Attentional bias to threat and gray matter volume morphology in high anxious individuals.

In a sample of highly anxious individuals, the relationship between gray matter volume brain morphology and attentional bias to threat was assessed. Participants performed a dot-probe task of attentional bias to threat and gray matter volume was acquired from whole brain structural T1-weighted magnetic resonance imaging scans. The results replicate previous findings in unselected samples that elevated attentional bias to threat is linked to greater gray matter volume in the middle frontal gyrus and superior frontal gyrus. In addition, we provide novel evidence that elevated attentional bias to threat is associated with greater gray matter volume in the inferior frontal gyrus, insula, cerebellum, and other distributed regions. Lastly, exploratory analyses provide initial evidence that distinct subregions of the right posterior parietal cortex may contribute to attentional bias in a sex-specific manner. Our results illuminate how differences in gray matter volume morphology relate to attentional bias to threat in anxious individuals. This knowledge could inform neurocognitive models of anxiety-related attentional bias to threat.

Sport-related concussion is associated with elevated anxiety, but not attentional bias to threat.

Primary Objective: Symptoms following concussion commonly include deficits in attentional processing and elevated anxiety. Prioritized allocation of attentional resources to threat-related information is referred to as attentional bias to threat, which is a cardinal symptom - and in some cases a causal factor in the development - of anxiety. Here, we aimed to assess two possibilities regarding the relationship between attentional bias and anxiety in the post-concussive phase of sport-related concussion: (1) attentional bias mediates the relationship between concussion and anxiety or (2) attentional bias and concussion are uniquely associated with anxiety.Research Design: A cross-sectional between-groups design was used to assess differences in anxiety and attentional bias to threat between collegiate athletes with a recent sport-related concussion and a matched control group.Methods and Procedures: Forty-two collegiate athletes, 21 with a sport-related concussion and 21 matched controls, completed the dot-probe task of attentional bias and an anxiety questionnaire.Main Outcomes and Results: Anxiety, but not attentional bias, is elevated in concussion. Additionally, concussion and attentional bias to threat appear to be uniquely associated with anxiety symptoms.Conclusions: Unique treatment/rehabilitation strategies should be considered for individuals with elevated anxiety following concussion.

Neural correlates of aversive anticipation: An activation likelihood estimate meta-analysis across multiple sensory modalities.

Anticipation is a universal preparatory response essential to the survival of an organism. Although meta-analytic synthesis of the literature exists for the anticipation of reward, a neuroimaging-based meta-analysis of the neural mechanisms of aversive anticipation is lacking. To address this gap in the literature, we ran an activation likelihood estimate (ALE) meta-analysis of 63 fMRI studies of aversive anticipation across multiple sensory modalities. Results of the ALE meta-analysis provide evidence for a core circuit involved in aversive anticipation, including the anterior insula, anterior cingulate cortex, mid-cingulate cortex, amygdala, thalamus, and caudate nucleus among other regions. Direct comparison of aversive anticipation studies using tactile versus visual stimuli identified additional regions involved in sensory specific aversive anticipation across these sensory modalities. Results from complementary multi-study voxel-wise and NeuroSynth analyses generally provide converging evidence for a core circuit involved in aversive anticipation. The multi-study voxel-wise analyses also implicate a more widespread preparatory response across sensory, motor, and cognitive control regions during more prolonged periods of aversive anticipation. The potential roles of these structures in anticipatory processing as well as avenues for future research are discussed.

Variability in anterior insula grey matter volume correlates with awareness for peri-threshold backward-masked fearful faces.

The threshold for conscious perception of stimuli within the environment varies from individual to individual. Functional neuroimaging studies have suggested that insular cortex activity is positively correlated with perceptual awareness. However, few studies have tested the relationship between awareness and structural variability in the insula. The purpose of this study was to examine structural differences in brain morphology related to perceptual awareness of fearful faces. This study hypothesized that there would be a positive correlation between insular grey matter volume and scores on the forced-choice awareness check task. The forced-choice awareness check task was designed to assess awareness for the presence and location of backward masked fearful and neutral faces, masked with neutral faces. The participants responded by indicating the side on which the masked fearful face appeared, or whether there were two neutral faces. The task included a total of 60 trials. T1-weighted magnetic resonance images were collected to measure grey matter volumes. Individuals that were more aware of backward masked fearful faces had greater grey matter volume in the insula, middle cingulate, anterior temporal pole, ventral striatum, and hippocampus.

Temporal dynamics in attention bias: effects of sex differences, task timing parameters, and stimulus valence.

