A neural oscillatory signature of sustained anxiety.

BACKGROUND: Anxiety is a sustained response to uncertain threats; yet few studies have explored sustained neurobiological activities underlying anxious states, particularly spontaneous neural oscillations. To address this gap, we reanalysed magnetoencephalographic (MEG) data recorded during induced anxiety to identify differences in sustained oscillatory activity between high- and low-anxiety states. METHODS: We combined data from three previous MEG studies in which healthy adults (total N = 51) were exposed to alternating periods of threat of unpredictable shock and safety while performing a range of cognitive tasks (passive oddball, mixed-saccade or stop-signal tasks). Spontaneous, band-limited, oscillatory activity was extracted from middle and late intervals of the threat and safe periods, and regional power distributions were reconstructed with adaptive beamforming. Conjunction analyses were used to identify regions showing overlapping spectral power differences between threat and safe periods across the three task paradigms. RESULTS: MEG source analyses revealed a robust and widespread reduction in beta (14-30 Hz) power during threat periods in bilateral sensorimotor cortices extending into right prefrontal regions. Alpha (8-13 Hz) power reductions during threat were more circumscribed, with notable peaks in left intraparietal sulcus and thalamus. CONCLUSIONS: Threat-induced anxiety is underpinned by a sustained reduction in spontaneous beta- and alpha-band activity in sensorimotor and parietal cortical regions. This general oscillatory pattern likely reflects a state of heightened action readiness and vigilance to cope with uncertain threats. Our findings provide a critical reference for which to identify abnormalities in cortical oscillatory activities in clinically anxious patients as well as evaluating the efficacy of anxiolytic treatments.

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).

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.

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.

Neurophysiological and clinical effects of the NMDA receptor antagonist lanicemine (BHV-5500) in PTSD: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with hyperarousal and stress reactivity, features consistent with behavioral sensitization. In this Phase 1b, parallel-arm, randomized, double-blind, placebo-controlled trial, we tested whether the selective low-trapping N-methyl-D-aspartate receptor (NMDAR) antagonist [Lanicemine (BHV-5500)] blocks expression of behavioral sensitization. METHODS: Twenty-four participants with elevated anxiety potentiated startle (APS) and moderate-to-severe PTSD symptoms received three infusions of lanicemine 1.0 mg/ml (100 mg) or matching placebo (0.9% saline) (1:1 ratio), over a 5-day period. The primary outcome was change in APS from baseline to end of third infusion. We also examined changes in EEG gamma-band oscillatory activity as measures of NMDAR target engagement and explored Clinician-Administered PTSD Scale (CAPS-5) hyperarousal scores. RESULTS: Lanicemine was safe and well-tolerated with no serious adverse events. Using Bayesian statistical inference, the posterior probability that lanicemine outperformed placebo on APS T-score after three infusions was 38%. However, after the first infusion, there was a 90% chance that lanicemine outperformed placebo in attenuating APS T-score by a standardized effect size more than 0.4. CONCLUSION: We demonstrated successful occupancy of lanicemine on NMDAR using gamma-band EEG and effects on hyperarousal symptoms (Cohen's d = 0.75). While lanicemine strongly attenuated APS following a single infusion, differential changes from placebo after three infusions was likely obscured by habituation effects. To our knowledge, this is the first use of APS in the context of an experimental medicine trial of a NMDAR antagonist in PTSD. These findings support selective NMDAR antagonism as a viable pharmacological strategy for salient aspects of PTSD.

Fear conditioning and extinction in alcohol dependence: Evidence for abnormal amygdala reactivity.

