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Temporally unpredictable stimuli influence behavior across species, as previously demonstrated for sequences of simple threats and rewards with fixed or variable onset. Neuroimaging studies have identified a specific frontolimbic circuit that may become engaged during the anticipation of temporally unpredictable threat (U-threat). However, the neural mechanisms underlying processing of temporally unpredictable reward (U-reward) are incompletely understood. It is also unclear whether these processes are mediated by overlapping or distinct neural systems. These knowledge gaps are noteworthy given that disruptions within these neural systems may lead to maladaptive response to uncertainty. Here, using functional magnetic resonance imaging data from a sample of 159 young adults, we showed that anticipation of both U-threat and U-reward elicited activation in the right anterior insula, right ventral anterior nucleus of the thalamus and right inferior frontal gyrus. U-threat also activated the right posterior insula and dorsal anterior cingulate cortex, relative to U-reward. In contrast, U-reward elicited activation in the right fusiform and left middle occipital gyrus, relative to U-threat. Although there is some overlap in the neural circuitry underlying anticipation of U-threat and U-reward, these processes appear to be largely mediated by distinct circuits. Future studies are needed to corroborate and extend these preliminary findings.

Identifying neurobehavioral correlates of suicidal ideation can help detect those most vulnerable for suicide among high-risk groups, such as those with internalizing psychopathology. Individuals with elevated sensitivity to uncertain threat (U-threat) have a strong preference for known outcomes relative to unknown outcomes and often experience high levels of chronic distress. We therefore hypothesized that among individuals with internalizing psychopathology, those with heightened reactivity to U-threat would be especially prone to suicidal ideation as a means to escape uncertainty. The present study examined whether in two independent samples suicidal ideation was associated with heightened startle response to U-threat, and whether the effects were specific to responses U-threat relative to predictable threat (P-threat). Study 1 was a sample of treatment-seeking patients (N = 99) and Study 2 was a community sample (N = 102). Participants in both samples met current DSM-5 criteria for an anxiety and/or depressive disorder. In Study 1, current suicidal ideation was positively associated with startle potentiation to U-threat. Similarly, in Study 2, a lifetime history of suicidal ideation was positively associated with startle potentiation to U-threat. The relation between suicidal ideation and startle potentiation to U-threat remained when adjusting for number of internalizing diagnoses. Heightened reactivity to U-threat may therefore characterize those with a propensity for suicidal ideation among individuals with internalizing psychopathology.

Aberrant threat reactivity has been implicated in the pathophysiology of posttraumatic stress disorder (PTSD); however, the literature on this association is mixed. One factor that may contribute to this inconsistent association is differences in severity of posttraumatic stress symptoms (PTSSs) across studies, but no studies have tested this hypothesis. The relation between PTSD and threat reactivity may also differ between unpredictable threats (U-threats) and predictable threats (P-threats), given burgeoning evidence to support a particular role for aberrant responding to U-threat in PTSD. The present study examined how PTSS severity relates to startle potentiation to U-threat and P-threat in a trauma-exposed community sample (N = 258). There was a negative linear, but not quadratic, relation between PTSS severity and startle potentiation to U-threat, but not P-threat. Blunted defensive responding to U-threat may therefore contribute to higher levels of PTSSs and may represent a novel treatment target for higher levels of PTSSs.

Despite decades of research on the physiological and psychological effects of the menstrual cycle, studies have not sufficiently adopted consistent methods for operationalizing the menstrual cycle. This has resulted in substantial confusion in the literature and limited possibilities to conduct systematic reviews and meta-analyses. In order to facilitate more rapid accumulation of knowledge on cycle effects, the present paper offers a set of integrative guidelines and standardized tools for studying the menstrual cycle as an independent variable. We begin with (1) an overview of the menstrual cycle and (2) premenstrual disorders, followed by (3) recommendations and tools regarding data collection in cycle studies. These recommendations address selecting the appropriate study design and sampling strategy, managing demand characteristics, identifying a sample of naturally-cycling individuals, and measuring menstrual bleeding dates, ovarian hormones, and ovulation. We proceed with suggestions for (4) data preparation and coding of cycle day and phases, as well as (5) data visualization, statistical modeling, and interpretation of menstrual cycle associations. We also provide (6) recommendations for using menses start day and ovulation testing to schedule visits in laboratory studies and end with a (7) comprehensive summary and conclusion. Regardless of whether the influence of the menstrual cycle is of central interest in a study or should be controlled to accurately assess the effects of another variable, the use of these recommendations and tools will help make study results more meaningful and replicable.

