Sleep quality impacts the link between reactivity to uncertain threat and anxiety and alcohol use in youth.

Individual differences in reactivity to unpredictable threat (U-threat) have repeatedly been linked to symptoms of anxiety and drinking behavior. An emerging theory is that individuals who are hyper-reactive to U-threat experience chronic anticipatory anxiety, hyperarousal, and are vulnerable to excessive alcohol use via negative reinforcement processes. Notably, anxiety and alcohol use commonly relate to disruptions in sleep behavior and recent findings suggest that sleep quality may impact the link between reactivity to U-threat and psychiatric symptoms and behaviors. The aim of the current study was to examine the unique and interactive effects of reactivity to U-threat and sleep quality on anxiety symptoms and drinking behavior in a cohort of youth, ages 16-19 years. Participants (N = 112) completed a well-validated threat-of-shock task designed to probe individual differences in reactivity to U-threat and predictable threat (P-threat). Startle eyeblink potentiation was recorded during the task as an index of aversive reactivity. Participants also completed well-validated self-report measures of anxiety and depression symptoms, lifetime alcohol use, and current sleep quality. Results revealed significant startle reactivity to U-threat by sleep quality interactions on anxiety symptoms and lifetime drinking behavior. At high levels of sleep disturbance (only), greater reactivity to U-threat was associated with greater anxiety symptoms and total number of lifetime alcoholic beverages. These results suggest that sensitivity to uncertainty and chronic hyperarousal increases anxiety symptoms and alcohol use behavior, particularly in the context of poor sleep quality.

Anxiety Sensitivity and Intolerance of Uncertainty: Transdiagnostic Risk Factors for Anxiety as Targets to Reduce Risk of Suicide.

PURPOSE OF REVIEW: Suicide has a profound impact on individuals, families, and society. One prominent, if understudied, risk factor for suicide is anxiety. More than 70% of people with at least one suicide attempt meet diagnostic criteria for an anxiety disorder. There are several limitations to exploring the associations between anxiety and suicide using diagnosis-based classification systems. A better approach would be to consider transdiagnostic risk factors for anxiety. RECENT FINDINGS: Through a negative reinforcement model of suicide, anxiety sensitivity (AS) and intolerance of uncertainty (IU) appear to exacerbate the experience of unpleasant anxiety sensations and likely contribute to chronic suicide risk as well as acute suicidal acts. Although more research is needed to clarify the mechanisms through which AS and IU confer risk, brief interventions may offer an ideal suicide prevention strategy for anxious people.

Impact of Trauma Type on Startle Reactivity to Predictable and Unpredictable Threats.

ABSTRACT: Trauma exposure has been repeatedly linked to psychophysiological threat reactivity, although the directionality of this association has been inconsistent. Several factors likely contribute to inconsistent findings including type of trauma and threat paradigm. The present study therefore examined the impact of trauma type on psychophysiological reactivity to predictable (P-) and unpredictable (U-) threat in young adults (N = 112). Participants were classified into three groups: history of interpersonal or noninterpersonal trauma, or no history of trauma. Startle eyeblink potentiation was recorded during a well-validated threat-of-shock paradigm. Results indicated individuals with interpersonal trauma exposure displayed exaggerated startle reactivity to U-threat (only) compared with both other groups. In contrast, individuals with noninterpersonal trauma exhibited blunted startle reactivity to U-threat (only) compared with both other groups. Findings reveal that trauma and threat type influence threat reactivity and that those with a history of interpersonal trauma may uniquely display exaggerated sensitivity to stressors that are uncertain.

Human Plasma BDNF Is Associated With Amygdala-Prefrontal Cortex Functional Connectivity and Problem Drinking Behaviors.

BACKGROUND: Preclinical studies suggest that decreased levels of brain-derived neurotrophic factor in the amygdala play a role in anxiety and alcohol use disorder. The association between brain-derived neurotrophic factor levels and amygdala function in humans with alcohol use disorder is still unclear, although neuroimaging studies have also implicated the amygdala in alcohol use disorder and suggest that alcohol use disorder is associated with disrupted functional connectivity between the amygdala and prefrontal cortex during aversive states. METHODS: The current study investigated whether plasma brain-derived neurotrophic factor levels in individuals with and without alcohol use disorder (n = 57) were associated with individual differences in amygdala reactivity and amygdala-prefrontal cortex functional connectivity during 2 forms of aversive responding captured via functional magnetic resonance imaging: anxiety elicited by unpredictable threat of shock and fear elicited by predictable threat of shock. We also examined whether brain-derived neurotrophic factor and brain function were associated with binge drinking episodes and alcohol use disorder age of onset. RESULTS: During anxiety, but not fear, lower levels of plasma brain-derived neurotrophic factor were associated with less connectivity between the left amygdala and the medial prefrontal cortex and the inferior frontal gyrus. In addition, within individuals with alcohol use disorder (only), lower levels of brain-derived neurotrophic factor and amygdala-medial prefrontal cortex functional connectivity during anxiety were associated with more binge episodes within the past 60 days and a lower age of alcohol use disorder onset. There were no associations between brain-derived neurotrophic factor levels and focal amygdala task reactivity. CONCLUSIONS: Together, the results indicate that plasma brain-derived neurotrophic factor levels are related to amygdala circuit functioning in humans, particularly during anxiety, and these individual differences may relate to drinking behaviors.

