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Atypical antipsychotic drugs (AAPDs) are widely used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of AAPD treatment before the brain is fully developed. Indeed, we and others have previously reported that treatment of adolescent rats with olanzapine (OLA; a widely prescribed AAPD) on postnatal days 28–49, under dosing conditions that approximate those employed therapeutically in humans, causes long-term behavioral and neurobiological perturbations. We have begun to study the mechanisms of these effects. Dopamine (DA) and serotonin (5HT) regulate many neurodevelopmental processes. Currently approved AAPDs exert their therapeutic effects principally through their DAergic activities, although in schizophrenia (SZ) and some other diseases for which AAPDs are prescribed, DAergic dysfunction is accompanied by abnormalities of glutamatergic (GLUergic) and γ-aminobutyric acidergic (GABAergic) transmission. Here, we use proton magnetic resonance spectroscopy ( 1 H MRS) to investigate the effects of adolescent OLA administration on GABA and GLU levels. We found that the treatment caused long-term reductions in the levels of both GLU and GABA in the nucleus accumbens (NAc) of adult rats treated with OLA during adolescence. The NAc is a key node in the brain's “reward” system, whose function is also disrupted in schizophrenia. Further research into potential, OLA-induced changes in the levels of GLU and GABA in the NAc and other brain areas, and the dynamics and mechanisms of those changes, are an essential step for devising new adjunct therapies for existing AAPDs and for designing new drugs that increase therapeutic effects and reduce long-term abnormalities when administered to pediatric patients. [ABSTRACT FROM AUTHOR]

Abstract: Galantamine, a drug used to treat Alzheimer''s disease, has recently emerged as a potential medical countermeasure against the toxicity of organophosphorus (OP) compounds, including the nerve agent soman. Here, magnetic resonance imaging (MRI) was used to characterize the neurotoxic effects of soman and the ability of galantamine to prevent these effects in guinea pigs, the best non-primate model to predict the effectiveness of antidotes against OP toxicity in humans. The brains of treated and untreated guinea pigs were imaged using a clinical 3.0 Tesla MRI scanner at 48h before and 6–7h, 48h and 7 days after their challenge with 1.0xLD50 soman (26.6μg/kg, sc). Significant brain atrophy was observed among all untreated animals at 7 days after their challenge with soman. In mildly intoxicated animals, significant shortening of spin–spin relaxation times (T2) was observed in the thalamus and amygdala at 7h after the challenge. In severely intoxicated animals, T2 values and T2-weighted signal intensities increased significantly in the piriform cortex, hippocampus, thalamus and amygdala; in most regions, changes were long-lasting. Voxel-based morphometric analysis of the images revealed that other brain regions were also damaged in these animals. Neuronal loss was confirmed histopathologically. In animals that were treated with galantamine (8mg/kg, im) 30min prior to the exposure to soman, T2, T2-weighted signal intensities, and CSF volumes were largely unaffected. It is, therefore, concluded that galantamine can effectively prevent the structural brain damage induced by an acute exposure to soman. [Copyright &y& Elsevier]

Elevated plasma neurofilament light chain (NfL) is associated with dementia though underlying mechanisms remain unknown. We examined cross-sectional relationships of time-dependent plasma NfL with selected brain structural magnetic resonance imaging (sMRI) prognostic markers of dementia. The sample was drawn from the Healthy Aging in Neighborhoods of Diversity Across the Life Span (HANDLS) study, selecting participants with complete v 1 (2004–2009) and v 2 (2009–2013) plasma NfL exposure and ancillary sMRI data at v scan (2011–2015, n = 179, mean v 1 to v scan time: 5.4 years). Multivariable-adjusted linear regression models were conducted, overall, by sex, and race, correcting for multiple testing with q-values. NfL (v1) was associated with larger WMLV (both Log e transformed), after 5–6 years' follow-up, overall (β = +2.131 ± 0.660, b = +0.29, p = 0.001, and q = 0.0029) and among females. NfLv 2 was linked to a 125 mm3 lower left hippocampal volume (p = 0.004 and q = 0.015) in reduced models, mainly among males, as was observed for annualized longitudinal change in NfL (δNfL bayes). Among African American adults, NfL v1 was inversely related to total, gray and white matter volumes. Plasma NfL may reflect future brain pathologies in middle-aged adults. [ABSTRACT FROM AUTHOR]

