AN FMRI STUDY EXAMINING THE EFFECTS OF ACUTE D-CYCLOSERINE ADMINISTRATION ON BRAIN ACTIVATIONS AND COGNITIVE FUNCTIONING IN SPIDER PHOBIA

Specific phobias are among the most commonly diagnosed psychiatric disorders. Exposure and Response Prevention (ERP) has become the treatment of choice for specific phobias, and is believed to operate on the basis of fear extinction. Animal studies have shown that acute administration of D-cycloserine (DCS) prior to exposure to a feared stimulus enhances extinction of that fear. Clinical studies in humans have recently demonstrated that DCS facilitates the effects of ERP therapy, presumably through enhancement of memory encoding and consolidation. However, the neural mechanisms underlying these potential benefits of DCS are not understood. The current study used fMRI to examine brain function in subjects with specific phobia and healthy control participants, with and without DCS. The primary objectives of this study were to examine the effects of DCS on 1) neural activity during phobic symptom provocation and 2) neuropsychological functioning. Results provide evidence that DCS enhances activity in prefrontal cortex (PFC), anterior cingulate cortex (ACC), and insular cortex during phobic symptom provocation. This suggests that DCS may enhance cognitive control and interoceptive integration during emotional processing. Neuropsychological assessment provided evidence that specific phobia is associated with subtle differences in cognitive functioning, most notably on decision-making and strategic organization. DCS also had an effect on cognitive functioning, but the direction of influence depended upon clinical anxiety symptoms. The current study is the first investigation of acute DCS effects on neural processing during phobic symptom provocation. It is also the first study to examine acute DCS effects on neuropsychological functioning. Results provide direction for future research examining the use of acute DCS administration in enhancing fear extinction, exposure therapy, and cognitive functioning in general

Computer-Based Executive Function Training for Combat Veterans With PTSD: A Pilot Clinical Trial Assessing Feasibility and Predictors of Dropout

Background: While evidence-based PTSD treatments are often efficacious, 20–50% of individuals continue to experience significant symptoms following treatment. Further, these treatments do not directly target associated neuropsychological deficits. Here, we describe the methods and feasibility for computer-based executive function training (EFT), a potential alternative or adjunctive PTSD treatment.Methods: Male combat veterans with full or partial PTSD (n = 20) and combat-exposed controls (used for normative comparison; n = 20) completed clinical, neuropsychological and functional neuroimaging assessments. Those with PTSD were assigned to EFT (n = 13) or placebo training (word games; n = 7) at home for 6 weeks, followed by repeat assessment. Baseline predictors of treatment completion were explored using logistic regressions. Individual feedback and changes in clinical symptoms, neuropsychological function, and neural activation patterns are described.Results: Dropout rates for EFT and placebo training were 38.5 and 57.1%, respectively. Baseline clinical severity and brain activation (i.e., prefrontal-insula-amygdala networks) during an emotional anticipation task were predictive of treatment completion. Decreases in clinical symptoms were observed following treatment in both groups. EFT participants improved on training tasks but not on traditional neuropsychological assessments. All training completers indicated liking EFT, and indicated they would engage in EFT (alone or as adjunctive treatment) if offered.Conclusion: Results provide an initial framework to explore the feasibility of placebo-controlled, computerized, home-based executive function training (EFT) on psychological and neuropsychological function and brain activation in combat veterans with PTSD. Clinical severity and neural reactivity to emotional stimuli may indicate which veterans will complete home-based computerized interventions. While EFT may serve as a potential alternative or adjunctive PTSD treatment, further research is warranted to address compliance and determine whether EFT may benefit functioning above and beyond placebo interventions

Preliminary Evidence for the Impact of Combat Experiences on Gray Matter Volume of the Posterior Insula

Background: Combat-exposed veteran populations are at an increased risk for developing cardiovascular disease. The anterior cingulate cortex (ACC) and insula have been implicated in both autonomic arousal to emotional stressors and homeostatic processes, which may contribute to cardiovascular dysfunction in combat veteran populations. The aim of the present study was to explore the intersecting relationships of combat experiences, rostral ACC and posterior insula volume, and cardiovascular health in a sample of combat veterans. Method: Twenty-four male combat veterans completed clinical assessment of combat experiences and posttraumatic stress symptoms. Subjects completed a magnetic resonance imaging scan and autosegmentation using FreeSurfer was used to estimate regional gray matter volume (controlling for total gray matter volume) of the rostral ACC and posterior insula. Flow-mediated dilation (FMD) was conducted to assess cardiovascular health. Theil-sen robust regressions andWelch’s analysis of variance were used to examine relationships of combat experiences and PTSD symptomology with (1) FMD and (2) regional gray matter volume. Results: Increased combat experiences, deployment duration, and multiple deployments were related to smaller posterior insula volume. Combat experiences were marginally associated with poorer cardiovascular health. However, cardiovascular health was not related to rostral ACC or posterior insula volume. Conclusion: The present study provides initial evidence for the relationships of combat experiences, deployment duration, and multiple deployments with smaller posterior insula volume. Results may suggest that veterans with increased combat experiences may exhibit more dysfunction regulating the autonomic nervous system, a key function of the posterior insula. However, the relationship between combat and cardiovascular health was not mediated by regional brain volume. Future research is warranted to further clarify the cardiovascular or functional impact of smaller posterior insula volume in combat veterans

Protocol for a randomized controlled trial examining multilevel prediction of response to behavioral activation and exposure-based therapy for generalized anxiety disorder.