Background Delineating specific clinical phenotypes of anxiety disorders is a crucial step toward better classification and understanding of these conditions. The present study sought to identify differential aversive responses to predictable and unpredictable threat of shock in healthy comparisons and in nonmedicated anxiety patients with and without a history of panic attacks (PAs). Methods In this study, 143 adults (72 healthy control subjects; 71 patients with generalized, social, or both generalized and social anxiety disorders, 24 with and 47 without PAs) were exposed to three conditions: 1) predictable shocks signaled by a cue, 2) unpredictable shocks, and 3) no shock. Startle magnitude was used to assess aversive responses. Results Across disorders, a history of PAs was specifically associated with hypersensitivity to unpredictable threat. By disorder, social anxiety disorder was associated with hypersensitivity to predictable threat, whereas generalized anxiety disorder was associated with exaggerated baseline startle. Conclusions These results identified three physiological patterns. The first is hypersensitivity to unpredictable threat in individuals with PAs. The second is hypersensitivity to predictable threat, which characterizes social anxiety disorder. The third is enhanced baseline startle in generalized anxiety disorder, which may reflect propensity for self-generated anxious thoughts in the absence of imminent danger. These results inform current thinking by linking specific clinical features to particular physiology profiles.

Asian Americans are one of the fastest growing minority group in the United States; however, mental health within this population segment, particularly anxiety disorders, remains significantly understudied. Both the heterogeneity within the Asian American population, along with the multidimensional nature of anxiety, contribute to difficulties in understanding anxiety in this population. The present paper will review two sources of heterogeneity within anxiety in Asian Americans: (1) cultural variables and (2) mechanisms or components of anxiety. Specifically, we will examine four cultural variables most commonly found in research related to anxiety in Asian Americans: acculturation, affect valuation, loss of face, and individualism-collectivism. We will also discuss ways to parse anxiety through a Research Domain Criteria (RDoC) framework, specifically focusing on sensitivity to acute and potential threat, constructs within the Negative Valence System. We also present previously unpublished preliminary data to illustrate one way of examining ethnic differences in anxiety using an RDoC framework. Finally, this paper offers recommendations for future work in this area.

BackgroundHeightened reactivity to unpredictable threat (U-threat) is a core individual difference factor underlying fear-based psychopathology. Little is known, however, about whether reactivity to U-threat is a stable marker of fear-based psychopathology or if it is malleable to treatment. The aim of the current study was to address this question by examining differences in reactivity to U-threat within patients before and after 12-weeks of selective serotonin reuptake inhibitors (SSRIs) or cognitive-behavioral therapy (CBT).MethodsParticipants included patients with principal fear (n= 22) and distress/misery disorders (n= 29), and a group of healthy controls (n= 21) assessed 12-weeks apart. A well-validated threat-of-shock task was used to probe reactivity to predictable (P-) and U-threat and startle eyeblink magnitude was recorded as an index of defensive responding.ResultsAcross both assessments, individuals with fear-based disorders displayed greater startle magnitude to U-threat relative to healthy controls and distress/misery patients (who did not differ). From pre- to post-treatment, startle magnitude during U-threat decreased only within the fear patients who received CBT. Moreover, within fear patients, the magnitude of decline in startle to U-threat correlated with the magnitude of decline in fear symptoms. For the healthy controls, startle to U-threat across the two time points was highly reliable and stable.ConclusionsTogether, these results indicate that startle to U-threat characterizes fear disorder patients and is malleable to treatment with CBT but not SSRIs within fear patients. Startle to U-threat may therefore reflect an objective, psychophysiological indicator of fear disorder status and CBT treatment response.

Emotion-modulated startle is a frequently used method in affective science. Although there is a growing literature on the reliability of this measure, it is presently unclear how many startle responses are necessary to obtain a reliable signal. The present study therefore evaluated the reliability of startle responding as a function of number of startle responses (NoS) during a widely used threat-of-shock paradigm, the NPU-threat task, in a clinical (N = 205) and non-clinical (N = 92) sample. In the clinical sample, internal consistency was also examined independently for healthy controls vs. those with panic disorder and/or major depression and retest reliability was assessed as a function of NoS. Although results varied somewhat by diagnosis and for retest reliability, the overall pattern of results suggested that six startle responses per condition were necessary to obtain acceptable reliability in clinical and non-clinical samples during this threat-of-shock paradigm in the present study.