Data from diffusion magnetic resonance imaging (dMRI) can be used to reconstruct fiber tracts, for example, in muscle and white matter. Estimation of fiber orientations (FOs) is a crucial step in the reconstruction process and these estimates can be corrupted by noise. In this paper, a new method called Fiber Orientation Reconstruction using Neighborhood Information (FORNI) is described and shown to reduce the effects of noise and improve FO estimation performance by incorporating spatial consistency. FORNI uses a fixed tensor basis to model the diffusion weighted signals, which has the advantage of providing an explicit relationship between the basis vectors and the FOs. FO spatial coherence is encouraged using weighted ℓ 1 -norm regularization terms, which contain the interaction of directional information between neighbor voxels. Data fidelity is encouraged using a squared error between the observed and reconstructed diffusion weighted signals. After appropriate weighting of these competing objectives, the resulting objective function is minimized using a block coordinate descent algorithm, and a straightforward parallelization strategy is used to speed up processing. Experiments were performed on a digital crossing phantom, ex vivo tongue dMRI data, and in vivo brain dMRI data for both qualitative and quantitative evaluation. The results demonstrate that FORNI improves the quality of FO estimation over other state of the art algorithms. [ABSTRACT FROM AUTHOR]

Plasma neurofilament light chain (NfL)'s link to dementia may be mediated through white matter integrity (WMI). In this study, we examined plasma NfL's relationships with diffusion tensor magnetic resonance imaging markers: global and cortical white matter fractional anisotropy (FA) and trace (TR). Plasma NfL measurements at 2 times (v 1 : 2004–2009 and v 2 : 2009–2013) and ancillary dMRI (v scan : 2011–2015) were considered (n = 163, mean time v 1 to v scan = 5.4 years and v 2 to v scan : 1.1 years). Multivariable-adjusted regression models, correcting for multiple-testing revealed that, overall, higher NfL v1 was associated with greater global TR (β ± SE: +0.0000560 ± 0.0000186, b = 0.27, p = 0.003, q = 0.012), left frontal WM TR (β ± SE: + 0.0000706 ± 0.0000201, b ± 0.30, p = 0.001, q = 0.0093) and right frontal WM TR (β ± SE: + 0.0000767 ± 0.000021, b ± 0.31, p < 0.001, q = 0.0093). These associations were mainly among males and White adults. Among African American adults only, NfL v2 was associated with greater left temporal lobe TR. "Tracking high" in NfL was associated with reduced left frontal FA (Model 2, body mass index-adjusted: β ± SE:-0.01084 ± 0.00408, p = 0.009). Plasma NfL is a promising biomarker predicting future brain white matter integrity (WMI) in middle-aged adults. [ABSTRACT FROM AUTHOR]

• Greater RDW v1 was associated with poorer WMI, among males only, particularly in terms of lower mean global fractional anisotropy (FA). • No such associations were found for anemia and δRDW (overall or sex-specific), or for RDW exposures among females and the non-anemic group. Anemia (blood hemoglobin [Hb] <13 g/dL among males; <12 g/dL among females) and elevated red cell distribution width (RDW) are potential risk factors for reduced brain white matter integrity (WMI), reflected by lower fractional anisotropy or increased mean diffusivity. Cross-sectional data with exposure-outcome lag time was used, whereby hematological exposures (RDW and Hb) and covariates were compiled from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study with available visit 1 (v 1 ; 2004–2009) and/or v 2 (2009–2013) data; while diffusion tensor magnetic resonance imaging (dMRI) outcome data were collected at HANDLS SCAN visit (v scan : 2011–2015, n = 214, mean follow-up from v 1 ±SD: 5.6 ± 1.8 year). Multivariable-adjusted linear regression analyses were conducted, overall, stratifying by sex, and further restricting to the nonanemic for RDW exposures in part of the analyses. Among males, RDW (v1) was linked with lower global mean fractional anisotropy (standardized effect size b = −0.30, p = 0.003, q < 0.05; basic model), an association only slightly attenuated with further covariate adjustment. Anemia was not a risk factor for poor WMI, independently of RDW. Ultimately, pending further longitudinal evidence, initial RDW appears to be associated with poorer WMI among males. [ABSTRACT FROM AUTHOR]

