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Oguz I.,University of North Carolina at Chapel Hill | Lee J.,UNC | Budin F.,University of North Carolina at Chapel Hill | Rumple A.,University of North Carolina at Chapel Hill | And 5 more authors.
Progress in Biomedical Optics and Imaging - Proceedings of SPIE | Year: 2011

3D Magnetic Resonance (MR) and Diffusion Tensor Imaging (DTI) have become important noninvasive tools for the study of animal models of brain development and neuropathologies. Fully automated analysis methods adapted to rodent scale for these images will allow highthroughput studies. A fundamental first step for most quantitative analysis algorithms is skullstripping, which refers to the segmentation of the image into two tissue categories, brain and non-brain. In this manuscript, we present a fully automatic skull-stripping algorithm in an atlasbased manner. We also demonstrate how to either modify an external atlas or to build an atlas from the population itself to present a self-contained approach. We applied our method to three datasets of rat brain scans, at different ages (PND5, PND14 and adult), different study groups (control, ethanol exposed, intrauterine cocaine exposed), as well as different image acquisition parameters. We validated our method by comparing the automated skull-strip results to manual delineations performed by our expert, which showed a discrepancy of less than a single voxel on average. We thus demonstrate that our algorithm can robustly and accurately perform the skull-stripping within one voxel of the manual delineation, and in a fraction of the time it takes a human expert. © 2011 Copyright Society of Photo-Optical Instrumentation Engineers (SPIE).

Berger L.,University of Wisconsin - Milwaukee | Brondino M.,University of Wisconsin - Milwaukee | Gwyther R.,Bowles Center for Alcohol Studies | Garbutt J.C.,Bowles Center for Alcohol Studies | Garbutt J.C.,University of North Carolina at Chapel Hill
Journal of the American Board of Family Medicine | Year: 2016

Background: In a recent study conducted in a family medicine setting, the medication acamprosate was found not to be efficacious in the treatment of alcohol dependence, but a drinking goal of abstinence was found to have positive effects on alcohol use outcomes. The purpose of this secondary analysis was to further understand which patients with an alcohol use disorder may be most successfully treated in a primary care setting. Methods: The study was exploratory and used a trajectory-based approach based on data from the acamprosate treatment trial of 100 participants (recruited mostly by advertisement) who were randomly assigned to receive either acamprosate or a matching placebo. Post hoc trajectories of alcohol use before treatment were identified to examine whether trajectory classes and their interactions with treatment arm (acamprosate or placebo), pretreatment drinking goal (abstinence or a reduction), and time predicted alcohol use outcomes. Results: Three distinct trajectory classes were identified: frequent drinkers, nearly daily drinkers, and consistent daily drinkers. Consistent daily drinkers with a goal of abstinence significantly improved over time on the primary outcome measure of percent days abstinent when compared with frequent and nearly daily drinkers. In addition, all participants with a goal of abstinence, regardless of trajectory class, significantly reduced their percentage of heavy drinking days over time. Conclusions: Patients with an alcohol use disorder who have a drinking goal of abstinence, in particular consistent daily drinkers, may maximally benefit from alcohol use disorder treatment, including the use of medication, in a primary care setting.

Lovinger D.M.,U.S. National Institutes of Health | Kash T.L.,Bowles Center for Alcohol Studies
Alcohol research : current reviews | Year: 2015

Long-lasting changes in synaptic function (i.e., synaptic plasticity) have long been thought to contribute to information storage in the nervous system. Although synaptic plasticity mainly has adaptive functions that allow the organism to function in complex environments, it is now clear that certain events or exposure to various substances can produce plasticity that has negative consequences for organisms. Exposure to drugs of abuse, in particular ethanol, is a life experience that can activate or alter synaptic plasticity, often resulting in increased drug seeking and taking and in many cases addiction.Two brain regions subject to alcohol's effects on synaptic plasticity are the striatum and bed nucleus of the stria terminalis (BNST), both of which have key roles in alcohol's actions and control of intake. The specific effects depend on both the brain region analyzed (e.g., specific subregions of the striatum and BNST) and the duration of ethanol exposure (i.e., acute vs. chronic). Plastic changes in synaptic transmission in these two brain regions following prolonged ethanol exposure are thought to contribute to excessive alcohol drinking and relapse to drinking. Understanding the mechanisms underlying this plasticity may lead to new therapies for treatment of these and other aspects of alcohol use disorder.

