Neuroimaging-based classification of PTSD using data-driven computational approaches: A multisite big data study from the ENIGMA-PGC PTSD consortium.

BACKGROUND: Recent advances in data-driven computational approaches have been helpful in devising tools to objectively diagnose psychiatric disorders. However, current machine learning studies limited to small homogeneous samples, different methodologies, and different imaging collection protocols, limit the ability to directly compare and generalize their results. Here we aimed to classify individuals with PTSD versus controls and assess the generalizability using a large heterogeneous brain datasets from the ENIGMA-PGC PTSD Working group. METHODS: We analyzed brain MRI data from 3,477 structural-MRI; 2,495 resting state-fMRI; and 1,952 diffusion-MRI. First, we identified the brain features that best distinguish individuals with PTSD from controls using traditional machine learning methods. Second, we assessed the utility of the denoising variational autoencoder (DVAE) and evaluated its classification performance. Third, we assessed the generalizability and reproducibility of both models using leave-one-site-out cross-validation procedure for each modality. RESULTS: We found lower performance in classifying PTSD vs. controls with data from over 20 sites (60 % test AUC for s-MRI, 59 % for rs-fMRI and 56 % for d-MRI), as compared to other studies run on single-site data. The performance increased when classifying PTSD from HC without trauma history in each modality (75 % AUC). The classification performance remained intact when applying the DVAE framework, which reduced the number of features. Finally, we found that the DVAE framework achieved better generalization to unseen datasets compared with the traditional machine learning frameworks, albeit performance was slightly above chance. CONCLUSION: These results have the potential to provide a baseline classification performance for PTSD when using large scale neuroimaging datasets. Our findings show that the control group used can heavily affect classification performance. The DVAE framework provided better generalizability for the multi-site data. This may be more significant in clinical practice since the neuroimaging-based diagnostic DVAE classification models are much less site-specific, rendering them more generalizable.

The impact of mindfulness training on posttraumatic stress disorder symptoms, subjective sleep quality, and objective sleep outcomes in police officers.

OBJECTIVE: Sleep disturbances cooccur with posttraumatic stress disorder (PTSD) and are often correlated with PTSD severity. Previous research has shown that sleep problems mediate the relationship between PTSD and negative physical and mental health outcomes but has relied on self-reported sleep quality. We tested the effects of mindfulness training-previously shown to improve sleep quality and reduce PTSD symptoms-on subjective and objective sleep metrics and relationships with reduced PTSD symptoms. METHOD: Following baseline data collection in 114 law enforcement officers, we randomly assigned participants to either an 8-week mindfulness training group or a waitlist control group. We repeated assessments immediately posttraining and at 3-month follow-up. Self-reported PTSD symptoms and subjective sleep quality were measured at each visit with the PTSD checklist and Pittsburgh Sleep Quality Index (PSQI), respectively. Participants also wore a Fitbit Charge 2 continuously over the course of a 4- to 6-day work week following each visit, from which we extracted two distinct objective sleep metrics: total minutes of sleep and sleep efficiency. RESULTS: At baseline, PTSD symptoms were correlated with PSQI scores but not objective Fitbit metrics. Relative to waitlist, mindfulness training led to improved subjective sleep quality and reduced PTSD symptoms. Reduced PTSD symptoms mediated the improvement in subjective sleep quality following mindfulness training. Neither objective sleep metric demonstrated improvements following mindfulness training, nor did these metrics mediate reduced PTSD symptoms. CONCLUSIONS: This study provides evidence linking improved subjective sleep quality, but not objective sleep markers, to reductions in PTSD symptoms following mindfulness training. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Mental Health Stigma and Help-Seeking Intentions in Police Employees.

Mental health problems among police employees are exacerbated by negative attitudes and beliefs around mental health help-seeking that are perpetuated by police culture. We collected anonymous survey data from 259 civilian and commissioned police employees in a mid-sized, Midwestern U.S. city to test hypothesized relationships among help-seeking stigma, help-seeking attitudes, and intended help-seeking behavior. Results demonstrated that mental help-seeking stigma was negatively associated with help-seeking attitudes, and in turn with reduced mental health help-seeking intentions. Structural equation modeling provided support for a model linking help-seeking stigma, help-seeking attitudes, and intentions to seek help. This path model was moderated by psychological distress and previous participation in mindfulness training, which had opposing effects on help-seeking stigma and (indirectly) on intended help-seeking. Results provide insight into policies, practices, and interventions that police agencies may enact to combat stigma, positively influence mental health help-seeking, and improve the mental health and well-being of police employees and the broader community.

