Early-stage volume losses in the corpus callosum and thalamus predict the progression of brain atrophy in patients with multiple sclerosis.

BACKGROUND: A method that can be used in the early stage of multiple sclerosis (MS) to predict the progression of brain volume loss (BVL) has not been fully established. METHODS: To develop a method of predicting progressive BVL in patients with MS (pwMS), eighty-two consecutive Japanese pwMS-with either relapsing-remitting MS (86%) or secondary progressive MS (14%)-and 41 healthy controls were included in this longitudinal retrospective analysis over an observational period of approximately 3.5 years. Using a hierarchical cluster analysis with multivariate imaging data obtained by FreeSurfer analysis, we classified the pwMS into clusters. RESULTS: At baseline and follow-up, pwMS were cross-sectionally classified into three major clusters (Clusters 1, 2, and 3) in ascending order by disability and BVL. Among the patients included in Cluster 1 at baseline, approximately one-third of patients (12/52) transitioned into Cluster 2 at follow-up. The volumes of the corpus callosum, the thalamus, and the whole brain excluding the ventricles were significantly decreased in the transition group compared with the nontransition group and were found to be the most important predictors of transition. CONCLUSION: Decreased volumes of the corpus callosum and thalamus in the relatively early stage of MS may predict the development of BVL.

Direct interhemispheric cortical communication via thalamic commissures: a new white matter pathway in the primate brain.

Cortical neurons of eutherian mammals project to the contralateral hemisphere, crossing the midline primarily via the corpus callosum and the anterior, posterior, and hippocampal commissures. We recently reported and named the thalamic commissures (TCs) as an additional interhemispheric axonal fiber pathway connecting the cortex to the contralateral thalamus in the rodent brain. Here, we demonstrate that TCs also exist in primates and characterize the connectivity of these pathways with high-resolution diffusion-weighted MRI, viral axonal tracing, and fMRI. We present evidence of TCs in both New World (Callithrix jacchus and Cebus apella) and Old World primates (Macaca mulatta). Further, like rodents, we show that the TCs in primates develop during the embryonic period, forming anatomical and functionally active connections of the cortex with the contralateral thalamus. We also searched for TCs in the human brain, showing their presence in humans with brain malformations, although we could not identify TCs in healthy subjects. These results pose the TCs as a vital fiber pathway in the primate brain, allowing for more robust interhemispheric connectivity and synchrony and serving as an alternative commissural route in developmental brain malformations.

Threat and adaptation: The maternal lived experience of continuing pregnancy after receiving a prenatal diagnosis of agenesis of the corpus callosum.

One stated objective of prenatal screening and diagnosis is the preparation for delivering a baby with medical needs or disability, however, psychosocial outcomes of parents who received a prenatal diagnosis suggest that this objective is not yet realised. Preparation may be complicated by diagnostic and prognostic uncertainty. A prenatal diagnosis that includes significant uncertainty due to the heterogeneous presentations, classifications, causes and outcomes is agenesis of the corpus callosum. As a neuroanatomical anomaly identified in the second or third trimesters, the diagnosis is likely to cause distress for expectant mothers, yet there is limited guidance for holistic support. To begin to address the paucity of research, this hermeneutic phenomenological study sought to explore, and provide a telling of the maternal experience of continuing pregnancy after a prenatal diagnosis of agenesis of the corpus callosum. Through interviews and a series of online, asynchronous and facilitated focus groups, lived experiences during pregnancy from the time of diagnosis to birth were explored with 26 mothers who participated in this international study. Themes were constructed through reflexive thematic analysis to describe the experience of the lived phenomenon. The first theme, Under Threat, included subthemes of The Threat to the Life of the Baby and Threatened Image of the Expected Family. The second theme, Day to Day Toward Adaptation, included subthemes of Holding it Together and Falling Apart, and More Than Information, Searching for Meaning, Hope and Control. To realise the commonly stated objective of prenatal diagnosis, to support maternal preparation, healthcare professionals require awareness of the profound, yet individual experience of prenatal diagnosis to adequately respond and support mothers through their continued pregnancies. Healthcare services should be designed to flexibly respond in a woman- and family-centred manner to reduce the threat and support maternal adaptation after a prenatal diagnosis.

