Shared and distinct biological mechanisms for anxiety and sensory over-responsivity in youth with autism versus anxiety disorders.

Sensory over-responsivity (SOR) is a prevalent cross-diagnostic condition that is often associated with anxiety. The biological mechanisms underlying the co-occurrence of SOR and anxiety symptoms are not well understood, despite having important implications for targeted intervention. We therefore investigated the unique associations of SOR and anxiety symptoms with physiological and neural responses to sensory stimulation for youth with anxiety disorders (ANX), autism spectrum disorder (ASD), or typical development (TD). Age/IQ-matched youth aged 8-18 years (22 ANX; 30 ASD; 22 TD) experienced mildly aversive tactile and auditory stimuli during functional magnetic resonance imaging and then during skin conductance response (SCR) and heart rate (HR) measurements. Caregivers reported on participants' SOR and anxiety symptoms. ASD/ANX youth had elevated SOR and anxiety symptoms compared to TD. ASD/ANX youth showed similar, heightened brain responses to sensory stimulation compared to TD youth, but brain responses were more highly related to SOR symptoms in ASD youth and to anxiety symptoms in ANX youth. Across ASD/ANX youth, anxiety symptoms uniquely related to greater SCR whereas SOR uniquely related to greater HR responses to sensory stimulation. Behavioral and neurobiological over-responsivity to sensory stimulation was shared across diagnostic groups. However, findings support SOR and anxiety as distinct symptoms with unique biological mechanisms, and with different relationships to neural over-reactivity dependent on diagnostic group. Results indicate a need for targeted treatment approaches.

A multi-modal assessment of fear conditioning in adolescent anorexia nervosa.

OBJECTIVE: Anorexia nervosa (AN) is a pernicious psychiatric disorder which is principally characterized by a fear of weight gain. Notwithstanding the centrality of fear in the psychopathology of AN, controlled assessments of negative valence systems are lacking. Herein we assess fear conditioning in adolescent females with AN. METHOD: Adolescent girls (Mage = 14.6 years, ±1.57) with DSM-5 diagnoses of AN (N = 25) and age-matched control girls (Mage = 14.8 years, ±1.46) with no DSM-5 diagnoses (N = 25) completed structured clinical interviews and participated in a classical three-phase Pavlovian fear conditioning paradigm. Participants with comorbid anxiety disorders were excluded. Skin conductance response (SCR) was measured, alongside self-reported fear, valence, and fear expectancy ratings. RESULTS: Both groups demonstrated significant differential acquisition across all four measures. Regarding group comparisons, no differences emerged for self-reported fear, valence, and fear expectancy ratings during acquisition, although for SCR, those with AN demonstrated reduced physiological arousal relative to controls. Both groups demonstrated significant differential extinction for unconditioned stimuli (US) expectancy, self-report fear, and self-report valence. No statistically significant group differences were evident during extinction to the conditioned stimuli (CS)+, on any outcome measure. However, controls reported more positive valence to the CS- than those with AN. CONCLUSIONS: Contrary to our hypotheses, our preliminary assessment did not find support for elevated fear responding among adolescent girls with AN with regards to fear acquisition or extinction. These data suggest that AN in adolescent girls may not be associated with a heightened propensity to acquire fear, but conversely, may suggest that exposure treatments for AN may be helpful, since extinction learning is intact in AN. PUBLIC SIGNIFICANCE: AN is characterized by fear-related symptoms, including food and weight-related fear, and behavioral avoidance, yet controlled studies assessing fear learning are limited. Our preliminary assessment of adolescent AN indicates no abnormalities in fear learning among adolescents with AN. These findings may inform existing mechanistic models of AN psychopathology, and the development of exposure-based treatments for AN.

Ambiguity drives higher-order Pavlovian learning.

