Transcutaneous Auricular Vagus Nerve Stimulation Attenuates Early Increases in Heart Rate Associated With the Cold Pressor Test.

INTRODUCTION: Transcutaneous auricular vagus nerve stimulation (taVNS) may be useful in treating disorders characterized by chronic parasympathetic disinhibition. Acute taVNS decreases resting heart rate in healthy individuals, but little is known regarding the effects of taVNS on the cardiac response to an acute stressor. To investigate effects on the acute stress response, we investigated how taVNS affected heart rate changes during a cold pressor test (CPT), a validated stress induction technique that reliably elicits a sympathetic stress response with marked increases in heart rate, anxiety, stress, and pain. MATERIALS AND METHODS: We recruited 24 healthy adults (ten women, mean age = 29 years) to participate in this randomized, crossover, exploratory trial. Each subject completed two taVNS treatments (one active, one sham) paired with CPTs in the same session. Order of active versus sham stimulation was randomized. Heart rate, along with ratings of anxiety, stress, and pain, was collected before, during, and after each round of taVNS/sham + CPT. RESULTS: In both stimulation conditions, heart rate was elevated from baseline in response to the CPT. Analyses also revealed a difference between active and sham taVNS during the first 40 seconds of the CPT (Δ heart rate [HR] = 12.75 ± 7.85 in the active condition; Δ HR = 16.09 ± 11.43 in the sham condition, p = 0.044). There were no significant differences in subjective ratings between active and sham taVNS. CONCLUSIONS: In this randomized, sham-controlled study, taVNS attenuated initial increases in HR in response to the CPT. Future studies are needed to investigate the effects of various taVNS doses and parameters on the CPT, in addition to other forms of stress induction. CLINICAL TRIAL REGISTRATION: The Clinicaltrials.gov registration number for the study is NCT00113453.

Psychometric Properties of the Iranian Version of Contrast Avoidance Questionnaires: Could Contrast Avoidance Be a New Transdiagnostic Construct?

The contrast avoidance model (CAM) hypothesizes that individuals with chronic worry recruit worry to create and maintain a negative emotional state to avoid sudden increases in negative emotions. Preliminary evidence using the contrast avoidance questionnaires (CAQs) suggests that there might be a similar mechanism across mood and other anxiety disorders. To continue to assess the CAQs, they should be adapted for other languages and evaluated across multiple symptom domains. The present study aimed to develop the Persian versions of the CAQs and examine the transdiagnostic nature of CAM across two studies. A large Persian-speaking college student sample (Total n = 1438) was used to evaluate the factor structure of the CAQs (Study 1) and the psychometric properties of CAQs (Study 2). Results supported the two-factor structure of the CAQ-W (worry) and CAQ-GE (general emotion). Results showed that CAQ-W was a significant predictor of anxiety-related measures. However, CAQ-GE and IUS-12 significantly predicted depressive and other symptoms over the CAQ-W. Results demonstrated excellent psychometric properties. They indicate that contrast avoidance, measured via CAQ-GE, could be a transdiagnostic construct, and CAQ-W may be more sensitive to anxiety-specific contrast avoidance among Persian speaking and/or Iranian individuals.

The influence of self-focused attention on emotional picture processing: An ERP study.

Research has documented neurophysiological indicators of anticipation (Stimulus Preceding Negativity [SPN]) and perception (Late Positive Potential [LPP]) of threat, yet little is known as to how self-focused attention manipulations influence emotion processing within the context of cued picture viewing. With self-referent attention moderating attention to external stimuli, it is necessary to document how self-focused attention impacts attention and the ability to emotionally process external threat. The goal of the present study was to evaluate the impact of self-focused attention on the anticipation and perceptual processing of unpleasant pictures within a cued-picture viewing paradigm among 33 participants. Overall, the results suggest that the self-focused attention manipulations disrupted anticipation but not processing of pictures, as indexed by the SPN and LPP respectively. Self-focused attention appears to disrupt the preparatory attention for upcoming unpleasant stimuli, potentially through loading cognitive resources or activation of associative defensive responding. Collectively, these findings demonstrate the impact of self-focused attention within the context of emotional picture processing and suggest further areas of investigation.

