Threat of shock increases distractor susceptibility during the short-term maintenance of visual information.

Elevated arousal in anxiety is thought to affect attention control. To test this, we designed a visual short-term memory (VSTM) task to examine distractor suppression during periods of threat and no-threat. We hypothesized that threat would impair performance when subjects had to filter out large numbers of distractors. The VSTM task required subjects to attend to one array of squares while ignoring a separate array. The number of target and distractor squares varied systematically, with high (four squares) and low (two squares) target and distractor conditions. This study comprised two separate experiments. Experiment 1 used startle responses and white noise as to directly measure threat-induced anxiety. Experiment 2 used BOLD to measure brain responses. For Experiment 1, subjects showed significantly larger startle responses during threat compared to safe period, supporting the validity of the threat manipulation. For Experiment 2, we found that accuracy was affected by threat, such that the distractor load negatively impacted accuracy only in the threat condition. We also found threat-related differences in parietal cortex activity. Overall, these findings suggest that threat affects distractor susceptibility, impairing filtering of distracting information. This effect is possibly mediated by hyperarousal of parietal cortex during threat.

Sexual dimorphism in anxiety is programmed in-utero by sex-steroids: Proof of concept using a disease-model and stress responses to COVID pandemic.

Sex differences in the psychological impact of the COVID-19 pandemic have been consistently reported, showing disproportionally high rates of anxiety/distress in women relative to men. The mechanisms underlying this sexual dimorphism remain unclear. The present study queries the potential protective role of early hyperandrogenism on brain development. A natural model of sex-steroids abnormality, classic congenital adrenal hyperplasia (CAH), was used to test this question. CAH is characterized by adrenal androgen overproduction in utero (prenatal) through the neonatal critical developmental period. An online survey collected information on subjective responses to the COVID-19 pandemic. Matched on demographic variables, 60 adults carrying a diagnosis of classic CAH and 240 adults from the general population (non-CAH) were compared on levels of anxiety/distress in the first year of the COVID-19 pandemic (May 2020-April 2021). Structural Equation Modeling was used to test the modulation by CAH status of Sex effects on anxiety/distress. Results revealed lower levels of anxiety/distress in the female CAH group compared to the other 3 groups (male CAH, female non-CAH, and male non-CAH). This finding suggests that pre-neonatal hyperandrogenism might impact the development of neural circuits underlying anxiety processes, in a way that enhances resilience to chronic stress.

Threat of shock increases distractor susceptibility during the short-term maintenance of visual information.

BACKGROUND: Work on anxiety related attention control deficits suggests that elevated arousal impacts the ability to filter out distractors. To test this, we designed a task to look at distractor suppression during periods of threat. We administered trials of a visual short-term memory (VSTM) task, during periods of unpredictable threat, and hypothesized that threat would impair performance during trials where subjects were required to filter out large numbers of distractors. METHOD: Experiment 1 involved fifteen healthy participants who completed one study visit. They performed four runs of a VSTM task comprising 32 trials each. Participants were presented with an arrow indicating left or right, followed by an array of squares. They were instructed to remember the target side and disregard the distractors on the off-target side. A subsequent target square was shown, and participants indicated whether it matched one of the previously presented target squares. The trial conditions included 50% matches and 50% mismatches, with an equal distribution of left and right targets. The number of target and distractor squares varied systematically, with high (4 squares) and low (2 squares) target and distractor conditions. Trials alternated between periods of safety and threat, with startle responses recorded using electromyography (EMG) following white noise presentations. Experiment 2 involved twenty-seven healthy participants who completed the same VSTM task inside an MRI scanner during a single study visit. The procedure mirrored that of Experiment 1, except for the absence of white noise presentations. RESULTS: For Experiment 1, subjects showed significantly larger startle responses during threat compared to safe period, supporting the validity of the threat manipulation. However, results suggested that the white noise probes interfered with performance. For Experiment 2, we found that both accuracy was affected by threat, such that distractor load negatively impacted accuracy only in the threat condition. CONCLUSION: Overall, these findings suggest that threat affects distractor susceptibility during the short-term maintenance of visual information. The presence of threat makes it more difficult to filter out distracting information. We believe that this is related to hyperarousal of parietal cortex, which has been observed during unpredictable threat.