Behavioral and neural sensitivity to uncertain threat in individuals with alcohol use disorder: Associations with drinking behaviors and motives.

A developing theory is that individuals with alcohol use disorder (AUD) display exaggerated reactivity to threats that are uncertain (U-threat), which facilitates excessive drinking as a means of avoidance-based coping. There is a promising initial behavioral evidence supporting this theory; however, the neural bases of reactivity to U-threat in individuals with AUD have not been examined. The extent to which biomarkers of U-threat reactivity map onto drinking behaviors and coping motives for alcohol use is also unknown. The current study therefore examined group differences in behavioral and neural reactivity to U-threat in adults with and without AUD. The study also tested whether behavior and brain responses to U-threat correlate with problematic drinking and coping motivated drinking. Volunteers (n = 65) with and without a history of AUD (38 AUD, 27 controls) were included and completed a well-validated threat-of-shock task to probe responses to U-threat and predictable threat (P-threat) while startle eyeblink potentiation was collected. Individuals also completed a newly designed, analogous version of the task during functional magnetic resonance imaging (fMRI). Results indicated that individuals with AUD displayed greater startle magnitude during U-threat, but not P-threat, and greater right insula and dorsal anterior cingulate cortex (dACC) activation during both forms of threat compared with controls. Startle magnitude and insula activation during U-threat positively correlated with self-reported problem drinking and coping motives for alcohol use. Findings demonstrate that individuals with AUD display exaggerated sensitivity to U-threat at the behavioral and neural level and that these multimethod biomarkers tap into negative reinforcement processes of alcohol abuse.

The Relation Between Posttraumatic Stress Symptom Severity and Startle Potentiation to Predictable and Unpredictable Threat.

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.

Neural correlates of inhibition and reward are negatively associated.

Individuals with impulsive and addictive disorders, including drug addiction, binge eating/obesity, and problem gambling, exhibit both impaired control over behavior and heightened sensitivity to reward. However, it is not known whether such deviation in inhibitory and reward circuitry among clinical populations is a cause or consequence of the disorders. Recent evidence suggests that these constructs may be related at the neural level, and together, increase risk for engaging in maladaptive behaviors. The current study examined the degree to which brain function during inhibition relates to brain function during receipt of reward in healthy young adults who have not yet developed problem behaviors. Participants completed the stop signal task to assess inhibitory control and the doors task to assess reactivity to monetary reward (win vs loss) during functional magnetic resonance imaging (fMRI). Brain activation during response inhibition was negatively correlated with brain activation during reward. Specifically, less brain activation in right prefrontal regions during inhibition, including the right inferior frontal gyrus, middle frontal gyrus, and supplementary motor area, was associated with greater brain activation in left ventral striatum during receipt of monetary reward. Moreover, these associations were stronger in binge drinkers compared to non-binge drinkers. These findings suggest that the systems are related even before the onset of impulsive or addictive disorders. As such, it is possible that the association between inhibitory and reward circuitry may be a prospective marker of risk.

Acute calming effects of alcohol are associated with disruption of the salience network.