In the natural world, stimulus-outcome associations are often ambiguous, and most associations are highly complex and situation-dependent. Learning to disambiguate these complex associations to identify which specific outcomes will occur in which situations is critical for survival. Pavlovian occasion setters are stimuli that determine whether other stimuli will result in a specific outcome. Occasion setting is a well-established phenomenon, but very little investigation has been conducted on how occasion setters are disambiguated when they themselves are ambiguous (i.e., when they do not consistently signal whether another stimulus will be reinforced). In two preregistered studies, we investigated the role of higher-order Pavlovian occasion setting in humans. We developed and tested the first computational model predicting direct associative learning, traditional occasion setting (i.e., 1st-order occasion setting), and 2nd-order occasion setting. This model operationalizes stimulus ambiguity as a mechanism to engage in higher-order Pavlovian learning. Both behavioral and computational modeling results suggest that 2nd-order occasion setting was learned, as evidenced by lack and presence of transfer of occasion setting properties when expected and the superior fit of our 2nd-order occasion setting model compared to the 1st-order occasion setting or direct associations models. These results provide a controlled investigation into highly complex associative learning and may ultimately lead to improvements in the treatment of Pavlovian-based mental health disorders (e.g., anxiety disorders, substance use).

Associations between physiological and neural measures of sensory reactivity in youth with autism.

BACKGROUND: Individuals with Autism Spectrum Disorder (ASD) commonly show sensory over-responsivity (SOR), an impairing condition related to over-reactive brain and behavioral responses to aversive stimuli. While individuals with ASD often show atypically high physiological arousal, it is unclear how this relates to sensory reactivity. We therefore investigated how physiological arousal relates to brain and behavioral indices of SOR, to inform understanding of the biological mechanisms underlying SOR and to determine whether physiological measures are associated with SOR-related brain responses. METHODS: Youth aged 8-18 (49 ASD; 30 age- and performance-IQ-matched typically developing (TD)) experienced mildly aversive tactile and auditory stimuli first during functional magnetic resonance imaging (N = 41 ASD, 26 TD) and then during skin conductance (SCR) (N = 48 ASD, 28 TD) and heart rate (HR) measurements (N = 48 ASD, 30 TD). Parents reported on their children's SOR severity. RESULTS: Autism Spectrum Disorder youth overall displayed greater SCR to aversive sensory stimulation than TD youth and greater baseline HR. Within ASD, higher SOR was associated with higher mean HR across all stimuli after controlling for baseline HR. Furthermore, the ASD group overall, and the ASD-high-SOR group in particular, showed reduced HR deceleration/greater acceleration to sensory stimulation compared to the TD group. Both SCR and HR were associated with brain responses to sensory stimulation in regions previously associated with SOR and sensory regulation. CONCLUSIONS: Autism Spectrum Disorder youth displayed heightened physiological arousal to mildly aversive sensory stimulation, with HR responses in particular showing associations with brain and behavioral measures of SOR. These results have implications for using psychophysiological measures to assess SOR, particularly in individuals with ASD who cannot undergo MRI.

Positive affect predicts less reacquisition of fear: relevance for long-term outcomes of exposure therapy.

Much emphasis in fear conditioning research is placed on understanding extinction learning, partly because of its application in treating anxiety disorders. Return of fear after extinction is a problem affecting long-term maintenance of treatment gains. The present study evaluated whether positive affect (PA) is associated with lower rates of reacquisition, or, an increase in fear following re-pairings of the conditional stimulus (CS+) and unconditional stimulus (US; e.g. electric shock) after extinction. Results showed that higher PA before and after extinction was associated with less CS+ fear during reacquisition as measured by skin conductance arousal and US expectancy. Conversely, negative affect was not associated with reacquisition of fear using any measure. These results provide implications for reducing reacquisition with exposure therapy for anxiety disorders.

Post-extinction conditional stimulus valence predicts reinstatement fear: relevance for long-term outcomes of exposure therapy.

Exposure therapy for anxiety disorders is translated from fear conditioning and extinction. While exposure therapy is effective in treating anxiety, fear sometimes returns after exposure. One pathway for return of fear is reinstatement: unsignaled unconditional stimuli following completion of extinction. The present study investigated the extent to which valence of the conditional stimulus (CS+) after extinction predicts return of CS+ fear after reinstatement. Participants (N = 84) engaged in a differential fear conditioning paradigm and were randomised to reinstatement or non-reinstatement. We hypothesised that more negative post-extinction CS+ valence would predict higher CS+ fear after reinstatement relative to non-reinstatement and relative to extinction retest. Results supported the hypotheses and suggest that strategies designed to decrease negative valence of the CS+ may reduce the return of fear via reinstatement following exposure therapy.

Positive mood induction does not reduce return of fear: A virtual reality exposure study for public speaking anxiety.