Coping in the Clinic: Effects of Clinically Elevated Anxiety on Dynamic Neurophysiological Mechanisms of Escape/Avoidance Preparation.

BACKGROUND: Treatments for anxiety and related disorders target exaggerated escape/avoidance as a core feature, but current methods fail to improve escape/avoidance habits for many treatment-seeking individuals. To support developing tools that increase treatment efficacy by targeting mechanisms more directly, the current work examined potential distinctions in the neurophysiologies of escape and avoidance and tested how clinical anxiety affects these neurophysiologies. METHODS: Twenty-five treatment-seeking individuals with varied principal diagnoses (e.g., generalized anxiety disorder, posttraumatic stress disorder) and 20 non-treatment-seeking control subjects participated. In the study task, approximately 5.25-second cues predicted aversive images that could be avoided (blocked by a button press before image onset), escaped (ended by a button press after image onset), or not controlled. To examine neural processing and defensive response modulation, anticipatory event-related potentials were derived, and startle reflexes were probed throughout each cue. RESULTS: Multidimensional profiles were observed such that 1) anticipatory event-related potential enhancement was only reliable during avoidance preparation, and event-related potentials potentially reflected perceived/instrumental control; and 2) startle reflexes were inhibited during avoidance preparation, relatively enhanced during escape preparation, and further enhanced during uncontrollable anticipation, thus potentially reflecting fear-related activation. Treatment-seeking status, then, did not affect cortical processing, but it did moderate context-dependent fear (if individuals with severe depression were excluded) such that treatment-seeking individuals without depression showed exaggerated startle during escape, but not avoidance, preparation. CONCLUSIONS: Data suggest a specific effect of anxiety on fear system activation during preparation to escape aversion. This effect warrants further investigation as a precision target for interventions that directly modulate the specific underlying neural circuitry.

Documenting the late positive potential towards self-imagery within social anxiety.

Models of social anxiety propose that negative self-imagery is a maintenance factor of psychopathology, yet the mechanisms of this relationship are unclear. One proposed mechanism is attention towards self-images. However, self-image creation does not occur in isolation and is likely influenced by other mechanisms, such as anticipatory processing (AP). The current study aimed to investigate how trait social anxiety and AP influence motivated attention during self-imagery (i.e., late-positive potential; LPP). Participants (N = 40) with a mean age of 18.95 (SD = 1.22) completed AP manipulations and a self-imagery task. Results revealed that participants with high levels of social anxiety who engaged in AP demonstrated blunted LPP activity in the late time window (6000-10,000 ms) relative to those who engaged in Distraction. These results suggest that motivated attention towards self-imagery may be impacted by anticipatory processing, but less influenced by the valence of self-imagery. Given previous research has been limited in methodology, this study expands upon current research by documenting the neural mechanisms of self-imagery manipulations within social anxiety.

Independent Psychometric Evaluation and Predictive Utility of The Social Anxiety Questionnaire.

The Social Anxiety Questionnaire (SAQ) is a 10-item measure of social anxiety developed to comprehensively and concisely target the mechanisms described in Clark and Wells' model of social anxiety and address the breadth of social anxiety symptoms which may not all be encompassed in existing questionnaires. The aim of the current studies is to independently investigate the factor structure of the SAQ (i.e., Study 1 and 2) and determine its predictive validity and utility (i.e., Study 3 and 4). Data were collected across 4 studies to evaluate the factor structure and utility. Overall, the results suggest that a total summed score of the SAQ appeared to capture unique aspects of social anxiety that may not be captured using a single measure and appears to provide utility in experimental manipulations of theoretical maintenance factors. The current study was limited by a convenience sample and future research should continue to document the psychometric properties and clinical utility of this novel measure of social anxiety. The SAQ may show promise in both correlational and experimental research but future research should consider further evaluation of its utility.