Prior studies indicate that anxiety disorders are associated with heightened sensitivity to uncertain threat (U threat). Individual differences in reactivity to U threat have been measured in the laboratory with two methodologies-startle eyeblink potentiation and fMRI. While startle and fMRI are purported to relate to each other, very little research exists on whether individual differences in one measure are associated with individual differences in another and, thus, whether startle and fMRI capture shared mechanisms. Therefore, the current study was designed to investigate if and where in the brain measures of startle potentiation and fMRI BOLD signal correlate during response to U threat across two independent samples. Participants in both studies completed two threat anticipation tasks-once during collection of startle potentiation and once during fMRI. In Study 1 (n = 43), the startle and fMRI tasks both used electric shock as the threat. As an extension, in Study 2 (n = 38), the startle task used electric shock but the fMRI task used aversive images. Despite these methodological differences, greater startle potentiation to U threat was associated with greater dorsal anterior cingulate, caudate, and orbitofrontal cortex reactivity to U threat in both samples. The findings suggest that startle and fMRI measures of responding to U threat overlap, and points toward an integrated brain-behavior profile of aberrant U threat responding.

Heightened responsivity to unpredictable, and perhaps predictable, threat characterizes some internalizing disorders and may be vulnerability factors for psychopathology as well. However, few studies have directly tested whether individual differences in unpredictable and/or predictable threat responding longitudinally predict symptoms of psychopathology and functional outcomes. Examining functioning is particularly important given that functioning is separable from symptoms of psychopathology. The present study examined whether electromyography startle measures of predictable and/or unpredictable threat responding was associated with interviewer-assessed symptoms of internalizing psychopathology and functional impairment at baseline (n = 409) and one-year follow-up (n = 104). Elevated startle responding to unpredictable and predictable threat longitudinally predicted a worsening of functioning over time and this effect was independent of change of symptoms over time. Importantly, threat responding at baseline predicted functional impairment during the follow-up independent of the effects of DSM-defined fear-based (e.g., panic disorder) or distress-misery (e.g., major depressive disorder) internalizing disorders. These findings provide initial support for the incremental validity of neurobiological vulnerability markers of threat responding over and above DSM disorders and highlight the importance of distinguishing functional outcomes from symptom outcomes.

Heightened reactivity to uncertain threat (U-threat) is an important individual difference factor that may characterize fear-based internalizing psychopathologies (IPs) and distinguish them from distress/misery IPs. To date, however, the majority of existing research examining reactivity to U-threat has been within individuals with panic disorder and major depressive disorder (MDD) and no prior study has directly tested this hypothesis across multiple IPs. The current study therefore explored whether heightened reactivity to U-threat is a psychophysiological indicator of fear-based psychopathology across 5 groups: current (a) social anxiety disorder (SAD); (b) specific phobia (SP); (c) generalized anxiety disorder (GAD); (d) MDD; and (c) individuals with no history of psychopathology (controls). All 160 adults completed a well-validated threat-of-shock task designed to probe responses to predictable (P-) and U-threat. Startle eyeblink potentiation was recorded as an index of aversive arousal. Results indicated that individuals with SAD and SP evidenced greater startle potentiation to U-threat, but not P-threat, relative to individuals with GAD, MDD, and controls (who did not differ). The current findings, along with the prior panic disorder and MDD literature, suggest that heightened reactivity to U-threat is a psychophysiological indicator of fear-based disorders and could represent a neurobiological organizing principle for internalizing psychopathology. The findings also suggest that individuals with fear disorders generally display a hypersensitivity to uncertain aversive events, which could contribute to their psychopathology. (PsycINFO Database Record

Exaggerated anxious responding to unpredictable threat (U-threat) is a core feature of panic disorder (PD). However, it is unknown whether this abnormality is specific to the diagnosis of PD or would manifest along a continuum of panic symptomatology (PS). In addition, little is known about the neural processes underlying this abnormality among those high in PS. Finally, no studies have tested whether startle potentiation and limbic neural reactivity—commonly used indices of U-threat responsivity—are associated and therefore reflect common abnormalities. These questions were investigated in 42 adults with a range of PS. U-threat responding was measured twice during threat of shock—once with startle and once with functional magnetic resonance imaging. As hypothesized, PS positively predicted startle potentiation and dACC reactivity to U-threat. Startle potentiation and dACC activation to U-threat were positively associated. These results suggest a biobehavioral profile of aberrant responding to U-threat associated with PS.