New methods of calculating indices from the dot-probe task measure temporal dynamics in attention bias or fluctuations in attention bias towards and away from emotional stimuli over time. However, it is unclear how task-specific parameters such as stimulus valence and stimulus onset asynchrony (SOA) as well as participant sex affect temporal dynamics in attention bias. To address this, male and female participants (N = 106) completed either a fearful or happy face dot-probe task with four levels of SOA (84 ms, 168 ms, 336 ms, and 672 ms). Results suggest that temporal dynamics in attention bias are (1) greatest at the longest SOA, (2) greater in females, and (3) insensitive to stimulus valence. These findings indicate that participant sex and task timing, but not stimulus valence, are related to temporal dynamics in attention bias and should be considered in future studies utilizing this approach.

Extended testing with the dot-probe task increases test-retest reliability and validity.

The dot-probe task is used to measure attentional biases toward threat. However, the test-retest reliability and validity of the task have been called into question. No studies to date have included an extended number of testing sessions or tailored the task to individual participants by incorporating self-relevant stimuli-doing so may improve reliability. Here, participants provided 10 words that caused them anxiety and 10 neutral words which were incorporated into a dot-probe task for 6 sessions. The test-retest reliability of their bias indices was stronger in bottom-target trials relative to top-target trials and stronger among later relative to earlier sessions. State and trait anxiety were moderately correlated with bias indices in later sessions, but not earlier sessions. Overall reaction time in each session was moderately correlated with state and trait anxiety. These results suggest that including extended testing may facilitate dot-probe task test-retest reliability and validity.

Climate change images produce an attentional bias associated with pro-environmental disposition.

Humans have developed mechanisms to prioritize certain sensory input(s). Emotionally salient stimuli automatically capture observers' attention at the cost of less salient information. This prioritized processing is called attentional bias. Images of climate change have been found to elicit emotional responses. Yet, to date, there is no research assessing the extent to which climate change-relevant images produce an attentional bias. In a sample of college students (N = 39), we found that (1) climate change-related images capture attention and that (2) this attentional bias is related to individual differences in environmental disposition. Thus, images of climate change are salient-attention grabbing-signals related to pro-environmental orientation.

In the presence of conflicting gaze cues, fearful expression and eye-size guide attention.

Humans are social beings that often interact in multi-individual environments. As such, we are frequently confronted with nonverbal social signals, including eye-gaze direction, from multiple individuals. Yet, the factors that allow for the prioritisation of certain gaze cues over others are poorly understood. Using a modified conflicting gaze paradigm, we tested the hypothesis that fearful gaze would be favoured amongst competing gaze cues. We further hypothesised that this effect is related to the increased sclera exposure, which is characteristic of fearful expressions. Across three experiments, we found that fearful, but not happy, gaze guides observers' attention over competing non-emotional gaze. The guidance of attention by fearful gaze appears to be linked to increased sclera exposure. However, differences in sclera exposure do not prioritise competing gazes of other types. Thus, fearful gaze guides attention among competing cues and this effect is facilitated by increased sclera exposure - but increased sclera exposure per se does not guide attention. The prioritisation of fearful gaze over non-emotional gaze likely represents an adaptive means of selectively attending to survival-relevant spatial locations.

Acute psychological stress induces short-term variable immune response.

In spite of advances in understanding the cross-talk between the peripheral immune system and the brain, the molecular mechanisms underlying the rapid adaptation of the immune system to an acute psychological stressor remain largely unknown. Conventional approaches to classify molecular factors mediating these responses have targeted relatively few biological measurements or explored cross-sectional study designs, and therefore have restricted characterization of stress-immune interactions. This exploratory study analyzed transcriptional profiles and flow cytometric data of peripheral blood leukocytes with physiological (endocrine, autonomic) measurements collected throughout the sequence of events leading up to, during, and after short-term exposure to physical danger in humans. Immediate immunomodulation to acute psychological stress was defined as a short-term selective up-regulation of natural killer (NK) cell-associated cytotoxic and IL-12 mediated signaling genes that correlated with increased cortisol, catecholamines and NK cells into the periphery. In parallel, we observed down-regulation of innate immune toll-like receptor genes and genes of the MyD88-dependent signaling pathway. Correcting gene expression for an influx of NK cells revealed a molecular signature specific to the adrenal cortex. Subsequently, focusing analyses on discrete groups of coordinately expressed genes (modules) throughout the time-series revealed immune stress responses in modules associated to immune/defense response, response to wounding, cytokine production, TCR signaling and NK cell cytotoxicity which differed between males and females. These results offer a spring-board for future research towards improved treatment of stress-related disease including the impact of stress on cardiovascular and autoimmune disorders, and identifies an immune mechanism by which vulnerabilities to these diseases may be gender-specific.

Circuit-wide structural and functional measures predict ventromedial prefrontal cortex fear generalization: implications for generalized anxiety disorder.

