Psychophysiological hallmarks of posttraumatic stress disorder (PTSD) include exaggerated fear responses, impaired inhibition and extinction of conditioned fear, and decreased discrimination between safety and fear cues. This increased fear load associated with PTSD can be a barrier to effective therapy thus indicating the need for new treatments to reduce fear expression in people with PTSD. One potential biological target for reducing fear expression in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is dysregulated in PTSD. Recent translational rodent studies and cross-sectional clinical studies have shown that dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD leads to a decrease in the fear responses characteristic of PTSD. These data, taken together, suggest that dexamethasone may serve as a novel pharmacologic intervention for heightened fear responses in PTSD. We conducted a double-blind, placebo-controlled trial to test our hypothesis that dexamethasone administration and the concomitant suppression of HPA axis hyperactivity would attenuate fear expression and enhance fear extinction in individuals with PTSD. Study participants (n = 62) were recruited from Grady Memorial Hospital in Atlanta, GA. Participants were randomized to receive dexamethasone or placebo prior to fear conditioning and extinction, in a counterbalanced design (treatments separated by a week). Both PTSD- (n = 37) and PTSD+ (n = 25) participants showed significant startle increases in the presence of the danger signal during placebo and dexamethasone treatments (all p < 0.05). However, only PTSD- control participants showed decreases in fear-potentiated startle across extinction blocks during both conditions (p's ≤ 0.001), with PTSD+ participants showing deficits in fear extinction and safety discrimination in the placebo condition. Notably, extinction and discrimination deficits in PTSD+ subjects were markedly reversed with dexamethasone (p < 0.001). These data suggest that dexamethasone may serve as a pharmacological agent with which to facilitate fear extinction and discrimination in individuals with PTSD.
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Thea Hammerschmidt;
Markus P. Kummer;
Dick Terwel;
Ana Martinez;
Ali Gorji;
Hans-Christian Pape;
Karen Rommelfanger;
Jason Schroeder;
Monika Stoll;
Joachim Schultze;
David Weinshenker;
Michael T. Heneka
Background: Degeneration of the locus coeruleus (LC), the major noradrenergic nucleus in the brain, occurs early and is ubiquitous in Alzheimer's disease (AD). Experimental lesions to the LC exacerbate AD-like neuropathology and cognitive deficits in several transgenic mouse models of AD. Because the LC contains multiple neuromodulators known to affect amyloid β toxicity and cognitive function, the specific role of noradrenaline (NA) in AD is not well understood. Methods: To determine the consequences of selective NA deficiency in an AD mouse model, we crossed dopamine β-hydroxylase (DBH) knockout mice with amyloid precursor protein (APP)/presenilin-1 (PS1) mice overexpressing mutant APP and PS1. Dopamine β-hydroxylase (-/-) mice are unable to synthesize NA but otherwise have normal LC neurons and co-transmitters. Spatial memory, hippocampal long-term potentiation, and synaptic protein levels were assessed. Results: The modest impairments in spatial memory and hippocampal long-term potentiation displayed by young APP/PS1 or DBH (-/-) single mutant mice were augmented in DBH (-/-)/APP/PS1 double mutant mice. Deficits were associated with reduced levels of total calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptor 2A and increased N-methyl-D-aspartate receptor 2B levels and were independent of amyloid β accumulation. Spatial memory performance was partly improved by treatment with the NA precursor drug L-threo-dihydroxyphenylserine. Conclusions: These results indicate that early LC degeneration and subsequent NA deficiency in AD may contribute to cognitive deficits via altered levels of calcium/calmodulin-dependent protein kinase II and N-methyl-D-aspartate receptors and suggest that NA supplementation could be beneficial in early AD.