Inverse association between stress induced cortisol elevations and negative emotional reactivity to stress in humans.

Greater cortisol reactivity to stress is often assumed to lead to heightened negative affective reactivity to stress. Conversely, a growing body of evidence demonstrates mood-protective effects of cortisol elevations in the context of acute stress. We administered a laboratory-based stressor, the Trier Social Stress Test (TSST), and measured cortisol and emotional reactivity in 68 adults (48 women) between the ages of 25 and 65. In accordance with our pre-registered hypothesis (https://osf.io/t8r3w) and prior research, negative affective reactivity was inversely related to cortisol reactivity assessed immediately after the stressor. We found that greater cortisol response to acute stress is associated with smaller increases in negative affect, consistent with mood-protective effects of cortisol elevations in response to acute stress.

Perceived stress associations with hippocampal-dependent behavior and hippocampal subfield volume.

Background: Individual differences in stress appraisals influence trajectories of risk and resilience following exposure to chronic and acute stressors. Smaller hippocampal volume may contribute to elevated stress appraisals via deficient pattern separation, a process depending on dentate gyrus (DG)/CA3 hippocampal subfields. Here, we investigated links between perceived stress, DG/CA3 volume, and behavioral pattern separation to test hypothesized mechanisms underlying stress-related psychopathology. Methods: We collected the Perceived Stress Scale (PSS) and ratings of subjective stress reactivity during the Trier Social Stress Test (TSST) from 71 adult community participants. We obtained high-resolution T2 MRI scans and used Automatic Segmentation of Hippocampal Subfields to estimate DG/CA3 volume in 56 of these participants. Participants completed the mnemonic similarity task, which provides a behavioral index of pattern separation. Analyses investigated associations between perceived stress, DG/CA3 volume, and behavioral pattern separation, controlling for age, gender, hemisphere, and intracranial volume. Results: Greater PSS scores and TSST subjective stress reactivity were each independently related to poorer behavioral pattern separation, together accounting for 15% of variance in behavioral performance in a simultaneous regression. Contrary to hypotheses, DG/CA3 volume was not associated with either stress measure, although exploratory analyses suggested a link between hippocampal volume asymmetry and PSS scores. Conclusions: We observed novel associations between laboratory and questionnaire measures of perceived stress and a behavioral assay of pattern separation. Additional work is needed to clarify the involvement of the hippocampus in this stress-behavior relationship and determine the relevance of behavioral pattern separation for stress-related disorders.

The effects of perceived stress and anhedonic depression on mnemonic similarity task performance.

Previous research has demonstrated hippocampal alterations in individuals experiencing elevated stress. The Mnemonic Similarity Task (MST) is a hippocampal-dependent task sensitive to age-related hippocampal decline, but it is unknown how performance on this task is related to one's experience of daily stress. We conducted separate discovery and replication analyses in 510 participants who completed the MST across four different Mechanical Turk studies. We hypothesized that higher scores on the Perceived Stress Scale would be associated with poorer discrimination of "lure" items from previously seen targets - a behavioral index of pattern separation - but not with recognition memory. The zero-order relationship between perceived stress and lure discrimination was not significant in the discovery or replication sample. Exploratory analyses involving anhedonic depression symptoms (from the Mood and Anxiety Symptoms Questionnaire) revealed a robust perceived stress*anhedonic depression interaction in the discovery sample that was confirmed in the replication sample. In both samples, individuals with low but not high anhedonic depression symptoms showed an inverse association between perceived stress and lure discrimination ability. Contrary to hypotheses, a similar interaction was observed for recognition memory. The novel association between perceived stress and behavioral pattern separation suggests a candidate behavioral process associated with stress-related hippocampal deficits. The specificity of this effect for individuals with low anhedonic depression symptoms - and the lack of behavioral specificity - highlight the need for additional research to unpack the clinical and neurobiological significance of these findings.

Long-term Meditation Training Is Associated with Enhanced Subjective Attention and Stronger Posterior Cingulate-Rostrolateral Prefrontal Cortex Resting Connectivity.