Previous laboratory work has shown that induction of positive mood prior to fear extinction decreases the negative valence of the conditional stimulus (CS) and reduces reinstatement of fear. Before translating these insights to clinical practice, it is important to test this strategy in anxious individuals. Students with a high fear of public speaking (N = 62) were randomized to either a positive mood induction, a negative mood induction, or no induction control group. All participants performed two weekly sessions of virtual reality exposure and a 1-week follow-up test including a spontaneous recovery test and reinstatement test after a social rejection (unconditional stimulus). We used self-reported fear measures and skin conductance responses. We expected that the positive group, compared to the other groups, would evaluate the CS (i.e., speaking in front of an audience) as less negative following exposure and would show less spontaneous recovery and reinstatement of fear following a social rejection. Although mood was successfully manipulated, there were no group differences in CS valence following exposure. In all conditions, VR exposure successfully reduced public speaking fear, and these effects were stable at follow-up. In contrast with expectations, the positive group showed more spontaneous recovery of CS negative valence than the negative group. To conclude, we found no evidence that positive mood induction prior to exposure optimizes exposure effects for anxious individuals.

Computationally-defined markers of uncertainty aversion predict emotional responses during a global pandemic.

Exposure to stressful life events involving threat and uncertainty often results in the development of anxiety. However, the factors that confer risk and resilience for anxiety following real world stress at a computational level remain unclear. We identified core components of uncertainty aversion moderating response to stress posed by the COVID-19 pandemic derived from computational modeling of decision making. Using both cross-sectional and longitudinal analyses, we investigated both immediate effects at the onset of the stressor, as well as medium-term changes in response to persistent stress. 479 subjects based in the United States completed a decision-making task measuring risk aversion, loss aversion, and ambiguity aversion in the early stages of the pandemic (March 2020). Self-report measures targeting threat perception, anxiety, and avoidant behavior in response to the pandemic were collected at the same time point and 8 weeks later (May 2020). Cross-sectional analyses indicated that higher risk aversion predicted higher perceived threat from the pandemic, and ambiguity aversion for guaranteed gains predicted perceived threat and pandemic-related anxiety. In longitudinal analyses, ambiguity aversion for guaranteed gains predicted greater increases in perceived infection likelihood. Together, these results suggest that individuals who have a low-level aversion toward uncertainty show stronger negative emotional reactions to both the onset and persistence of real-life stress. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Diagnostic overlap of generalized anxiety disorder and major depressive disorder in a primary care sample.

BACKGROUND: Generalized anxiety disorder (GAD) and major depressive disorder (MDD) are highly comorbid. A possible explanation is that they share four symptoms according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revision (DSM-IV-TR). The present study addressed the symptom overlap of people meeting DSM-IV-TR diagnostic criteria for GAD, MDD, or both to investigate whether comorbidity might be explained by overlapping diagnostic criteria. METHODS: Participants (N = 1,218) were enrolled in the Coordinated Anxiety Learning and Management study (a randomized effectiveness clinical trial in primary care). Hypotheses were (1) the comorbid GAD/MDD group endorses the overlapping symptoms more than the nonoverlapping symptoms, and (2) the comorbid GAD/MDD group endorses the overlapping symptoms more than GAD only or MDD only groups, whereas differences would not occur for nonoverlapping symptoms. RESULTS: The overlapping GAD/MDD symptoms were endorsed more by the comorbid group than the MDD group but not the GAD group when covarying for total symptom endorsement. Similarly, the comorbid group endorsed the overlapping symptoms more than the nonoverlapping symptoms and did not endorse the nonoverlapping symptoms more than the GAD or MDD groups when covarying for total symptom endorsement. CONCLUSIONS: The results suggest that comorbidity of GAD and MDD is strongly influenced by diagnostic overlap. Results are discussed in terms of errors of diagnostic criteria, as well as models of shared psychopathology that account for diagnostic criteria overlap.

Optimizing exposure therapy with an inhibitory retrieval approach and the OptEx Nexus.