Hayes D.M.,University of North Carolina at Chapel Hill | Fee J.R.,University of North Carolina at Chapel Hill | McCown T.J.,Gene Therapy Center | Knapp D.J.,Bowles Center for Alcohol Studies | And 10 more authors.
Addiction Biology | Year: 2012

Neuropeptide Y (NPY) and protein kinase A (PKA) have been implicated in neurobiological responses to ethanol. We have previously reported that mutant mice lacking normal production of the RIIβ subunit of PKA (RIIβ-/- mice) show enhanced sensitivity to the locomotor stimulant effects of ethanol and increased behavioral sensitization relative to littermate wild-type RIIβ+/+ mice. We now report that RIIβ-/- mice also show increased NPY immunoreactivity in the nucleus accumbens (NAc) core and the ventral striatum relative to RIIβ+/+ mice. These observations suggest that elevated NPY signaling in the NAc and/or striatum may contribute to the increased sensitivity to ethanol-induced behavioral sensitization that is a characteristic of RIIβ-/- mice. Consistently, NPY-/- mice failed to display ethanol-induced behavioral sensitization that was evident in littermate NPY+/+ mice. To examine more directly the role of NPY in the locomotor stimulant effects of ethanol, we infused a recombinant adeno-associated virus (rAAV) into the region of the NAc core of DBA/2J mice. The rAAV-fibronectin (FIB)-NPY 13-36 vector expresses and constitutively secretes the NPY fragment NPY 13-36 (a selective Y 2 receptor agonist) from infected cells in vivo. Mice treated with the rAAV-FIB-NPY 13-36 vector exhibited reduced expression of ethanol-induced behavioral sensitization compared with mice treated with a control vector. Taken together, the current data provide the first evidence that NPY signaling in the NAc core and the Y 2 receptor modulate ethanol-induced behavioral sensitization. © 2011 Society for the Study of Addiction.

Huang M.M.,Bowles Center for Alcohol Studies | Overstreet D.H.,Bowles Center for Alcohol Studies | Overstreet D.H.,University of North Carolina at Chapel Hill | Knapp D.J.,Bowles Center for Alcohol Studies | And 9 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010

In abstinent alcoholics, stress induces negative affect - a response linked to craving and relapse. In rats, repeated stresses at weekly intervals before 5-day ethanol diet sensitize withdrawalinduced anxiety-like behavior ("anxiety") that is blocked by a corticotrophin-releasing factor 1 (CRF-1)-receptor antagonist. Current experiments were performed to identify brain sites that support CRF involvement in stress sensitization of ethanol withdrawal-induced anxiety-like behavior. First, different doses of CRF microinjected weekly into the central amygdala (CeA) before ethanol exposure produced a dose-related sensitization of anxiety during ethanol withdrawal. Subsequently, CRF microinjection into the basolateral amygdala, dorsal raphe nucleus (DRN), or dorsal bed nucleus of the stria terminalis (d-BNST) also sensitized ethanol withdrawal-induced anxiety. In contrast, sensitization of ethanol withdrawal-induced anxiety was not observed after weekly CRF administration into the ventral-BNST, CA1-hippocampal region, or hypothalamic-paraventricular nucleus. Then, experiments documented the CRF receptor subtype responsible for CRF and stress sensitization of withdrawal-induced anxiety. Systemic administration of a CRF-1 receptor antagonist before CRF microinjection into the CeA, DRN, or d-BNST prevented CRF-induced sensitization of anxiety during ethanol withdrawal. Furthermore, repeated microinjections of urocortin-3, a CRF-2 receptor agonist, into the CRF-positive sites did not sensitize anxiety after withdrawal from ethanol. Finally, microinjection of a CRF-1 receptor antagonist into the CeA, DRN, or d-BNST before stress blocked sensitization of anxiety-like behavior induced by the repeated stress/ethanol withdrawal protocol. These results indicate that CRF released by stress acts on CRF-1 receptors within specific brain regions to produce a cumulative adaptation that sensitizes anxiety-like behavior during withdrawal from chronic ethanol exposure. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.

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