Cu,Zn-Superoxide Dismutase has Minimal Effects Against Cuprizone-Induced Demyelination, Microglial Activation, and Neurogenesis Defects in the C57BL/6 Mouse Hippocampus.

Cuprizone causes consistent demyelination and oligodendrocyte damage in the mouse brain. Cu,Zn-superoxide dismutase 1 (SOD1) has neuroprotective potential against various neurological disorders, such as transient cerebral ischemia and traumatic brain injury. In this study, we investigated whether SOD1 has neuroprotective effects against cuprizone-induced demyelination and adult hippocampal neurogenesis in C57BL/6 mice, using the PEP-1-SOD1 fusion protein to facilitate the delivery of SOD1 protein into hippocampal neurons. Eight weeks feeding of cuprizone-supplemented (0.2%) diets caused a significant decrease in myelin basic protein (MBP) expression in the stratum lacunosum-moleculare of the CA1 region, the polymorphic layer of the dentate gyrus, and the corpus callosum, while ionized calcium-binding adapter molecule 1 (Iba-1)-immunoreactive microglia showed activated and phagocytic phenotypes. In addition, cuprizone treatment reduced proliferating cells and neuroblasts as shown using Ki67 and doublecortin immunostaining. Treatment with PEP-1-SOD1 to normal mice did not show any significant changes in MBP expression and Iba-1-immunoreactive microglia. However, Ki67-positive proliferating cells and doublecortin-immunoreactive neuroblasts were significantly decreased. Simultaneous treatment with PEP-1-SOD1 and cuprizone-supplemented diets did not ameliorate the MBP reduction in these regions, but mitigated the increase of Iba-1 immunoreactivity in the corpus callosum and alleviated the reduction of MBP in corpus callosum and proliferating cells, not neuroblasts, in the dentate gyrus. In conclusion, PEP-1-SOD1 treatment only has partial effects to reduce cuprizone-induced demyelination and microglial activation in the hippocampus and corpus callosum and has minimal effects on proliferating cells in the dentate gyrus.

Long-term follow-up of a randomized controlled trial of choline for neurodevelopment in fetal alcohol spectrum disorder: corpus callosum white matter microstructure and neurocognitive outcomes.

BACKGROUND: Fetal alcohol spectrum disorder (FASD) is a lifelong condition. Early interventions targeting core neurocognitive deficits have the potential to confer long-term neurodevelopmental benefits. Time-targeted choline supplementation is one such intervention that has been shown to provide neurodevelopmental benefits that emerge with age during childhood. We present a long-term follow-up study evaluating the neurodevelopmental effects of early choline supplementation in children with FASD approximately 7 years on average after an initial efficacy trial. METHODS: The initial study was a randomized, double-blind, placebo-controlled trial of choline vs. placebo in 2.5 to 5 year olds with FASD. Participants in this long-term follow-up study include 18 children (9 placebo; 9 choline) seen 7 years on average following initial trial completion. The mean age at follow-up was 11.0 years old. Diagnoses were 28% fetal alcohol syndrome (FAS), 28% partial FAS, and 44% alcohol-related neurodevelopmental disorder. The follow-up included measures of executive functioning and an MRI scan. RESULTS: Children who received choline had better performance on several tasks of lower-order executive function (e.g., processing speed) and showed higher white matter microstructure organization (i.e., greater axon coherence) in the splenium of the corpus callosum compared to the placebo group. CONCLUSIONS: These preliminary findings, although exploratory at this stage, highlight potential long-term benefits of choline as a neurodevelopmental intervention for FASD and suggest that choline may affect white matter development, representing a potential target of choline in this population. TRIAL REGISTRATION: Prior to enrollment, this trial was registered with clinicaltrials.gov ( NCT01149538 ) on June 23, 2010.

Impact of chronic exposure to legacy environmental contaminants on the corpus callosum microstructure: A diffusion MRI study of Inuit adolescents.