BackgroundWhen sober, problematic drinkers display exaggerated reactivity to threats that are uncertain (U-threat). Since this aversive affective state can be alleviated via acute alcohol intoxication, it has been posited that individuals who exhibit heightened reactivity to U-threat at baseline are motivated to use alcohol as a means of avoidance-based coping, setting the stage for excessive drinking. To date, however, no study has attempted to characterize the dispositional nature of exaggerated reactivity to U-threat and test whether it is a vulnerability factor or exclusively a disease marker of problematic alcohol use.MethodThe current investigation utilized a family study design to address these gaps by examining whether (1) reactivity to U-threat is associated with risk for problematic alcohol use, defined by family history of alcohol use disorder (AUD) and (2) reactivity to U-threat is correlated amongst adult biological siblings. A total of 157 families, and 458 individuals, participated in the study and two biological siblings completed a threat-of-shock task designed to probe reactivity to U-threat and predictable threat (P-threat). Startle potentiation was collected as an index of aversive responding.ResultsWithin biological siblings, startle potentiation to U-threat [intraclass correlation (ICC) = 0.35] and P-threat (ICC = 0.63) was significantly correlated. In addition, independent of an individuals’ own AUD status, startle potentiation to U-threat, but not P-threat, was positively associated with risk for AUD (i.e. AUD family history).ConclusionThis suggests that heightened reactivity to U-threat may be a familial vulnerability factor for problematic drinking and a novel prevention target for AUD.

Background Recent laboratory studies have shown that acute alcohol intoxication selectively and effectively dampens aversive responding to uncertain threat. An emerging hypothesis is that individuals who exhibit heightened reactivity to uncertain threat may be especially motivated to use alcohol to dampen their distress, setting the stage for negative reinforcement processes to drive excessive alcohol use. However, no study to date has directly examined whether current problematic drinkers exhibit heightened reactivity to uncertain threat as would be expected. Methods The present study was therefore designed to examine the association between current problematic alcohol use and reactivity to uncertain threat during sobriety in two, independent samples. In Study 1 (n = 221) and Study 2 (n = 74), adult participants completed the same well-validated threat-of-shock task which separately probes responses to temporally predictable and unpredictable threat. Startle potentiation was measured as an index of aversive responding. Problematic alcohol use was defined as number of binge episodes within the past 30 days in Study 1 and total scores on a self-report measure of hazardous drinking in Study 2. Results As hypothesized, across both studies greater levels of problematic drinking were associated with greater startle potentiation to unpredictable threat. In Study 2, hazardous drinking scores were also positively associated with startle potentiation to predictable threat. Conclusions The findings are notably consistent with the notion that heightened reactivity to uncertain threat is an important individual difference factor associated with the onset and/or maintenance of problematic drinking behaviors and may therefore be a novel prevention and intervention target.

Personality traits relate to risk for psychopathology and can inform predictions about treatment outcome. In an effort to obtain a comprehensive index of personality, informant reports of personality are sometimes obtained in addition to self-reports of personality. However, there is limited research comparing the validity of self- and informant reports of personality, particularly among those with internalizing psychopathology. This is important given that informants may provide an additional (and perhaps different) perspective on individuals' personality. The present study therefore compared how both reports of positive affectivity (PA) and negative affectivity (NA) relate to psychophysiological and subjective measures of emotional responding to positive and negative stimuli. Given that our sample (n = 117) included individuals with no history of psychopathology, as well as individuals with major depressive disorder (MDD) and/or panic disorder (PD), we were also able to explore whether these internalizing diagnoses moderated the association between personality reports and measures of emotional responding. Informant-reported PA predicted physiological responses to positive stimuli (but not negative). Informant-reported NA predicted physiological responses to negative stimuli (but not positive). Self-reported personality did not predict physiological responding, but did predict subjectively measured emotional responding (NA for negative responding, PA for positive responding). Diagnoses of internalizing psychopathology (PD or MDD) did not moderate these associations. Results suggest self- and informant reports of personality may each provide valid indices of an individual's emotional response tendencies, but predict different aspects of those tendencies.

