Development of the Blast Ordnance and Occupational Exposure Measure for Self-Reported Lifetime Blast Exposures.

INTRODUCTION: To address the military gap in the standardized collection of lifetime blast exposures across clinical and research endeavors, researchers at the National Intrepid Center of Excellence (NICoE) completed a quality improvement project that utilized systematic, iterative focus groups that leveraged the input from various stakeholders including subject matter experts, clinical providers, and service members (SMs) to develop a comprehensive, self-report blast exposure inventory that could be completed within 5-10 minutes. This manuscript outlines the process of the development of this inventory. MATERIALS AND METHODS: This project included three phases of focus groups that occurred at the NICoE between August 2020 and March 2021 to collect feedback and input from relevant military stakeholders. The study team utilized related assessments available in the literature, together with clinical experience with the NICoE patient population, to inform the development of an initial draft inventory. Phase 1 consisted of blast injury research subject matter experts who had extensive experience researching and providing clinical care to SMs exposed to blast. Phase 2 consisted of NICoE clinicians across numerous clinical specialties. Phase 3 included current active duty patients in the NICoE intensive outpatient program. RESULTS: Following completion of the focus groups, a lifetime blast exposure inventory was developed in the form of a single page table including incoming, outgoing, training, and operational exposures and broken down by levels of weapon systems as well as breaching and explosive ordnance disposal exposures. In addition, select questions related to the first and most recent blast exposures and experience as an instructor for explosive ordnance disposal- and breaching-related training were included. CONCLUSIONS: Researchers at the NICoE developed a self-report blast exposure inventory through a quality improvement project that included active, ongoing participation and feedback of clinical experts and military SMs. The end result is a brief, single page inventory that can be administered within 5-10 minutes. Although additional research is needed to refine and validate the inventory, the project team believes that the tool begins to address a long-standing gap in the DoD in the standardized collection of lifetime blast exposures.

Decreases in White Matter Integrity of Ventro-Limbic Pathway Linked to Post-Traumatic Stress Disorder in Mild Traumatic Brain Injury.

Post-traumatic stress disorder (PTSD) is commonly observed in military service members with mild traumatic brain injury (mTBI); however, the relationship between mTBI and PTSD is complex and not well understood. The present study aims to elucidate a link between the degree of alteration in limbic system-related white matter tracts and PTSD symptoms in an mTBI population. Diffusion-tensor imaging (DTI) with probabilistic tractography of the fronto-limbic pathways revealed decreased white matter integrity in the uncinate fasciculus in those with co-morbid mTBI and PTSD (n = 34), relative to those with only mTBI (n = 35). Additionally, fractional anisotropy (FA) and radial diffusivity (RD) measures in the bilateral uncinate fasciculus correlated with Post-Traumatic Stress Disorder Checklist Civilian version (PCL-C) scores, and primarily within the avoidance and re-experiencing domains. Findings from this study suggest the degree of traumatic injury within the limbic system could be directly related to post-traumatic stress and post-concussive symptoms, with disrupted white matter leading to significant PTSD outcomes.

An Exploratory Study of Exercise-related Effects on Memory and Hippocampal Connectivity in Schizophrenia.

Memory impairment in schizophrenia has been linked to abnormal functioning of fronto-temporal networks. In this pilot study, we investigated whether 12-weeks of exercise improved hippocampal-dependent memory functions and resting-state functional connectivity in middle-aged adults with schizophrenia. The exercise regimen was feasible, well-attended, and safe. There was a pre- to post-intervention increase in spatial memory accuracy that was correlated to an increase in hippocampal-prefrontal cortex connectivity. No increase was found in pattern separation performance or hippocampal volume. A controlled trial is needed to replicate these findings and elucidate the functional brain networks underlying exercise-induced cognitive improvement in schizophrenia.

The Adolescent Brain Cognitive Development (ABCD) study: Imaging acquisition across 21 sites.

The ABCD study is recruiting and following the brain development and health of over 10,000 9-10 year olds through adolescence. The imaging component of the study was developed by the ABCD Data Analysis and Informatics Center (DAIC) and the ABCD Imaging Acquisition Workgroup. Imaging methods and assessments were selected, optimized and harmonized across all 21 sites to measure brain structure and function relevant to adolescent development and addiction. This article provides an overview of the imaging procedures of the ABCD study, the basis for their selection and preliminary quality assurance and results that provide evidence for the feasibility and age-appropriateness of procedures and generalizability of findings to the existent literature.