Mindfulness meditation has been shown to increase resting-state functional connectivity (rsFC) between the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC), which is thought to reflect improvements in shifting attention to the present moment. However, prior research in long-term meditation practitioners lacked quantitative measures of attention that would provide a more direct behavioral correlate and interpretational anchor for PCC-DLPFC connectivity and was inherently limited by small sample sizes. Moreover, whether mindfulness meditation primarily impacts brain function locally, or impacts the dynamics of large-scale brain networks, remained unclear. Here, we sought to replicate and extend prior findings of increased PCC-DLPFC rsFC in a sample of 40 long-term meditators (average practice = 3759 hr) who also completed a behavioral assay of attention. In addition, we tested a network-based framework of changes in interregional connectivity by examining network-level connectivity. We found that meditators had stronger PCC-rostrolateral prefrontal cortex (RLPFC) rsFC, lower connector hub strength across the default mode network, and better subjective attention, compared with 124 meditation-naive controls. Orienting attention positively correlated with PCC-RLPFC connectivity and negatively correlated with default mode network connector hub strength. These findings provide novel evidence that PCC-RLPFC rsFC may support attention orienting, consistent with a role for RLPFC in the attention shifting component of metacognitive awareness that is a core component of mindfulness meditation training. Our results further demonstrate that long-term mindfulness meditation may improve attention and strengthen the underlying brain networks.

Diversity of daily activities is associated with greater hippocampal volume.

Greater engagement in a range of daily activities is associated with better cognitive functioning (Lee et al., Lee et al., 2020). The hippocampus, a subcortical brain structure implicated in learning, memory, spatial navigation and other aspects of cognitive functioning, may be structurally sensitive to exposure to and engagement with novel experiences and environments. The present study tested whether greater activity diversity, defined as the range of common daily activities engaged in and the proportion of time spent in each, is associated with larger hippocampal volume. Greater diversity of activities, as measured using daily diaries across an 8-day period, was related to greater hippocampal volume averaged across the left and right hemispheres, even when adjusting for estimated intracranial volume, total activity time, sociodemographic factors, and self-reported physical health. These findings are broadly consistent with nonhuman animal studies, demonstrating a link between enriched environments and structural changes to the hippocampus. Future longitudinal and experimental work can elucidate causal and directional relationships between diversity of daily activities and hippocampal volume.

The Impact of Mindfulness Training on Police Officer Stress, Mental Health, and Salivary Cortisol Levels.

Unaddressed occupational stress and trauma contribute to elevated rates of mental illness and suicide in policing, and to violent and aggressive behavior that disproportionately impacts communities of color. Emerging evidence suggests mindfulness training with police may reduce stress and aggression and improve mental health, but there is limited evidence for changes in biological outcomes or the lasting benefits of mindfulness training. We conducted a randomized controlled trial (RCT) of 114 police officers from three Midwestern U.S. law enforcement agencies. We assessed stress-related physical and mental health symptoms, blood-based inflammatory markers, and hair and salivary cortisol. Participants were then randomized to an 8-week mindfulness intervention or waitlist control (WLC), and the same assessments were repeated post-intervention and at 3-month follow-up. Relative to waitlist control, the mindfulness group had greater improvements in psychological distress, mental health symptoms, and sleep quality post-training, gains that were maintained at 3-month follow-up. Intervention participants also had a significantly lower cortisol awakening response (CAR) at 3-month follow-up relative to waitlist control. Contrary to hypotheses, there were no intervention effects on hair cortisol, diurnal cortisol slope, or inflammatory markers. In summary, an 8-week mindfulness intervention for police officers led to self-reported improvements in distress, mental health, and sleep, and a lower CAR. These benefits persisted (or emerged) at 3-month follow-up, suggesting that this training may buffer against the long-term consequences of chronic stress. Future research should assess the persistence of these benefits over a longer period while expanding the scope of outcomes to consider the broader community of mindfulness training for police. Clinical Trial Registration: ClinicalTrials.gov#NCT03488875.

Trait Mindfulness Moderates the Association Between Stressor Exposure and Perceived Stress in Law Enforcement Officers.