Several personality traits are risk factors for psychopathology. As symptoms of psychopathology may influence self-rated personality, informant reports of personality are also sometimes collected. However, little is known about self-informant agreement in individuals with anxiety and/or depression. We investigated whether self-informant agreement on positive and negative affectivity (PA and NA) and anxiety sensitivity differs for individuals with major depressive disorder (MDD) and/or panic disorder (PD; total n = 117). Informant- and self-reported PA was correlated among those with MDD, but not among those without MDD. Informant- and self-reported anxiety sensitivity was correlated among those with PD, but not among those without PD. Informant- and self-reported NA was correlated irrespective of diagnosis. Results indicate that the agreement of self- and informant-reported personality may vary as a function of depression and/or anxiety disorders.

Studies suggest that individuals with alcohol use disorder (AUD) display abnormal neural error-processing, measured via the error-related negativity (ERN). The nature of the error-related abnormalities in AUD is unclear, however, as prior research has yielded discrepant findings. In addition, no study to date has attempted to characterize the dispositional nature of the ERN in AUD and directly test to what extent ERN amplitude reflects a risk factor, disease marker, and/or scar of AUD psychopathology. The current study compared ERN amplitude across 244 adult volunteers in the following five groups: 1) current AUD (n = 39), 2) AUD in remission (n = 60), 3) at-risk for AUD (n = 43), 4) psychiatric controls with comparable rates of internalizing psychopathology as the AUD groups (n = 53), and 5) healthy controls with no lifetime history of psychopathology (n = 49). Risk for AUD was defined as a positive, first-degree family history. All participants completed a well-validated flanker task, designed to robustly elicit the ERN, during continuous electroencephalographic (EEG) data collection. Results indicated that individuals with current AUD displayed smaller ERNs compared with individuals at-risk for AUD, with AUD in remission, psychiatric controls, and healthy controls. There were no differences amongst any of the other groups. This suggests that a blunted ERN may be concomitant with current AUD psychopathology and relatedly, a novel neurobiological AUD treatment target and/or objective marker of AUD disease status.

There is a growing literature associating anxiety disorders with an inability to inhibit defensive responding during safety conditions of threatening tasks. However, investigations on the relation between panic disorder (PD) and defensive responding to safety have yielded mixed results. A recent study from our laboratory revealed that intolerance of uncertainty (IU) moderates this association, such that only individuals with PD and a high IU exhibit heightened startle potentiation during safety. The mechanism underlying this relationship is unknown. Given that safety conditions typically alternate with periods of threat, cognitive flexibility (i.e., the ability to adjust one's habitual responding to a situation, given the input of new information) may be involved in the ongoing reappraisal of danger and adjustment of defensive responding. Thus, the present study sought to investigate whether deficits in cognitive flexibility mediate the association between IU and defensive responding to safety among a sample of 71 adults diagnosed with PD. As hypothesised, cognitive flexibility mediated the relationship between IU and heightened startle potentiation during safety conditions. This finding suggests that within this subgroup, a failure to inhibit defensive responding during safety conditions may be due to deficits in cognitive flexibility.

Posttraumatic stress disorder (PTSD) is highly prevalent and associated with impairment, even at the subthreshold level. It is therefore important to identify biological processes that contribute to the pathophysiology of posttraumatic stress symptoms (PTSS). Although neuroimaging research has highlighted the importance of heightened amygdala reactivity to aversive stimuli in PTSS, not all studies have yielded evidence of this relationship. Given that PTSS is comprised of four, factor analytically distinct dimensions of symptoms - re-experiencing, avoidance, hyperarousal, and negative cognitions and mood - it is possible that heightened amygdala reactivity to aversive stimuli is specific to certain PTSS clusters. In a sample of 45 trauma-exposed individuals, the present study therefore examined how specific PTSS clusters relate to amygdala responding during functional magnetic resonance imaging (fMRI) to both negative and positive emotional faces during a well-validated social-emotional task, the Emotional Face Assessment Task (EFAT). Results indicated that hyperarousal symptoms were positively associated with left amygdala reactivity across all emotional face conditions. There was no interaction of hyperarousal by condition (i.e., fearful, sad, angry, or happy faces), and other PTSS clusters were not associated with amygdala reactivity. These results indicate that the hyperarousal cluster of PTSS may have a unique relationship with amygdala reactivity to socioemotional information. The results also corroborate a growing literature suggesting that trauma-exposed individuals characterized by high PTSS hyperarousal symptoms may display exaggerated psychophysiological reactivity to appetitive and aversive stimuli.

