A One-Arm Pilot Trial of a Telehealth CBT-Based Group Intervention Targeting Transdiagnostic Risk for Emotional Distress.

The COVID-19 pandemic had a significant impact on mental health, straining an already overburdened healthcare system. A modular, transdiagnostic approach to treating psychopathology may be ideal to target common transdiagnostic risk factors for emotional distress and related disorders likely to be impacted by circumstances related to this once-in-a-lifetime environmental stressor. Anxiety sensitivity (AS), or fear of anxious arousal, intolerance of uncertainty (IU), or distress when confronted with uncertainty, and loneliness are three transdiagnostic risk factors impacted by the pandemic and robust predictors of emotional distress beyond that. We completed a pilot feasibility, acceptability, and utility trial of Coping Crew, our group, telehealth-delivered transdiagnostic treatment protocol in 17 participants who completed the intervention (M age = 22.00, SD = 4.46; 71% female). The intervention and study protocol were feasible to deliver and were rated as acceptable and useful to address intervention targets. Evidence was mixed regarding feasibility, acceptability, and usefulness of the mobile app component. Sixteen of 17 participants (94%) completed at least one survey a day on 80% of the days but only 6 participants (35%) completed at least 80% of the mobile app surveys delivered over the course of the intervention. Most participants rated use of the app as acceptable and relevant to psychological improvements made due to the intervention. Sizeable effect size reductions in transdiagnostic risk factors were found at post-intervention and maintained at 1- and 3-month follow-up, supporting next steps in the development of this modular transdiagnostic treatment.

Withdrawal catastrophizing scale: initial psychometric properties and implications for the study of opioid use disorder and hyperkatifeia.

Background: Discovery of modifiable factors influencing subjective withdrawal experience might advance opioid use disorder (OUD) research and precision treatment. This study explores one factor - withdrawal catastrophizing - a negative cognitive and emotional orientation toward withdrawal characterized by excessive fear, worry or inability to divert attention from withdrawal symptoms.Objectives: We define a novel concept - withdrawal catastrophizing - and present an initial evaluation of the Withdrawal Catastrophizing Scale (WCS).Methods: Prospective observational study (n = 122, 48.7% women). Factor structure (exploratory factor analysis) and internal consistency (Cronbach's α) were assessed. Predictive validity was tested via correlation between WCS and next-day subjective opiate withdrawal scale (SOWS) severity. The clinical salience of WCS was evaluated by correlation between WCS and withdrawal-motivated behaviors including risk taking, OUD maintenance, OUD treatment delay, history of leaving the hospital against medical advice and buprenorphine-precipitated withdrawal.Results: WCS was found to have a two-factor structure (distortion and despair), strong internal consistency (α = .901), and predictive validity - Greater withdrawal catastrophizing was associated with next-day SOWS (rs (99) = 0.237, p = .017). Withdrawal catastrophizing was also correlated with risk-taking behavior to relieve withdrawal (rs (119) = 0.357, p < .001); withdrawal-motivated OUD treatment avoidance (rs (119) = 0.421, p < .001), history of leaving the hospital against medical advice (rs (119) = 0.373, p < .001) and buprenorphine-precipitated withdrawal (rs (119) = 0.369, p < .001).Conclusion: This study provides first evidence of withdrawal catastrophizing as a clinically important phenomenon with implications for the future study and treatment of OUD.

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.

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.

Nociplastic Pain and Pain-Motivated Drinking in Alcohol Use Disorder.

Heavy chronic alcohol use may produce pain amplification through neurochemical and neuroplastic changes at multiple levels of the nervous system. Similar changes are thought to underlie nociplastic pain. The American College of Rheumatology Fibromyalgia Survey has been used as a surrogate for nociplastic pain, including among individuals with alcohol use disorder (AUD). However, studies linking nociplastic pain to pain-motivated drinking are lacking. The present study aimed to determine if nociplastic pain is associated with pain-motivated drinking in AUD. To achieve this aim, a new scale-the Pain-Motivated Drinking Scale (PMDS)-was developed to measure how often participants were motivated by pain to drink alcohol. Measurement properties of this new scale were determined, including its factor structure, internal consistency reliability, and construct validity. In this cross-sectional observational study, participants with AUD (n = 138) were consecutively recruited from the patient pool at an academic addiction treatment facility. Seventy-two percent (95, 72.0%) reported they drank alcohol "to get relief from physical pain" at least some of the time, and over forty-two percent (56, 42.4%) reported pain relief motivated their drinking at least half of the time. PMDS had a single-factor structure, strong internal consistency reliability, and construct validity. A multiple hierarchical linear regression was run to determine if nociplastic pain was associated with pain-motivated drinking. Nociplastic pain was associated with PMDS even after controlling for potential confounders and pain severity. These findings suggest nociplastic pain is uniquely associated with pain-motivated drinking in AUD. PERSPECTIVE: Nociplastic pain is independently associated with pain-motivated drinking in alcohol use disorder (AUD). The Pain-Motivated Drinking Scale (PMDS) is a new scale to measure how often people drink to cope with pain. PMDS has promising psychometric properties. Nociplastic pain may be uniquely associated with pain-motivated drinking in AUD.