BACKGROUND:Only 40-60% of patients with generalized anxiety disorder experience long-lasting improvement with gold standard psychosocial interventions. Identifying neurobehavioral factors that predict treatment success might provide specific targets for more individualized interventions, fostering more optimal outcomes and bringing us closer to the goal of "personalized medicine." Research suggests that reward and threat processing (approach/avoidance behavior) and cognitive control may be important for understanding anxiety and comorbid depressive disorders and may have relevance to treatment outcomes. This study was designed to determine whether approach-avoidance behaviors and associated neural responses moderate treatment response to exposure-based versus behavioral activation therapy for generalized anxiety disorder. METHODS/DESIGN:We are conducting a randomized controlled trial involving two 10-week group-based interventions: exposure-based therapy or behavioral activation therapy. These interventions focus on specific and unique aspects of threat and reward processing, respectively. Prior to and after treatment, participants are interviewed and undergo behavioral, biomarker, and neuroimaging assessments, with a focus on approach and avoidance processing and decision-making. Primary analyses will use mixed models to examine whether hypothesized approach, avoidance, and conflict arbitration behaviors and associated neural responses at baseline moderate symptom change with treatment, as assessed using the Generalized Anxiety Disorder-7 item scale. Exploratory analyses will examine additional potential treatment moderators and use data reduction and machine learning methods. DISCUSSION:This protocol provides a framework for how studies may be designed to move the field toward neuroscience-informed and personalized psychosocial treatments. The results of this trial will have implications for approach-avoidance processing in generalized anxiety disorder, relationships between levels of analysis (i.e., behavioral, neural), and predictors of behavioral therapy outcome. TRIAL REGISTRATION:The study was retrospectively registered within 21 days of first participant enrollment in accordance with FDAAA 801 with ClinicalTrials.gov, NCT02807480. Registered on June 21, 2016, before results

Are Consumers as Constrained as Hens are Confined? Brain Activations and Behavioral Choices after Informational Influence

In 2008, California passed Proposition 2, specifying confinement space for certain farm animals. Proposition 2 went into full effect January 2015 and has significant implications for egg production in California and possibly even interstate commerce. We examined the influence of promotional videos aired during the campaign on consumers’ willingness-to-pay for eggs produced in a more open production system (i.e., cage-free, free range) and corresponding neurofunctional activations during decisions. Forty-six participants (24 females), aged 18–55 years (M=29.65), were enrolled and performed a food decision-making task during fMRI scanning. In each decision, two options of identical one dozen cartons of eggs were presented simultaneously. Below each option were two attributes, describing price and production method. Cage free and free-range eggs were more expensive, at varying degrees. Participants were randomized to one of three 30-second video groups: pro-Proposition 2, anti-Proposition 2, and a Neutral flowing stream. Based on a whole brain analysis, participants in the pro-Proposition 2 video group (N=16) demonstrated significantly greater activations post-video compared to pre-video in left insular cortex and right occipital cortex. This change in insula activity may be indicative of increased social risk involved with the purchase of closed production method eggs, driving participants to increase their percentage of decisions to purchase the higher priced, open-method eggs. It is possible that the insula activation indicates that consumers are constrained to choosing the eggs produced under open-cage production methods, after viewing advertisements advocating for Proposition 2

Always on my mind: Cross-brain associations of mental health symptoms during simultaneous parent-child scanning.

How parents manifest symptoms of anxiety or depression may affect how children learn to modulate their own distress, thereby influencing the children's risk for developing an anxiety or mood disorder. Conversely, children's mental health symptoms may impact parents' experiences of negative emotions. Therefore, mental health symptoms can have bidirectional effects in parent-child relationships, particularly during moments of distress or frustration (e.g., when a parent or child makes a costly mistake). The present study used simultaneous functional magnetic resonance imaging (fMRI) of parent-adolescent dyads to examine how brain activity when responding to each other's costly errors (i.e., dyadic error processing) may be associated with symptoms of anxiety and depression. While undergoing simultaneous fMRI scans, healthy dyads completed a task involving feigned errors that indicated their family member made a costly mistake. Inter-brain, random-effects multivariate modeling revealed that parents who exhibited decreased medial prefrontal cortex and posterior cingulate cortex activation when viewing their child's costly error response had children with more symptoms of depression and anxiety. Adolescents with increased anterior insula activation when viewing a costly error made by their parent had more anxious parents. These results reveal cross-brain associations between mental health symptomatology and brain activity during parent-child dyadic error processing