The Effect of Phenazopyridine on Immediate Postoperative Voiding After Prolapse Surgery: A Randomized Controlled Trial.

OBJECTIVES: The objective of our study was to determine if phenazopyridine reduces void trial (VT) failure rates after prolapse surgery. METHODS: A single-institution randomized controlled trial was conducted comparing a second dose of phenazopyridine 200 mg on postoperative day 1 versus no additional phenazopyridine in women undergoing prolapse surgery. All subjects (including controls) received 200 mg of phenazopyridine preoperatively for ureteral patency verification. The intervention group received a second dose of phenazopyridine 200 mg the morning of postoperative day 1. The primary outcome was assessed using a standardized VT. Secondary outcomes included pain, opioid usage, urinary tract infections, and prolonged or recurrent urinary retention. An intent-to-treat analysis was performed with a χ2 test to compare failure rates between the intervention and control groups. RESULTS: We enrolled 152 women, and 76 were randomized to each group. There was no difference in VT failures between the 2 groups-34% failed without phenazopyridine on postoperative day 1, and 42% failed with phenazopyridine on postoperative day 1 (P = 0.326). Subject characteristics were similar across both groups. Pain scores immediately before the VT were 3 out of 10 in both groups (P = 0.206), with no difference in opioid consumption (P = 0.750). There were no differences in the rate of urinary tract infections or prolonged or recurrent urinary retention between the groups (P = 0.304 and P = 0.745). CONCLUSIONS: While previous studies suggested an improvement in immediate postoperative voiding with phenazopyridine, our randomized controlled trial does not support this.

Child maltreatment and cognitive vulnerabilities: Examining the link to posttraumatic stress symptoms.

Research attempting to identify pathways from childhood maltreatment to adulthood posttraumatic stress symptoms (PTSS) implicates cognitive vulnerabilities that may increase risk for mental health concerns. The present study examined two cognitive vulnerabilities and their relation to PTSS amongst individuals with and without childhood maltreatment histories: attentional control and repetitive negative thinking (RNT). This research surveyed college students (N = 376) on constructs of interest. Results revealed that attentional control and RNT demonstrated significant indirect effects on PTSS (95% CI =.0003, .0336 and 95% CI =.0643, .1857, respectively). Findings suggest that childhood maltreatment severity was related to decreased attentional control and increased RNT, which were then both related to increased PTSS. Interventions for increasing attentional control and decreasing RNT should be implemented and evaluated for young adults with early adversity currently experiencing PTSS.

Cognitive mechanisms influence the relationship between social anxiety and depression among college students.

OBJECTIVE: Social anxiety and depression are commonly comorbid and cause significant impairment in college students. Past research suggests that both poor attentional control and increased rumination are related to these disorders and independently mediate their relationship. Theory suggests that social anxiety loads working memory, thus decreasing attentional control, which influences rumination and depression. The current study aimed to investigate the potential combined influence of attention control and rumination on social anxiety and depression. Participants: Participants (80) were recruited from a large Midwestern university in September 2017. Methods: Participants completed questionnaires regarding social anxiety, attentional control, rumination, and depression and data were analyzed using bias-corrected bootstrapping analyses. Results: Results demonstrate a significant indirect relationship between social anxiety and depression through attentional control and rumination. Conclusions: Results indicated that college students with social anxiety may be at risk for depression due to decreased attentional control and increased rumination. Clinical implications are discussed.

Early childhood experiences and cognitive risk factors for anxiety symptoms among college students.

OBJECTIVE: Data indicate that adverse childhood experiences (ACEs) are a risk factor for cognitive and attentional vulnerabilities. A vulnerability linked to these impairments is repetitive negative thinking (RNT), and data suggest that RNT and anxiety symptoms may be moderated by attentional control. The current study investigated the effect of these risk factors on symptoms of anxiety. Participants: College students (N = 376) were recruited from a university. Methods: Participants were administered questionnaires online to assess retrospective ACEs, current RNT, attentional control, and anxiety symptoms. Results: There was an indirect effect of ACEs on anxiety symptoms through RNT. High attentional control moderated the indirect effects, such that high compared to low attentional control was associated with an increased effect of RNT on anxiety symptoms. Conclusions: Increased ACEs may be a risk factor for RNT among college students. Combined with high attentional control, these may be risk factors for anxiety symptoms.

