Occipital-temporal cortical tuning to semantic and affective features of natural images predicts associated behavioral responses.

In everyday life, people need to respond appropriately to many types of emotional stimuli. Here, we investigate whether human occipital-temporal cortex (OTC) shows co-representation of the semantic category and affective content of visual stimuli. We also explore whether OTC transformation of semantic and affective features extracts information of value for guiding behavior. Participants viewed 1620 emotional natural images while functional magnetic resonance imaging data were acquired. Using voxel-wise modeling we show widespread tuning to semantic and affective image features across OTC. The top three principal components underlying OTC voxel-wise responses to image features encoded stimulus animacy, stimulus arousal and interactions of animacy with stimulus valence and arousal. At low to moderate dimensionality, OTC tuning patterns predicted behavioral responses linked to each image better than regressors directly based on image features. This is consistent with OTC representing stimulus semantic category and affective content in a manner suited to guiding behavior.

The Computational and Neural Substrates of Ambiguity Avoidance in Anxiety.

Theoretical accounts have linked anxiety to intolerance of ambiguity. However, this relationship has not been well operationalized empirically. Here, we used computational and neuro-imaging methods to characterize anxiety-related differences in aversive decision-making under ambiguity and associated patterns of cortical activity. Adult human participants chose between two urns on each trial. The ratio of tokens ('O's and 'X's) in each urn determined probability of electrical stimulation receipt. A number above each urn indicated the magnitude of stimulation that would be received if a shock was delivered. On ambiguous trials, one of the two urns had tokens occluded. By varying the number of tokens occluded, we manipulated the extent of missing information. At higher levels of missing information, there is greater second order uncertainty, i.e., more uncertainty as to the probability of pulling a given type of token from the urn. Adult human participants demonstrated avoidance of ambiguous options which increased with level of missing information. Extent of 'information-level dependent' ambiguity aversion was significantly positively correlated with trait anxiety. Activity in both the dorsal anterior cingulate cortex and inferior frontal sulcus during the decision-making period increased as a function of missing information. Greater engagement of these regions, on high missing information trials, was observed when participants went on to select the ambiguous option; this was especially apparent in high trait anxious individuals. These findings are consistent with individuals vulnerable to anxiety requiring greater activation of frontal regions supporting rational decision-making to overcome a predisposition to engage in ambiguity avoidance at high levels of missing information.

Executive Function Assigns Value to Novel Goal-Congruent Outcomes.

People often learn from the outcomes of their actions, even when these outcomes do not involve material rewards or punishments. How does our brain provide this flexibility? We combined behavior, computational modeling, and functional neuroimaging to probe whether learning from abstract novel outcomes harnesses the same circuitry that supports learning from familiar secondary reinforcers. Behavior and neuroimaging revealed that novel images can act as a substitute for rewards during instrumental learning, producing reliable reward-like signals in dopaminergic circuits. Moreover, we found evidence that prefrontal correlates of executive control may play a role in shaping flexible responses in reward circuits. These results suggest that learning from novel outcomes is supported by an interplay between high-level representations in prefrontal cortex and low-level responses in subcortical reward circuits. This interaction may allow for human reinforcement learning over arbitrarily abstract reward functions.

Impaired adaptation of learning to contingency volatility in internalizing psychopathology.

Using a contingency volatility manipulation, we tested the hypothesis that difficulty adapting probabilistic decision-making to second-order uncertainty might reflect a core deficit that cuts across anxiety and depression and holds regardless of whether outcomes are aversive or involve reward gain or loss. We used bifactor modeling of internalizing symptoms to separate symptom variance common to both anxiety and depression from that unique to each. Across two experiments, we modeled performance on a probabilistic decision-making under volatility task using a hierarchical Bayesian framework. Elevated scores on the common internalizing factor, with high loadings across anxiety and depression items, were linked to impoverished adjustment of learning to volatility regardless of whether outcomes involved reward gain, electrical stimulation, or reward loss. In particular, high common factor scores were linked to dampened learning following better-than-expected outcomes in volatile environments. No such relationships were observed for anxiety- or depression-specific symptom factors.