Heightened threat perceptions and reduced stability in anxiety and fear among U.S. adults who carry handguns.

Firearm carrying is often motivated to provide safety and is correlated with increased anxiety related to elevated perceptions of the world as a dangerous place. No studies have investigated affective states among firearm owners as they occur in their natural environments. This study used ecological momentary assessment (EMA) to examine cognitive-affective states among firearm owners who carry handguns outside their home (n = 35), firearm owners who do not carry (n = 47), and non-firearm owners (n = 62). Participants completed a self-report questionnaire at baseline followed by EMA surveys of mood state with the Positive and Negative Affect Scale (PANAS) 6 times per day for 28 consecutive days. Carry handgun owners reported significantly higher threat perceptions, measured with the negative cognitions about the world subscale of the shortened Posttraumatic Cognitions Inventory (PTCI), than no-carry handgun owners (Mdiff=2.0, 95% CI=0.8-2.0, d=0.45, p = .001) and non-owners (Mdiff=1.8, 95% CI=0.6-2.9, d=0.42, p = .003). Groups did not significantly differ in mean momentary mood ratings assessed via EMA but stability in high-arousal negative arousal was significantly reduced among carry handgun owners (F(2, 150)= 3.7, p = .026). Results suggest firearm owners who carry handguns view the world as especially dangerous, are more likely to experience shifts in anxiety and fear, and take longer to recover from periods of elevated anxiety and fear.

Central sensitization in alcohol use disorder: correlates of pain, addiction and health-related quality of life.

BACKGROUND: Central sensitization is an important mechanism underlying many chronic pain conditions. Chronic pain and alcohol use disorder (AUD) are highly comorbid. Despite great scientific interest in brain mechanisms linking chronic pain and AUD, progress has been impeded by difficulty assessing central sensitization in AUD. OBJECTIVE: The present study is the first to employ a validated surrogate measure to describe central sensitization in a clinical sample with AUD. METHODS: Participants with AUD (n = 99) were recruited from an academic addiction treatment center. A well-established surrogate measure of central sensitization, The American College of Rheumatology Fibromyalgia Survey Criteria (ACRFMS) was administered. Participants also responded to questions about quality of life (RAND-36), and AUD. Descriptive analyses and Spearman's rho correlations were performed. RESULTS: Chronic pain and evidence of central sensitization were prevalent. Greater central sensitization was associated with worse health-related quality of life. Participants higher in central sensitization expressed greater endorsement of pain as a reason for AUD onset, maintenance, escalation, treatment delay, and relapse. CONCLUSION: The present study bolsters prior assertions that AUD and chronic pain might compound one another via progressive sensitization of shared brain circuitry. These results may inform future mechanistic research and precision AUD treatment.

Intolerance of Uncertainty and Cognition in Breast Cancer Survivors: The Mediating Role of Anxiety.

Cancer-related cognitive impairment (CRCI) is one of the most prevalent symptoms that breast cancer survivors experience. While cancer treatments are established contributors to CRCI, inter-individual differences in CRCI are not well understood. Individual differences in sensitivity to uncertainty are potential contributors to CRCI; however, no prior studies have attempted to examine this link in the context of breast cancer. To address the gap, we used preliminary findings from an ongoing cross-sectional study. A total of 38 women with stage I-III breast cancer (1-4 years post-treatment) were included in this study. Intolerance of uncertainty (IU) was assessed using the Intolerance of Uncertainty Scale. Self-reported cognitive function was assessed with the Neuro-QoL questionnaire. Anxiety was assessed using the Patient-Reported Outcomes Measurement System Bank. From this study, we found that anxiety mediates the association between IU and cognitive function of survivors. In other words, among post-menopausal breast cancer survivors, those with higher IU showed higher anxiety and consequently had lower cognitive function. This finding suggests that assessing IU may help predict the risk of CRCI. This study expands the current knowledge that addresses the importance of IU as a factor associated with cognitive health.