Periaqueductal gray matter and medial prefrontal cortex reflect negative prediction errors during differential conditioning.

Computational models of associative learning posit that negative prediction errors (PEs) arising from the omission of aversive outcomes weaken aversive Pavlovian associations during differential conditioning and extinction. It is possible that negative PEs may underlie exaggerated conditioned responses to the conditioned stimulus not paired with an aversitve outcome (CS-) during differential conditioning and to the conditioned stimulus originally paired with a aversive outcome (CS+) during extinction in patients with clinical anxiety disorders. Although previous research has demonstrated that manipulations of the periaqueductal gray matter (PAG) interfere with extinction learning in animals, the role of the PAG in processing negative PEs within the human brain is presently unclear. We set out to investigate how PAG responses and connectivity are impacted by negative PEs using ultra-high-field (7 T) functional magnetic resonance imaging and hierarchical Bayesian analysis. During differential conditioning, negative PEs were associated with larger responses within the lateral and dorsolateral PAG and increased connectivity between the dorsolateral PAG and medial areas of Brodmann area 9. Collectively, these results shed light on the association between activity within the PAG and medial prefrontal cortex and the omission of aversive outcomes during Pavlovian learning.

The Posterior Cingulate Cortex Reflects the Impact of Anxiety on Drift Rates During Cognitive Processing.

BACKGROUND: Generally, anxiety is thought to impair ongoing cognitive operations. Surprisingly, however, anxiety has been shown to improve performance during the Go/NoGo task. Understanding how anxiety can facilitate task performance may shed light on avenues to address the cognitive deficits commonly associated with anxiety. METHODS: A total of 39 participants (mean age ± SD = 27.5 ± 7.22 years; 18 women) performed a Go/NoGo task during periods of safety and periods of experimental anxiety, induced using the unpredictable delivery of aversive stimuli. Computational analysis and ultrahigh field (7T) functional magnetic resonance imaging were used to determine how induced anxiety affected computational processes and blood oxygen level-dependent responses during the task. RESULTS: Induced anxiety improved accuracy during the Go/NoGo task. Induced anxiety was associated with an amplified drift rate process, which is thought to reflect increased informational uptake. In addition, changes in drift rate during the anxiety condition were associated with enhanced blood oxygen level-dependent responses within the posterior cingulate cortex during Go trials. CONCLUSIONS: These results may reflect the impact of induced anxiety on the activity of neurons within the posterior cingulate cortex, whose activity patterns mimic the buildup of evidence accumulation. Collectively, these results shed light on the mechanisms underlying facilitated task performance and suggest that anxiety can improve cognitive processing by enhancing information uptake and increasing activity within the posterior cingulate cortex.

Examination of the COVID-19 Pandemic's Impact on Mental Health From Three Perspectives: Global, Social, and Individual.

The extent of the deleterious effects of the COVID-19 pandemic on mental health is recognized ubiquitously. However, these effects are subject to many modulatory factors from a plethora of domains of examination. It is important to understand the intersection of societal and individual levels for global stressors compared with local phenomena and physical-health outcomes. Here, we consider three perspectives: international/cultural, social, and individual. Both the enduring threat of COVID-19 infection and the protective measures to contain contagion have important consequences on individual mental health. These consequences, together with possible remedial interventions, are the focus of this article. We hope this work will stimulate more research and will suggest factors that need to be considered in the coordination of responses to a global threat, allowing for better preparation in the future.

Neural resources shift under Methylphenidate: A computational approach to examine anxiety-cognition interplay.

