune system but fail to preserve long‐term myelin health and do not prevent neurological decline. Studies over the past two decades have shown that the structurally related neuropeptides VIP and PACAP (vasoactive intestinal peptide and pituitary adenylate cyclase‐activating polypeptide, respectively) exhibit pronounced anti‐inflammatory activities and reduce clinical symptoms in MS disease models, largely via actions on their bivalent VIP receptor type 1 and 2. Here, using the cuprizone demyelination model, we demonstrate that PACAP and VIP, and strikingly the PACAP‐selective receptor PAC1 agonist maxadilan, prevented locomotor deficits in the horizontal ladder and open field tests. Moreover, only PACAP and maxadilan were able to prevent myelin deterioration, as assessed by a reduction in the expression of the myelin markers proteolipid protein 1, oligodendrocyte transcription factor 2, quaking‐7 (APC) and Luxol Fast Blue staining. Furthermore, PACAP and maxadilan (but not VIP), prevented striatal synaptic loss and diminished astrocyte and microglial activation in the corpus callosum of cuprizone‐fed mice. In vitro, PACAP or maxadilan prevented lipopolysaccharide (LPS)‐induced polarisation of primary astrocytes at 12–24 h, an effect that was not seen with maxadilan in LPS‐stimulated microglia. Taken together, our data demonstrates for the first time that PAC1 agonists provide distinctive protective effects against white matter deterioration, neuroinflammation and consequent locomotor dysfunctions in the cuprizone model. The results indicate that targeting the PAC1 receptor may provide a path to treat myelin‐related diseases in humans. [ABSTRACT FROM AUTHOR]

Autism is a neurodevelopmental disorder, the prevalence of which has increased dramatically in the United States over the past two decades. It is characterized by stereotyped behaviors and impairments in social interaction and communication. In this paper, we present evidence that autism can be viewed as a PIN1 deficiency syndrome. Peptidyl‐prolyl cis/trans isomerase, NIMA‐Interacting 1 (PIN1) is a peptidyl‐prolyl cis/trans isomerase, and it has widespread influences in biological organisms. Broadly speaking, PIN1 deficiency is linked to many neurodegenerative diseases, whereas PIN1 over‐expression is linked to cancer. Death‐associated protein kinase 1 (DAPK1) strongly inhibits PIN1, and the hormone melatonin inhibits DAPK1. Melatonin deficiency is strongly linked to autism. It has recently been shown that glyphosate exposure to rats inhibits melatonin synthesis as a result of increased glutamate release from glial cells and increased expression of metabotropic glutamate receptors. Glyphosate's inhibition of melatonin leads to a reduction in PIN1 availability in neurons. In this paper, we show that PIN1 deficiency can explain many of the unique morphological features of autism, including increased dendritic spine density, missing or thin corpus callosum, and reduced bone density. We show how PIN1 deficiency disrupts the functioning of powerful high‐level signaling molecules, such as nuclear factor erythroid 2‐related factor 2 (NRF2) and p53. Dysregulation of both of these proteins has been linked to autism. Severe depletion of glutathione in the brain resulting from chronic exposure to oxidative stressors and extracellular glutamate leads to oxidation of the cysteine residue in PIN1, inactivating the protein and further contributing to PIN1 deficiency. Impaired autophagy leads to increased sensitivity of neurons to ferroptosis. It is imperative that further research be conducted to experimentally validate whether the mechanisms described here take place in response to chronic glyphosate exposure and whether this ultimately leads to autism. [ABSTRACT FROM AUTHOR]

Background: The most compact portion of the corpus callosum (CC) is the corpus splenium (CS). Purpose: To evaluate the connection between clinical and demographic features to determine whether neuroimaging findings will be permanent or temporary in CS patients. Material and Methods: We enrolled 93 patients (age range = 18–86 years) with CS lesions. Demographic and clinical information were recorded. We examined the lesions depending on the location. Group 1 (n = 20) had lesions limited to the CS (egg-shaped or round); group 2 (n = 15) had "boomerang sign" lesions; and group 3 (n = 58) had splenium involvement in conditions affecting the whole brain (Boomerang sign+ plus). Results: Group 1 had a lower mean age, shorter disease duration, and fewer persistent lesions than others (P < 0.01, P < 0.001, and P < 0.001, respectively). The mean disease onset age (in years) in group 1 was higher than that of the other groups (P < 0.045). Group 2 had lower potassium (K) (P < 0.003) and red cell distribution width levels (P < 0.029) than the other groups. Age <41.5 years (P < 0.001), age at illness initiation <48.5 years (P < 0.002), disease duration <5.5 months (P < 0.001), and eosinophil level <0.29 uL (P 0.014) all point to temporary lesions. Conclusion: Cases with limited CS lesions have younger onset ages, lower disease onset ages, and shorter disease durations. Age, age of disease onset, disease duration, and eosinophil level are risk variables that affect whether CS lesions are permanent or temporary. [ABSTRACT FROM AUTHOR]