The ventromedial prefrontal cortex (vmPFC) plays a critical role in a number of evaluative processes, including risk assessment. Impaired discrimination between threat and safety is considered a hallmark of clinical anxiety. Here, we investigated the circuit-wide structural and functional mechanisms underlying vmPFC threat-safety assessment in humans. We tested patients with generalized anxiety disorder (GAD; n = 32, female) and healthy controls (n = 25, age-matched female) on a task that assessed the generalization of conditioned threat during fMRI scanning. The task consisted of seven rectangles of graded widths presented on a screen; only the midsize one was paired with mild electric shock [conditioned stimulus (CS)], while the others, safety cues, systematically varied in width by ±20, 40, and 60% [generalization stimuli (GS)] compared with the CS. We derived an index reflecting vmPFC functioning from the BOLD reactivity on a continuum of threat (CS) to safety (GS least similar to CS); patients with GAD showed less discrimination between threat and safety cues, compared with healthy controls (Greenberg et al., 2013b). Using structural, functional (i.e., resting-state), and diffusion MRI, we measured vmPFC thickness, vmPFC functional connectivity, and vmPFC structural connectivity within the corticolimbic systems. The results demonstrate that all three factors predict individual variability of vmPFC threat assessment in an independent fashion. Moreover, these neural features are also linked to GAD, most likely via an vmPFC fear generalization. Our results strongly suggest that vmPFC threat processing is closely associated with broader corticolimbic circuit anomalies, which may synergistically contribute to clinical anxiety.

Hyper-reactive human ventral tegmental area and aberrant mesocorticolimbic connectivity in overgeneralization of fear in generalized anxiety disorder.

The ventral tegmental area (VTA) has been primarily implicated in reward-motivated behavior. Recently, aberrant dopaminergic VTA signaling has also been implicated in anxiety-like behaviors in animal models. These findings, however, have yet to be extended to anxiety in humans. Here we hypothesized that clinical anxiety is linked to dysfunction of the mesocorticolimbic circuit during threat processing in humans; specifically, excessive or dysregulated activity of the mesocorticolimbic aversion circuit may be etiologically related to errors in distinguishing cues of threat versus safety, also known as "overgeneralization of fear." To test this, we recruited 32 females with generalized anxiety disorder and 25 age-matched healthy control females. We measured brain activity using fMRI while participants underwent a fear generalization task consisting of pseudo-randomly presented rectangles with systematically varying widths. A mid-sized rectangle served as a conditioned stimulus (CS; 50% electric shock probability) and rectangles with widths of CS ±20%, ±40%, and ±60% served as generalization stimuli (GS; never paired with electric shock). Healthy controls showed VTA reactivity proportional to the cue's perceptual similarity to CS (threat). In contrast, patients with generalized anxiety disorder showed heightened and less discriminating VTA reactivity to GS, a feature that was positively correlated with trait anxiety, as well as increased mesocortical and decreased mesohippocampal coupling. Our results suggest that the human VTA and the mesocorticolimbic system play a crucial role in threat processing, and that abnormalities in this system are implicated in maladaptive threat processing in clinical anxiety.

Influence of the BDNF genotype on amygdalo-prefrontal white matter microstructure is linked to nonconscious attention bias to threat.

Cognitive processing biases, such as increased attention to threat, are gaining recognition as causal factors in anxiety. Yet, little is known about the anatomical pathway by which threat biases cognition and how genetic factors might influence the integrity of this pathway, and thus, behavior. For 40 normative adults, we reconstructed the entire amygdalo-prefrontal white matter tract (uncinate fasciculus) using diffusion tensor weighted MRI and probabilistic tractography to test the hypothesis that greater fiber integrity correlates with greater nonconscious attention bias to threat as measured by a backward masked dot-probe task. We used path analysis to investigate the relationship between brain-derived nerve growth factor genotype, uncinate fasciculus integrity, and attention bias behavior. Greater structural integrity of the amygdalo-prefrontal tract correlates with facilitated attention bias to nonconscious threat. Genetic variability associated with brain-derived nerve growth factor appears to influence the microstructure of this pathway and, in turn, attention bias to nonconscious threat. These results suggest that the integrity of amygdalo-prefrontal projections underlie nonconscious attention bias to threat and mediate genetic influence on attention bias behavior. Prefrontal cognition and attentional processing in high bias individuals appear to be heavily influenced by nonconscious threat signals relayed via the uncinate fasciculus.

Reward dysfunction in major depression: multimodal neuroimaging evidence for refining the melancholic phenotype.