The reciprocal interplay between anxiety and cognition is well documented. Anxiety negatively impacts cognition, while cognitive engagement can down-regulate anxiety. The brain mechanisms and dynamics underlying such interplay are not fully understood. To study this question, we experimentally and orthogonally manipulated anxiety (using a threat of shock paradigm) and cognition (using methylphenidate; MPH). The effects of these manipulations on the brain and behavior were evaluated in 50 healthy participants (25 MPH, 25 placebo), using an n-back working memory fMRI task (with low and high load conditions). Behaviorally, improved response accuracy was observed as a main effect of the drug across all conditions. We employed two approaches to understand the neural mechanisms underlying MPH-based cognitive enhancement in safe and threat conditions. First, we performed a hypothesis-driven computational analysis using a mathematical framework to examine how MPH putatively affects cognitive enhancement in the face of induced anxiety across two levels of cognitive load. Second, we performed an exploratory data analysis using Topological Data Analysis (TDA)-based Mapper to examine changes in spatiotemporal brain activity across the entire cortex. Both approaches provided converging evidence that MPH facilitated greater differential engagement of neural resources (brain activity) across low and high working memory load conditions. Furthermore, load-based differential management of neural resources reflects enhanced efficiency that is most powerful during higher load and induced anxiety conditions. Overall, our results provide novel insights regarding brain mechanisms that facilitate cognitive enhancement under MPH and, in future research, may be used to help mitigate anxiety-related cognitive underperformance.

Striatal Activity to Reward Anticipation as a Moderator of the Association Between Early Behavioral Inhibition and Changes in Anxiety and Depressive Symptoms From Adolescence to Adulthood.

Importance: The early childhood temperament of behavioral inhibition (BI), characterized by inhibited and fearful behaviors, has been associated with heightened risk for anxiety and depression across the lifespan. Although several neurocognitive correlates underlying vulnerability to the development of anxiety among inhibited children have been identified, little is known about the neurocognitive correlates underlying vulnerability to the development of depression. Objective: To examine whether blunted striatal activation to reward anticipation, a well-documented neurocognitive vulnerability marker of depression, moderates the association between early BI and the developmental changes in depression and anxiety from adolescence to adulthood. Design, Setting, and Participants: Participants in this prospective longitudinal study were recruited at age 4 months between 1989 and 1993 in the US. Follow-up assessments extended into 2018 (age 26 years). Data were analyzed between September 2021 to March 2022. Main Outcomes and Measures: BI was measured through an observation paradigm in infancy (ages 14 and 24 months). Neural activity to anticipated rewards during a monetary incentive delay task was measured using functional magnetic resonance imaging in adolescence (between ages 15-18 years; 83 individuals had usable data). Anxiety and depressive symptoms were self-reported across adolescence to young adulthood (ages 15 and 26 years; n = 108). A latent change score model, accounting for the interdependence between anxiety and depression, tested the moderating role of striatal activity to reward anticipation in the association between early BI and changes in anxiety and depressive symptoms. A region of interest approach limited statistical tests to regions within the striatum (ie, nucleus accumbens, caudate head, caudate body, putamen). Results: Of 165 participants, 84 (50.1%) were female and 162 (98%) were White. Preliminary analyses revealed significant increases in anxiety and depressive symptoms across ages 15 to 26 years, as well as individual variation in the magnitude of changes. Main analyses showed that reduced activity in the nucleus accumbens to reward anticipation moderated the association between early BI and increases in depressive (ß = -0.32; b = -4.23; 95% CI, -7.70 to -0.76; P = .02), and more depressive symptoms at age 26 years (ß = -0.47; b = -5.09; 95% CI, -7.74 to -2.43; P < .001). However, there were no significant interactions associated with latent changes in anxiety across age nor anxiety at age 26 years. Activity in the caudate and putamen did not moderate these associations. Conclusions and Relevance: Blunted reward sensitivity in the ventral striatum may be a developmental risk factor connecting an inhibited childhood temperament and depression over the transition to adulthood. Future studies should examine the efficacy of prevention programs, which target maladaptive reward processing and motivational deficits among anxious youths, in reducing risks for later depression.

Longitudinal Trajectory of the Link Between Ventral Striatum and Depression in Adolescence.