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Sandra Weintraub;
Sureyya S. Dikmen;
Robert K. Heaton;
David S. Tulsky;
Philip David Zelazo;
Jerry Slotkin;
Noelle E. Carlozzi;
Patricia Bauer;
Kathleen Wallner-Allen;
Nathan Fox;
Richard Havlik;
Jennifer L. Beaumont;
Dan Mungas;
Jennifer J. Manly;
Claudia Moy;
Kevin Conway;
Emmeline Edwards;
Cindy J. Nowinski;
Richard Gershon
This study introduces a special series on validity studies of the Cognition Battery (CB) from the U.S. National Institutes of Health Toolbox for the Assessment of Neurological and Behavioral Function (NIHTB) (Gershon, Wagster et al., 2013) in an adult sample. This first study in the series describes the sample, each of the seven instruments in the NIHTB-CB briefly, and the general approach to data analysis. Data are provided on test-retest reliability and practice effects, and raw scores (mean, standard deviation, range) are presented for each instrument and the gold standard instruments used to measure construct validity. Accompanying papers provide details on each instrument, including information about instrument development, psychometric properties, age and education effects on performance, and convergent and discriminant construct validity. One study in the series is devoted to a factor analysis of the NIHTB-CB in adults and another describes the psychometric properties of three composite scores derived from the individual measures representing fluid and crystallized abilities and their combination. The NIHTB-CB is designed to provide a brief, comprehensive, common set of measures to allow comparisons among disparate studies and to improve scientific communication.
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Sureyya S. Dikmen;
Patricia Bauer;
Sandra Weintraub;
Dan Mungas;
Jerry Slotkin;
Jennifer L. Beaumont;
Richard Gershon;
Nancy R. Temkin;
Robert K. Heaton
Episodic memory is one of the most important cognitive domains that involves acquiring, storing and recalling new information. In this article, we describe a new measure developed for the NIH Toolbox, called the Picture Sequence Memory Test (PSMT) that is the first to examine episodic memory across the age range from 3 to 85. We describe the development of the measure and present validation data for ages 20 to 85. The PSMT involves presentation of sequences of pictured objects and activities in a fixed order on a computer screen and simultaneously verbally described, that the participant must remember and then reproduce over three learning trials. The results indicate good test-retest reliability and construct validity. Performance is strongly related to well-established gold standard measures of episodic memory and, as expected, much less well correlated with those of a measure of vocabulary. It shows clear decline with aging in parallel with a gold standard summary measure and relates to several other demographic factors and to self-reported general health status. The PSMT appears to be a reliable and valid test of episodic memory for adults, a finding similar to those found for the same measure with children.
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Rajamannar Ramasubbu;
Svetlana Masalovich;
Ismael Gaxiola;
Scott Peltier;
Paul Holtzheimer;
Christine Heim;
Bradley Goodyear;
Glenda MacQueen;
Helen S Mayberg
The experience of self is unique and pivotal to clinically relevant cognitive and emotional functions. However, well-controlled data on specialized brain regions and functional networks underlying the experience of self remain limited. This functional magnetic resonance imaging study investigated neural activity and connectivity specific to processing one's own face in healthy women by examining neural responses to the pictures of the subjects' own faces in contrast to faces of their own mothers, female friends and strangers during passive viewing, emotional and self-relevance evaluations. The processing of one's own face in comparison to processing of familiar faces revealed significant activity in right anterior insula (AI) and left inferior parietal lobule (IPL), and less activity in right posterior cingulate/precuneus (PCC/PCu) across all tasks. Further, the seed-based correlation analysis of right AI, and left IPL, showed differential functional networks in self and familiar faces contrasts. There were no differences in valence and saliency ratings between self and familiar others. Our preliminary results suggest that the self-experience cued by self-face is processed predominantly by brain regions and related networks that link interoceptive feelings and sense of body ownership to self-awareness and less by regions of higher order functioning such as autobiographical memories.