Purpose: Prostate brachytherapy (PB) entails the placement of radioactive sources throughout the entire prostate gland to treat localized cancer. Typically, the target volume in PB encompasses the entire prostate gland because of the inability to localize the cancer and the multifocal nature of this malignancy. However, because of the unique biochemical nature of the prostate gland, recent advances in magnetic resonance spectroscopic imaging (MRSI) of the prostate have allowed precise delineation of the cancer location within the prostate gland. This report reveals our initial experience of MRSI-guided PB.Methods: An MRSI study was obtained in 15 favorable-risk (prostate-specific antigen level ≤10 ng/mL, Gleason score ≤6, and clinical Stage ≤T2a) patients before their scheduled PB. The results of this study were used to internally map 7 × 7 × 9-mm volumes of prostate tissue to assign cancerous areas a higher dose of radiation. Such tumor-bearing areas had a low citrate/(choline+creatine) ratio consistent with cancer. On the basis of the anatomic MRI and MRSI correlation, three-dimensional coordinates were assigned to the locations of MRSI-defined cancer. The entire target volume was treated to 145 Gy using 125I. Abnormal citrate regions, termed the biologic tumor volume, were prescribed a dose of 130% of the target volume dose (188 Gy) to dose escalate in the abnormal citrate regions while respecting the normal radiation tolerances of the surrounding areas. Three-dimensional treatment planning was used to perform the implant.Results: Of the 15 prostate cancer patients evaluated, all had successful three-dimensional MRSI acquisition before their scheduled PB procedure. In 14 of the 15 patients planned with MRSI, the data were successfully incorporated into their treatment planning and were used to increase the radiation dose prescription to 130% in the MRSI-defined volumes. In 1 patient, MRSI revealed significant multifocal disease that made focal boosts impractical. Postimplant dosimetry confirmed a median V100 of 95% (range 89–98%) in the 15 evaluated patients for the prescription dose of 145 Gy to the target volume. Furthermore, the median BTV100 for the abnormal citrate region was 90% (range 80–100%) as determined by postimplant dosimetry. Urethral and rectal dose-volume histograms were within normal limits. Morbidity was comparable with that for conventionally treated patients.Conclusion: MRSI offers a promising new approach for the delivery of ionizing radiation in PB. Although this series was small and with a short follow-up, MRSI-guided implants are feasible and warrant further investigation as a means of improving the therapeutic ratio in PB. [Copyright &y& Elsevier]

Pronounced spin phase artifacts appear in diffusion-weighted imaging (DWI) with only minor subject motion. While DWI data corruption is often identified as signal drop out in diffusion-weighted (DW) magnitude images, DW phase images may have higher sensitivity for detecting subtle subject motion. This article describes a novel method to return a metric of subject motion, computed using an image texture analysis of the DW phase image. This Phase Image Texture Analysis for Motion Detection in dMRI (PITA-MDD) method is computationally fast and reliably detects subject motion from diffusion-weighted images. A threshold of the motion metric was identified to remove motion-corrupted slices, and the effect of removing corrupted slices was assessed on the reconstructed FA maps and fiber tracts. Using a motion-metric threshold to remove the motion-corrupted slices results in superior fiber tracts and fractional anisotropy maps. When further compared to a state-of-the-art magnitude-based motion correction method, PITA-MDD was able to detect comparable corrupted slices in a more computationally efficient manner. In this study, we evaluated the use of DW phase images to detect motion corruption. The proposed method can be a robust and fast alternative for automatic motion detection in the brain with multiple applications to inform prospective motion correction or as real-time feedback for data quality control during scanning, as well as after data is already acquired. [ABSTRACT FROM AUTHOR]