Behavioral and brain reactivity to uncertain stress prospectively predicts binge drinking in youth.

Prior studies show that individuals with alcohol use disorder exhibit exaggerated behavioral and brain reactivity to uncertain threats (U-threat). It is posited this brain-based factor emerges early in life and contributes to the onset and escalation of alcohol problems. However, no study to date has tested this theory using a longitudinal within-subjects design. Ninety-five young adults, ages 17-19, with minimal alcohol exposure and established risk factors for alcohol use disorder participated in this multi-session study with a 1-year tracking period. Startle eyeblink potentiation and brain activation were collected at separate baseline sessions during the well-validated No-Predictable-Unpredictable (NPU) threat-of-shock task designed to probe reactivity to U-threat and predictable threat (P-threat). Participants self-reported their drinking behavior over the past 90 days at baseline and one-year later. We fit a series of multilevel hurdle models to model the binary outcome of whether binge drinking occurred and the continuous outcome of number of binge drinking episodes. Zero-inflated binary submodels revealed that greater baseline startle reactivity, bilateral anterior insula (AIC) reactivity, and dorsal anterior cingulate cortex (dACC) reactivity to U-threat were associated with increased probability of binge drinking. There were no other associations between reactivity to U- and P-threat and probability of binge drinking and number of binging episodes. These results demonstrate that exaggerated reactivity to U-threat is a brain-based individual difference factor that connotes risk for problem drinking. These findings also add to a growing literature implicating AIC and dACC dysfunction in the pathophysiology of alcohol use disorder.

Neural reactivity to threat impacts the association between bullying victimization and suicide risk in youth.

Bullying victimization is a risk factor for suicidal ideation, suicide behaviors, and death by suicide in youth. However, not all victims of bullying report suicidal thoughts and behaviors, suggesting that there may be certain subgroups who are at high risk for suicide. Neuroimaging studies suggest that individual differences in neurobiological threat reactivity may contribute to increased vulnerability to suicide, particularly in the context of repeated exposure to bullying. The purpose of the present study was to examine the unique and interactive effects of past-year bullying victimization and neural reactivity to threat on suicide risk in youth. Ninety-one youth (ages 16-19) completed self-report measures of past-year bullying victimization and current suicide risk. Participants also completed a task designed to probe neural reactivity to threat. Specifically, participants passively viewed negative or neutral images during functional magnetic resonance imaging. Bilateral anterior insula (AIC) and amygdala (AMYG) reactivity to threat/negative images (>neutral images) was used to capture threat sensitivity. Greater bullying victimization was associated with increased suicide risk. There was also a bullying by AIC reactivity interaction such that among individuals with high AIC reactivity, greater bullying was associated with increased suicide risk. Among individuals with low AIC reactivity, there was no association between bullying and suicide risk. Results suggest that youth with increased AIC reactivity to threat may be particularly vulnerable to suicide in the context of bullying. These individuals may represent a high-risk group for subsequent suicide behavior and AIC function may be a promising objective prevention target.

Neural reactivity to neutral and aversive stimuli: Evidence for altered precuneus function in internalizing psychopathologies.

Individuals with internalizing psychopathologies (IPs) demonstrate a negativity bias in emotion and self-related processing that contributes to negative interpretation of neutral information. However, most neuroimaging studies of emotional experience in IPs do not specifically investigate reactivity to neutral stimuli. Thus, little is known about the neural processes underlying emotional experience for neutral stimuli and how those processes may differ between groups and during neutral versus negative stimuli. To address this gap, we asked: (1) does neural reactivity to neutral and negative stimuli differ between IPs and control groups in brain regions associated with emotional and self-referential processing, and (2) does neural activity during neutral condition relate to clinical symptoms? Adults with IPs (n = 103) and healthy volunteers (HVs; n = 40) completed a well-validated fMRI task probing neural responses to neutral and negative images. A flexible factorial model revealed a significant group-by-condition interaction, such that individuals with IPs had less precuneus activation during the neutral condition relative to HVs. In IPs, precuneus activation during the neutral condition was negatively correlated with depression symptom severity. Individuals with IPs demonstrate abnormal precuneus reactivity to neutral stimuli that is associated with depression symptoms. This may reflect altered default mode network activity and/or self-referential processing in IPs.