Fear conditioning and extinction (FCE) are vital processes in adaptive emotion regulation and disrupted in anxiety disorders. Despite substantial comorbidity between alcohol dependence (ALC) and anxiety disorders and reports of altered negative emotion processing in ALC, neural correlates of FCE in this clinical population remain unknown. Here, we used a 2-day fear learning paradigm in 43 healthy participants and 43 individuals with ALC at the National Institutes of Health. Main outcomes of this multimodal study included structural and functional brain magnetic resonance imaging, clinical measures, as well as skin conductance responses (SCRs) to confirm differential conditioning. Successful FCE was demonstrated across participants by differential SCRs in the conditioning phase and no difference in SCRs to the conditioned stimuli in the extinction phase. The ALC group showed significantly reduced blood oxygenation level-dependent responses in the right amygdala during conditioning (Cohen's d = .89, P(FWE) = .037) and in the left amygdala during fear renewal (Cohen's d = .68, P(FWE) = .039). Right amygdala activation during conditioning was significantly correlated with ALC severity (r = .39, P(Bonferroni) = .009), depressive symptoms (r = .37, P(Bonferroni) = .015), trait anxiety (r = .41, P(Bonferroni) = .006), and perceived stress (r = .45, P(Bonferroni) = .002). Our data suggest that individuals with ALC have dysregulated fear learning, in particular, dysregulated neural activation patterns, in the amygdala. Furthermore, amygdala activation during fear conditioning was associated with ALC-related clinical measures. The FCE paradigm may be a promising tool to investigate structures involved in negative affect regulation, which might inform the development of novel treatment approaches for ALC.

The translational neural circuitry of anxiety.

Anxiety is an adaptive response that promotes harm avoidance, but at the same time excessive anxiety constitutes the most common psychiatric complaint. Moreover, current treatments for anxiety-both psychological and pharmacological-hover at around 50% recovery rates. Improving treatment outcomes is nevertheless difficult, in part because contemporary interventions were developed without an understanding of the underlying neurobiological mechanisms that they modulate. Recent advances in experimental models of anxiety in humans, such as threat of unpredictable shock, have, however, enabled us to start translating the wealth of mechanistic animal work on defensive behaviour into humans. In this article, we discuss the distinction between fear and anxiety, before reviewing translational research on the neural circuitry of anxiety in animal models and how it relates to human neuroimaging studies across both healthy and clinical populations. We highlight the roles of subcortical regions (and their subunits) such as the bed nucleus of the stria terminalis, the amgydala, and the hippocampus, as well as their connectivity to cortical regions such as dorsal medial and lateral prefrontal/cingulate cortex and insula in maintaining anxiety responding. We discuss how this circuitry might be modulated by current treatments before finally highlighting areas for future research that might ultimately improve treatment outcomes for this common and debilitating transdiagnostic symptom.

Resting-state connectivity of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in clinical anxiety

Background: The central nucleus of the amygdala and bed nucleus of the stria terminalis are involved primarily in phasic and sustained aversive states. Although both structures have been implicated in pathological anxiety, few studies with a clinical population have specifically focused on them, partly because of their small size. Previous work in our group used high-resolution imaging to map the restingstate functional connectivity of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in healthy subjects at 7 T, confirming and extending structural findings in humans and animals, while providing additional insight into cortical connectivity that is potentially unique to humans. Methods: In the current follow-up study, we contrasted resting-state functional connectivity in the bed nucleus of the stria terminalis and central nucleus of the amygdala at 7 T between healthy volunteers (n = 30) and patients with generalized and/or social anxiety disorder (n = 30). Results: Results revealed significant voxel-level group differences. Compared with healthy volunteers, patients showed stronger resting-state functional connectivity between the central nucleus of the amygdala and the lateral orbitofrontal cortex and superior temporal sulcus. They also showed weaker resting-state functional connectivity between the bed nucleus of the stria terminalis and the dorsolateral prefrontal cortex and occipital cortex. Limitations: These findings depart from a previous report of resting-state functional connectivity in the central nucleus of the amygdala and bed nucleus of the stria terminalis under sustained threat of shock in healthy volunteers. Conclusion: This study provides functional MRI proxies of the functional dissociation of the bed nucleus of the stria terminalis and central nucleus of the amygdala, and suggests that resting-state functional connectivity of key structures in the processing of defensive responses do not recapitulate changes related to induced state anxiety. Future work needs to replicate and further probe the clinical significance of these findings.

