Cingulum is widely studied in healthy and psychiatric subjects. For cingulum analysis from diffusion tensor MR imaging, tractography and tract of interest method have been adopted for tract-based analysis. Because tractography performs fiber tracking according to local diffusion measures, they can be sensitive to noise and tracking errors can be accumulated along the fiber. For more accurate localization of cingulum, we attempt to define it by skeleton extraction using the tensors' information throughout the tract of cingulum simultaneously, which is quite different from the idea of tractography. In this study, we introduce an approach to extract the skeleton of cingulum using active contour model, which allows us to optimize the location of cingulum in a global sense based on the diffusion measurements along the entire tract and contour regularity. Validation of this method on synthetic and experimental data proved that our approach is able to reduce the influence of noise and partial volume effect, and extract the skeleton of cingulum robustly and reliably. Our proposed method provides an approach to localize cingulum robustly, which is a very important feature for tract-based analysis and can be of important practical utility.
Background:Implantation of human multipotent stromal cells from bone marrow (hMSCs) into the dentate gyrus of the hippocampus of mice was previously shown to stimulate proliferation, migration and neural differentiation of endogenous neural stem cells. We hypothesized that hMSCs would be beneficial in a mouse model of Huntington disease (HD) due to these neurogenic effects.
Results:We implanted hMSCs into the striatum of transgenic mice (N171-82Q) that are a model for HD. The implanted hMSCs rapidly disappeared over 3 to 15 days. However, they increased proliferation and neural differentiation of endogenous neural stem cells for up to 30 days. They also increased neurotrophic signaling and decreased atrophy of the striatum in 3-month old HD mice implanted with hMSCs one month earlier.
Conclusions:The results therefore suggested that neural implantation of hMSCs may be of benefit in HD but a number of parameters of dose, treatment schedule, and route of administration need to be optimized.
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Virginia A. Rauh;
Frederica P. Perera;
Megan K. Horton;
Robin M. Whyatt;
Ravi Bansal;
Xuejun Hao;
Jun Liu;
Dana Barr;
Theodore Slotkin;
Bradley S. Peterson
Prenatal exposure to chlorpyrifos (CPF), an organophosphate insecticide, is associated with neurobehavioral deficits in humans and animal models. We investigated associations between CPF exposure and brain morphology using magnetic resonance imaging in 40 children, 5.9-11.2 y, selected from a nonclinical, representative community-based cohort. Twenty high-exposure children (upper tertile of CPF concentrations in umbilical cord blood) were compared with 20 low-exposure children on cortical surface features; all participants had minimal prenatal exposure to environmental tobacco smoke and polycyclic aromatic hydrocarbons. High CPF exposure was associated with enlargement of superior temporal, posterior middle temporal, and inferior postcentral gyri bilaterally, and enlarged superior frontal gyrus, gyrus rectus, cuneus, and precuneus along the mesial wall of the right hemisphere. Group differences were derived from exposure effects on underlying white matter. A significant exposure x IQ interaction was derived from CPF disruption of normal IQ associations with surface measures in low-exposure children. In preliminary analyses, high-exposure children did not show expected sex differences in the right inferior parietal lobule and superior marginal gyrus, and displayed reversal of sex differences in the right mesial superior frontal gyrus, consistent with disruption by CPF of normal behavioral sexual dimorphisms reported in animal models. High-exposure children also showed frontal and parietal cortical thinning, and an inverse dose-response relationship between CPF and cortical thickness. This study reports significant associations of prenatal exposure to a widely used environmental neurotoxicant, at standard use levels, with structural changes in the developing human brain.
Adolescents living with human immunodeficiency virus (HIV) comprise approximately 12% of the HIV-positive population worldwide. HIV-positive adolescents experience a higher rate of clinical depression, a greater risk of sexual and drug abuse behaviors, and a decreased adherence to highly active antiretroviral therapies (HAART). Using adolescent HIV-1 transgenic rats (HIV-1 tg) that display related immune response alterations and pathologies, this study tested the hypothesis that developmental expression of HIV-1-related proteins induces a depressive-like phenotype that parallels a decrease in hippocampal cell proliferation and an increase in pro-inflammatory cytokine expression in the hippocampus. Consistent with this hypothesis, adolescent HIV-1 tg rats demonstrated a depressive-like behavioral phenotype, had decreased levels of cell proliferation, and exhibited elevated expression of monocyte chemotactic protein-1 (Mcp-1) in the hippocampus relative to controls. Subsequently, we tested the ability of meloxicam, a selective COX-2 inhibitor, to attenuate behavioral deficits via inflammatory mechanisms. Daily meloxicam treatments did not alter the behavioral profile despite effectively reducing hippocampal inflammatory gene expression. Together, these data support a biological basis for the co-morbid manifestation of depression in HIV-positive patients as early as in adolescence and suggest that modifications in behavior manifest independent of inflammatory activity in the hippocampus.