Neural indices of orienting, discrimination, and conflict monitoring after contextual fear and safety learning.

Investigations of fear conditioning have recently begun to evaluate contextual factors that affect attention-related processes. However, much of the extant literature does not evaluate how contextual fear learning influences neural indicators of attentional processes during goal-directed activity. The current study evaluated how early attention for task-relevant stimuli and conflict monitoring were affected when presented within task-irrelevant safety and threat contexts after fear learning. Participants (N = 72) completed a Flanker task with modified context before and after context-dependent fear learning. Flanker stimuli were presented in the same threat and safety contexts utilized in the fear learning task while EEG was collected. Results indicated increased early attention (N1) to flankers appearing in threat contexts and later increased neural indicators (P2) of attention to flankers appearing in safety contexts. Results of this study indicate that contextual fear learning modulates early attentional processes for task-relevant stimuli that appear in the context of safety and threat. Theoretical and clinical implications are discussed.

Assessing the psychometric properties of the Attentional Style Questionnaire.

Attentional control has grown in importance within theoretical and predictive models of psychopathology over past decades. The Attentional Style Questionnaire (ASQ) is a novel measure of internal and external attentional control. However, no study has independently validated this questionnaire. Two studies assessed the factor structure for the ASQ within an English-speaking population (Study 1), evaluated the construct and content validity, and assessed incremental predictability (Study 2). Results of Study 1 observed two factors that could be characterised as distractibility/cognitive avoidance and focusing, whereas the original study had observed factors defined as internal and external. Results of Study 2 confirmed the factor structure of Study 1, in addition to providing evidence for the ASQ's predictability for anxiety, depression and worry behaviours above established measures of attentional control. Overall, these results indicated that the ASQ measures factors of attentional control which provides incremental utility for predicting psychopathology. Implications on psychopathology and discrepancies to previous findings are discussed.

The role of excessive reassurance seeking: An eye tracking study of the indirect effect of social anxiety symptoms on attention bias.

High social anxiety is associated with increased attentional bias, and difficulties disengaging from relevant threat information, though social anxiety may also be associated with avoidance of threat. Few mechanisms of this relationship have been empirically evaluated, whereas theories and treatment manuals implicate avoidance and/or safety behaviors as significant agents of negative reinforcement for anxiety symptoms and search for threat. The current study sought to investigate one safety behavior, excessive reassurance seeking, as a mediator of the relationship between social anxiety and attention bias to disgust facial stimuli. Support was found for our hypotheses, such that social anxiety symptoms had an indirect effect on attention bias to disgust faces through increased reassurance seeking. These results suggest that reassurance seeking may result in disengagement of attention to threat stimuli. Specifically, social anxiety may result in a decreased threshold for negative social cues and therefore seek out reassurance feedback and avoid threatening stimuli. Future studies should test these directly and utilize a prospective design. The current study suggests that reassurance seeking may be involved in the attention bias process, providing additional data for current cognitive theories of social anxiety and additional support for reinforcement patterns of anxiety symptoms.

Examination of evaluative threat in worry: Insights from the Error-Related Negativity (ERN).

Recent research suggests atypical error-monitoring is important to understanding pathological anxiety. Because uncertainty is a transdiagnostic factor associated with anxiety and related disorders, recent research has begun to examine the influence of uncertainty in error-monitoring. Moreover, task irrelevant threat has been shown to influence cognitive performance in individuals with maladaptive anxiety. The current study aims to merge these literatures by examining the influence of task-irrelevant uncertain evaluative threat on error-monitoring using an event-related brain potential, the error-related negativity (ERN). Considering extensive literature indicating a relationship between worry and the ERN, worry was included as a continuous predictor in the analyses. Participants were randomly assigned to either a condition of negative or uncertain evaluative threat to determine their influence on error-monitoring in a Flankers task. Results for the ERN suggest that the ERN was significantly reduced only for the uncertain evaluative threat condition. The current study suggests that uncertain evaluative threat distractors result in a subsequent reduction in error-monitoring. This is consistent with literature suggesting that anxiety impairs inhibition of attentional processing of task irrelevant threatening information. This study adds to the burgeoning literature on the malleability of the ERN. Future research is needed to determine the mechanisms underlying this effect.