OBJECTIVE: Research in adolescent depression has found aberrant intrinsic functional connectivity (iFC) among the ventral striatum (VS) and several brain regions implicated in reward processing. The present study probes this question by taking advantage of the availability of data from a large youth cohort, the IMAGEN Consortium. METHODS: iFC data from 303 adolescents (48% of them female) were used to examine associations of VS connectivity at baseline (at age 14) with depressive disorders at baseline and at 2-year (N=250) and 4-year (N=219) follow-ups. Eleven regions of interest, key nodes of the reward system, were used to probe the reward network and calculate the connectivity strength of the VS within this network (VS connectivityrw). The main analyses assessed associations of VS connectivityrw with depressive disorders, anhedonia, and low mood using logistic regression. Autoregressive models accounting for carryover effects over time were conducted to further evaluate these brain-behavior associations. RESULTS: Higher right VS connectivityrw was associated with higher probability of depressive disorders at baseline (odds ratio=2.65, 95% CI=1.40, 5.05). This finding was confirmed in the autoregressive model, adjusting for carryover effects of the depressive disorders across the three time points. VS connectivityrw was not predictive of depressive disorders at follow-up assessments. Longitudinal associations between VS connectivityrw and anhedonia emerged in the structural equation model: left VS connectivityrw was associated with anhedonia at 2 years (odds ratio=2.20, 95% CI=1.54, 3.14), and right VS connectivityrw was linked to anhedonia at 4 years (odds ratio=1.87, 95% CI=1.09, 3.21). VS connectivityrw did not predict low mood at any time point in the structural equation model. CONCLUSIONS: The connectivity strength of the VS within the reward network showed distinct patterns of association with depressive disorders and anhedonia from mid to late adolescence, suggesting that the role of this circuitry in depression changes with age. This study replicates, in an independent sample, the association between the VS and depression previously reported in younger adolescents. The findings suggest a role of VS connectivityrw in anhedonia but not in low mood.

Dynamic Time Warping Identifies Functionally Distinct fMRI Resting State Cortical Networks Specific to VTA and SNc: A Proof of Concept.

Functional connectivity (FC) is determined by similarity between functional magnetic resonance imaging (fMRI) signals from distinct brain regions. However, traditional FC analyses ignore temporal phase differences. Here, we addressed this limitation, using dynamic time warping (DTW) within a machine-learning framework, to study cortical FC patterns of 2 spatially adjacent but functionally distinct subcortical regions, namely Substantia Nigra Pars Compacta (SNc) and ventral tegmental area (VTA). We evaluate: 1) the influence of pair of brain regions considered, 2) the influence of warping window sizes, 3) the classification efficacy of DTW, and 4) the uniqueness of features identified. Whole brain 7 Tesla resting state fMRI scans from 81 healthy participants were used. FC between 2 subcortical regions of interests (ROIs) and 360 cortical parcels were computed using: 1) Pearson correlations (PCs), 2) dynamic time-warped PCs (DTW-PC). The separability of SNc-cortical and VTA-cortical network was validated on 40 participants and tested on the remaining 41, using a support vector machine (SVM). The SVM separated the SNc-cortical versus VTA-cortical network with 74.39 and 97.56% test accuracy using PC and DTW-PC, respectively. SVM-recursive feature elimination yielded 20 DTW-PC features that most strongly contributed to the separation of the networks and revealed novel VTA versus SNc preferential connections (P < 0.05, Bonferroni-Holm corrected).

Threat-of-shock decreases emotional interference on affective stroop performance in healthy controls and anxiety patients.

Patients with anxiety disorders suffer from impaired concentration, potentially as a result of stronger emotional interference on attention. Studies using behavioural measures provide conflicting support for this hypothesis. Elevated state anxiety may be necessary to reliably document differences in emotional interference in patients versus healthy controls. The present study examines the effect of experimentally induced state anxiety (threat-of-shock) on attention interference by emotional stimuli. Anxiety patients (n = 36) and healthy controls (n = 32) completed a modified affective Stroop task during periods of safety and threat-of-shock. Results indicated that in both patients and controls, threat decreased negative, but not positive or neutral, emotional interference on attention (both p < .001). This finding supports a threat-related narrowing of attention whereby a certain level of anxiety decreases task-irrelevant processing.

Location-dependent threat and associated neural abnormalities in clinical anxiety.