The mood-altering properties of alcohol are a key motivation for drinking, and people commonly report that they drink alcohol to alleviate stress or to relax. To date, the neural processes associated with the self-reported calming effects of alcohol are not well understood. Existing data imply that alcohol may target and disrupt activity within anterior insula (aINS) and amygdala-based neural networks, which are regions implicated in threat detection and anxious responding. The aims of the current study were (1) to examine the acute effect of alcohol upon functional connectivity within aINS and amygdala circuits and (2) to assess relationships between alcohol effects on functional connectivity and self-reported subjective mood. Healthy men and women (N = 39) who reported regular binge drinking completed a within-subjects, double-blind, placebo-controlled pharmacological functional magnetic resonance imaging experiment with i.v. infusions of either alcohol or placebo. Infusion profiles were personalized for each participant and raised breath alcohol concentration to 80 mg percent. Before, during and after infusions, participants rated their subjective mood (stimulation, sedation and calm). Results showed that alcohol dampened functional connectivity between bilateral aINS seed-regions-of-interest and the dorsal anterior cingulate cortex (dACC), key nodes of the salience network. Additionally, the more that alcohol reduced right aINS-dACC functional connectivity, the calmer participants felt during alcohol administration. Alcohol had no effect on amygdala functional connectivity. These findings suggest that alcohol disrupts aINS-dACC functional connectivity, which may impair detection and appraisal of emotionally salient information and relate to acute relaxing effects of the drug.

Error-related brain activity and internalizing disorder symptom dimensions in depression and anxiety.

BACKGROUND: Research suggests that enhanced neural reactivity to errors, measured via the error-related negativity (ERN), is relatively unique to internalizing psychopathologies (IPs) and symptom clusters characterized by excessive worry and apprehension. However, no prior study has tested the association between the ERN and IP symptom dimensions in a heterogeneous, clinically representative patient population. The current study was designed to address this gap in the literature and clarify the role of the ERN in an adult IP treatment-seeking patient sample. METHOD: Eighty-five participants completed a well-validated flanker task known to robustly elicit the ERN and a battery of questionnaires assessing a range of IP symptoms. All participants had at least one IP diagnosis and over 75% had co-occurring IPs. A principal components analysis (PCA) was performed on the questionnaire data indicating two distinct factors that characterized the IP sample: affective distress/misery and fear-based anxiety. RESULTS: Analyses indicated that within this sample, an enhanced ERN, but not CRN, was associated with greater fear-based anxiety symptoms but had no relation with distress/misery symptoms. CONCLUSIONS: Together, these findings indicate that an enhanced ERN may not be specific to worry/apprehension and may extend to the IP fear dimension. The results also converge with a broader literature suggesting that fear-based psychopathology is characterized by an exaggerated reactivity to threat and this objective, psychophysiological response tendency may distinguish fear disorders from distress.

Preliminary Evidence for Disrupted Nucleus Accumbens Reactivity and Connectivity to Reward in Binge Drinkers.

AIMS: Dysfunctional brain reward circuitry, particularly in the nucleus accumbens (NAcc), has been proposed as a risk factor for alcohol use disorder (AUD). This risk factor may be evident in binge drinkers (BD), who are at high risk for developing AUD. We examined whole-brain and NAcc reactivity to reward in BD compared to non-binge drinkers (NBD), hypothesizing that groups would differ in their neural reactivity and connectivity. METHODS: Healthy BD (N = 27) and NBD (N = 23)-none meeting AUD criteria-completed a reward-guessing game, the 'Doors' task, during functional magnetic resonance imaging. We conducted an exploratory whole-brain search for group differences, but given our a priori hypotheses, we also extracted activation from the NAcc to examine reactivity during reward (Win > Loss) and functional connectivity (FC) to the prefrontal cortex. RESULTS: Compared to NBD, BD exhibited greater activation in both the right and left NAcc during reward relative to loss. Additionally, NBD drinkers exhibited positive FC between the NAcc and dorsal anterior cingulate (dACC) whereas the BD showed negative FC between these regions. Furthermore, less NAcc-dACC FC was related to more past month alcohol use. CONCLUSIONS: Our results provide preliminary evidence that BD exhibit greater NAcc activation during reward receipt relative to loss. This is consistent with the broader AUD literature and suggests aberrant neural reactivity may precede disorder onset. In addition, BD exhibited less NAcc-dACC FC, perhaps reflecting deficient regulation of activation to rewards compared to losses. This profile of reward brain circuitry could represent neural correlates of vulnerability for AUD. SHORT SUMMARY: Healthy binge drinkers, at risk for alcohol use disorder, exhibited greater nucleus accumbens activation during reward relative to loss. In addition, binge drinkers exhibited reduced connectivity between the nucleus accumbens and dorsal anterior cingulate, which was associated with more past month alcohol use.

Intolerance of uncertainty and insula activation during uncertain reward.