The relationship between social anxiety and heartbeat evoked potential amplitude.

Past research suggests that social anxiety is associated with increased processing of cardiac activity. Cognitive theories propose that this is one aspect of self-focus, which is driven by concerns that features of the self, such as anxiety symptoms, will elicit evaluation from others. We investigated the relationship of social anxiety to the cortical processing of heartbeats as reflected in the heartbeat evoked potential (HEP) during false feedback of accelerated heart rate. Thirty-eight participants with high social anxiety (HSA; n = 19) and non-elevated social anxiety (NSA; n = 19) completed a cognitive task during which false feedback of accelerated heart rate was randomly provided on 50% of trials. HEP amplitude was larger in HSAs, but not NSAs, during false heartbeat acceleration cues compared to standard cues. HEP amplitude also was larger in HSAs compared to NSAs during acceleration cues. HEP amplitude during acceleration cues, but not standard cues correlated with social anxiety. Within the first second after the R-peak, social anxiety correlated with voltage at Fz from 223 to 305 ms. Social concerns about the consequences of anxiety symptoms accounted for an indirect relationship between social anxiety and the HEP. These data extend prior evidence of increased processing of cardiac activity in socially anxious individuals, providing support for cognitive theories.

Pharmacogenetic Analysis of Functional Glutamate System Gene Variants and Clinical Response to Clozapine.

Altered glutamate neurotransmission is implicated in the etiology of schizophrenia (SCZ) and the pharmacogenetics of response to clozapine (CLZ), which is the drug of choice for treatment-resistant SCZ. Response to antipsychotic therapy is highly variable, although twin studies suggest a genetic component. We investigated the association of 10 glutamate system gene variants with CLZ response using standard genotyping procedures. GRM2 (rs4067 and rs2518461), SLC1A2 (rs4354668, rs4534557, and rs2901534), SLC6A9 (rs12037805, rs1978195, and rs16831558), GRIA1 (rs2195450), and GAD1 (rs3749034) were typed in 163 European SCZ/schizoaffective disorder patients deemed resistant or intolerant to previous pharmacotherapy. Response was assessed following 6 months of CLZ monotherapy using change in Brief Psychiatric Rating Scale (BPRS) scores. Categorical and continuous response variables were analyzed using χ2 tests and analysis of covariance, respectively. We report no significant associations following correction for multiple testing. Prior to correction, nominally significant associations were observed for SLC6A9, SLC1A2, GRM2, and GRIA1. Most notably, CC homozygotes of rs16831558 located in the glycine transporter 1 gene (SLC6A9) exhibited an allele dose-dependent improvement in positive symptoms compared to T allele carriers (puncorrected = 0.008, pcorrected = 0.08). To clarify the role of SLC6A9 in clinical response to antipsychotic medication, and CLZ in particular, this finding warrants further investigation in larger well-characterized samples.

Trait attentional control influences the relationship between repetitive negative thinking and psychopathology symptoms.

Repetitive negative thinking (RNT) has been implicated in several disorders (e.g., Clark (2005)). However, little research has examined how RNT influences other risk factors of psychopathology, such as attentional control. This study used prospective methodology to determine if relationships among various RNT styles and symptoms of psychological disorders are indirectly influenced by facets of attentional control. The sample included 376 participants who completed measures of RNT (worry, rumination, anticipatory processing, obsessions, intrusive thoughts and panic cognitions), psychopathology (generalized anxiety disorder, depression, social anxiety, obsessive-compulsive disorder, posttraumatic stress disorder, and panic disorder), and attentional control at two time points. Several relationships between RNT forms and symptom levels were indirectly predicted by the focusing subscale of attentional control; however, the patterns of these relationships differed based on the disorder. The shifting subscale did not indirectly predict any relationship. Therefore, it appears that low focusing may be a particular risk factor for the development of later RNT and/or psychopathology symptoms.