Anxiety disorders are characterized by maladaptive defensive responses to distal or uncertain threats. Elucidating neural mechanisms of anxiety is essential to understand the development and maintenance of anxiety disorders. In fMRI, patients with pathological anxiety (ANX, n = 23) and healthy controls (HC, n = 28) completed a contextual threat learning paradigm in which they picked flowers in a virtual environment comprising a danger zone in which flowers were paired with shock and a safe zone (no shock). ANX compared with HC showed 1) decreased ventromedial prefrontal cortex and anterior hippocampus activation during the task, particularly in the safe zone, 2) increased insula and dorsomedial prefrontal cortex activation during the task, particularly in the danger zone, and 3) increased amygdala and midbrain/periaqueductal gray activation in the danger zone prior to potential shock delivery. Findings suggest that ANX engage brain areas differently to modulate context-appropriate emotional responses when learning to discriminate cues within an environment.

COVID-19 and Mental Health: Predicted Mental Health Status is Associated with Clinical Symptoms and Pandemic-Related Psychological and Behavioral Responses.

BACKGROUND: The COVID-19 pandemic led to dramatic threats to health and social life. Study objectives - develop a prediction model leveraging subsample of known Patient/Controls and evaluate the relationship of predicted mental health status to clinical outcome measures and pandemic-related psychological and behavioral responses during lockdown (spring/summer 2020). METHODS: Online cohort study conducted by National Institute of Mental Health Intramural Research Program. Convenience sample of English-speaking adults (enrolled 4/4-5/16/20; n=1,992). Enrollment measures: demographics, clinical history, functional status, psychiatric and family history, alcohol/drug use. Outcome measures (enrollment and q2 weeks/6 months): distress, loneliness, mental health symptoms, and COVID-19 survey. NIMH IRP Patient/Controls survey responses informed assignment of Patient Probability Scores (PPS) for all participants. Regression models analyzed the relationship between PPS and outcome measures. OUTCOMES: Mean age 46.0 (±14.7), female (82.4%), white (88.9 %). PPS correlated with distress, loneliness, depression, and mental health factors. PPS associated with negative psychological responses to COVID-19. Worry about mental health (OR 1.46) exceeded worry about physical health (OR 1.13). PPS not associated with adherence to social distancing guidelines but was with stress related to social distancing and worries about infection of self/others. INTERPRETATION: Mental health status (PPS) was associated with concurrent clinical ratings and COVID-specific negative responses. A focus on mental health during the pandemic is warranted, especially among those with mental health vulnerabilities. We will include PPS when conducting longitudinal analyses of mental health trajectories and risk and resilience factors that may account for differing clinical outcomes. FUNDING: NIMH (ZIAMH002922); NCCIH (ZIAAT000030).

How does social evaluation influence Hot and Cool inhibitory control in adolescence?

The aim of the present study is to examine whether in Hot, i.e., affectively charged contexts, or cool, i.e., affectively neutral contexts, inhibitory control capacity increases or decreases under social evaluation in adolescents and adults. In two experiments, adolescents and young adults completed two Stroop-like tasks under either a social evaluation condition or an alone condition. The social evaluation condition comprised the presence of a peer (Experiment 1) or an expert (Experiment 2) playing the role of an evaluator, while under the alone condition, the task was performed alone. In the Cool Stroop task, participants had to refrain from reading color names to identify the ink color in which the words were printed. In the Hot Stroop task, participants had to determine the emotional expression conveyed by faces from the NimStim database while ignoring the emotion word displayed beneath. The results were similar in both experiments. In adolescents, social evaluation by a peer (Experiment 1) or by an expert (Experience 2) facilitated Hot but not cool inhibitory control. In adults, social evaluation had no effect on Hot or cool inhibitory control. The present findings expand our understanding of the favorable influence of socioemotional context on Hot inhibitory control during adolescence in healthy individuals.

The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study.

