Translating a rodent measure of negative bias into humans: the impact of induced anxiety and unmedicated mood and anxiety disorders.

BACKGROUND: Mood and anxiety disorders are ubiquitous but current treatment options are ineffective for many sufferers. Moreover, a number of promising pre-clinical interventions have failed to translate into clinical efficacy in humans. Improved treatments are unlikely without better animal-human translational pipelines. Here, we translate a rodent measure of negative affective bias into humans, exploring its relationship with (1) pathological mood and anxiety symptoms and (2) transient induced anxiety. METHODS: Adult participants (age = 29 ± 11) who met criteria for mood or anxiety disorder symptomatology according to a face-to-face neuropsychiatric interview were included in the symptomatic group. Study 1 included N = 77 (47 = asymptomatic [female = 21]; 30 = symptomatic [female = 25]), study 2 included N = 47 asymptomatic participants (25 = female). Outcome measures were choice ratios, reaction times and parameters recovered from a computational model of reaction time - the drift diffusion model (DDM) - from a two-alternative-forced-choice task in which ambiguous and unambiguous auditory stimuli were paired with high and low rewards. RESULTS: Both groups showed over 93% accuracy on unambiguous tones indicating intact discrimination, but symptomatic individuals demonstrated increased negative affective bias on ambiguous tones [proportion high reward = 0.42 (s.d. = 0.14)] relative to asymptomatic individuals [0.53 (s.d. = 0.17)] as well as a significantly reduced DDM drift rate. No significant effects were observed for the within-subjects anxiety-induction. CONCLUSIONS: Humans with pathological anxiety symptoms directly mimic rodents undergoing anxiogenic manipulation. The lack of sensitivity to transient anxiety suggests the paradigm might be more sensitive to clinically relevant symptoms. Our results establish a direct translational pipeline (and candidate therapeutics screen) from negative affective bias in rodents to pathological mood and anxiety symptoms in humans.

The impact of threat of shock-induced anxiety on the neural substrates of memory encoding and retrieval.

Dysfunctional memory processes are widely reported in anxiety disorders, but the underlying neurocognitive mechanisms are unclear. Recent work shows that the impact of anxiety on memory depends on the context and memory modality. For instance, threat of shock, a translational within-subject anxiety induction, has been shown to impair the encoding of facial stimuli, while improving spatial working memory (WM) accuracy. The present study aimed to delineate the neural circuitry regulating these opposing behavioural effects. Thirty-three healthy volunteers performed the previously assessed facial recognition and a spatial WM tasks inside an fMRI scanner, under alternating within-subject conditions of threat or safe from shock across encoding and retrieval. Facial recognition impairments were replicated when threat was selectively induced at encoding. Neuroimaging results suggest that this effect was driven by increased competition for attentional resources within the anterior cingulate cortex, in which activation correlated positively with stress levels. The impact of threat on spatial WM performance did not, however, replicate in the fMRI environment. Nevertheless, state-dependent hippocampal activation was observed in both tasks. These findings suggest a neurocognitive mechanism by which anxiety impairs facial recognition as well as a state-dependent hippocampal activation pattern, which may putatively underline retrieval of negative experiences in anxiety.

Altered learning under uncertainty in unmedicated mood and anxiety disorders.

Anxiety is characterized by altered responses under uncertain conditions, but the precise mechanism by which uncertainty changes the behaviour of anxious individuals is unclear. Here we probe the computational basis of learning under uncertainty in healthy individuals and individuals suffering from a mix of mood and anxiety disorders. Participants were asked to choose between four competing slot machines with fluctuating reward and punishment outcomes during safety and stress. We predicted that anxious individuals under stress would learn faster about punishments and exhibit choices that were more affected by those punishments, thus formalizing our predictions as parameters in reinforcement learning accounts of behaviour. Overall, the data suggest that anxious individuals are quicker to update their behaviour in response to negative outcomes (increased punishment learning rates). When treating anxiety, it may therefore be more fruitful to encourage anxious individuals to integrate information over longer horizons when bad things happen, rather than try to blunt their responses to negative outcomes.

Adaptation of social and non-social cues to direction in adults with autism spectrum disorder and neurotypical adults with autistic traits.

Perceptual constancy strongly relies on adaptive gain control mechanisms, which shift perception as a function of recent sensory history. Here we examined the extent to which individual differences in magnitude of adaptation aftereffects for social and non-social directional cues are related to autistic traits and sensory sensitivity in healthy participants (Experiment 1); and also whether adaptation for social and non-social directional cues is differentially impacted in adults with Autism Spectrum Disorder (ASD) relative to neurotypical (NT) controls (Experiment 2). In Experiment 1, individuals with lower susceptibility to adaptation aftereffects, i.e. more 'veridical' perception, showed higher levels of autistic traits across social and non-social stimuli. Furthermore, adaptation aftereffects were predictive of sensory sensitivity. In Experiment 2, only adaptation to eye-gaze was diminished in adults with ASD, and this was related to difficulties categorizing eye-gaze direction at baseline. Autism Diagnostic Observation Schedule (ADOS) scores negatively predicted lower adaptation for social (head and eye-gaze direction) but not non-social (chair) stimuli. These results suggest that the relationship between adaptation and the broad socio-cognitive processing style captured by 'autistic traits' may be relatively domain-general, but in adults with ASD diminished adaptation is only apparent where processing is most severely impacted, such as the perception of social attention cues.

The impact of induced anxiety on affective response inhibition.