OBJECTIVES: To test the magnitude of the relationship between self-reported stressor exposure and perceived stress in police officers using a novel measure of daily work events, and whether dispositional mindfulness and resilience moderate this relationship. METHODS: A total of 114 law enforcement officers from a mid-sized Midwestern US city completed daily logs of job stressors and associated perceived stress, as well as additional self-report measures of perceived stress, trait mindfulness and resilience, and demographics and work information. Principal component analysis (PCA) was used to cluster job stressors into a smaller number of components in a data-driven manner. Linear mixed-effects models were used to test the relationship between stressor exposure and perceived stress for each component, and the moderation of this relationship by trait mindfulness and resilience. RESULTS: The PCA categorized stressor exposure into three components: (1) acute or traumatic line-of-duty stressors, (2) routine daily stressors, and (3) interpersonal stressors. Results of mixed models showed robust positive relationships between self-reported stressor exposure and corresponding perceived stress across all 3 components. Dispositional mindfulness (but not resilience) moderated the association between stressor exposure and perceived stress for routine stressors, such that individuals with higher dispositional mindfulness showed a relatively attenuated relationship between exposure to routine daily stressors and resulting perceived stress. CONCLUSIONS: Police officers high in dispositional mindfulness may experience daily routine stressors as less stressful, which can reduce the accumulation of general stress in the long term and which could help buffer against negative health outcomes associated with perceived stress. TRIAL REGISTRATION: Clinicaltrials.gov/ct2/show/NCT03488875. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12671-021-01707-4.

Mindfulness training reduces PTSD symptoms and improves stress-related health outcomes in police officers.

Law enforcement officers are regularly exposed directly and indirectly to a wide variety of traumatic stressors, which take place against a backdrop of high levels of organizational stressors. Consequently, this group is at elevated risk for posttraumatic stress disorder (PTSD) and other negative physical and mental health outcomes, yet there are few empirically supported interventions to proactively mitigate the effects of occupational stress for this population. Recent studies suggest that training in mindfulness meditation may reduce perceived stress and improve related physical and mental health outcomes in this group. We sought to demonstrate feasibility, acceptability, and adherence for an 8-week mindfulness training program in 30 officers from a mid-sized, Midwestern U.S. police department, replicate findings of improved stress-related health outcomes, and provide novel evidence for reduced PTSD symptoms. All 30 officers completed the training, with high rates of class attendance, substantial out-of-class practice time, and good acceptability of the training and teachers. We replicated findings of reduced post-training perceived stress, sleep disturbances, anxiety, and burnout. We also identified novel evidence for reduced PTSD symptoms that persisted at a 5-month follow-up assessment. These results indicate key targets for future investigation in larger, mechanistic, randomized controlled trials of mindfulness training in police officers.

Altered white matter microstructural organization in posttraumatic stress disorder across 3047 adults: results from the PGC-ENIGMA PTSD consortium.

A growing number of studies have examined alterations in white matter organization in people with posttraumatic stress disorder (PTSD) using diffusion MRI (dMRI), but the results have been mixed which may be partially due to relatively small sample sizes among studies. Altered structural connectivity may be both a neurobiological vulnerability for, and a result of, PTSD. In an effort to find reliable effects, we present a multi-cohort analysis of dMRI metrics across 3047 individuals from 28 cohorts currently participating in the PGC-ENIGMA PTSD working group (a joint partnership between the Psychiatric Genomics Consortium and the Enhancing NeuroImaging Genetics through Meta-Analysis consortium). Comparing regional white matter metrics across the full brain in 1426 individuals with PTSD and 1621 controls (2174 males/873 females) between ages 18-83, 92% of whom were trauma-exposed, we report associations between PTSD and disrupted white matter organization measured by lower fractional anisotropy (FA) in the tapetum region of the corpus callosum (Cohen's d = -0.11, p = 0.0055). The tapetum connects the left and right hippocampus, for which structure and function have been consistently implicated in PTSD. Results were consistent even after accounting for the effects of multiple potentially confounding variables: childhood trauma exposure, comorbid depression, history of traumatic brain injury, current alcohol abuse or dependence, and current use of psychotropic medications. Our results show that PTSD may be associated with alterations in the broader hippocampal network.

A common neural substrate for elevated PTSD symptoms and reduced pulse rate variability in combat-exposed veterans.

Previous studies have identified reduced heart rate variability (HRV) in post-traumatic stress disorder (PTSD), which may temporally precede the onset of the disorder. A separate line of functional neuroimaging research in PTSD has consistently demonstrated hypoactivation of the ventromedial prefrontal cortex (vmPFC), a key aspect of a descending neuromodulatory system that exerts inhibitory control over heart rate. No research to date, however, has simultaneously investigated whether altered vmPFC activation is associated with reduced HRV and elevated PTSD symptoms in the same individuals. Here, we collected fMRI data during alternating conditions of threat of shock and safety from shock in 51 male combat-exposed veterans with either high or low levels of PTSD symptoms. Pulse rate variability (PRV)-a HRV surrogate calculated from pulse oximetry-was assessed during a subsequent resting scan. Correlational analyses tested for hypothesized relationships between reduced vmPFC activation, lower PRV, and elevated PTSD symptomatology. We found that PTSD re-experiencing symptoms were inversely associated with high-frequency (HF)-PRV, thought to primarily reflect parasympathetic control of heart rate, in veterans with elevated PTSD symptoms. Reduced vmPFC activation for the contrast of safety-threat was associated both with lower HF-PRV and elevated PTSD re-experiencing symptoms. These results tie together previous observations of reduced HRV/PRV and impaired vmPFC function in PTSD and call for further research on reciprocal brain-body relationships in understanding PTSD pathophysiology.