Exercise modulates the interaction between cognition and anxiety in humans.

Despite interest in exercise as a treatment for anxiety disorders the mechanism behind the anxiolytic effects of exercise is unclear. Two observations motivate the present work. First, engagement of attention control during increased working memory (WM) load can decrease anxiety. Second, exercise can improve attention control. Therefore, exercise could boost the anxiolytic effects of increased WM load via its strengthening of attention control. Anxiety was induced by threat of shock and was quantified with anxiety-potentiated startle (APS). Thirty-five healthy volunteers (19 male, age M = 26.11, SD = 5.52) participated in two types of activity, exercise (biking at 60-70% of heart rate reserve) and control-activity (biking at 10-20% of heart rate reserve). After each activity, participants completed a WM task (n-back) at low- and high-load during safe and threat. Results were not consistent with the hypothesis: exercise vs. control-activity increased APS in high-load (p = .03). However, this increased APS was not accompanied with threat-induced impairment in WM performance (p = .37). Facilitation of both task-relevant stimulus processing and task-irrelevant threat processing, concurrent with prevention of threat interference on cognition, suggests that exercise increases cognitive ability. Future studies should explore how exercise affects the interplay of cognition and anxiety in patients with anxiety disorders.

Effect of Threat on Right dlPFC Activity during Behavioral Pattern Separation.

It has long been established that individuals with anxiety disorders tend to overgeneralize attributes of fearful stimuli to nonfearful stimuli, but there is little mechanistic understanding of the neural system that supports overgeneralization. To address this gap in our knowledge, this study examined effect of experimentally induced anxiety in humans on generalization using the behavioral pattern separation (BPS) paradigm. Healthy subjects of both sexes encoded and retrieved novel objects during periods of safety and threat of unpredictable shocks while we recorded brain activity with fMRI. During retrieval, subjects were instructed to differentiate among new, old, and altered images. We hypothesized that the hippocampus and dorsolateral prefrontal cortex (dlPFC) would play a key role in the effect of anxiety on BPS. The dlPFC, but not the hippocampus, showed increased activity for altered images compared with old images when retrieval occurred during periods of threat compared with safety. In addition, accuracy for altered items retrieved during threat was correlated with dlPFC activity. Together, these results suggest that overgeneralization in anxiety patients may be mediated by an inability to recruit the dlPFC, which mediates the cognitive control needed to overcome anxiety and differentiate between old and altered items during periods of threat.SIGNIFICANCE STATEMENT Anxiety and posttraumatic stress disorder patients generalize fear to nonfearful fear stimuli, making it difficult to regulate anxiety. Understanding how anxiety affects generalization is key to understanding the overgeneralization experienced by these patients. We examined this relationship in healthy subjects by studying how threat of shock affects neural responses to previously encountered stimuli. Although previous studies point to hippocampal involvement, we found that threat affected activity in the dorsolateral prefrontal cortex (dlPFC), rather than the hippocampus, when subjects encountered slightly altered versions of the previously encountered items. Importantly, this dlPFC activity predicted performance for these items. Together, these results suggest that the dlPFC is important for discrimination during elevated anxiety and that overgeneralization may reflect a deficit in dlPFC-mediated cognitive control.

Intrinsic functional connectivity of the central nucleus of the amygdala and bed nucleus of the stria terminalis.