Individuals with high intolerance of uncertainty (IU) have been shown to exhibit abnormal threat responding, which may be mediated by hyperactive anterior insula (aINS) response to uncertainty. Research has indicated that individuals with high IU also exhibit abnormal positive valence responding, suggesting that IU may impact responding to uncertainty regardless of the valence of the potential outcome. To date, no study has investigated the neural processes associated with IU and response to uncertain positive stimuli, such as rewards. Therefore, this study was designed to examine the association between individual differences in IU and neural activation during uncertain reward using functional magnetic resonance imaging (fMRI). Thirty-seven adults completed a self-report measure of IU and a reward task during fMRI. Consistent with the threat literature, greater IU was associated with increased aINS activation during uncertain reward. This association was more robust for the prospective IU subscale, a dimension characterized by worry about future events. Together with prior studies, these findings provide evidence that IU is related to abnormal threat and reward responding, and that these deficits may be similarly linked to hyperactive aINS response to uncertainty.

Agreement Between Self- and Informant-Reported Ratings of Personality Traits: The Moderating Effects of Major Depressive and/or Panic Disorder.

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.

Cognitive flexibility mediates the relation between intolerance of uncertainty and safety signal responding in those with panic disorder.

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.

Cannabinoid modulation of amygdala subregion functional connectivity to social signals of threat.

BACKGROUND: Δ(9)-Tetrahydrocannabinol has been shown to modulate anxiety and facilitate the extinction of fear by inhibiting amygdala reactivity. Since functional coupling between the amygdala and prefrontal cortex is implicated in affective processes, it is possible that Δ(9)-tetrahydrocannabinol affects amygdala-prefrontal cortex functional connectivity in ways that differ across amygdala subregions: basolateral, centromedial, and superficial. METHODS: The aim of the study was to examine the effects of Δ(9)-tetrahydrocannabinol on functional connectivity between amygdala subregions and the prefrontal cortex during socio-emotional threat in healthy adults using a double-blind, placebo-controlled, within-subjects design. Sixteen subjects completed a functional magnetic resonance imaging task designed to probe amygdala responses to social threat. Amygdala subregion-prefrontal cortex functional connectivity was compared between Δ(9)-tetrahydrocannabinol and placebo using generalized psychophysiological interaction analyses. RESULTS: Findings indicated that Δ(9)-tetrahydrocannabinol enhanced basolateral and superficial amygdala connectivity to the rostral anterior cingulate/medial prefrontal cortex. CONCLUSION: These effects, including Δ(9)-tetrahydrocannabinol's potential ability to reduce threat perception or enhance socio-emotional regulation, may help understand the neurocircuitry of affect.

Does anxiety sensitivity correlate with startle habituation? An examination in two independent samples.

Individuals with anxiety disorders have previously demonstrated abnormal habituation to aversiveness over time. As anxiety sensitivity (AS), or an individuals' propensity to fear of anxiety-related sensations, has been shown to be a risk factor for anxiety disorders (particularly panic disorder), the present study examined whether AS was also associated with abnormal habituation. This association was examined in two independent samples of undergraduates (Ntotal=178). Habituation was operationalised as the reduction in startle response to multiple startle probes presented over 2.5 minutes and three definitions of this reduction were employed. Results indicated that individuals with higher levels of AS evidenced deficits in startle habituation, but the strength of this relationship was somewhat dependent on the definition of startle habituation, with the most robust definition being an analysis of participants' individual slopes across all nine blinks. The present findings suggest that startle habituation is a key mechanism underlying AS, and may help elucidate the role this risk factor plays in the pathogenesis of anxiety disorders.

Are individual differences in appetitive and defensive motivation related? A psychophysiological examination in two samples.

Appetitive and defensive motivation account for a good deal of variance in personality and mental health, but whether individual differences in these systems are correlated or orthogonal has not been conclusively established. Previous investigations have generally relied on self-report and have yielded conflicting results. We therefore assessed the relation between psychophysiological indices of appetitive and defensive motivation during elicitation of these motivational states: specifically, frontal electroencephalogram asymmetry during reward anticipation and startle response during anticipation of predictable or unpredictable threat of shock. Results in a sample of psychopathology-free community members (n=63), an independent sample of undergraduates with a range of internalising symptoms (n=64), and the combination of these samples (n=127) revealed that differences in responding to the two tasks were not significantly correlated. Average coefficients approached zero in all three samples (community: .04, undergraduate: -.01, combined: .06). Implications of these findings for research on normal and abnormal personality are discussed.

Impact of handgun ownership and biological sex on startle reactivity to predictable and unpredictable threats.