RATIONALE: Arginine vasopressin (AVP) is a neuropeptide that modulates both physiological and emotional responses to threat. Until recently, drugs that target vasopressin receptors (V1a) in the human central nervous system were unavailable. The development of a novel V1a receptor antagonist, SRX246, permits the experimental validation of vasopressin's role in the regulation of anxiety and fear in humans. OBJECTIVES: Here, we examined the effects of SRX246 in a proof-of-concept translational paradigm of fear (phasic response to imminent threat) and anxiety (prolonged response to potential threat). METHODS: Healthy volunteers received both SRX246 and placebo in a randomized, double-blind, counter-balanced order separated by a 5-7-day wash-out period. Threat consisted of unpleasant electric shocks. The "NPU" threat test probed startle reactivity during predictable threat (i.e., fear-potentiated startle) and unpredictable threat (i.e., anxiety-potentiated startle). RESULTS: As predicted, SRX246 decreased anxiety-potentiated startle independent of fear-potentiated startle. CONCLUSIONS: As anxiety-potentiated startle is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as SSRIs and benzodiazepines, the V1a receptor is a promising novel treatment target.

Prefrontal Responses during Proactive and Reactive Inhibition Are Differentially Impacted by Stress in Anorexia and Bulimia Nervosa.

Binge eating is a distressing, transdiagnostic eating disorder symptom associated with impulsivity, particularly in negative mood states. Neuroimaging studies of bulimia nervosa (BN) report reduced activity in frontostriatal regions implicated in self-regulatory control, and an influential theory posits that binge eating results from self-regulation failures under stress. However, there is no direct evidence that psychological stress impairs self-regulation in binge-eating disorders, or that any such self-regulatory deficits generalize to binge eating in underweight individuals (i.e., anorexia nervosa bingeing/purging subtype; AN-BP). We therefore determined the effect of acute stress on inhibitory control in 85 women (BN, 33 women; AN-BP, 22 women; 30 control participants). Participants underwent repeated functional MRI scanning during performance of the Stop-signal anticipation task, a validated measure of proactive (i.e., anticipation of stopping) and reactive (outright stopping) inhibition. Neural and behavioral responses to induced stress and a control task were evaluated on 2 consecutive days. Women with BN had reduced proactive inhibition, while prefrontal responses were increased in both AN-BP and BN. Reactive inhibition was neurally and behaviorally intact in both diagnostic groups. Both AN-BP and BN groups showed distinct stress-induced changes in inferior and superior frontal activity during both proactive and reactive inhibition. However, task performance was unaffected by stress. These results offer novel evidence of reduced proactive inhibition in BN, yet inhibitory control deficits did not generalize to AN-BP. Our findings identify intriguing alterations of stress responses and inhibitory function associated with binge eating, but they counsel against stress-induced failures of inhibitory control as a comprehensive explanation for loss-of-control eating.SIGNIFICANCE STATEMENT Binge eating is a common psychiatric syndrome that feels uncontrollable to the sufferer. Theoretically, it has been related to reduced self-regulation under stress, but there remains no direct evidence for this link in binge-eating disorders. Here, we examined how experimentally induced stress affected response inhibition in control participants and women with anorexia nervosa and bulimia nervosa. Participants underwent repeated brain scanning under stressful and neutral conditions. Although patient groups had intact action cancellation, the slowing of motor responses was impaired in bulimia nervosa, even when the likelihood of having to stop increased. Stress altered brain responses for both forms of inhibition in both groups, yet performance remained unimpaired. These findings counsel against a simple model of stress-induced disinhibition as an adequate explanation for binge eating.

Dissociable hormonal profiles for psychopathology and stress in anorexia and bulimia nervosa.

BACKGROUND: Anorexia nervosa (AN) and bulimia nervosa (BN) are complex psychiatric conditions, in which both psychological and metabolic factors have been implicated. Critically, the experience of stress can precipitate loss-of-control eating in both conditions, suggesting an interplay between mental state and metabolic signaling. However, associations between psychological states, symptoms and metabolic processes in AN and BN have not been examined. METHODS: Eighty-five women (n = 22 AN binge/purge subtype, n = 33 BN, n = 30 controls) underwent remote salivary cortisol sampling and a 2-day, inpatient study session to examine the effect of stress on cortisol, gut hormones [acyl-ghrelin, peptide tyrosine tyrosine (PYY) and glucagon-like peptide-1] and food consumption. Participants were randomized to either an acute stress induction or control task on each day, and plasma hormones were serially measured before a naturalistic, ad libitum meal. RESULTS: Cortisol-awakening response was augmented in AN but not in BN relative to controls, with body mass index explaining the most variance in post-awakening cortisol (36%). Acute stress increased acyl-ghrelin and PYY in AN compared to controls; however, stress did not alter gut hormone profiles in BN. Instead, a group-by-stress interaction showed nominally reduced cortisol reactivity in BN, but not in AN, compared to controls. Ad libitum consumption was lower in both patient groups and unaffected by stress. CONCLUSIONS: Findings extend previous reports of metabolic dysfunction in binge-eating disorders, identifying unique associations across disorders and under stress. Moreover, we observed disrupted homeostatic signaling in AN following psychological stress, which may explain, in part, the maintenance of dysregulated eating in this serious illness.