Exposure to environmental contaminants is an important public health concern for the Inuit population of northern Québec, who have been exposed to mercury (Hg), polychlorinated biphenyls (PCBs) and lead (Pb). During the last 25 years, the Nunavik Child Development Study (NCDS) birth cohort has reported adverse associations between these exposures and brain function outcomes. In the current study, we aimed to determine whether contaminant exposure is associated with alterations of the corpus callosum (CC), which plays an important role in various cognitive, motor and sensory function processes. Magnetic resonance imaging (MRI) was administered to 89 NCDS participants (mean age ± SD = 18.4 ± 1.2). Diffusion-weighted imaging was assessed to characterize the microstructure of the CC white matter in 7 structurally and functionally distinct regions of interest (ROIs) using a tractography-based segmentation approach. The following metrics were computed: fiber tract density, fractional anisotropy (FA), axial diffusivity (AD) and radial diffusivity (RD). Multiple linear regression models adjusted for sex, age, current alcohol/drug use and fish nutrients (omega-3 fatty acids and selenium) were conducted to assess the association between diffusion-weighted imaging metrics and Hg, PCB 153 and Pb concentrations obtained at birth in the cord blood and postnatally (mean values from blood samples at 11 and 18 years of age). Exposures were not associated with fiber tract density. Nor were significant associations found with cord and postnatal blood Pb concentrations for FA. However, pre- and postnatal Hg and PCB concentrations were significantly associated with higher FA of several regions of the CC, namely anterior midbody, posterior midbody, isthmus, and splenium, with the most pronounced effects observed in the splenium. FA results were mainly associated with lower RD. This study shows that exposure to Hg and PCB 153 alters the posterior microstructure of the CC, providing neuroimaging evidence of how developmental exposure to environmental chemicals can impair brain function and behavior in late adolescence.

Marchiafava-Bignami disease presenting as reversible coma.

Marchiafava-Bignami disease (MBD) is a rare demyelinating condition of the corpus callosum and subcortical white matter that is most commonly seen in alcoholic patients. The course of the disease varies with symptoms that range from dementia to complete coma; severe intermittent sympathetic storming with abnormal posturing is often reported in literature. It is presumably secondary to a deficiency of B complex vitamins, specifically thiamine and many patients have clinical improvement after repletion of B vitamins. We present a case of a 35-year-old man who developed MBD secondary to polysubstance misuse without history of alcohol use. His clinical course was complicated by persistent comatose state with autonomic dysfunction. After the administration of high-dose thiamine and vitamin C and E, the patient regained consciousness and was able to follow commands within 48 hours. Furthermore, this case showed recognising brain MRI findings for MBD is a crucial step in disease identification.

Distinct Roles of Rodent Thalamus and Corpus Callosum in Seizure Generalization.

OBJECTIVE: Bilateral synchronous cortical activity occurs during sleep, attention, and seizures. Canonical models place the thalamus at the center of bilateral cortical synchronization because it generates bilateral sleep spindle oscillations and primarily generalized absence seizures. However, classical studies suggest that the corpus callosum mediates bilateral cortical synchronization. METHODS: We mapped the spread of right frontal lobe-onset, focal to bilateral seizures in mice and modified it using chemo and optogenetic suppression of motor thalamic nucleus and corpus callosotomy. RESULTS: Seizures from the right cortex spread faster to the left cortex than to the left thalamus. The 2 thalami have minimal monosynaptic commissural connections compared to the massive commissure corpus callosum. Chemogenetic and closed-loop optogenetic inhibition of the right ventrolateral thalamic nucleus did not alter inter-hemispheric seizure spread. However, anterior callosotomy delayed bilateral seizure oscillations. INTERPRETATION: Thalamocortical oscillations amplify focal onset motor seizures, and corpus callosum spreads them bilaterally. ANN NEUROL 2022;91:682-696.

Longitudinal thalamic white and grey matter changes associated with visual hallucinations in Parkinson's disease.