The current research aims to verify the existence of differences between male patients with multiple sclerosis and healthy people in the accuracy and speed of Tactile Interhemispheric Transfer, and to verify the existence of differences between female patients with multiple sclerosis and healthy women in the accuracy and speed of Tactile Interhemispheric Transfer. In addition to verifying the presence of differences between male and female patients with multiple sclerosis in the accuracy and speed of Tactile Interhemispheric Transfer. The research relied on the comparative descriptive approach, and the research sample consisted of (30) participants from patients with multiple sclerosis, and a group of healthy people consisting of (30) participants. The study used the following tests (tactile recognition test on objects and Determine finger positions test) to apply to the sample members. The results of the study revealed: 1. There are differences between healthy males and patients in the speed and accuracy of Tactile Interhemispheric Transfer on the tests used in the study, in favor of healthy males. 2. There are differences between healthy females and patients in the speed and accuracy of Tactile Interhemispheric Transfer on the tests used in the study in favor of healthy females. 3. While the results of the study also revealed to us the presence of differences between healthy females and patients in (accuracy of transition in the presence of a time interval) in favor of female patients on the tactile recognition test. 4. The results also revealed the presence of differences between male and female patients with multiple sclerosis in the speed and accuracy of Tactile Interhemispheric Transfer in favor of females. [ABSTRACT FROM AUTHOR]

Agenesis of the corpus callosum is a rare congenital condition, present at birth, characterized by the partial or complete absence of the corpus callosum. Although the exact causes are usually unknown, the condition can be inherited either as an autosomal recessive trait or as an X-linked dominant trait [1]. Alternatively, it may result from an infection or injury during the 20th to 22nd weeks of pregnancy, which can lead to disruptions in the development of the fetal brain, or it may be caused by toxic factors, such as fetal alcohol syndrome [2]. We present the case of a 2-month-old male patient with acute surgical pathology that began at birth and rapidly progressed to severe infection, requiring sustained antibiotic treatment and assisted respiration. The presence of muscular hypotonia and tonic-clonic seizures at home, following the first hospitalization, necessitated readmission to another university clinic, where he was also diagnosed with agenesis of the corpus callosum. The management of this case required special attention to clinical manifestations, rapid identification of complications, appropriate therapeutic management, and essential collaboration among members of the medical team. [ABSTRACT FROM AUTHOR]

Cerebral palsy (CP) is a common neurodevelopmental disorder characterized by pronounced motor dysfunction and resulting in physical disability. Neural precursor cells (NPCs) have shown therapeutic promise in mouse models of hypoxic-ischemic (HI) perinatal brain injury, which mirror hemiplegic CP. Constraint-induced movement therapy (CIMT) enhances the functional use of the impaired limb and has emerged as a beneficial intervention for hemiplegic CP. However, the precise mechanisms and optimal application of CIMT remain poorly understood. The potential synergy between a regenerative approach using NPCs and a rehabilitation strategy using CIMT has not been explored. We employed the Rice–Vannucci HI model on C57Bl/6 mice at postnatal day (PND) 7, effectively replicating the clinical and neuroanatomical characteristics of hemiplegic CP. NPCs were transplanted in the corpus callosum (CC) at PND21, which is the age corresponding to a 2-year-old child from a developmental perspective and until which CP is often not formally diagnosed, followed or not by Botulinum toxin injections in the unaffected forelimb muscles at PND23, 26, 29 and 32 to apply CIMT. Both interventions led to enhanced CC myelination and significant functional recovery (as shown by rearing and gait analysis testing), through the recruitment of endogenous oligodendrocytes. The combinatorial treatment indicated a synergistic effect, as shown by newly recruited oligodendrocytes and functional recovery. This work demonstrates the mechanistic effects of CIMT and NPC transplantation and advocates for their combined therapeutic potential in addressing hemiplegic CP. [ABSTRACT FROM AUTHOR]