Pregabalin effects on neural response to emotional faces

Pregabalin has shown promise in the treatment of anxiety disorders. Previous functional magnetic resonance imaging (fMRI) studies indicate agents used to treat anxiety, e.g., SSRIs and benzodiazepines, attenuate amygdala, insula, and medial prefrontal cortex (mPFC) activation during emotional processing. Our prior study has shown that during anticipation of an emotional stimulus, pregabalin attenuates amygdala and insula activation but increases medial PFC activation. In this study, we examined whether, similar to SSRIs and benzodiazepines, pregabalin attenuates amygdala, insula, and medial PFC during emotional face processing. Sixteen healthy volunteers underwent a double-blind within-subjects fMRI study investigating effects of placebo, 50 mg, and 200 mg pregabalin on neural activation during an emotional face-matching task. Linear mixed model analysis revealed that pregabalin dose-dependently attenuated left amygdala activation during fearful face-matching and left anterior insula activation during angry face-matching. The 50 mg dose exhibited more robust effects than the 200 mg dose in the right anterior insula and ventral ACC. Thus, pregabalin shares some similarity to SSRIs and benzodiazepines in attenuating anger and fear-related insula and amygdala activation during emotional face processing. However, there is evidence that a subclinical 50 mg dose of pregabalin produced more robust and widespread effects on neural responses in this paradigm than the more clinically relevant 200 mg dose. Taken together, pregabalin has a slightly different effect on brain activation as it relates to anticipation and emotional face processing, which may account for its unique characteristic as an agent for the treatment of anxiety disorders

EEG Microstates Temporal Dynamics Differentiate Individuals with Mood and Anxiety Disorders From Healthy Subjects

Electroencephalography (EEG) measures the brain’s electrophysiological spatio-temporal activities with high temporal resolution. Multichannel and broadband analysis of EEG signals is referred to as EEG microstates (EEG-ms) and can characterize such dynamic neuronal activity. EEG-ms have gained much attention due to the increasing evidence of their association with mental activities and large-scale brain networks identified by functional magnetic resonance imaging (fMRI). Spatially independent EEG-ms are quasi-stationary topographies (e.g., stable, lasting a few dozen milliseconds) typically classified into four canonical classes (microstates A through D). They can be identified by clustering EEG signals around EEG global field power (GFP) maxima points. We examined the EEG-ms properties and the dynamics of cohorts of mood and anxiety (MA) disorders subjects (n = 61) and healthy controls (HCs; n = 52). In both groups, we found four distinct classes of EEG-ms (A through D), which did not differ among cohorts. This suggests a lack of significant structural cortical abnormalities among cohorts, which would otherwise affect the EEG-ms topographies. However, both cohorts’ brain network dynamics significantly varied, as reflected in EEG-ms properties. Compared to HC, the MA cohort features a lower transition probability between EEG-ms B and D and higher transition probability from A to D and from B to C, with a trend towards significance in the average duration of microstate C. Furthermore, we harnessed a recently introduced theoretical approach to analyze the temporal dependencies in EEG-ms. The results revealed that the transition matrices of MA group exhibit higher symmetrical and stationarity properties as compared to HC ones. In addition, we found an elevation in the temporal dependencies among microstates, especially in microstate B for the MA group. The determined alteration in EEG-ms temporal dependencies among the cohorts suggests that brain abnormalities in mood and anxiety disorders reflect aberrant neural dynamics and a temporal dwelling among ceratin brain states (i.e., mood and anxiety disorders subjects have a less dynamicity in switching between different brain states)

A Nonlinear Simulation Framework Supports Adjusting for Age When Analyzing BrainAGE

Several imaging modalities, including T1-weighted structural imaging, diffusion tensor imaging, and functional MRI can show chronological age related changes. Employing machine learning algorithms, an individual's imaging data can predict their age with reasonable accuracy. While details vary according to modality, the general strategy is to: (1) extract image-related features, (2) build a model on a training set that uses those features to predict an individual's age, (3) validate the model on a test dataset, producing a predicted age for each individual, (4) define the “Brain Age Gap Estimate” (BrainAGE) as the difference between an individual's predicted age and his/her chronological age, (5) estimate the relationship between BrainAGE and other variables of interest, and (6) make inferences about those variables and accelerated or delayed brain aging. For example, a group of individuals with overall positive BrainAGE may show signs of accelerated aging in other variables as well. There is inevitably an overestimation of the age of younger individuals and an underestimation of the age of older individuals due to “regression to the mean.” The correlation between chronological age and BrainAGE may significantly impact the relationship between BrainAGE and other variables of interest when they are also related to age. In this study, we examine the detectability of variable effects under different assumptions. We use empirical results from two separate datasets [training = 475 healthy volunteers, aged 18–60 years (259 female); testing = 489 participants including people with mood/anxiety, substance use, eating disorders and healthy controls, aged 18–56 years (312 female)] to inform simulation parameter selection. Outcomes in simulated and empirical data strongly support the proposal that models incorporating BrainAGE should include chronological age as a covariate. We propose either including age as a covariate in step 5 of the above framework, or employing a multistep procedure where age is regressed on BrainAGE prior to step 5, producing BrainAGE Residualized (BrainAGER) scores