OBJECTIVE: Visual hallucinations are common in Parkinson's disease (PD) and associated with worse outcomes. Large-scale network imbalance is seen in PD-associated hallucinations, but mechanisms remain unclear. As the thalamus is critical in controlling cortical networks, structural thalamic changes could underlie network dysfunction in PD hallucinations. METHODS: We used whole-brain fixel-based analysis and cortical thickness measures to examine longitudinal white and grey matter changes in 76 patients with PD (15 hallucinators, 61 non-hallucinators) and 26 controls at baseline, and after 18 months. We compared white matter and cortical thickness, adjusting for age, gender, time-between-scans and intracranial volume. To assess thalamic changes, we extracted volumes for 50 thalamic subnuclei (25 each hemisphere) and mean fibre cross-section (FC) for white matter tracts originating in each subnucleus and examined longitudinal change in PD-hallucinators versus non-hallucinators. RESULTS: PD hallucinators showed white matter changes within the corpus callosum at baseline and extensive posterior tract involvement over time. Less extensive cortical thickness changes were only seen after follow-up. White matter connections from the right medial mediodorsal magnocellular thalamic nucleus showed reduced FC in PD hallucinators at baseline followed by volume reductions longitudinally. After follow-up, almost all thalamic subnuclei showed tract losses in PD hallucinators compared with non-hallucinators. INTERPRETATION: PD hallucinators show white matter loss particularly in posterior connections and in thalamic nuclei, over time with relatively preserved cortical thickness. The right medial mediodorsal thalamic nucleus shows both connectivity and volume loss in PD hallucinations. Our findings provide mechanistic insights into the drivers of network imbalance in PD hallucinations and potential therapeutic targets.

Corpus callosum size, hypnotic susceptibility and empathy in women with alleged mediumship: a controlled study.

AIM: Evidence indicates that highly hypnotizable subjects may have larger area of the rostrum of the corpus callosum (CC). Mediumship can be defined as the alleged ability to communicate regularly with deceased personalities, and self-hypnosis is postulated as an underlying mechanism for this ability. Therefore, we aimed to investigate the CC area, hypnotic susceptibility, self-reported dissociation, and empathy in alleged mediums in comparison with healthy, non-medium controls. METHODS: The study sample consisted of 16 Spiritist mediums (medium group (MG)) and 16 non-medium controls. Magnetic resonance imaging scans were performed to measure the CC areas (total and subdivisions). The Harvard Group Scale of Hypnotic Susceptibility was used to assess hypnotizability, and self-reported measures were used to investigate anomalous experiences, mental health using the Self-Reporting Questionnaire-SRQ, dissociative experiences using the Dissociative Experiences Scale, and empathy using the Interpersonal Reactivity Index. RESULTS: No between-group differences were found in the total or subdivided CC areas or in hypnotizability, with both groups showing intermediate levels. The rostrum of the CC area and hypnotizability were not correlated. The MG presented with significantly more anomalous experiences, but the two groups had similar scores for dissociation, empathy, and mental health. CONCLUSION: The normal CC areas found in the MG are in contrast with the abnormal results typically observed in subjects with psychotic and dissociative disorders. Although hypnotizability was not different between groups, further studies are needed to replicate these findings in other samples.

[Effects of electroacupuncture on myelin-related protein in corpus callosum of rats with focal cerebral ischemia].

OBJECTIVE: To observe the effect of electroacupuncture(EA)on the expression of myelin basic protein (MBP), axon growth inhibitor Nogo-A and Nogo receptor (NgR) in corpus callosum of rats with focal cerebral ischemia, so as to explore the mechanism of EA underlying improving ischemic white matter injury. METHODS: Fourty male SD rats were randomly divided into normal, sham operation, model and EA groups, with 10 rats in each group. The focal cerebral ischemia rat model was established by occlusion of the middle cerebral artery (MCAO). EA was applied to "Baihui"(GV20) and "Zusanli"(ST36) on the left side for 30 min, once daily for 14 days. Neurological function score and the adhensive removal test were used to evaluate neurological deficit severity; Hematoxylin-esion staining was used to observe the pathological changes in myelin of corpus callosum and luxol fast blue（LFB） staining was used to observe the myelin of corpus callosum. Immunohistochemical staining and Western blot were used to detect the expressions of MBP、Nogo-A and NgR in the ischemic corpus callosum. RESULTS: After MCAO, the neurological function score was significantly increased (P<0.05), the time required for contact with tape and tape removal was longer (P<0.001), the intensity of LFB staining and the expression of MBP decreased, while the veside area and the expression of Nogo-A and its receptor NgR increased (P<0.01, P<0.05) in the model group relevant to the normal and sham operation groups. The fiber arrangement of the corpus callosum on the ischemic side was disordered and a large amount of myelin sheath was lost in the model group. Following the treatment, the neurological deficit score of EA group was gradually decreased and significantly decreased on the 3rd, 7th and 14th day (P<0.05), and the time to remove the adhesive tape was shortened at the 7th and 14th day (P<0.001). The shape of the corpus callosum in the EA group was close to normal, and the myelin structure was relatively complete. The intensity of LFB staining and the expression of MBP was increased (P<0.05, P<0.01) while the expression of Nogo-A and its receptor NgR were decreased in the EA group relevant to the model group (P<0.01). CONCLUSION: EA can play a protective role in myelin of the corpus callosum after cerebral ischemia, which may be related to down-regulating the expressions of Nogo-A and NgR.