Summary Background In four previous studies, we have delineated the role of positive circuit coupling between the dorsal medial prefrontal (anterior cingulate) cortex and the amygdala during aversive processing in healthy people under stress. This translational circuit—the aversive amplification circuit—is thought to drive adaptive, harm-avoidant behaviour in threatening environments. We assess the role of this circuit in the pathological manifestation of anxiety disorders. Methods For this single-site study, 45 unmedicated participants (22 with generalised and/or social anxiety disorder and 23 healthy controls) were recruited via advertisements from the metropolitan area of Washington, DC (USA). People who applied to participate in the study had to pass an initial telephone screen and comprehensive screening by a clinician at the National Institutes of Health (NIH; Bethesda, MD, USA). People with a contraindicated medical disorder, past or current psychiatric disorders other than anxiety disorders, and those using psychoactive medications or illicit drugs were excluded. Eligible individuals could participate as either a healthy control or a patient, depending on diagnosis. They were asked to use a button box to complete a simple emotion identification task (fearful vs happy faces; 44 trials of each) during functional MRI at the NIH. Functional imaging analysis consisted of event-related activation analysis and psychophysiological interaction connectivity analysis of regions coupled with the amygdala during task performance. Findings A diagnosis-by-valence interaction was recorded in whole-brain amygdala connectivity within the dorsal medial prefrontal (anterior cingulate) cortex clusters identified in our previous study, driven by significantly increased circuit coupling during processing of fearful faces versus happy faces in anxious, but not healthy, participants. Importantly, and in accordance with contemporary theoretical approaches to psychiatry, circuit coupling correlated positively with self-reported anxious symptoms, which provides evidence of a continuous association between the circuit and subjective symptoms. Interpretation In this study and our previous work, we track the functional role of one neural circuit from its involvement in adaptive threat biases under stress, to its chronic engagement in anxiety disorders in the absence of experimentally induced stress. Thus, we uniquely map a mood and anxiety-related circuit across its adaptive and maladaptive stages. Clinically, this study could provide a step towards a more mechanistic continuum-based approach to anxiety disorder diagnosis and might ultimately lead to more targeted treatments for patients with anxiety disorders. Funding National Institute of Mental Health, USA, and Medical Research Council

Posttraumatic stress symptoms (PTSS) are associated with significant distress and impairment. Research has therefore focused on identifying neurobehavioral deficits that contribute to the pathophysiology of PTSS. One issue that has contributed to difficulty in identifying these deficits is the highly heterogeneous nature of PTSS. PTSS is comprised of four, factor analytically distinct dimensions of symptoms – re-experiencing, avoidance, hyperarousal, and negative cognitions and mood. It is therefore unlikely that there is one single mechanism that accounts for all of PTSS and elucidating neurobehavioral deficits associated with specific PTSS symptom dimensions may better inform clinical prevention and intervention efforts. Within the broader internalizing disorder literature, two key constructs that contribute to psychopathology are aberrant neural reactivity to threat and reward. However, the literature linking PTSS to these deficits is mixed, suggesting that aberrant neural reactivity to threat or reward may be specific to certain PTSS dimensions. In a sample of 51 trauma-exposed adults with a range PTSS, the present study therefore examined how the four dimensions of PTSS uniquely relate to two well-validated event-related potential (ERP) neural indices of threat and reward reactivity – the error-related negativity (ERN) and reward-related positivity (RewP), respectively. Results indicated that hyperarousal symptoms were associated with enhanced ERN, and enhanced RewP. In contrast, negative cognitions and mood symptoms were uniquely associated with a more blunted RewP. These results indicate that certain PTSS symptom dimensions have unique relations with neural indicators of threat and reward reactivity and may therefore have distinct pathophysiologies.

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.