Behavioral differences between men and women have been studied extensively, as have differences in brain anatomy. However, most studies have focused on differences in gray matter, while white matter has been much less studied. We conducted a comprehensive study of 77 deep white matter tracts to analyze their volumetric and microstructural variability between men and women in the full Human Connectome Project (HCP) cohort of 1065 healthy individuals aged 22–35 years. We found a significant difference in total brain volume between men and women (+ 12.6% in men), consistent with the literature. 16 tracts showed significant volumetric differences between men and women, one of which stood out due to a larger effect size: the corpus callosum genu, which was larger in women (+ 7.3% in women, p = 5.76 × 10–19). In addition, we found several differences in microstructural parameters between men and women, both using standard Diffusion Tensor Imaging (DTI) parameters and more complex microstructural parameters from the Neurite Orientation Dispersion and Density Imaging (NODDI) model, with the tracts showing the greatest differences belonging to motor (cortico-spinal tracts, cortico-cerebellar tracts) or limbic (cingulum, fornix, thalamo-temporal radiations) systems. These microstructural differences may be related to known behavioral differences between the sexes in timed motor performance, aggressiveness/impulsivity, and social cognition. [ABSTRACT FROM AUTHOR]

Pontocerebellar hypoplasia type 10 (PCH10) due to CLP1 gene mutations is characterized by structural brain anomalies, progressive microcephaly, severe intellectual and physical disabilities, and spasticity. In this follow-up study, evolution of phenotypic and neurological characteristics of patients with PCH10 is discussed. Phenotype, growth parameters, motor functions, developmental tests, spasticity assessments, functional independence assessments, electroencephalography (EEG), and brain magnetic resonance imaging (MRI) of 10 patients with PCH10 were monitored on separate examinations. Alterations were recorded. Patients were followed-up for an average of 2.83 years. The tone of the upper extremities was significantly higher than that of the lower extremities, according to Modified Ashworth Scale (MAS) values. Sixty percent of patients could sit unsupported; 20% achieved supported sitting initially but lost the ability during follow-up. Absence of grabbing or sitting was observed in 20% of patients. During follow-up, one person achieved supported sitting and one person achieved head holding. Only one patient was able to speak a few words. Cerebellar atrophy (two of 10), pons hypoplasia (four of 10), cortical atrophy (seven of 10), enlarged ventricles (10 of 10), thinning of the corpus callosum (10 of 10), hypomyelination (six of 10), and increased white matter signal intensity (six of 10) were the observed MRI findings. Progressive cerebral and cerebellar atrophy was demonstrated radiologically for the first time in a PCH10 cohort. It is of crucial importance to identify these patients promptly with the help of dysmorphic findings and spasticity being pronounced in the upper extremities. Furthermore, we note that phenotypic and neurological examination findings tend to change slightly over time. [ABSTRACT FROM AUTHOR]

Background: Neuronal ceroid lipofuscinoses are a genetically heterogeneous group of inherited lysosomal storage disorders. Kufs disease is the predominant form of neuronal ceroid lipofuscinosis in adults, but it's rare and challenging to diagnose. Case description: The proband initially presented with cognitive deterioration and parkinsonian traits. At 35, he was admitted to hospital following a tonic–clonic seizure. Brain magnetic resonance imaging showed atrophy of the cerebral cortex and cerebellum, enlarged ventricles, and thinned corpus callosum. The proband's younger brother and sister were also affected, and the clinical phenotype within the family was consistent. Whole-exome Sequencing of the proband revealed a novel homozygous mutation in CLN6 (NM_017882: c.425A > G, p. Tyr142Cys). Co-segregation analysis revealed that two other affected individuals carried a homozygous mutation at the same locus, with both parents exhibiting heterozygous mutations of c.425A > G. Conclusion: Our study not only provides insights into the clinical presentation and development of the disease within the affected family but also expanded the mutational and phenotypical spectrum of the CLN6 gene. [ABSTRACT FROM AUTHOR]