Elevated perceived threat is associated with reduced hippocampal volume in combat veterans.

Reduced hippocampal volume is frequently observed in posttraumatic stress disorder (PTSD), but the psychological processes associated with these alterations remain unclear. Given hippocampal involvement in memory and contextual representations of threat, we investigated relationships between retrospectively reported combat exposure, perceived threat, and hippocampal volume in trauma-exposed veterans. T1-weighted anatomical MRI scans were obtained from 56 veterans (4 women, 52 men; 39 with elevated PTSD symptoms, "PTSS" group) and hippocampal volume was estimated using automatic segmentation tools in FreeSurfer. Hippocampal volume was regressed on self-reported perceived threat from the Deployment Risk and Resilience Inventory, and combat exposure from the Combat Exposure Scale. As a secondary analysis, hippocampal volume was regressed on Clinician-Administered PTSD Scale (CAPS) symptoms. In veterans with elevated PTSD symptoms, hippocampal volume was inversely related to perceived threat while deployed while controlling for self-reported combat exposure. Hippocampal volume was also inversely correlated with avoidance/numbing CAPS symptoms. Future research should clarify the temporal milieu of these effects and investigate whether individual differences in hippocampal structure and function contribute to heightened threat appraisal at the time of trauma vs. subsequently elevated appraisals of traumatic events.

Behavioral and neural indices of affective coloring for neutral social stimuli.

Emotional processing often continues beyond the presentation of emotionally evocative stimuli, which can result in affective biasing or coloring of subsequently encountered events. Here, we describe neural correlates of affective coloring and examine how individual differences in affective style impact the magnitude of affective coloring. We conducted functional magnetic resonance imaging in 117 adults who passively viewed negative, neutral and positive pictures presented 2 s prior to neutral faces. Brain responses to neutral faces were modulated by the valence of preceding pictures, with greater activation for faces following negative (vs positive) pictures in the amygdala, dorsomedial and lateral prefrontal cortex, ventral visual cortices, posterior superior temporal sulcus, and angular gyrus. Three days after the magnetic resonance imaging scan, participants rated their memory and liking of previously encountered neutral faces. Individuals higher in trait positive affect and emotional reappraisal rated faces as more likable when preceded by emotionally arousing (negative or positive) pictures. In addition, greater amygdala responses to neutral faces preceded by positively valenced pictures were associated with greater memory for these faces 3 days later. Collectively, these results reveal individual differences in how emotions spill over onto the processing of unrelated social stimuli, resulting in persistent and affectively biased evaluations of such stimuli.

Successful face recognition is associated with increased prefrontal cortex activation in autism spectrum disorder.

This study examines whether deficits in visual information processing in autism-spectrum disorder (ASD) can be offset by the recruitment of brain structures involved in selective attention. During functional MRI, 12 children with ASD and 19 control participants completed a selective attention one-back task in which images of faces and houses were superimposed. When attending to faces, the ASD group showed increased activation relative to control participants within multiple prefrontal cortex areas, including dorsolateral prefrontal cortex (DLPFC). DLPFC activation in ASD was associated with increased response times for faces. These data suggest that prefrontal cortex activation may represent a compensatory mechanism for diminished visual information processing abilities in ASD.

Dissecting the anticipation of aversion reveals dissociable neural networks.

The anticipation of future adversity confers adaptive benefits by engaging a suite of preparatory mechanisms, but this process can also be deleterious when carried out in excess. Neuroscientific investigations have largely treated anticipation as a unitary process, but we show here using functional magnetic resonance imaging that distinct stages of aversive anticipation are supported by dissociable neural mechanisms. Immediate anticipatory responses were observed in regions associated with threat detection and early processing of predictive cues, including the orbitofrontal cortex and pregenual anterior cingulate cortex, as well as the amygdala for individuals with elevated anxiety symptoms. Sustained anticipatory activity was observed in the forebrain/bed nucleus of the stria terminalis, anterior insula, anterior mid-cingulate cortex (aMCC), and midbrain/periaqueductal gray, regions associated with anxiety, interoception, and defensive behavior. The aMCC showed increased functional coupling with the midbrain during sustained anticipation of aversion, highlighting a circuit critical for the expression of preparatory fear responses. These data implicate distinct sets of regions that are active during different temporal stages of anticipation, and provide insight into how the human brain faces the future both adaptively and maladaptively.