Probing behavioral responses to food: development of a food-specific go/no-go task.

The ability to exert self-control in the face of appetitive, alluring cues is a critical component of healthy development. The development of behavioral measures that use disease-relevant stimuli can greatly improve our understanding of cue-specific impairments in self-control. To produce such a tool relevant to the study of eating and weight disorders, we modified the traditional go/no-go task to include food and non-food targets. To confirm that performance on this new task was consistent with other go/no-go tasks, it was given to 147 healthy, normal weight volunteers between the ages of 5 and 30. High-resolution photos of food or toys were used as the target and nontarget stimuli. Consistent with expectations, overall improvements in accuracy were seen from childhood to adulthood. Participants responded more quickly and made more commission errors to food cues compared to nonfood cues (F(1,140)=21.76, P<0.001), although no behavioral differences were seen between low- and high-calorie food cues for this non-obese, healthy developmental sample. This novel food-specific go/no-go task may be used to track the development of self-control in the context of food cues and to evaluate deviations or deficits in the development of this ability in individuals at risk for eating problem behaviors and disorders.

Adolescents let sufficient evidence accumulate before making a decision when large incentives are at stake.

Adolescent decision-making has been described as impulsive and suboptimal in the presence of incentives. In this study we examined the neural substrates of adolescent decision-making using a perceptual discrimination task for which small and large rewards were associated with correctly detecting the direction of motion of a cloud of moving dots. Adults showed a reward bias of faster reaction times on trials for which the direction of motion was associated with a large reward. Adolescents, in contrast, were slower to make decisions on trials associated with large rewards. This behavioral pattern in adolescents was paralleled by greater recruitment of fronto-parietal regions important in representing the accumulation of evidence sufficient for selecting one choice over its alternative and the certainty of that choice. The findings suggest that when large incentives are dependent on performance, adolescents may require more evidence to accumulate prior to responding, to be certain to maximize their gains. Adults, in contrast, appear to be quicker in evaluating the evidence for a decision when primed by rewards. Overall these findings suggest that rather than reacting hastily, adolescents can be incentivized to take more time to make decisions when large rewards are at stake. A video abstract of this article can be viewed at http://youtu.be/1g4F5vzFDl0.

Behavioral and neural correlates of delay of gratification 40 years later.

We examined the neural basis of self-regulation in individuals from a cohort of preschoolers who performed the delay-of-gratification task 4 decades ago. Nearly 60 individuals, now in their mid-forties, were tested on "hot" and "cool" versions of a go/nogo task to assess whether delay of gratification in childhood predicts impulse control abilities and sensitivity to alluring cues (happy faces). Individuals who were less able to delay gratification in preschool and consistently showed low self-control abilities in their twenties and thirties performed more poorly than did high delayers when having to suppress a response to a happy face but not to a neutral or fearful face. This finding suggests that sensitivity to environmental hot cues plays a significant role in individuals' ability to suppress actions toward such stimuli. A subset of these participants (n = 26) underwent functional imaging for the first time to test for biased recruitment of frontostriatal circuitry when required to suppress responses to alluring cues. Whereas the prefrontal cortex differentiated between nogo and go trials to a greater extent in high delayers, the ventral striatum showed exaggerated recruitment in low delayers. Thus, resistance to temptation as measured originally by the delay-of-gratification task is a relatively stable individual difference that predicts reliable biases in frontostriatal circuitries that integrate motivational and control processes.

Atypical prefrontal connectivity in attention-deficit/hyperactivity disorder: pathway to disease or pathological end point?