The central nucleus of the amygdala (CeA) and bed nucleus of the stria terminalis (BNST), two nuclei within the central extended amygdala, function as critical relays within the distributed neural networks that coordinate sensory, emotional, and cognitive responses to threat. These structures have overlapping anatomical projections to downstream targets that initiate defensive responses. Despite these commonalities, researchers have also proposed a functional dissociation between the CeA and BNST, with the CeA promoting responses to discrete stimuli and the BNST promoting responses to diffuse threat. Intrinsic functional connectivity (iFC) provides a means to investigate the functional architecture of the brain, unbiased by task demands. Using ultra-high field neuroimaging (7-Tesla fMRI), which provides increased spatial resolution, this study compared the iFC networks of the CeA and BNST in 27 healthy individuals. Both structures were coupled with areas of the medial prefrontal cortex, hippocampus, thalamus, and periaqueductal gray matter. Compared to the BNST, the bilateral CeA was more strongly coupled with the insula and regions that support sensory processing, including thalamus and fusiform gyrus. In contrast, the bilateral BNST was more strongly coupled with regions involved in cognitive and motivational processes, including the dorsal paracingulate gyrus, posterior cingulate cortex, and striatum. Collectively, these findings suggest that responses to sensory stimulation are preferentially coordinated by the CeA and cognitive and motivational responses are preferentially coordinated by the BNST.

Statistical power comparisons at 3T and 7T with a GO / NOGO task.

The field of cognitive neuroscience is weighing evidence about whether to move from standard field strength to ultra-high field (UHF). The present study contributes to the evidence by comparing a cognitive neuroscience paradigm at 3 Tesla (3T) and 7 Tesla (7T). The goal was to test and demonstrate the practical effects of field strength on a standard GO/NOGO task using accessible preprocessing and analysis tools. Two independent matched healthy samples (N = 31 each) were analyzed at 3T and 7T. Results show gains at 7T in statistical strength, the detection of smaller effects and group-level power. With an increased availability of UHF scanners, these gains may be exploited by cognitive neuroscientists and other neuroimaging researchers to develop more efficient or comprehensive experimental designs and, given the same sample size, achieve greater statistical power at 7T.

Exercise decreases defensive responses to unpredictable, but not predictable, threat.

BACKGROUND: Research supports the anxiolytic effect of exercise, but the mechanism underlying this effect is unclear. This study examines the influence of exercise in healthy controls on two distinct defensive states implicated in anxiety disorders: fear, a phasic response to a predictable threat, and anxiety, a sustained response to an unpredictable threat. METHODS: Thirty-four healthy volunteers (17 male, age M = 26.18, SD = 5.6) participated in sessions of exercise (biking at 60-70% of heart rate reserve) and control (biking at 10-20% of heart rate reserve) activity for 30 min, separated by 1 week. Threat responses were measured by eyeblink startle and assessed with the "Neutral-Predictable-Unpredictable threat test," which includes a neutral (N) and two threat conditions, one with predictable (P) and one with unpredictable (U) shock. RESULTS: Results show that exercise versus control activity reduces startle potentiation during unpredictable threat (P = .031), but has no effect on startle potentiation during predictable threat (P = .609). CONCLUSIONS: These results suggest that exercise reduces defensive response to unpredictable, but not predictable, threat, a dissociation that may help inform clinical indications for this behavioral intervention, as well as provide clues to its underlying neurobehavioral mechanisms.

Startling Differences: Using the Acoustic Startle Response to Study Sex Differences and Neurosteroids in Affective Disorders.

PURPOSE OF REVIEW: Neuroactive steroid hormones, such as estradiol and progesterone, likely play a role in the pathophysiology of female-specific psychiatric disorders such as premenstrual dysphoric disorder (PMDD) and postpartum depression and may contribute to the marked sex differences observed in the incidence and presentation of affective disorders. However, few tools are available to study the precise contributions of these neuroactive steroids (NSs). In this review, we propose that the acoustic startle response (ASR), an objective measure of an organism's response to an emotional context or stressor, is sensitive to NSs. As such, the ASR represents a unique translational tool that may help to elucidate the contribution of NSs to sex differences in psychiatric disorders. RECENT FINDINGS: Findings suggest that anxiety-potentiated startle (APS) and prepulse inhibition of startle (PPI) are the most robust ASR paradigms for assessing contribution of NSs to affective disorders, while affective startle response modulation (ASRM) appears less diagnostic of sex or menstrual cycle (MC) effects. However, few studies have appropriately used ASR to test a priori hypotheses about sex or MC differences. We recommend that ASR studies account for sex as a biological variable (SABV) and hormonal status to further knowledge of NS contribution to affective disorders.