Research from recent decades has highlighted the distinction between excitatory and inhibitory Pavlovian learning mechanisms. Based on this distinction, state-of-the-art exposure therapy for anxiety disorders emphasizes inhibitory learning and retrieval as its primary mechanism for long-term reduction in fear, anxiety, and avoidance. Seven years ago, we (Craske, et al., 2014) summarized exposure therapy from an inhibitory learning approach, focusing on eight exposure optimization strategies. Here, we update this model based on recent work and describe how to conduct exposure therapy from an inhibitory retrieval approach and encourage further empirical investigation of its basic premises. To this end, we guide the reader in the use of the OptEx Nexus: a clinician's tool for conducting exposure therapy from an inhibitory retrieval approach. We categorize exposure strategies as fundamental (expectancy violation, attention to feared stimulus/situation, removal of safety signals, and mental rehearsal after exposure), advanced (deepened extinction, occasional reinforced extinction), and promoting generalization of learning (retrieval cues, multiple contexts, stimulus variability, positive affect). We additionally discuss extinction learning with distal future feared outcomes, the role of avoidance, and alternative models/approaches to exposure therapy, including counterconditioning, novelty-enhanced extinction, latent cause models, and reconsolidation. Lastly, we illustrate clinical implementation via vignettes of exposure therapy from an inhibitory retrieval approach (see Supplemental materials).

Neural, physiological, and psychological markers of appetitive conditioning in anorexia nervosa: a study protocol.

BACKGROUND: Anorexia nervosa (AN) is a chronic and disabling psychiatric condition characterized by low hedonic drive towards food, and is thought to be inclusive of altered dimensions of reward processing. Whether there exists a fundamental aberrancy in the capacity to acquire and maintain de novo hedonic associations-a critical component of hedonic responding-has never been studied in AN. METHODS: This multi-modal study will employ a 2-day Pavlovian appetitive conditioning paradigm to interrogate the (1) acquisition, (2) extinction, (3) spontaneous recovery and (4) reinstatement of appetitive learning in adolescents and young adults with AN. Participants will be 30 currently ill, underweight individuals with AN; 30 weight-restored individuals with AN; and 30 age-matched healthy controls, all aged 12-22 years. All subjects will undergo clinical assessment, followed by the 2-day appetitive conditioning task during which fMRI, pupillometry, heart rate deceleration, and subjective ratings will be acquired. DISCUSSION: This study will be the first to interrogate appetitive conditioning in AN-a disorder characterized by altered hedonic responding to food. Results will help establish objective biomarkers of appetitive conditioning in AN and lay the groundwork for developing novel lines of treatment for AN and other psychiatric disorders involving diminished ability to experience pleasure and reward. TRIAL REGISTRATION: Pending. INTENDED REGISTRY: Clinicaltrials.gov.

A Decision Architecture for Safety Computations.

Accurately estimating safety is critical to pursuing nondefensive survival behaviors. However, little attention has been paid to how the human brain computes safety. We conceptualize a model that consists of two components: (i) threat-oriented evaluations that focus on threat value, imminence, and predictability; and (ii) self-oriented evaluations that focus on the agent's experience, strategies, and ability to control the situation. Our model points to the dynamic interaction between these two components as a mechanism of safety estimation. Based on a growing body of human literature, we hypothesize that distinct regions of the ventromedial prefrontal cortex (vmPFC) respond to threat and safety to facilitate survival decisions. We suggest safety is not an inverse of danger, but reflects independent computations that mediate defensive circuits and behaviors.

Economic Decisions with Ambiguous Outcome Magnitudes Vary with Low and High Stakes but Not Trait Anxiety or Depression.

Most of life's decisions involve risk and uncertainty regarding whether reward or loss will follow. Decision makers often face uncertainty not only about the likelihood of outcomes (what are the chances that I will get a raise if I ask my supervisor? What are the chances that my supervisor will be upset with me for asking?) but also the magnitude of outcomes (if I do get a raise, how large will it be? If my supervisor gets upset, how bad will the consequences be for me?). Only a few studies have investigated economic decision making with ambiguous likelihoods, and even fewer have investigated ambiguous outcome magnitudes. In the present report, we investigated the effects of ambiguous outcome magnitude, risk, and gains/losses in an economic decision-making task with low stakes (Study 1; $3.60-$5.70; N = 367) and high stakes (Study 2; $6-$48; N = 210) using a within-subjects design. We conducted computational modeling to determine individuals' preferences/aversions for ambiguous outcome magnitudes, risk, and gains/losses. We additionally investigated the association between trait anxiety and trait depression and decision-making parameters. Our results show that increasing stakes increased ambiguous gain aversion and unambiguous risk aversion but increased ambiguous sure loss preference; participants also became more averse to ambiguous sure gains relative to unambiguous risky gains. There were no significant effects of trait anxiety or trait depression on economic decision making. Our results suggest that as stakes increase, people tend to avoid uncertainty in the gain domain (especially ambiguous gains) but prefer ambiguous vs unambiguous sure losses.