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.

Reward-related neural dysfunction in youth with a history of suicidal ideation: The importance of temporal predictability.

Abnormal reward processing is an important yet understudied risk factor for suicide. Recent neuroimaging studies have found that suicidality is associated with abnormal reward-related neural reactivity and connectivity across a wide range of brain regions and circuits. The varying, and oftentimes discrepant, findings have hindered progress in elucidating the neurobiological link between reward processing dysfunction and suicide risk. Some of this variability is likely related to different reward-related paradigms that are utilized across studies. The primary aim of the current study was to address these issues by comparing neural reactivity between youth with and without a history of suicidal ideation during direct manipulation of reward parameters. A total of 108 unmedicated youth, ages 17-19, were classified into two groups: 1) history of suicidal ideation (n = 39) and 2) no history of suicidal ideation (n = 69). All participants completed a novel reward anticipation task probing anticipation of predictable (P-reward) and unpredictable (U-reward) monetary reward. Results revealed that compared with controls, youth with a history of suicidal ideation exhibited increased neural activation in the dorsal anterior cingulate cortex (dACC) and right anterior insula (aINS) during anticipation of U-reward. There were no group differences during anticipation of P-reward. These findings suggest that propensity for suicidal ideation may be related to specific abnormalities during anticipation of U-reward, but not P-reward.

Impact of alcohol use, combat exposure, and posttraumatic stress on verbal and visual working memory performance in post-9/11 veterans.

OBJECTIVE: Posttraumatic stress disorder (PTSD) and alcohol use (AU) are highly prevalent and comorbid among post-9/11 U.S. military veterans. Both issues are associated with working memory (WM) deficits, but have rarely been studied concurrently in cognitive studies of post-9/11 veterans. They also have been measured inconsistently, with variable outcomes, in prior veteran studies despite their relevance to new intervention paradigms involving WM. METHOD: The present study evaluated 52 post-9/11 veterans [predominantly male (94.2%); White (44.2%) or Black (36.5%); 50% being diagnosed with PTSD based on CAPS-5 results] with objectively verified valid neuropsychological test performance on measures of PTSD, AU, combat exposure, and verbal and visual WM. RESULTS: PTSD was not associated with verbal or visual WM performances, whereas AU and combat exposure were significantly associated with poorer visual WM performances. CONCLUSIONS: AU and prior combat exposure may influence visual WM performances in post-9/11 veterans, which is relevant to novel PTSD treatment paradigms. This sample was limited to mostly male and White or Black participants, and future studies should focus on sampling more heterogeneous groups of veterans with regard to sex and ethnicity. Improvements in specification/multimodal WM assessment are important for future research, as these may directly impact developing intervention efforts. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

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.

Acute orexin antagonism selectively modulates anticipatory anxiety in humans: implications for addiction and anxiety.

Research indicates that heightened anticipatory anxiety underlies several forms of psychopathology. Anticipatory anxiety can be reliably and objectively measured in the laboratory using the No-Predictable-Unpredictable (NPU) threat paradigm. The NPU paradigm is an ideal research tool for the NIH 'Fast-Fail' approach of screening promising compounds and testing human target engagement. Evidence from preclinical studies suggests that the hypocretin/orexin (ORX) hypothalamic neuropeptide system is a potential means for modulating anticipatory anxiety and disrupting stress-related alcohol use. The current study tested this question using a psychophysiological probe of the ORX system in humans. We examined whether a single dose of suvorexant (SUV; 10 mg; dual ORX receptor antagonist) can effectively and selectively target a well-validated human laboratory index of exaggerated anticipatory anxiety using a within-subjects placebo-controlled design. A total of twenty-one volunteers completed two laboratory sessions during acute administration of 10 mg SUV or placebo. Across sessions, we administered the NPU paradigm probing sustained anticipatory anxiety and fear while startle eyeblink was recorded as an index of aversive reactivity. Questionnaires assessing mood states and subjective drug effects were also collected. Results indicated SUV was well-tolerated. Compared with placebo, SUV was associated with decreased startle reactivity during anticipatory anxiety but not fear or no-threat conditions. Therefore, SUV selectively and effectively reduced objective indicators of anticipatory anxiety in humans and engaged our laboratory target of psychopathology. ORX antagonism may be a promising strategy for modulating human anxiety and potentially, stress-related alcohol use.