Effect of Prefrontal Cortex Stimulation on Regulation of Amygdala Response to Threat in Individuals With Trait Anxiety: A Randomized Clinical Trial.

Importance: Transcranial direct current stimulation (tDCS) of the dorsolateral prefrontal cortex (DLPFC) is under clinical investigation as a treatment for major depressive disorder. However, the mechanisms of action are unclear, and there is a lack of neuroimaging evidence, particularly among individuals with affective dysfunction. Furthermore, there is no direct causal evidence among humans that the prefrontal-amygdala circuit functions as described in animal models (ie, that increasing activity in prefrontal cortical control regions inhibits amygdala response to threat). Objective: To determine whether stimulation of the prefrontal cortex reduces amygdala threat reactivity in individuals with trait anxiety. Design, Setting, and Participants: This community-based randomized clinical trial used a double-blind, within-participants design (2 imaging sessions per participant). Eighteen women with high trait anxiety (age range, 18-42 years) who scored greater than 45 on the trait measure of State-Trait Anxiety Inventory were randomized to receive active or sham tDCS of the DLPFC during the first session and the other intervention during the next session. Each intervention was followed immediately by a functional imaging scan during which participants performed an attentional task requiring them to ignore threatening face distractors. Data were collected from May 7 to October 6, 2015. Main Outcomes and Measures: Amygdala threat response, measured with functional magnetic resonance imaging. Results: Data from 16 female participants (mean age, 23 years; range, 18-42 years), with 8 in each group, were analyzed. Compared with sham stimulation, active DLPFC stimulation significantly reduced bilateral amygdala threat reactivity (z = 3.30, P = .04) and simultaneously increased activity in cortical regions associated with attentional control (z = 3.28, P < .001). In confirmatory behavioral analyses, there was a mean improvement in task accuracy of 12.2% (95% CI, 0.30%-24.0%; mean [SD] difference in number of correct answers, 2.2 [4.5]; t15 = 1.94, P = .04) after active DLPFC stimulation. Conclusions and Relevance: These results reveal a causal role for prefrontal regulation of amygdala function in attentional capture by threat in individuals with high trait anxiety. The finding that prefrontal stimulation acutely increases attentional control signals and reduces amygdala threat reactivity may indicate a neurocognitive mechanism that could contribute to tDCS treatment effects in affective disorders. Trial Registration: isrctn.org Identifier: ISRCTN78638425.

Stratification of MDD and GAD patients by resting state brain connectivity predicts cognitive bias.

Patients with Generalized Anxiety Disorder (GAD) and Major Depressive Disorder (MDD) show between-group comorbidity and symptom overlap, and within-group heterogeneity. Resting state functional connectivity might provide an alternate, biologically informed means by which to stratify patients with GAD or MDD. Resting state functional magnetic resonance imaging data were acquired from 23 adults with GAD, 21 adults with MDD, and 27 healthy adult control participants. We investigated whether within- or between-network connectivity indices from five resting state networks predicted scores on continuous measures of depression and anxiety. Successful predictors were used to stratify participants into two new groups. We examined whether this stratification predicted attentional bias towards threat and whether this varied between patients and controls. Depression scores were linked to elevated connectivity within a limbic network including the amygdala, hippocampus, VMPFC and subgenual ACC. Patients with GAD or MDD with high limbic connectivity showed poorer performance on an attention-to-threat task than patients with low limbic connectivity. No parallel effect was observed for control participants, resulting in an interaction of clinical status by resting state group. Our findings provide initial evidence for the external validity of stratification of MDD and GAD patients by functional connectivity markers. This stratification cuts across diagnostic boundaries and might valuably inform future intervention studies. Our findings also highlight that biomarkers of interest can have different cognitive correlates in individuals with versus without clinically significant symptomatology. This might reflect protective influences leading to resilience in some individuals but not others.

Anxiety, Depression, and Decision Making: A Computational Perspective.