Pavlovian occasion setting in human fear and appetitive conditioning: Effects of trait anxiety and trait depression.

Contexts and discrete stimuli often hierarchically influence the association between a stimulus and outcome. This phenomenon, called occasion setting, is central to modulation-based Pavlovian learning. We conducted two experiments with humans in fear and appetitive conditioning paradigms, training stimuli in differential conditioning, feature-positive discriminations, and feature-negative discriminations. We also investigated the effects of trait anxiety and trait depression on these forms of learning. Results from both experiments showed that participants were able to successfully learn which stimuli predicted the electric shock and monetary reward outcomes. Additionally, as hypothesized, the stimuli trained as occasion setters had little-to-no effect on simple reinforced or non-reinforced stimuli, suggesting the former were indeed occasion setters. Lastly, in fear conditioning, trait anxiety was associated with increases in fear of occasion setter/conditional stimulus compounds; in appetitive conditioning, trait depression was associated with lower expectations of monetary reward for the trained negative occasion setting compound and transfer of the negative occasion setter to the simple reinforced stimulus. These results suggest that clinically anxious individuals may have enhanced fear of occasion setting compounds, and clinically depressed individuals may expect less reward with compounds involving the negative occasion setter.

Changes in risk perception and self-reported protective behaviour during the first week of the COVID-19 pandemic in the United States.

Efforts to change behaviour are critical in minimizing the spread of highly transmissible pandemics such as COVID-19. However, it is unclear whether individuals are aware of disease risk and alter their behaviour early in the pandemic. We investigated risk perception and self-reported engagement in protective behaviours in 1591 United States-based individuals cross-sectionally and longitudinally over the first week of the pandemic. Subjects demonstrated growing awareness of risk and reported engaging in protective behaviours with increasing frequency but underestimated their risk of infection relative to the average person in the country. Social distancing and hand washing were most strongly predicted by the perceived probability of personally being infected. However, a subgroup of individuals perceived low risk and did not engage in these behaviours. Our results highlight the importance of risk perception in early interventions during large-scale pandemics.

Pilot for novel context generalization paradigm.

BACKGROUND AND OBJECTIVES: Following an aversive experience, fears often generalize across contexts. Contextual fear generalization is modeled in a laboratory paradigm in which one context (CTX+) is paired with an aversive unconditional stimulus (US), while the other context (CTX-) is not. The current study sought to validate a novel paradigm assessing contextual fear generalization, and to determine the extent to which stress and anxiety symptoms enhanced contextual fear generalization. METHODS: Fifty-nine participants were randomized to a stress induction or control arithmetic test, followed by a differential context fear conditioning paradigm. One to three days later, participants completed a generalization gradient test with CTX+, CTX, and four generalization contexts. RESULTS: We found successful contextual fear conditioning on measures of US expectancy, self-report fear and valence, and startle reflex, and linear generalization across the contextual gradient on expectancies and self-report measures. Acute stress induction impaired learning of the US-CTX + association during context fear acquisition. Anxiety significantly predicted greater contextual fear generalization as measured by US expectancy. LIMITATIONS: Our study provides pilot data introducing a novel fear conditioning paradigm to assess contextual generalization of fear. There is a need for further replication to validate its utility. CONCLUSIONS: Findings suggest that individuals high in anxiety show greater contextual fear generalization as measured by US expectancy. Results are discussed in terms of potential mechanisms that contribute to pervasive anxiety.

Positive Affect as a Buffer between Chronic Stress and Symptom Severity of Emotional Disorders.