Reduced structural connectivity of a major frontolimbic pathway in generalized anxiety disorder.

CONTEXT: Emotion regulation deficits figure prominently in generalized anxiety disorder (GAD) and in other anxiety and mood disorders. Research examining emotion regulation and top-down modulation has implicated reduced coupling of the amygdala with prefrontal cortex and anterior cingulate cortex, suggesting altered frontolimbic white matter connectivity in GAD. OBJECTIVES: To investigate structural connectivity between ventral prefrontal cortex or anterior cingulate cortex areas and the amygdala in GAD and to assess associations with functional connectivity between those areas. DESIGN: Participants underwent diffusion-tensor imaging and functional magnetic resonance imaging. SETTING: University magnetic resonance imaging facility. PARTICIPANTS: Forty-nine patients with GAD and 39 healthy volunteer control subjects, including a matched subset of 21 patients having GAD without comorbid Axis I diagnoses and 21 healthy volunteers matched for age, sex, and education. MAIN OUTCOME MEASURES: The mean fractional anisotropy values in the left and right uncinate fasciculus, as measured by tract-based analysis for diffusion-tensor imaging data. RESULTS: Lower mean fractional anisotropy values in the bilateral uncinate fasciculus indicated reduced frontolimbic structural connectivity in patients with GAD. This reduction in uncinate fasciculus integrity was most pronounced for patients without comorbidity and was not observed in other white matter tracts. Across all participants, higher fractional anisotropy values were associated with more negative functional coupling between the pregenual anterior cingulate cortex and the amygdala during the anticipation of aversion. CONCLUSIONS: Reduced structural connectivity of a major frontolimbic pathway suggests a neural basis for emotion regulation deficits in GAD. The functional significance of these structural differences is underscored by decreased functional connectivity between the anterior cingulate cortex and the amygdala in individuals with reduced structural integrity of the uncinate fasciculus.

Bidirectional communication between amygdala and fusiform gyrus during facial recognition.

Decades of research have documented the specialization of fusiform gyrus (FG) for facial information processes. Recent theories indicate that FG activity is shaped by input from amygdala, but effective connectivity from amygdala to FG remains undocumented. In this fMRI study, 39 participants completed a face recognition task. 11 participants underwent the same experiment approximately four months later. Robust face-selective activation of FG, amygdala, and lateral occipital cortex were observed. Dynamic causal modeling and Bayesian Model Selection (BMS) were used to test the intrinsic connections between these structures, and their modulation by face perception. BMS results strongly favored a dynamic causal model with bidirectional, face-modulated amygdala-FG connections. However, the right hemisphere connections diminished at time 2, with the face modulation parameter no longer surviving Bonferroni correction. These findings suggest that amygdala strongly influences FG function during face perception, and that this influence is shaped by experience and stimulus salience.

Uncertainty is associated with biased expectancies and heightened responses to aversion.

Uncertainty is an omnipresent force in peoples' lives that has been shown to amplify the negative impact of aversive events. This amplified aversiveness, together with the negative attitudes that individuals can have toward uncertainty, suggests that a cue indicating uncertainty about future events might be associated with biased expectancies of negative outcomes or biased contingency estimates, similar to biases that have been observed for traditional fear-relevant cues, such as snakes or spiders. Participants in this study saw three different cues: one that indicated with certainty that an aversive picture would follow, one that indicated with certainty that a neutral picture would follow, and one that indicated uncertainty about whether an aversive or neutral picture would follow. Online self-report data revealed negatively biased expectancies of aversion after uncertain cues. The degree of this online expectancy bias predicted participants' estimates, at the conclusion of the experiment, of the relationship between uncertain cues and aversive pictures. Aversive pictures after the uncertain cue (relative to those after the certain cue) were accompanied by increased skin conductance responses and self-reported negative mood. These findings that uncertainty is accompanied by biased expectancies of aversion and heightened responses to aversion warrant extensions of this research in anxiety disorders, given evidence for intolerance of uncertainty and anticipatory dysfunction in the pathology of such disorders.