This study was designed to test the hypothesis that prenatal exposure of guinea pigs to the organophosphorus (OP) pesticide chlorpyrifos (CPF) disrupts the structural and functional integrity of the brain. Pregnant guinea pigs were injected with chlorpyrifos (25 mg/kg, s.c.) or vehicle (peanut oil) once per day for 10 consecutive days, starting approximately on the 50th day of gestation. Cognitive behavior of female offspring was examined starting at 40–45 post-natal days (PND) using the Morris water maze (MWM), and brain structural integrity was analyzed at PND 70 using magnetic resonance imaging (MRI) methods, including T 2 -weighted anatomical scans and diffusion kurtosis imaging (DKI). The offspring of exposed mothers had significantly decreased body weight and brain volume, particularly in the frontal regions of the brain including the striatum. Furthermore, the offspring demonstrated significant spatial learning deficits in MWM recall compared to the vehicle group. Diffusion measures revealed reduced white matter integrity within the striatum and amygdala that correlated with spatial learning performance. These findings reveal the lasting effect of prenatal exposure to CPF as well as the danger of mother to child transmission of CPF in the environment. [ABSTRACT FROM AUTHOR]

Abstract: In this study we investigated the functional connectivity in 23 Mild TBI (mTBI) patients with and without memory complaints using resting state fMRI in the sub-acute stage of injury as well as a group of control participants. Results indicate that mTBI patients with memory complaints performed significantly worse than patients without memory complaints on tests assessing memory from the Automated Neuropsychological Assessment Metrics (ANAM). Altered functional connectivity was observed between the three groups between the default mode network (DMN) and the nodes of the task positive network (TPN). Altered functional connectivity was also observed between both the TPN and DMN and nodes associated with the Salience Network (SN). Following mTBI there is a reduction in anti-correlated networks for both those with and without memory complaints for the DMN, but only a reduction in the anti-correlated network in mTBI patients with memory complaints for the TPN. Furthermore, an increased functional connectivity between the TPN and SN appears to be associated with reduced performance on memory assessments. Overall the results suggest that a disruption in the segregation of the DMN and the TPN at rest may be mediated through both a direct pathway of increased FC between various nodes of the TPN and DMN, and through an indirect pathway that links the TPN and DMN through nodes of the SN. This disruption between networks may cause a detrimental impact on memory functioning following mTBI, supporting the Default Mode Interference Hypothesis in the context of mTBI related memory deficits. [Copyright &y& Elsevier]

Highlights: [•] We developed an automatic rat brain extraction algorithm, called the Rat Brain Deformable model method (RBD). [•] RBD is based on the deformable surface model. [•] RBD outperformed the existing rat brain extraction methods. [•] RBD achieved a higher accuracy of >92% volume overlap for brain extraction. [•] RBD was also robust against signal inhomogeneity in the images. [Copyright &y& Elsevier]

Abstract: This study was designed to test the hypothesis that in vivo magnetic resonance imaging (MRI) and spectroscopy (MRS) can detect in adulthood the neurotoxic effects of a single exposure of prepubertal guinea pigs to the organophosphorus pesticide chlorpyrifos. Twelve female guinea pigs were given either a single dose of chlorpyrifos (0.6×LD50 or 300mg/kg, sc) or peanut oil (vehicle; 0.5ml/kg, sc) at 35–40 days of age. One year after the exposure, the animals were tested in the Morris water maze. Three days after the end of the behavioral testing, the metabolic and structural integrity of the brain of the animals was examined by means of MRI/MRS. In the Morris water maze, the chlorpyrifos-exposed guinea pigs showed significant memory deficit. Although no significant anatomical differences were found between the chlorpyrifos-exposed guinea pigs and the control animals by in vivo MRI, the chlorpyrifos-exposed animals showed significant decreases in hippocampal myo-inositol concentration using MRS. The present results indicate that a single sub-lethal exposure of prepubertal guinea pigs to the organophosphorus pesticide chlorpyrifos can lead to long-term memory deficits that are accompanied by significant reductions in the levels of hippocampal myo-inositol. [Copyright &y& Elsevier]