Electrocortical measures of win and loss processing are associated with mesocorticolimbic functional connectivity: A combined ERP and rs-fMRI study.

The reward positivity (RewP) event-related potential is a well-validated measure of reward processing implicated in internalizing psychopathologies. The RewP is thought to reflect reward reactivity in the mesocorticolimbic system; however, it is not clear how the RewP is related to the functional connectivity of reward-related brain regions. The current study examined associations between the RewP (Win and Loss residuals) and resting-state fMRI (rs-fMRI), among adults with internalizing psychopathology (IP) and healthy controls (HC). All participants (N = 102) completed a validated monetary reward task during electroencephalogram and rs-fMRI. Regression analyses were conducted with (1) RewP-Win residual amplitude and striatal seeds (caudate, putamen, nucleus accumbens) and (2) RewP-Loss residual amplitude and anterior cingulate cortex (ACC) seeds. Overall, individuals with greater RewP-Win residual amplitude demonstrated increased rs-fMRI connectivity between striatal regions and the medial prefrontal cortex, as well as the parahippocampal gyrus, but decreased connectivity between striatal regions and regions involved in cognitive control and sensorimotor processing. Greater RewP-Loss residual was related to greater connectivity between the ACC and regions involved in reward/loss processing and motor control, but decreased connectivity between the ACC and regions involved in cognitive control. Relationships between the RewP and rs-fMRI were generally consistent across IP and HC. However, a few patterns were unique to IP. Results indicate the RewP is associated with resting-state functional connectivity of reward- and loss-related brain regions, suggesting connectivity of the mesocorticolimbic system may be an important individual difference factor in dimensions of attainment of reward and loss.

Association between startle reactivity to uncertain threats and structural brain volume.

Sensitivity to uncertain threat (U-threat) is a clinically important individual difference factor in multiple psychopathologies. Recent studies have implicated a specific frontolimbic circuit as a key network involved in the anticipation of aversive stimuli. In particular, the insula, thalamus, and dorsal anterior cingulate cortex (dACC) have recently been found to be robustly activated by anticipation of U-threat. However, no study to date has examined the association between U-threat reactivity and structural brain volume. In the present study, we utilized a pooled sample of 186 young adult volunteers who completed a structural MRI scan and the well-validated No-Predictable-Unpredictable (NPU) threat of electric shock task. Startle eyeblink potentiation was collected during the NPU task as an objective index of aversive reactivity. ROI-based analyses revealed that increased startle reactivity to U-threat was associated with reduced gray matter volume in the right insula and bilateral thalamus, but not the dACC. These results add to a growing literature implicating the insula and thalamus as core nodes involved in individual differences in U-threat reactivity.

Neural and self-report indices of cognitive reappraisal moderate the association between sensitivity to uncertain threat and problem alcohol use.

Exaggerated reactivity to threats that are uncertain (U-threat) is a risk factor for problem alcohol use. Data suggest that exaggerated reactivity to U-threat is associated with chronic anxiety and motivation for coping-oriented drinking. Not all individuals with high U-threat reactivity engage in excessive drinking and theory and research suggest that individual differences in emotion regulation, particularly frequency and effectiveness of cognitive reappraisal, are potential moderators of this well-established link. The aim of the current study was to test this hypothesis using a multimodal laboratory design. A total of 83 volunteers with depression and/or anxiety completed a well-validated threat sensitivity task and two complimentary assessments of cognitive reappraisal. Threat sensitivity was measured using startle eyeblink potentiation during threat-of-electric shock. Cognitive reappraisal was measured using self-report and estimates of prefrontal cortex activation (PFC; i.e., ventrolateral, dorsolateral and dorsomedial) during instructed reappraisal during functional magnetic resonance imaging. Results revealed self-reported and PFC indices of reappraisal were correlated within-subjects. Additionally, self-reported and ventrolateral (vlPFC) activation during reappraisal moderated the association between reactivity to U-threat and problem alcohol use. Across both measures, at low engagement in reappraisal, greater startle reactivity to U-threat was associated with greater problem alcohol use. At high engagement in reappraisal, there was no association between U-threat reactivity and problem alcohol use. Together, the findings reveal that exaggerated reactivity to U-threat may be a particularly robust risk factor for problem alcohol use in the context of impaired or ineffective emotion regulation.