Patients with anxiety disorders rely on bilateral dlPFC activation during verbal working memory.

One of the hallmarks of anxiety disorders is impaired cognitive control, affecting working memory (WM). The dorsolateral prefrontal cortex (dlPFC) is critical for WM; however, it is still unclear how dlPFC activity relates to WM impairments in patients. Forty-one healthy volunteers and 32 anxiety (general and/or social anxiety disorder) patients completed the Sternberg WM paradigm during safety and unpredictable shock threat. On each trial, a series of letters was presented, followed by brief retention and response intervals. On low- and high-load trials, subjects retained the series (five and eight letters, respectively) in the original order, while on sort trials, subjects rearranged the series (five letters) in alphabetical order. We sampled the blood oxygenation level-dependent activity during retention using a bilateral anatomical dlPFC mask. Compared to controls, patients showed increased reaction time during high-load trials, greater right dlPFC activity and reduced dlPFC activity during threat. These results suggest that WM performance for patients and controls may rely on distinct patterns of dlPFC activity with patients requiring bilateral dlPFC activity. These results are consistent with reduced efficiency of WM in anxiety patients. This reduced efficiency may be due to an inefficient allocation of dlPFC resources across hemispheres or a decreased overall dlPFC capacity.

A generalized workflow for conducting electric field-optimized, fMRI-guided, transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a noninvasive method to stimulate the cerebral cortex that has applications in psychiatry, such as in the treatment of depression and anxiety. Although many TMS targeting methods that use figure-8 coils exist, many do not account for individual differences in anatomy or are not generalizable across target sites. This protocol combines functional magnetic resonance imaging (fMRI) and iterative electric-field (E-field) modeling in a generalized approach to subject-specific TMS targeting that is capable of optimizing the stimulation site and TMS coil orientation. To apply this protocol, the user should (i) operationally define a region of interest (ROI), (ii) generate the head model from the structural MRI data, (iii) preprocess the functional MRI data, (iv) identify the single-subject stimulation site within the ROI, and (iv) conduct E-field modeling to identify the optimal coil orientation. In comparison with standard targeting methods, this approach demonstrates (i) reduced variability in the stimulation site across subjects, (ii) reduced scalp-to-cortical-target distance, and (iii) reduced variability in optimal coil orientation. Execution of this protocol requires intermediate-level skills in structural and functional MRI processing. This protocol takes ~24 h to complete and demonstrates how constrained fMRI targeting combined with iterative E-field modeling can be used as a general method to optimize both the TMS coil site and its orientation.

A way forward for anxiolytic drug development: Testing candidate anxiolytics with anxiety-potentiated startle in healthy humans.

This review introduces a research strategy that may radically transform the pursuit of new anxiolytics, via the use of human models of anxiety in healthy individuals. Despite enormous investments in developing novel pharmacological treatments for anxiety disorders, pharmacotherapy for these conditions remains suboptimal. Most candidate anxiolytics from animal studies fail in clinical trials. We propose an additional screening step to help select candidate anxiolytics before launching clinical trials. This intermediate step moves the evidence for the potential anxiolytic property of candidate drugs from animals to humans, using experimental models of anxiety in healthy individuals. Anxiety-potentiated startle is a robust translational model of anxiety. The review of its face, construct, and predictive validity as well as its psychometric properties in humans establishes it as a promising tool for anxiolytic drug development. In conclusion, human models of anxiety may stir a faster, more efficient path for the development of clinically effective anxiolytics.