Studying the effects of experimentally induced anxiety in healthy volunteers may increase our understanding of the mechanisms underpinning anxiety disorders. Experimentally induced stress (via threat of unpredictable shock) improves accuracy at withholding a response on the sustained attention to response task (SART), and in separate studies improves accuracy to classify fearful faces, creating an affective bias. Integrating these findings, participants at two public science engagement events (n = 46, n = 55) were recruited to explore the effects of experimentally induced stress on an affective version of the SART. We hypothesized that we would see an improved accuracy at withholding a response to affectively congruent stimuli (i.e. increased accuracy at withholding a response to fearful 'no-go' distractors) under threat of shock. Induced anxiety slowed reaction time, and at the second event quicker responses were made to fearful stimuli. However, we did not observe improved inhibition overall during induced anxiety, and there was no evidence to suggest an interaction between induced anxiety and stimulus valence on response accuracy. Indeed Bayesian analysis provided decisive evidence against this hypothesis. We suggest that the presence of emotional stimuli might make the safe condition more anxiogenic, reducing the differential between conditions and knocking out any threat-potentiated improvement.

Modeling Avoidance in Mood and Anxiety Disorders Using Reinforcement Learning.

BACKGROUND: Serious and debilitating symptoms of anxiety are the most common mental health problem worldwide, accounting for around 5% of all adult years lived with disability in the developed world. Avoidance behavior-avoiding social situations for fear of embarrassment, for instance-is a core feature of such anxiety. However, as for many other psychiatric symptoms the biological mechanisms underlying avoidance remain unclear. METHODS: Reinforcement learning models provide formal and testable characterizations of the mechanisms of decision making; here, we examine avoidance in these terms. A total of 101 healthy participants and individuals with mood and anxiety disorders completed an approach-avoidance go/no-go task under stress induced by threat of unpredictable shock. RESULTS: We show an increased reliance in the mood and anxiety group on a parameter of our reinforcement learning model that characterizes a prepotent (pavlovian) bias to withhold responding in the face of negative outcomes. This was particularly the case when the mood and anxiety group was under stress. CONCLUSIONS: This formal description of avoidance within the reinforcement learning framework provides a new means of linking clinical symptoms with biophysically plausible models of neural circuitry and, as such, takes us closer to a mechanistic understanding of mood and anxiety disorders.

Enhanced Risk Aversion, But Not Loss Aversion, in Unmedicated Pathological Anxiety.

BACKGROUND: Anxiety disorders are associated with disruptions in both emotional processing and decision making. As a result, anxious individuals often make decisions that favor harm avoidance. However, this bias could be driven by enhanced aversion to uncertainty about the decision outcome (e.g., risk) or aversion to negative outcomes (e.g., loss). Distinguishing between these possibilities may provide a better cognitive understanding of anxiety disorders and hence inform treatment strategies. METHODS: To address this question, unmedicated individuals with pathological anxiety (n = 25) and matched healthy control subjects (n = 23) completed a gambling task featuring a decision between a gamble and a safe (certain) option on every trial. Choices on one type of gamble-involving weighing a potential win against a potential loss (mixed)-could be driven by both loss and risk aversion, whereas choices on the other type-featuring only wins (gain only)-were exclusively driven by risk aversion. By fitting a computational prospect theory model to participants' choices, we were able to reliably estimate risk and loss aversion and their respective contribution to gambling decisions. RESULTS: Relative to healthy control subjects, pathologically anxious participants exhibited enhanced risk aversion but equivalent levels of loss aversion. CONCLUSIONS: Individuals with pathological anxiety demonstrate clear avoidance biases in their decision making. These findings suggest that this may be driven by a reduced propensity to take risks rather than a stronger aversion to losses. This important clarification suggests that psychological interventions for anxiety should focus on reducing risk sensitivity rather than reducing sensitivity to negative outcomes per se.

Towards an emotional 'stress test': a reliable, non-subjective cognitive measure of anxious responding.

Response to stress or external threats is a key factor in mood and anxiety disorder aetiology. Current measures of anxious responding to threats are limited because they largely rely on retrospective self-report. Objectively quantifying individual differences in threat response would be a valuable step towards improving our understanding of anxiety disorder vulnerability. Our goal is to therefore develop a reliable, objective, within-subject 'stress-test' of anxious responding. To this end, we examined threat-potentiated performance on an inhibitory control task from baseline to 2-4 weeks (n = 50) and again after 5-9 months (n = 22). We also describe single session data for a larger sample (n = 157) to provide better population-level estimates of task performance variance. Replicating previous findings, threat of shock improved distractor accuracy and slowed target reaction time on our task. Critically, both within-subject self-report measures of anxiety (ICC = 0.66) and threat-potentiated task performance (ICC = 0.58) showed clinically useful test-retest reliability. Threat-potentiated task performance may therefore hold promise as a non-subjective measure of individual anxious responding.

A striking reduction of simple loudness adaptation in autism.

Reports of sensory disturbance, such as loudness sensitivity or sound intolerance, are ubiquitous in Autism Spectrum Disorder (ASD) but a mechanistic explanation for these perceptual differences is lacking. Here we tested adaptation to loudness, a process that regulates incoming sensory input, in adults with ASD and matched controls. Simple loudness adaptation (SLA) is a fundamental adaptive process that reduces the subjective loudness of quiet steady-state sounds in the environment over time, whereas induced loudness adaptation (ILA) is a means of generating a reduction in the perceived volume of louder sounds. ASD participants showed a striking reduction in magnitude and rate of SLA relative to age and ability-matched typical adults, but in contrast ILA remained intact. Furthermore, rate of SLA predicted sensory sensitivity coping strategies in the ASD group. These results provide the first evidence that compromised neural mechanisms governing fundamental adaptive processes might account for sound sensitivity in ASD.