Research has demonstrated that stressors play a critical role in the development of generalized anxiety disorder (GAD), social anxiety disorder (SAD), and major depressive disorder (MDD). Separately, deficits in positive affect (PA) have been identified in GAD, SAD, and MDD. While previous research has linked the buffering effects of PA in chronic illness, such effects have yet to be investigated for chronic stressors and emotional disorder-related symptom severity. The purpose of the present study was to examine PA as a moderator of chronic interpersonal and non-interpersonal stress on GAD, SAD, and MDD symptom severity. Using a multilevel statistical approach with a sample of adolescents and young adults (N=463), PA was found to significantly moderate the relationship between chronic interpersonal stress and symptom severity for MDD and SAD. Findings suggest that in times of chronic interpersonal stress, higher PA may serve as a buffer from development of SAD and MDD symptoms.

Pavlovian extinction of fear with the original conditional stimulus, a generalization stimulus, or multiple generalization stimuli.

Exposure therapy for anxiety disorders is derived from Pavlovian extinction learning. With the aim of optimizing exposure therapy, the present study evaluated the effects of multiple extinction stimuli on inhibitory learning. In a differential fear conditioning procedure, participants were randomized to one of three extinction conditions: Extinction_CS+ received nine presentations of the original conditional stimulus (CS+); Extinction_Singular received nine presentations of a generalization stimulus (GS; stimulus similar to the CS+); and Extinction_Variety received one presentation each of nine GSs. One week later, participants returned for extinction test to the CS+, CS-, a GS from Extinction_Variety (Variable_GS), the GS from Extinction_Singular (Single_GS), and a novel GS (Novel_GS). Results showed that Extinction_CS+ exhibited less fear of the CS+ than Extinction_Singular (two dependent measures) and Extinction_Variety (three dependent measures). Additionally, Extinction_Singular had more fear of the Variable_GS than Extinction_Variety (two dependent measures) and Extinction_CS+ (one dependent measure). The results suggest that conducting extinction to the CS+ lessens conditional fear of the CS + more than extinction with GSs. Additionally, extinction with a variety of GSs lessens fear of those GSs more than repeated extinction with one GS. Results are discussed with relevance to exposure therapy for anxiety disorders.

The effect of positive mood induction on reducing reinstatement fear: Relevance for long term outcomes of exposure therapy.

While exposure therapy is effective in treating anxiety, fear can return after exposure. Return of fear can be understood through mechanisms of extinction learning. One form of return of fear is reinstatement, or, the fear that results from an unsignaled unconditional stimulus (US) presentation after extinction. Though the conditional response (CR; e.g., fear) typically reduces during extinction, the excitatory conditional stimulus (CS+) valence remains negative. The more negative the CS+ valence after the end of extinction, the greater the fear at reinstatement. The current study evaluated the degree to which positive mood induction (positive imagery training; PIT) compared to control (positive verbal training; PVT) before extinction a) decreased CS+ negative valence during extinction and b) reduced reinstatement fear. Compared to PVT, PIT a) increased positive affect, b) decreased post-extinction CS+ negative valence, and c) reduced reinstatement responding as measured by eye blink startle reflex (when shock was used at reinstatement) and self-report fear (regardless of reinstatement US type). Results suggest that increasing positive affect prior to exposure therapy could reduce relapse through reinstatement.

A randomized controlled trial of a self-guided, multimedia, stress management and resilience training program.

BACKGROUND: Stress is a common and costly behavioral health issue. Technology-based behavioral health programs (e.g., computer or web-based programs) are effective for treating anxiety or depression. These programs increase availability of evidence-based interventions to individuals who are not able or willing to receive such in-person treatments. Stress management training has empirical support, but little data exists on its efficacy with stressed but healthy individuals, and there are no prior studies employing a self-guided, multimedia intervention. We conducted a randomized controlled trial of a self-guided, multimedia stress management and resilience training program (SMART-OP) with a stressed but healthy sample. METHODS: Participants (N = 66) were randomized to SMART-OP or an attention control (AC) group that received marketed videos and published material on stress management. Participants were evaluated on self-report measures and Trier Social Stress Test (TSST) performance. Analyses were based on study completers (N = 59). RESULTS: SMART-OP group reported significantly less stress, more perceived control over stress, and rated SMART-OP as significantly more useful than AC. During the TSST, the data suggests the SMART-OP group showed greater within-task α-amylase recovery at post-assessment. CONCLUSIONS: SMART-OP is highly usable and is a more effective and useful stress management training program than an educational comparison.