Impaired discriminative fear conditioning during later training trials differentiates generalized anxiety disorder, but not panic disorder, from healthy control participants.

BACKGROUND: Fear conditioning is implicated as a central psychopathological mechanism of anxiety disorders. People with anxiety disorders typically demonstrate reduced affective discrimination between conditioned danger and safety cues. Here, affective discrimination refers to the ability to selectively display fear to dangerous but not safe situations. Though both generalized anxiety disorder (GAD) and panic disorder (PD) are linked to impaired affective discrimination, the clinical phenomenology of these disorders suggests that people with GAD versus PD might be less able to overcome such deficits. It is unclear how this potential difference would manifest during lab-based conditioning. METHODS: We used a classical fear conditioning paradigm over two discrimination training sessions to examine whether those with GAD, but not PD, would display persistent discrimination deficits. Sixty-seven participants (21 GAD, 19 PD, 27 Healthy Controls) completed a task in which conditioned fear was measured psychophysiologically (fear-potentiated startle), behaviorally, and via self-report. RESULTS: Although similar levels of impaired discrimination were found for both GAD and PD groups during initial training, such impairments tended to persist across a subsequent training session only for patients with GAD when compared with Controls. CONCLUSION: Our results provide a foundation for additional research of discrimination deficits in specific anxiety disorders, with an ultimate goal of improved customization of psychological treatments.

Interaction of induced anxiety and verbal working memory: influence of trait anxiety.

This study examines the influence of trait anxiety on working memory (WM) in safety and threat. Interactions between experimentally induced anxiety and WM performance (on different cognitive loads) have been reported in healthy, nonanxious subjects. Differences in trait anxiety may moderate these interactions. Accordingly, these interactions may be potentiated by high trait anxiety (HTA), or show a resilient pattern that protects cognitive performance. HTA and low trait anxiety (LTA) were defined by a median split of scores on the trait component of the state-trait anxiety inventory. Sustained anxiety was evoked by a probabilistic exposure to an aversive scream, and was measured by eyeblink startle and self-report. WM was tested using an n-back task (1-, 2-, and 3-back). Results revealed that, as expected, the HTA group reported greater anxiety during the task. However, trait anxiety did not impact the modulation of WM performance by induced anxiety. Notably, HTA influenced anxiety-potentiated startle (startle during threat minus startle during safe; APS) differently as a function of memory load. Accordingly, APS decreased with increasing WM load, but HTA antagonized this reduction. The HTA group showed no impairment on the 3-back WM task despite a higher APS. The amplified APS could be associated with the increase in effort-related cognitive arousal. Furthermore, this third replication of the interaction of induced anxiety by load on WM performance testifies to the robustness of the unique interplay between anxiety and WM.

Resting state connectivity of the human habenula at ultra-high field.

The habenula, a portion of the epithalamus, is implicated in the pathophysiology of depression, anxiety and addiction disorders. Its small size and connection to other small regions prevent standard human imaging from delineating its structure and connectivity with confidence. Resting state functional connectivity is an established method for mapping connections across the brain from a seed region of interest. The present study takes advantage of 7T fMRI to map, for the first time, the habenula resting state network with very high spatial resolution in 32 healthy human participants. Results show novel functional connections in humans, including functional connectivity with the septum and bed nucleus of the stria terminalis (BNST). Results also show many habenula connections previously described only in animal research, such as with the nucleus basalis of Meynert, dorsal raphe, ventral tegmental area (VTA), and periaqueductal grey (PAG). Connectivity with caudate, thalamus and cortical regions such as the anterior cingulate, retrosplenial cortex and auditory cortex are also reported. This work, which demonstrates the power of ultra-high field for mapping human functional connections, is a valuable step toward elucidating subcortical and cortical regions of the habenula network.