Susceptibility of subregions of prefrontal cortex and corpus callosum to damage by high-dose oxytocin-induced labor in male neonatal mice.

Induction and augmentation of labor is one of the most common obstetrical interventions. However, this intervention is not free of risks and could cause adverse events, such as hyperactive uterine contraction, uterine rupture, and amniotic-fluid embolism. Our previous study using a new animal model showed that labor induced with high-dose oxytocin (OXT) in pregnant mice resulted in massive cell death in selective brain regions, specifically in male offspring. The affected brain regions included the prefrontal cortex (PFC), but a detailed study in the PFC subregions has not been performed. In this study, we induced labor in mice using high-dose OXT and investigated neonatal brain damage in detail in the PFC using light and electron microscopy. We found that TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were detected more abundantly in infralimbic (IL) and prelimbic (PL) cortex of the ventromedial PFC (vmPFC) in male pups delivered by OXT-induced labor than in the control male pups. These Iba-1-positive microglial cells were engulfing dying cells. Additionally, we also noticed that in the forceps minor (FMI) of the corpus callosum (CC), the number of TUNEL-positive or pyknotic nuclei and Iba-1-positive microglial cells were largely increased and Iba-1-positive microglial cells phagocytosed massive dying cells in male pups delivered by high-dose OXT-induced labor. In conclusion, IL and PL of the vmPFC and FMI of the CC, were susceptible to brain damage in male neonates after high-dose OXT-induced labor.

Expression of orexin-A (hypocretin-A) in the hypothalamus after traumatic brain injury: A postmortem evaluation.

Traumatic brain injury (TBI) is one of the leading causes of mortality and morbidity. The key component of TBI pathophysiology is traumatic axonal injury (TAI), commonly referred to as diffuse axonal injury (DAI). Coma is a serious complication which can occur following traumatic brain injury (TBI). Recently, studies have shown that the central orexinergic/ hypocretinergic system exhibit prominent arousal promoting actions. Therefore, the purpose of this study is to investigate by immunohistochemistry the expression of beta-amyloid precursor protein (ß-APP) in white matter of parasagittal region, corpus callosum and brainstem and the expression of orexin-A (ORXA) in the hypothalamus after traumatic brain injury. RESULTS: DAI was found in 26 (53.06%) cases, assessed with ß-APP immunohistochemical staining in parasagittal white matter, corpus callosum and brainstem. Orexin-A immunoreactivity in hypothalamus was completely absent in 5 (10.2%) of the cases; moderate reduction of ORXA was observed in 9 (18.4%) of the cases; and severe reduction was observed in 7 (14.3%) of the cases. A statistically significant correlation was found between ß-APP immunostaining in white matter, corpus callosum and brainstem in relation to survival time (p < 0.002, p < 0.003 and p < 0.005 respectively). A statistically positive correlation was noted between ORX-A immunoreactivity in hypothalamus to survival time (p < 0.003). An inverse correlation was noted between the expression of ß-APP in the regions of brain studied to the expression of ORX-A in the hypothalamus of the cases studied (p < 0.005). CONCLUSIONS: The present study demonstrated by immunohistochemistry that reduction of orexin-A neurons in the hypothalamus, involved in coma status and arousal, enhanced the immunoexpression of ß-APP in parasagital white matter, corpus callosum and brainstem.