In everyday life, the outcomes of our actions are rarely certain. Further, we often lack the information needed to precisely estimate the probability and value of potential outcomes as well as how much effort will be required by the courses of action under consideration. Under such conditions of uncertainty, individual differences in the estimation and weighting of these variables, and in reliance on model-free versus model-based decision making, have the potential to strongly influence our behavior. Both anxiety and depression are associated with difficulties in decision making. Further, anxiety is linked to increased engagement in threat-avoidance behaviors and depression is linked to reduced engagement in reward-seeking behaviors. The precise deficits, or biases, in decision making associated with these common forms of psychopathology remain to be fully specified. In this article, we review evidence for which of the computations supporting decision making are altered in anxiety and depression and consider the potential consequences for action selection. In addition, we provide a schematic framework that integrates the findings reviewed and will hopefully be of value to future studies.

Distinct frontal and amygdala correlates of change detection for facial identity and expression.

Recruitment of 'top-down' frontal attentional mechanisms is held to support detection of changes in task-relevant stimuli. Fluctuations in intrinsic frontal activity have been shown to impact task performance more generally. Meanwhile, the amygdala has been implicated in 'bottom-up' attentional capture by threat. Here, 22 adult human participants took part in a functional magnetic resonance change detection study aimed at investigating the correlates of successful (vs failed) detection of changes in facial identity vs expression. For identity changes, we expected prefrontal recruitment to differentiate 'hit' from 'miss' trials, in line with previous reports. Meanwhile, we postulated that a different mechanism would support detection of emotionally salient changes. Specifically, elevated amygdala activation was predicted to be associated with successful detection of threat-related changes in expression, over-riding the influence of fluctuations in top-down attention. Our findings revealed that fusiform activity tracked change detection across conditions. Ventrolateral prefrontal cortical activity was uniquely linked to detection of changes in identity not expression, and amygdala activity to detection of changes from neutral to fearful expressions. These results are consistent with distinct mechanisms supporting detection of changes in face identity vs expression, the former potentially reflecting top-down attention, the latter bottom-up attentional capture by stimulus emotional salience.

Functional Connectivity under Anticipation of Shock: Correlates of Trait Anxious Affect versus Induced Anxiety.

Sustained anxiety about potential future negative events is an important feature of anxiety disorders. In this study, we used a novel anticipation of shock paradigm to investigate individual differences in functional connectivity during prolonged threat of shock. We examined the correlates of between-participant differences in trait anxious affect and induced anxiety, where the latter reflects changes in self-reported anxiety resulting from the shock manipulation. Dissociable effects of trait anxious affect and induced anxiety were observed. Participants with high scores on a latent dimension of anxious affect showed less increase in ventromedial pFC-amygdala connectivity between periods of safety and shock anticipation. Meanwhile, lower levels of induced anxiety were linked to greater augmentation of dorsolateral pFC-anterior insula connectivity during shock anticipation. These findings suggest that ventromedial pFC-amygdala and dorsolateral pFC-insula networks might both contribute to regulation of sustained fear responses, with their recruitment varying independently across participants. The former might reflect an evolutionarily old mechanism for reducing fear or anxiety, whereas the latter might reflect a complementary mechanism by which cognitive control can be implemented to diminish fear responses generated due to anticipation of aversive stimuli or events. These two circuits might provide complementary, alternate targets for exploration in future pharmacological and cognitive intervention studies.

Seeing the world through non rose-colored glasses: anxiety and the amygdala response to blended expressions.