Anxiety Patients Show Reduced Working Memory Related dlPFC Activation During Safety and Threat.

BACKGROUND: Anxiety patients exhibit deficits in cognitive tasks that require prefrontal control of attention, including those that tap working memory (WM). However, it is unclear whether these deficits reflect threat-related processes or symptoms of the disorder. Here, we distinguish between these hypotheses by determining the effect of shock threat versus safety on the neural substrates of WM performance in anxiety patients and healthy controls. METHODS: Patients, diagnosed with generalized and/or social anxiety disorder, and controls performed blocks of an N-back WM task during periods of safety and threat of shock. We recorded blood-oxygen-level dependent (BOLD) activity during the task, and investigated the effect of clinical anxiety (patients vs. controls) and threat on WM load-related BOLD activation. RESULTS: Behaviorally, patients showed an overall impairment in both accuracy and reaction time compared to controls, independent of threat. At the neural level, patients showed less WM load-related activation in the dorsolateral prefrontal cortex, a region critical for cognitive control. In addition, patients showed less WM load-related deactivation in the ventromedial prefrontal cortex and posterior cingulate cortex, which are regions of the default mode network. Most importantly, these effects were not modulated by threat. CONCLUSIONS: This work suggests that the cognitive deficits seen in anxiety patients may represent a key component of clinical anxiety, rather than a consequence of threat.

Effect of anxiety on behavioural pattern separation in humans.

Behavioural pattern separation (BPS), the ability to distinguish among similar stimuli based on subtle physical differences, has been used to study the mechanism underlying stimulus generalisation. Fear overgeneralisation is often observed in individuals with posttraumatic stress disorder and other anxiety disorders. However, the relationship between anxiety and BPS remains unclear. The purpose of this study was to determine the effect of anxiety (threat of shock) on BPS, which was assessed across separate encoding and retrieval sessions. Images were encoded/retrieved during blocks of threat or safety in a 2 × 2 factorial design. During retrieval, participants indicated whether images were new, old, or altered. Better accuracy was observed for altered images encoded during periods of threat compared to safety, but only if those images were also retrieved during periods of safety. These results suggest that overgeneralisation in anxiety may be due to altered pattern separation.

Induced-anxiety differentially disrupts working memory in generalized anxiety disorder.

BACKGROUND: Anxiety is characterized by a bias towards threatening information, anxious apprehension, and disrupted concentration. Previous research in healthy subjects suggests that working memory (WM) is disrupted by induced anxiety, but that increased task-demand reduces anxiety and WM is preserved. However, it is unknown if patients with generalized anxiety disorder (GAD) can similarly normalize their performance on difficult WM tasks while reducing their anxiety. Increased threat-related bias and impoverished top-down control in trait anxiety suggests that patients may not reap the same cognitive and emotional benefits from demanding tasks that those low in anxiety. Here we examine this possibility using a WM task of varying difficulty. METHODS: GAD patients (N = 30) and healthy controls (N = 30) performed an n-back task (no-load, 1-back, 2-back, and 3-back) while at risk for shock (threat) or safe from shock (safe). Anxiety was measured via startle reflex and self-report. RESULTS: As predicted, healthy controls' performance was impaired under threat during low-load tasks and facilitated during high-load tasks. In contrast, GAD patients' performance was impaired under threat regardless of WM load. Anxiety was reduced as cognitive load increased in both groups. CONCLUSIONS: The divergence of emotion regulation (reduction) and performance (persistent impairment) in the patient but not the control group, suggests that different top-down mechanisms may be operating to reduce anxiety. Continued WM disruption in patients indicates that attentional resources are allocated to emotion regulation instead of goal-directed behavior. Implications for our understanding of cognitive disruption in patients, and related therapeutic interventions are discussed.