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Tanya T. Nguyen;
Leila Glass;
Claire Coles;
Julie A Kable;
Philip A. May;
Wendy O. Kalberg;
Elizabeth R. Sowell;
Kenneth L. Jones;
Edward P. Riley;
Sarah N. Mattson
Prenatal alcohol exposure and attention-deficit/hyperactivity disorder (ADHD) result in behavioral issues related to poor executive function (EF). This overlap may hinder clinical identification of alcohol-exposed children. This study examined the relation between parent and neuropsychological measures of EF and whether parent ratings aid in differential diagnosis. Neuropsychological measures of EF, including the Delis-Kaplan Executive Function System (D-KEFS), were administered to four groups of children (8-16 years): alcohol-exposed with ADHD (AE+, n=80), alcohol-exposed without ADHD (AE-, n=36), non-exposed with ADHD (ADHD, n=93), and controls (CON, n=167). Primary caregivers completed the Behavior Rating Inventory of Executive Function (BRIEF). For parent ratings, multivariate analyses of variance revealed main effects of Exposure and ADHD and an interaction between these factors, with significant differences between all groups on nearly all BRIEF scales. For neuropsychological measures, results indicated main effects of Exposure and ADHD, but no interaction. Discriminant function analysis indicated the BRIEF accurately classifies groups. These findings confirm compounded behavioral, but not neuropsychological, effects in the AE+ group over the other clinical groups. Parent-report was not correlated with neuropsychological performance in the clinical groups and may provide unique information about neurobehavior. Parent-report measures are clinically useful in predicting alcohol exposure regardless of ADHD. Results contribute to a neurobehavioral profile of prenatal alcohol exposure.
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Zvinka Z. Zlatar;
Stephen Towler;
Keith McGregor;
Joseph M. Dzierzewski;
Andrew Bauer;
Stephanie Phan;
Matthew Cohen;
Michael Marsiske;
Todd M. Manini;
Bruce Crosson
Functional magnetic resonance imaging (fMRI) studies have identified consistent age-related changes during various cognitive tasks, such that older individuals display more positive and less negative task-related activity than young adults. Recently, evidence shows that chronic physical exercise may alter aging-related changes in brain activity; however, the effect of exercise has not been studied for the neural substrates of language function. Additionally, the potential mechanisms by which aging alters neural recruitment remain understudied. To address these points, the present study enrolled elderly adults who were either sedentary or physically active to characterize the neural correlates of language function during semantic fluency between these groups in comparison to a young adult sample. Participants underwent fMRI during semantic fluency and transcranial magnetic stimulation to collect the ipsilateral silent period, a measure of interhemispheric inhibition. Results indicated that sedentary older adults displayed reductions in negative task-related activity compared to the active old group in areas of the attention network. Longer interhemispheric inhibition was associated with more negative task-related activity in the right and left posterior perisylvian cortex, suggesting that sedentary aging may result in losses in task facilitatory cortical inhibition. However, these losses may be mitigated by regular engagement in physical exercise.
This article primarily represents the contributions of two young investigators to the understanding of the neuropsychological consequences of epilepsy and its treatment. The authors have reviewed two key areas of importance: the complex relationship between cognitive dysfunction and epilepsy and the risks of cognitive dysfunction in children as a consequence of in utero exposure to antiepileptic drug treatment. The work of two young investigators is presented and future research needs are outlined.
Intranasal oxytocin (IN-OT) modulates social perception and cognition in humans and could be an effective pharmacotherapy for treating social impairments associated with neuropsychiatric disorders, like autism. However, it is unknown how IN-OT modulates social cognition, its effect after repeated use, or its impact on the developing brain. Animal models are urgently needed. This study examined the effect of IN-OT on social perception in monkeys using tasks that reveal some of the social impairments seen in autism. Six rhesus macaques ( Macaca mulatta, 4 males) received a 48. IU dose of OT or saline placebo using a pediatric nebulizer. An hour later, they performed a computerized task (the dot-probe task) to measure their attentional bias to social, emotional, and nonsocial images. Results showed that IN-OT significantly reduced monkeys' attention to negative facial expressions, but not neutral faces or clip art images and, additionally, showed a trend to enhance monkeys' attention to direct vs. averted gaze faces. This study is the first to demonstrate an effect of IN-OT on social perception in monkeys, IN-OT selectively reduced monkey's attention to negative facial expressions, but not neutral social or nonsocial images. These findings complement several reports in humans showing that IN-OT reduces the aversive quality of social images suggesting that, like humans, monkey social perception is mediated by the oxytocinergic system. Importantly, these results in monkeys suggest that IN-OT does not dampen the emotional salience of social stimuli, but rather acts to affect the evaluation of emotional images during the early stages of information processing.