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Jean-Louis Vincent;
James A Russell;
Matthias Jacob;
Greg Martin;
Bertrand Guidet;
Jan Wernerman;
Ricard Ferrer Roca;
Stuart A McCluskey;
Luciano Gattinoni
Each year, about six million children, including 1.5 million infants, in the United States undergo surgery with general anesthesia, often requiring repeated exposures. However, a crucial question remains of whether neonatal anesthetics are safe for the developing central nervous system (CNS). General anesthesia encompasses the administration of agents that induce analgesic, sedative, and muscle relaxant effects. Although the mechanisms of action of general anesthetics are still not completely understood, recent data have suggested that anesthetics primarily modulate two major neurotransmitter receptor groups, either by inhibiting N-methyl-D-aspartate (NMDA) receptors, or conversely by activating γ-aminobutyric acid (GABA) receptors. Both of these mechanisms result in the same effect of inhibiting excitatory activity of neurons. In developing brains, which are more sensitive to disruptions in activity-dependent plasticity, this transient inhibition may have longterm neurodevelopmental consequences. Accumulating reports from preclinical studies show that anesthetics in neonates cause cellular toxicity including apoptosis and neurodegeneration in the developing brain. Importantly, animal and clinical studies indicate that exposure to general anesthetics may affect CNS development, resulting in long-lasting cognitive and behavioral deficiencies, such as learning and memory deficits, as well as abnormalities in social memory and social activity. While the casual relationship between cellular toxicity and neurological impairments is still not clear, recent reports in animal experiments showed that anesthetics in neonates can affect neurogenesis, which could be a possible mechanism underlying the chronic effect of anesthetics. Understanding the cellular and molecular mechanisms of anesthetic effects will help to define the scope of the problem in humans and may lead to preventive and therapeutic strategies. Therefore, in this review, we summarize the current evidence on neonatal anesthetic effects in the developmental CNS and discuss how factors influencing these processes can be translated into new therapeutic strategies.
The GluN2D subunit of the NMDA receptor is prominently expressed in the basal ganglia and associated brainstem nuclei, including the subthalamic nucleus (STN), globus pallidus, striatum, and substantia nigra. However, little is known about how GluN2D-containing NMDA receptors contribute to synaptic activity in these regions. Using Western blotting of STN tissue punches, we demonstrated that GluN2D is expressed in the rat STN throughout development [age postnatal day 7 (P7)-P60] and in the adult (age P120). Immunoelectron microscopy of the adult rat brain showed that GluN2D is predominantly expressed in dendrites, unmyelinated axons, and axon terminals within the STN. Using subunit-selective allosteric modulators of NMDA receptors (TCN-201, ifenprodil, CIQ, and DQP-1105), we provide evidence that receptors containing the GluN2B and GluN2D subunits mediate responses to exogenously applied NMDA and glycine, as well as synaptic NMDA receptor activation in the STN of rat brain slices. EPSCs in the STN were mediated primarily by AMPA and NMDA receptors and GluN2D-containing NMDA receptors controlled the slow deactivation time course of EPSCs in the STN. In vivo recordings from the STN of anesthetized adult rats demonstrated that the spike firing rate was increased by the GluN2C/D potentiator CIQ and decreased by the GluN2C/D antagonist DQP-1105, suggesting that NMDA receptor activity can influence STN output. These data indicate that the GluN2B and GluN2D NMDA receptor subunits contribute to synaptic activity in the STN and may represent potential therapeutic targets for modulating subthalamic neuron activity in neurological disorders such as Parkinson’s disease.
Hemorrhagic strok e is a devastating disease that lacks effective therapies. In the present investigation, we tested 6-bromoindirubin-3¢-oxime (BIO) as a selective glycogen synthase kinase-3b (GSK-3b) inhibitor in a mouse model of intracerebral hemorrhage (ICH). ICH was induced by injection of collagenase IV into the striatum of 8- to 10-week-old C57BL/6 mice. BIO (8 µg/kg, IP) was administered following either an acute delivery (0–2 h delay) or a prolonged regimen (every 48 h starting at 3 days post-ICH). At 2 days post-ICH, the acute BIO treatment significantly reduced the hematoma volume. In the perihematoma regions, BIO administration blocked GSK-3b phosphorylation/activation, increased Bcl-2 and b-catenin levels, and significantly increased viability of neurons and other cell types. The prolonged BIO regimen maintained a higher level of b-catenin, upregulated VEGF and BDNF, and promoted neurogenesis and angiogenesis in peri-injury zones at 14 days after ICH. The BIO treatment also promoted proliferation of neural stem cells (NSCs) and migration of nascent DCX + neuroblasts from the subventricular zone (SVZ) to the lesioned cortex. BIO improved functional outcomes on both the neurological severity score and rotarod tests. The findings of this study corroborate the neuroprotective and regenerative effects of BIO and suggest that the Wnt/GSK-3b/b-catenin pathway may be explored for the treatment of acute or chronic ICH.
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Ioannis Karakis;
Matthew P. Pase;
Alexa Beiser;
Sarah L. Booth;
Paul F. Jacques;
Gail Rogers;
Charles DeCarli;
Ramachandran S. Vasan;
Thomas J. Wang;
Jayandra J. Himali;
Cedric Annweiler;
Sudha Seshadri
Background: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts.
Objective: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer's disease (AD), MRI markers of brain aging, and neuropsychological function.
Methods: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n=1663), multiple neuropsychological tests (n=1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n=1139).
Results: In adjusted models, participants with vitamin D deficiency (n=104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (β=-0.03 to -0.05±0.02) and the Hooper Visual Organization Test (β=-0.09 to -0.12±0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (β=-0.01±0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD.
Conclusions: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.