Electrocortical Evidence of Enhanced Performance Monitoring in Social Anxiety.

Self-focused attention is thought to be a key feature of social anxiety disorder. Yet few studies have used event-related potentials (ERPs) to examine whether socially anxious individuals display greater monitoring of their performance and attention to their errors. Similarly, only a few studies have used ERPs to examine how social anxiety is related to processing of performance feedback. Individuals with high (n=26) and low (n=28) levels of social anxiety completed a trial-and-error learning task. Self-focus was manipulated using false heart-rate feedback during a random subset of trials. Performance feedback was given using emotional and neutral faces in a positive context (correct=happy face; incorrect=neutral face) and negative context (correct=neutral face; incorrect=disgust face) in order to investigate biased interpretation and attention to feedback. Socially anxious subjects displayed enhanced amplitude of the ERN and CRN, suggesting greater response monitoring, and enhanced Pe amplitude, suggesting greater processing of errors relative to the low social anxiety group. No group differences were observed with respect to feedback processing. Before learning stimulus-response mappings in the negative context, the FRN was larger for self-focus compared to standard trials and marginally larger for socially anxious subjects compared to controls. These findings support cognitive models and suggest avenues for future research.

Genetic association analysis of N-methyl-D-aspartate receptor subunit gene GRIN2B and clinical response to clozapine.

OBJECTIVE: Approximately 30% of patients with schizophrenia fail to respond to antipsychotic therapy and are classified as having treatment-resistant schizophrenia. Clozapine is the most efficacious drug for treatment-resistant schizophrenia and may deliver superior therapeutic effects partly by modulating glutamate neurotransmission. Response to clozapine is highly variable and may depend on genetic factors as indicated by twin studies. We investigated eight polymorphisms in the N-methyl-D-aspartate glutamate receptor subunit gene GRIN2B with response to clozapine. METHODS: GRIN2B variants were genotyped using standard TaqMan procedures in 175 European patients with schizophrenia deemed resistant or intolerant to treatment. Response was assessed using change in Brief Psychiatric Rating Scale scores following six months of clozapine therapy. Categorical and continuous response was assessed using chi-squared test and analysis of covariance, respectively. RESULTS: No associations were observed between the variants and response to clozapine. A-allele carriers of rs1072388 responded marginally better to clozapine therapy than GG-homozygotes; however, the difference was not statistically significant (p = 0.067, uncorrected). CONCLUSIONS: Our findings do not support a role for these GRIN2B variants in altering response to clozapine in our sample. Investigation of additional glutamate variants in clozapine response is warranted.

Real-time monitoring of peptide grafting onto chitosan films using capillary electrophoresis.

Chitosan, being antimicrobial and biocompatible, is attractive as a cell growth substrate. To improve cell attachment, arginine-glycine-aspartic acid-serine (RGDS) peptides were covalently grafted to chitosan films, through the widely used coupling agents 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC-HCl) and N-hydroxysuccinimide (NHS), via the carboxylic acid function of the RGDS molecule. The grafting reaction was monitored, for the first time, in real time using free-solution capillary electrophoresis (CE). This enabled fast separation and determination of the peptide and all other reactants in one separation with no sample preparation. Covalent RGDS peptide grafting onto the chitosan film surface was demonstrated using solid-state NMR of swollen films. CE indicated that oligomers of RGDS, not simply RGDS, were grafted on the film, with a likely hyperbranched structure. To assess the functional properties of the grafted films, cell growth was compared on control and peptide-grafted chitosan films. Light microscopy and polymerase chain reaction (PCR) analysis demonstrated greatly improved cell attachment to RGDS-grafted chitosan films.