Fear to predictable threat and anxiety to unpredictable threat reflect distinct processes mediated by different brain structures, the central nucleus of the amygdala and the bed nucleus of the stria terminalis (BNST), respectively. This study tested the hypothesis that the corticotropin-releasing factor (CRF1) antagonist GSK561679 differentially reduces anxiety but increases fear in humans. A total of 31 healthy females received each of four treatments: placebo, 50 mg GSK561679 (low-GSK), 400 mg GSK561679 (high-GSK), and 1 mg alprazolam in a crossover design. Participants were exposed to three conditions during each of the four treatments. The three conditions included one in which predictable aversive shocks were signaled by a cue, a second during which shocks were administered unpredictably, and a third condition without shock. Fear and anxiety were assessed using the acoustic startle reflex. High-GSK had no effect on startle potentiation during unpredictable threat (anxiety) but increased startle potentiation during the predictable condition (fear). Low-GSK did not affect startle potentiation across conditions. Consistent with previous findings, alprazolam reduced startle potentiation during unpredictable threat but not during predictable threat. The increased fear by high-GSK replicates animal findings and suggests a lift of the inhibitory effect of the BNST on the amygdala by the CRF1 antagonist.

An inability to inhibit aversive responding during conditions that signal safety may be a core dysfunction associated with anxiety disorders. However, there has been inconsistent evidence as to whether individuals with panic disorder (PD) exhibit aversive responding during safety signals. It is therefore possible that only certain subgroups of PD patients, particularly those with high levels of intolerance of uncertainty (IU), evidence this type of abnormal responding. The aim of the current study was to examine whether IU moderates the association between PD and startle potentiation during (a) safety and (b) threat periods during a threat-of-shock task. Participants included 172 adults, 74 of which had current diagnoses of PD. Results indicated that at high levels of IU, PD was associated with greater startle potentiation during safety. At low levels of IU, PD was not associated with startle potentiation during safety. IU did not moderate the effect of PD on threat responding. These results suggest that PD patients with high levels of IU fail to inhibit aversive responding during safety, possibly due to a tendency to interpret distal threat as distressing.

Anxiety disorders can be treated both pharmacologically and psychologically, but many individuals either fail to respond to treatment or relapse. Improving outcomes is difficult, in part because we have incomplete understanding of the neurobiological mechanisms underlying current treatments. In a sequence of studies, we have identified ‘affective bias-related’ amygdala–medial cortical coupling as a candidate substrate underlying adaptive anxiety (that is, anxiety elicited by threat of shock in healthy individuals) and shown that it is also chronically engaged in maladaptive anxiety disorders. We have provided evidence that this circuit can be modulated pharmacologically, but whether this mechanism can be shifted by simple psychological instruction is unknown. In this functional magnetic resonance imaging study, we extend a previously used translational anxiety induction (threat of shock) in healthy subjects (N=43) and cognitive task to include an element of instructed attentional control. Replicating our previous findings, we show that induced anxiety engages ‘affective bias-related’ amygdala-dorsal medial frontal coupling during the processing of emotional faces. By contrast, instructing subjects to attend to neutral shapes (and ignore faces) disengages this circuitry and increases putative ‘attentional control-related’ coupling between the amygdala and a more rostral prefrontal region. These neural coupling changes are accompanied by corresponding modulation of behavioural performance. Taken together, these findings serve to further highlight the potential role of amygdala–medial frontal coupling in the pathogenesis of anxiety and highlight a mechanism by which it can be modulated via psychological instructions. This, in turn, generates hypotheses for future work exploring the mechanisms underlying psychological therapeutic interventions for anxiety.

The potency of an unconditioned stimulus (UCS) can impact the degree of fear learning. One of the most common and effective UCSs is an electric shock, which is inappropriate for certain populations (e.g., children). To address this need, a novel fear learning paradigm was recently developed that uses a fearful female face and scream as the UCS. The present study directly compared the efficacy of the screaming female UCS and a traditional shock UCS in two fear learning paradigms. Thirty-six young adults completed two fear learning tasks and a measure of trait anxiety; fear learning was indexed with fear-potentiated startle (FPS) and self-reported fear ratings. Results indicated comparable FPS across the two tasks. However, larger overall startle responses were exhibited in the shock task, and participants rated the shock UCS and overall task as more aversive than the screaming female. In addition, trait anxiety was only related to FPS in the fear learning task that employed a shock as the UCS. Taken together, results indicate that, although both UCS paradigms can be used for fear conditioning (i.e., to produce differences between CS + and CS −), the shock UCS paradigm is more aversive and potentially more sensitive to individual differences in anxiety.