Mindfulness and Attention Deficit Hyperactivity Disorder: A Neuropsychological Perspective.

ABSTRACT: Understanding the underlying mechanisms of mindfulness has been a hot topic in recent years, not only in clinical fields but also in neuroscience. Most neuroimaging findings demonstrate that critical brain regions involved in mindfulness are responsible for cognitive functions and mental states. However, the brain is a complex system operating via multiple circuits and networks, rather than isolated brain regions solely responsible for specific functions. Mindfulness-based treatments for attention deficit hyperactivity disorder (ADHD) have emerged as promising adjunctive or alternative intervention approaches. We focus on four key brain circuits associated with mindfulness practices and effects on symptoms of ADHD and its cognitive dysfunction, including executive attention circuit, sustained attention circuit, impulsivity circuit, and hyperactivity circuit. We also expand our discussion to identify three key brain networks associated with mindfulness practices, including central executive network, default mode network, and salience network. We conclude by suggesting that more research efforts need to be devoted into identifying putative neuropsychological mechanisms of mindfulness on how it alleviates ADHD symptoms.

Effects of Venlafaxine, Risperidone and Febuxostat on Cuprizone-Induced Demyelination, Behavioral Deficits and Oxidative Stress.

Multiple sclerosis (MS) is a demyelinating, autoimmune disease that affects a large number of young adults. Novel therapies for MS are needed considering the efficiency and safety limitations of current treatments. In our study, we investigated the effects of venlafaxine (antidepressant, serotonin-norepinephrine reuptake inhibitor), risperidone (atypical antipsychotic) and febuxostat (gout medication, xanthine oxidase inhibitor) in the cuprizone mouse model of acute demyelination, hypothesizing an antagonistic effect on TRPA1 calcium channels. Cuprizone and drugs were administered to C57BL6/J mice for five weeks and locomotor activity, motor performance and cold sensitivity were assessed. Mice brains were harvested for histological staining and assessment of oxidative stress markers. Febuxostat and metabolites of venlafaxine (desvenlafaxine) and risperidone (paliperidone) were tested for TRPA1 antagonistic activity. Following treatment, venlafaxine and risperidone significantly improved motor performance and sensitivity to a cold stimulus. All administered drugs ameliorated the cuprizone-induced deficit of superoxide dismutase activity. Desvenlafaxine and paliperidone showed no activity on TRPA1, while febuxostat exhibited agonistic activity at high concentrations. Our findings indicated that all three drugs offered some protection against the effects of cuprizone-induced demyelination. The agonistic activity of febuxostat can be of potential use for discovering novel TRPA1 ligands.

A rare presentation of Susac syndrome: Report of three pediatric cases.

Susac syndrome is a rare disorder that is clinically characterized by encephalopathy, retinopathy and hearing loss. Most of the reported cases in the literature are adult patients, pediatric presentation is extremely rare. Here we present three pediatric patients aged between 10-15; diagnosed as Susac syndrome. They all had thalamic involvement in addition to typical callosal lesions. All of the three patients had a monophasic course and good treatment response.

Development of human white matter pathways in utero over the second and third trimester.

During the second and third trimesters of human gestation, rapid neurodevelopment is underpinned by fundamental processes including neuronal migration, cellular organization, cortical layering, and myelination. In this time, white matter growth and maturation lay the foundation for an efficient network of structural connections. Detailed knowledge about this developmental trajectory in the healthy human fetal brain is limited, in part, due to the inherent challenges of acquiring high-quality MRI data from this population. Here, we use state-of-the-art high-resolution multishell motion-corrected diffusion-weighted MRI (dMRI), collected as part of the developing Human Connectome Project (dHCP), to characterize the in utero maturation of white matter microstructure in 113 fetuses aged 22 to 37 wk gestation. We define five major white matter bundles and characterize their microstructural features using both traditional diffusion tensor and multishell multitissue models. We found unique maturational trends in thalamocortical fibers compared with association tracts and identified different maturational trends within specific sections of the corpus callosum. While linear maturational increases in fractional anisotropy were seen in the splenium of the corpus callosum, complex nonlinear trends were seen in the majority of other white matter tracts, with an initial decrease in fractional anisotropy in early gestation followed by a later increase. The latter is of particular interest as it differs markedly from the trends previously described in ex utero preterm infants, suggesting that this normative fetal data can provide significant insights into the abnormalities in connectivity which underlie the neurodevelopmental impairments associated with preterm birth.