Extant literature suggests that many individuals obtain firearms because they perceive the world as unsafe and believe that firearm ownership increases physical protection. Converging evidence suggests that firearm owners are vulnerable to uncertainty and experience chronic anticipatory anxiety in daily life; however, biological sex is thought to potentially moderate this association. Studies have yet to examine this hypothesis using objective markers of anticipatory anxiety. The present study therefore examined the impact of handgun ownership and biological sex on psychophysiological reactivity to predictable (P-) and unpredictable (U-) threat (N = 133). Male and female adult participants were classified into two groups: a) individuals who do not currently own any handguns (n = 52), and b) individuals who currently own one or more handguns (n = 81). Startle eyeblink potentiation was recorded as an index of aversive reactivity during a well-validated threat-of-shock paradigm designed to probe anticipatory anxiety (during U-threat) and fear (during P-threat). Results revealed no main effect of group on startle reactivity to P- or U-threat. Females displayed greater startle reactivity to threat (P- and U-) compared with males. The main effect was qualified by a significant group x biological sex interaction. Male handgun owners exhibited greater startle to U-threat, but not P-threat, relative to non-handgun owners. There was no effect of group on startle reactivity in females. Findings revealed that biological sex and threat type influenced threat reactivity. Male handgun owners displayed increased sensitivity to stressors that are uncertain, which may reflect an objective mechanism related to firearm ownership.

Relation between Respiratory Sinus Arrythymia and Startle Response during Predictable and Unpredictable Threat.

Research suggests that lower respiratory sinus arrhythmia (RSA) is associated with greater aversive responding. One physiological indicator of aversive responding is startle potentiation. While a few studies have demonstrated an inverse association between RSA and startle potentiation, no study to date has distinguished whether this relation is similar for predictable versus unpredictable aversive stimuli. This is an important distinction, given that degree of predictability has been shown to be an important determinant of aversive responding. The present study examined whether resting RSA was associated with startle eye blink responding during predictable and unpredictable threat of electric shock. Resting RSA was collected during a 6-minute seated baseline phase at the beginning of the experimental session. Participants then completed a computerized startle task in which predictable and unpredictable shocks were administered. Results indicated that lower resting RSA was associated with greater startle potentiation during unpredictable threat, but not during predictable threat. These findings are consistent with a growing body of literature suggesting that individual differences in RSA are associated with aversive responding, and extend previous work by suggesting that RSA may be more robustly associated with a heightened sensitivity to unpredictable threat. This pattern of results may have implications for the understanding of pathological anxiety given that individuals with anxiety disorders typically exhibit low RSA and heightened responding during unpredictable threat.

The role of gender and race in the relation between adolescent distress tolerance and externalizing and internalizing psychopathology.

Distress tolerance (DT) is an established construct contributing to the onset and maintenance of psychopathology in adulthood; however, few studies have examined the role of DT in older adolescent psychopathology. Emerging data suggest that gender and race may influence this relation. Therefore, the current study examined the relation between gender, race, and DT on parent-reported internalizing and externalizing DSM-oriented symptoms among a community sample of 128, 14-18 year old adolescents. Results indicated a moderating effect of gender on affective problems, such that females with low DT, but not males, displayed significantly greater affective problems. Findings also indicated a significant moderating effect of race, such that Caucasians with low DT, but not African Americans, displayed significantly higher somatic, oppositional defiant, and conduct problems. These findings suggest that DT is an important clinical variable in older adolescence, particularly among Caucasians and females.

Intolerance of uncertainty and functional connectivity of the anterior insula during anticipation of unpredictable reward.

Individuals with high intolerance of uncertainty (IU) tend to display maladaptive cognitive, behavioral, physiological, and/or neural responses during anticipation of uncertain or ambiguous outcomes, both positive and negative in valence. Importantly, high IU has been proposed as a key transdiagnostic phenotypic risk factor for the onset and maintenance of several psychiatric disorders. Within the context of reward processing, high IU has been related to dysfunctional reward anticipation, which may be mediated by hyperactive anterior insula (AIC) response to uncertainty. The present study further investigated the relationship between the AIC and IU by examining the association between individual differences in IU and task-based functional connectivity of the right AIC using functional magnetic resonance imaging (fMRI). Participants (N = 171) completed a self-report measure of IU and a reward anticipation task during fMRI. Generalized psychophysiological interaction (gPPI) analyses were performed with a seed in the right AIC. In the U-threat model, we found that greater self-reported levels of IU were correlated with increased functional connectivity between the right AIC and the dorsal anterior cingulate cortex (dACC) and the right dorsolateral prefrontal cortex (dlPFC). In the P-threat model, we did not find these associations, perhaps indicating that they may be more robust during uncertainty. These preliminary findings suggest that parts of salience and central executive control networks may be impacted by and underlie the expression of IU. Future studies should examine the generalizability of these findings to clinical populations and investigate how disruption of these functional networks may contribute to psychopathology.