Anxious individuals have a greater tendency to categorize faces with ambiguous emotional expressions as fearful (Richards et al., 2002). These behavioral findings might reflect anxiety-related biases in stimulus representation within the human amygdala. Here, we used functional magnetic resonance imaging (fMRI) together with a continuous adaptation design to investigate the representation of faces from three expression continua (surprise-fear, sadness-fear, and surprise-sadness) within the amygdala and other brain regions implicated in face processing. Fifty-four healthy adult participants completed a face expression categorization task. Nineteen of these participants also viewed the same expressions presented using type 1 index 1 sequences while fMRI data were acquired. Behavioral analyses revealed an anxiety-related categorization bias in the surprise-fear continuum alone. Here, elevated anxiety was associated with a more rapid transition from surprise to fear responses as a function of percentage fear in the face presented, leading to increased fear categorizations for faces with a mid-way blend of surprise and fear. fMRI analyses revealed that high trait anxious participants also showed greater representational similarity, as indexed by greater adaptation of the Blood Oxygenation Level Dependent (BOLD) signal, between 50/50 surprise/fear expression blends and faces from the fear end of the surprise-fear continuum in both the right amygdala and right fusiform face area (FFA). No equivalent biases were observed for the other expression continua. These findings suggest that anxiety-related biases in the processing of expressions intermediate between surprise and fear may be linked to differential representation of these stimuli in the amygdala and FFA. The absence of anxiety-related biases for the sad-fear continuum might reflect intermediate expressions from the surprise-fear continuum being most ambiguous in threat-relevance.

Anxious individuals have difficulty learning the causal statistics of aversive environments.

Statistical regularities in the causal structure of the environment enable us to predict the probable outcomes of our actions. Environments differ in the extent to which action-outcome contingencies are stable or volatile. Difficulty in being able to use this information to optimally update outcome predictions might contribute to the decision-making difficulties seen in anxiety. We tested this using an aversive learning task manipulating environmental volatility. Human participants low in trait anxiety matched updating of their outcome predictions to the volatility of the current environment, as predicted by a Bayesian model. Individuals with high trait anxiety showed less ability to adjust updating of outcome expectancies between stable and volatile environments. This was linked to reduced sensitivity of the pupil dilatory response to volatility, potentially indicative of altered norepinephrinergic responsivity to changes in this aspect of environmental information.

Unraveling the anxious mind: anxiety, worry, and frontal engagement in sustained attention versus off-task processing.

Much remains unknown regarding the relationship between anxiety, worry, sustained attention, and frontal function. Here, we addressed this using a sustained attention task adapted for functional magnetic resonance imaging. Participants responded to presentation of simple stimuli, withholding responses to an infrequent "No Go" stimulus. Dorsolateral prefrontal cortex (DLPFC) activity to "Go" trials, and dorsal anterior cingulate (dACC) activity to "No Go" trials were associated with faster error-free performance; consistent with DLPFC and dACC facilitating proactive and reactive control, respectively. Trait anxiety was linked to reduced recruitment of these regions, slower error-free performance, and decreased frontal-thalamo-striatal connectivity. This indicates an association between trait anxiety and impoverished frontal control of attention, even when external distractors are absent. In task blocks where commission errors were made, greater DLPFC-precuneus and DLPFC-posterior cingulate connectivity were associated with both trait anxiety and worry, indicative of increased off-task thought. Notably, unlike trait anxiety, worry was not linked to reduced frontal-striatal-thalamo connectivity, impoverished frontal recruitment, or slowed responding during blocks without commission errors, contrary to accounts proposing a direct causal link between worry and impoverished attentional control. This leads us to propose a new model of the relationship between anxiety, worry and frontal engagement in attentional control versus off-task thought.

Moderate threat causes longer lasting disruption to processing in anxious individuals.

Anxiety is associated with increased attentional capture by threat. Previous studies have used simultaneous or briefly separated (<1 s) presentation of threat distractors and target stimuli. Here, we tested the hypothesis that high trait anxious participants would show a longer time window within which distractors cause disruption to subsequent task processing, and that this would particularly be observed for stimuli of moderate or ambiguous threat value. A novel temporally separated emotional distractor task was used. Face or house distractors were presented for 250 ms at short (∼1.6 s) or long (∼3 s) intervals prior to a letter string comprising Xs or Ns. Trait anxiety was associated with slowed identification of letter strings presented at long intervals after face distractors with part surprise/part fear expressions. In other words, these distractors had an impact on high anxious individuals' speed of target identification seconds after their offset. This was associated with increased activity in the fusiform gyrus and amygdala and reduced dorsal anterior cingulate recruitment. This pattern of activity may reflect impoverished recruitment of reactive control mechanisms to damp down stimulus-specific processing in subcortical and higher visual regions. These findings have implications for understanding how threat-related attentional biases in anxiety may lead to dysfunction in everyday settings where stimuli of moderate, potentially ambiguous, threat value such as those used here are fairly common, and where attentional disruption lasting several seconds may have a profound impact.