Chromatin remodeler Arid1a regulates subplate neuron identity and wiring of cortical connectivity.

Loss-of-function mutations in chromatin remodeler gene ARID1A are a cause of Coffin-Siris syndrome, a developmental disorder characterized by dysgenesis of corpus callosum. Here, we characterize Arid1a function during cortical development and find unexpectedly selective roles for Arid1a in subplate neurons (SPNs). SPNs, strategically positioned at the interface of cortical gray and white matter, orchestrate multiple developmental processes indispensable for neural circuit wiring. We find that pancortical deletion of Arid1a leads to extensive mistargeting of intracortical axons and agenesis of corpus callosum. Sparse Arid1a deletion, however, does not autonomously misroute callosal axons, implicating noncell-autonomous Arid1a functions in axon guidance. Supporting this possibility, the ascending axons of thalamocortical neurons, which are not autonomously affected by cortical Arid1a deletion, are also disrupted in their pathfinding into cortex and innervation of whisker barrels. Coincident with these miswiring phenotypes, which are reminiscent of subplate ablation, we unbiasedly find a selective loss of SPN gene expression following Arid1a deletion. In addition, multiple characteristics of SPNs crucial to their wiring functions, including subplate organization, subplate axon-thalamocortical axon cofasciculation ("handshake"), and extracellular matrix, are severely disrupted. To empirically test Arid1a sufficiency in subplate, we generate a cortical plate deletion of Arid1a that spares SPNs. In this model, subplate Arid1a expression is sufficient for subplate organization, subplate axon-thalamocortical axon cofasciculation, and subplate extracellular matrix. Consistent with these wiring functions, subplate Arid1a sufficiently enables normal callosum formation, thalamocortical axon targeting, and whisker barrel development. Thus, Arid1a is a multifunctional regulator of subplate-dependent guidance mechanisms essential to cortical circuit wiring.

Diffuse white matter loss in a transgenic rat model of cerebral amyloid angiopathy.

Diffuse white matter (WM) disease is highly prevalent in elderly with cerebral small vessel disease (cSVD). In humans, cSVD such as cerebral amyloid angiopathy (CAA) often coexists with Alzheimer's disease imposing a significant impediment for characterizing their distinct effects on WM. Here we studied the burden of age-related CAA pathology on WM disease in a novel transgenic rat model of CAA type 1 (rTg-DI). A cohort of rTg-DI and wild-type rats was scanned longitudinally using MRI for characterization of morphometry, cerebral microbleeds (CMB) and WM integrity. In rTg-DI rats, a distinct pattern of WM loss was observed at 9 M and 11 M. MRI also revealed manifestation of small CMB in thalamus at 6 M, which preceded WM loss and progressively enlarged until the moribund disease stage. Histology revealed myelin loss in the corpus callosum and thalamic CMB in all rTg-DI rats, the latter of which manifested in close proximity to occluded and calcified microvessels. The quantitation of CAA load in rTg-DI rats revealed that the most extensive microvascular Aß deposition occurred in the thalamus. For the first time using in vivo MRI, we show that CAA type 1 pathology alone is associated with a distinct pattern of WM loss.

The diffusion-tensor imaging reveals alterations in water diffusion parameters in acute pediatric concussion.

Wide-spread visualization methods which are computed tomography (CT) and magnetic resonance imaging (MRI) are not sensitive to mild traumatic brain injury (mTBI). However, mTBI may cause changes of cerebral microstructure that could be found using diffusion-tensor imaging. The aim of this study is to reveal the impact of acute mTBI (no more than 3 days after trauma) on diffusion parameters in corpus callosum, corticospinal tract, and thalamus in children (aged 14-18). Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were analyzed. Significant increase in FA and decrease in ADC were observed in thalamus. The trend to an increase in FA is observed in corpus callosum.