Functional neuroimaging studies have identified multiple nodes of dysfunction in frontostriatal and mesocorticolimbic networks in attention-deficit/hyperactivity disorder (ADHD). Yet relatively few studies have examined how structural and functional connectivity between nodes in these networks might relate to the behavioral symptoms of ADHD. Moreover, it is unknown whether abnormalities in connectivity are a primary cause of symptoms or arise secondary to common etiologic mechanisms. We review the most recent diffusion tensor imaging and functional magnetic resonance imaging studies of connectivity in ADHD to characterize associations between frontostriatal connectivity abnormalities and the behavioral symptoms of inattention and impulsivity in ADHD. Furthermore, we examine how structural and functional connectivity measures relate to environmental and genetic pathways to ADHD. Diffusion tensor imaging studies indicate that ADHD is associated with significant irregularities in white matter microstructure, especially in frontostriatal and select corticocortical tracts. Resting state functional magnetic resonance imaging studies implicate altered connectivity within a default mode network of structures active during introspective, task-free processes and disrupted interactions between this network and frontostriatal attentional systems. Deficits in functional connectivity within frontostriatal and mesocorticolimbic networks might give rise, in part, to ADHD symptoms. Conversely, structural connectivity deficits and ADHD symptoms might arise incidentally from a common etiologic mechanism, involving altered modulation of synaptic potentiation and pruning by dopamine and other factors during development. Collectively, these studies suggest that the core symptoms of ADHD might derive from dysregulated modulation of cortical plasticity in the developing brain, resulting in altered patterns of corticocortical connectivity that might persist into adulthood.

'Willpower' over the life span: decomposing self-regulation.

In the 1960s, Mischel and colleagues developed a simple 'marshmallow test' to measure preschoolers' ability to delay gratification. In numerous follow-up studies over 40 years, this 'test' proved to have surprisingly significant predictive validity for consequential social, cognitive and mental health outcomes over the life course. In this article, we review key findings from the longitudinal work and from earlier delay-of-gratification experiments examining the cognitive appraisal and attention control strategies that underlie this ability. Further, we outline a set of hypotheses that emerge from the intersection of these findings with research on 'cognitive control' mechanisms and their neural bases. We discuss implications of these hypotheses for decomposing the phenomena of 'willpower' and the lifelong individual differences in self-regulatory ability that were identified in the earlier research and that are currently being pursued.

A genetic variant BDNF polymorphism alters extinction learning in both mouse and human.

Mouse models are useful for studying genes involved in behavior, but whether they are relevant to human behavior is unclear. Here, we identified parallel phenotypes in mice and humans resulting from a common single-nucleotide polymorphism in the brain-derived neurotrophic factor (BDNF) gene, which is involved in anxiety-related behavior. An inbred genetic knock-in mouse strain expressing the variant BDNF recapitulated the phenotypic effects of the human polymorphism. Both were impaired in extinguishing a conditioned fear response, which was paralleled by atypical frontoamygdala activity in humans. Thus, this variant BDNF allele may play a role in anxiety disorders showing impaired learning of cues that signal safety versus threat and in the efficacy of treatments that rely on extinction mechanisms, such as exposure therapy.

Nuclear factor 90 mediates activation of the cellular antiviral expression cascade.

Viral infection triggers a cascade of interferon response genes, but the mechanisms that prime such innate antiviral defenses are poorly understood. Among candidate cellular mediators of the antiviral response are the double-stranded RNA (dsRNA)-binding proteins. Here we show that a C-terminal variant of the ubiquitous dsRNA-binding protein, nuclear factor 90 (NF90ctv), can activate the interferon response genes in the absence of viral infection. NF90ctv-expressing cells were infected with the syncytium-inducing HIV-1 strain NL4-3 and were shown to inhibit viral replication. To gain insight into this mechanism of protection, we analyzed the expression profiles of NF90ctv-positive cells as compared with parental cells transduced with the empty vector. Of the 5600 genes represented on the expression arrays, 90 displayed significant (4-fold or more) changes in mRNA levels in NF90-expressing cells. About 50% are known interferon alpha/beta-stimulated genes. The microarray expression data were confirmed by quantitative reverse transcriptase-polymerase chain reaction analysis of six representative interferon-inducible genes. Electrophoretic mobility shift assays showed that the biological response is mediated by the activation of transcription factors in NF90ctv-expressing cells. Functional significance of the activated transcription complex was evaluated by transfection assays with luciferase reporter constructs driven by the interferon-inducible promoter from the 2'-5'-oligoadenylate synthetase (p69) gene. Resistance to HIV-1, caused by the expression of NF90ctv in the cell culture system, appears to be mediated in part by the induction of interferon response genes. This leads to a hypothesis as to the mechanism of action of NF90 in mediating endogenous antiviral responses.