Resting state correlates of subdimensions of anxious affect.

Resting state fMRI may help identify markers of risk for affective disorder. Given the comorbidity of anxiety and depressive disorders and the heterogeneity of these disorders as defined by DSM, an important challenge is to identify alterations in resting state brain connectivity uniquely associated with distinct profiles of negative affect. The current study aimed to address this by identifying differences in brain connectivity specifically linked to cognitive and physiological profiles of anxiety, controlling for depressed affect. We adopted a two-stage multivariate approach. Hierarchical clustering was used to independently identify dimensions of negative affective style and resting state brain networks. Combining the clustering results, we examined individual differences in resting state connectivity uniquely associated with subdimensions of anxious affect, controlling for depressed affect. Physiological and cognitive subdimensions of anxious affect were identified. Physiological anxiety was associated with widespread alterations in insula connectivity, including decreased connectivity between insula subregions and between the insula and other medial frontal and subcortical networks. This is consistent with the insula facilitating communication between medial frontal and subcortical regions to enable control of physiological affective states. Meanwhile, increased connectivity within a frontoparietal-posterior cingulate cortex-precunous network was specifically associated with cognitive anxiety, potentially reflecting increased spontaneous negative cognition (e.g., worry). These findings suggest that physiological and cognitive anxiety comprise subdimensions of anxiety-related affect and reveal associated alterations in brain connectivity.

Fear-conditioning mechanisms associated with trait vulnerability to anxiety in humans.

Investigations of fear conditioning in rodents and humans have illuminated the neural mechanisms underlying cued and contextual fear. A critical question is how personality dimensions such as trait anxiety act through these mechanisms to confer vulnerability to anxiety disorders, and whether humans' ability to overcome acquired fears depends on regulatory skills not characterized in animal models. In a neuroimaging study of fear conditioning in humans, we found evidence for two independent dimensions of neurocognitive function associated with trait vulnerability to anxiety. The first entailed increased amygdala responsivity to phasic fear cues. The second involved impoverished ventral prefrontal cortical (vPFC) recruitment to downregulate both cued and contextual fear prior to omission (extinction) of the aversive unconditioned stimulus. These two dimensions may contribute to symptomatology differences across anxiety disorders; the amygdala mechanism affecting the development of phobic fear and the frontal mechanism influencing the maintenance of both specific fears and generalized anxiety.

Trait anxiety and impoverished prefrontal control of attention.

Many neurocognitive models of anxiety emphasize the importance of a hyper-responsive threat-detection system centered on the amygdala, with recent accounts incorporating a role for prefrontal mechanisms in regulating attention to threat. Here we investigated whether trait anxiety is associated with a much broader dysregulation of attentional control. Volunteers performed a response-conflict task under conditions that posed high or low demands on attention. High trait-anxious individuals showed reduced prefrontal activity and slower target identification in response to processing competition when the task did not fully occupy attentional resources. The relationship between trait anxiety and prefrontal recruitment remained after controlling for state anxiety. These findings indicate that trait anxiety is linked to impoverished recruitment of prefrontal attentional control mechanisms to inhibit distractor processing even when threat-related stimuli are absent. Notably, this deficit was observed when ongoing task-related demands on attention were low, potentially explaining the day-to-day difficulties in concentration that are associated with clinical anxiety.

Neural mechanisms underlying selective attention to threat.

Biased competition models of selective attention suggest that attentional competition is influenced both by bottom-up sensory mechanisms sensitive to stimulus salience and top-down control mechanisms that support the processing of task-relevant stimuli. This provides a framework for investigating the neural mechanisms underlying selective attention to threat. Both subcortical regions implicated in threat detection--specifically the amygdala--and prefrontal cortical regions implicated in top-down attentional control are activated in response to task-irrelevant threat stimuli. A number of questions including the automaticity of the amygdala response to threat distractors, the modulation by anxiety of the amygdala and prefrontal response to these stimuli, and the impact of genetic and environmental factors upon this circuitry are addressed. The empirical literature is considered in the context of theoretical accounts of the neural substrate of selective attention and conscious awareness. It is suggested that the neural activity provoked by a given visual stimulus is influenced by factors impacting upon the strength of the bottom-up trace (e.g., presentation time, backward masking), stimulus salience (including threat relatedness), competition with other visual stimuli for perceptual processing resources, and the augmentation of the stimulus trace by allocation of top-down attentional resources. Individual differences in trait and state anxiety, and in genetic makeup, are thought to modulate the influence of stimulus valence and top-down attention through their impact upon amygdala and prefrontal function.

COMT val158met genotype affects recruitment of neural mechanisms supporting fluid intelligence.

Fluid intelligence (g(f)) influences performance across many cognitive domains. It is affected by both genetic and environmental factors. Tasks tapping g(f) activate a network of brain regions including the lateral prefrontal cortex (LPFC), the presupplementary motor area/anterior cingulate cortex (pre-SMA/ACC), and the intraparietal sulcus (IPS). In line with the "intermediate phenotype" approach, we assessed effects of a polymorphism (val(158)met) in the catechol-O-methyltransferase (COMT) gene on activity within this network and on actual task performance during spatial and verbal g(f) tasks. COMT regulates catecholaminergic signaling in prefrontal cortex. The val(158) allele is associated with higher COMT activity than the met(158) allele. Twenty-two volunteers genotyped for the COMT val(158)met polymorphism completed high and low g(f) versions of spatial and verbal problem-solving tasks. Our results showed a positive effect of COMT val allele load upon the blood oxygen level-dependent response in LPFC, pre-SMA/ACC, and IPS during high g(f) versus low g(f) task performance in both spatial and verbal domains. These results indicate an influence of the COMT val(158)met polymorphism upon the neural circuitry supporting g(f). The behavioral effects of val allele load differed inside and outside the scanner, consistent with contextual modulation of the relation between COMT val(158)met genotype and g(f) task performance.

Neurocognitive mechanisms of anxiety: an integrative account.

Anxiety can be hugely disruptive to everyday life. Anxious individuals show increased attentional capture by potential signs of danger, and interpret expressions, comments and events in a negative manner. These cognitive biases have been widely explored in human anxiety research. By contrast, animal models have focused upon the mechanisms underlying acquisition and extinction of conditioned fear, guiding exposure-based therapies for anxiety disorders. Recent neuroimaging studies of conditioned fear, attention to threat and interpretation of emotionally ambiguous stimuli indicate common amygdala-prefrontal circuitry underlying these processes, and suggest that the balance of activity within this circuitry is altered in anxiety, creating a bias towards threat-related responses. This provides a focus for future translational research, and targeted pharmacological and cognitive interventions.

Neural processing of fearful faces: effects of anxiety are gated by perceptual capacity limitations.

Debate continues as to the automaticity of the amygdala's response to threat. Accounts taking a strong automaticity line suggest that the amygdala's response to threat is both involuntary and independent of attentional resources. Building on these accounts, prominent models have suggested that anxiety modulates the output of an amygdala-based preattentive threat evaluation system. Here, we argue for a modification of these models. Functional magnetic resonance imaging data were collected while volunteers performed a letter search task of high or low perceptual load superimposed on fearful or neutral face distractors. Neither high- nor low-anxious volunteers showed an increased amygdala response to threat distractors under high perceptual load, contrary to a strong automaticity account of amygdala function. Under low perceptual load, elevated state anxiety was associated with a heightened response to threat distractors in the amygdala and superior temporal sulcus, whereas individuals high in trait anxiety showed a reduced prefrontal response to these stimuli, consistent with weakened recruitment of control mechanisms used to prevent the further processing of salient distractors. These findings suggest that anxiety modulates processing subsequent to competition for perceptual processing resources, with state and trait anxiety having distinguishable influences upon the neural mechanisms underlying threat evaluation and "top-down" control.