Reward dysfunction is thought to play a core role in the pathophysiology of major depressive disorder (MDD). Event-related potential (ERP) and functional magnetic resonance imaging (fMRI) studies have identified reward processing deficits in MDD, but these methods have yet to be applied together in a single MDD sample. We utilized multimodal neuroimaging evidence to examine reward dysfunction in MDD. Further, we explored how neurobiological reward dysfunction would map onto subtypes of MDD. The feedback negativity (FN), an ERP index of reward evaluation, was recorded in 34 unmedicated depressed individuals and 42 never-depressed controls during a laboratory gambling task. Ventral striatal (VS) activation to reward was recorded in a separate fMRI session, using an identical task, among a subgroup of 24 depressed individuals and a comparison group of 18 non-depressed controls. FN amplitude was blunted in MDD. This effect was driven by a MDD subgroup characterized by impaired mood reactivity to positive events, a core feature of melancholic MDD. A similar pattern was observed for VS activation, which was also blunted among the MDD subgroup with impaired mood reactivity. Neither FN amplitude nor VS activation was related to the full, DSM-defined melancholic or atypical MDD subtypes. Across the MDD sample, FN amplitude and VS activation were correlated, indicating convergence across methods. These results indicate that not all MDD is characterized by reward dysfunction, and that there is meaningful heterogeneity in reward processing within MDD. The current study offers neurobiological evidence that impaired mood reactivity is a key phenotypic distinction for subtyping MDD, and further suggests that the existing melancholic phenotype may require further refinement.

The fine line between 'brave' and 'reckless': amygdala reactivity and regulation predict recognition of risk.

BACKGROUND: High sensation-seekers (HSS) pursue novelty even at the cost of self-harm. When challenged, HSS are less anxious, show blunted physiological (cortisol, startle) and neurobiological (prefrontal-limbic) responses, and devalue aversive outcomes. Here, we investigate how these features interact under conditions of physical danger, in distinguishing between adaptive and maladaptive approaches to risk. METHODS: We recruited a cohort of individuals who voluntarily sought out recreational exposure to physical risk, and obtained serial cortisol values over two time-locked days. On the 'baseline' day, we scanned subjects' brains with functional and structural MRI; on the 'skydiving day,' subjects completed a first-time tandem skydive. During neuroimaging, subjects viewed cues that predicted aversive noise; neural data were analyzed for prefrontal-limbic reactivity (activation) and regulation (non-linear complexity), as well as cortical thickness. To probe threat perception, subjects identified aggression for ambiguous faces morphed between neutral and angry poles. RESULTS: Individuals with prefrontal-limbic meso-circuits with less balanced regulation between excitatory and inhibitory components showed both diminished cortisol/anxiety responses to their skydives, as well as less accurate perceptual recognition of threat. This impaired control was localized to the inferior frontal gyrus, with associated cortical thinning. Structural equation modeling suggests that sensation-seeking is primarily mediated via threat-perception, which itself is primarily mediated via neural reactivity and regulation. CONCLUSIONS: Our results refine the sensation-seeking construct to provide important distinctions (brain-based, but with endocrine and cognitive consequences) between the brave, who feel fear but nonetheless overcome it, and the reckless, who fail to recognize danger. This distinction has important real-world implications, as those who fail to recognize risk are less likely to mitigate it.

Attending to the fear in your eyes: facilitated orienting and delayed disengagement.

Fearful facial expressions convey threat-related information and automatically elicit modulations in spatial attention. The eye-region appears to be a particularly important feature for recognising and responding to fearful faces. However, it is unknown as to whether or not fearful eyes initiate modulations in spatial attention. In the current study, three dot-probe experiments with fearful and neutral eye stimuli were performed. The results of Experiment 1 demonstrate that fearful eyes capture spatial attention through facilitated attentional orienting to threat and delayed attentional disengagement from threat. In Experiments 2 and 3, these attentional effects were replicated, while ruling out the influence of overall size/shape and brightness differences between fearful and neutral eyes, respectively. Thus, fearful eye-whites appear to be a salient feature of fearful facial expressions that elicit modulations in spatial attention.

Climate change on the brain: Neural correlates of climate anxiety.

Climate change is a global crisis impacting individuals' mental health. Climate anxiety is an emerging area of interest within popular culture and the scientific community. Yet, little is known about the mechanisms underlying climate anxiety. We provide evidence that climate anxiety is related to gray matter volume in the midcingulate cortex as well as its level of functional connectivity with the insula cortex. These neuroanatomical and neurofunctional features of climate anxiety are involved in identifying and anticipating potential threats within the environment and preparing an appropriate action response to such threats. These neural correlates align with those observed in anxiety disorders. Yet, climate anxiety itself as well as the neural correlates of climate anxiety were related to pro-environmental behavior. This may suggest that the midcingulate and insula are part of a network linked to an adaptive aspect of climate anxiety in motivating behavioral engagement.

Ventromedial prefrontal cortex reactivity is altered in generalized anxiety disorder during fear generalization.

BACKGROUND: Fear generalization is thought to contribute to the development and maintenance of anxiety symptoms and accordingly has been the focus of recent research. Previously, we reported that in healthy individuals (N = 25) neural reactivity in the insula, anterior cingulate cortex (ACC), supplementary motor area (SMA), and caudate follow a generalization gradient with a peak response to a conditioned stimulus (CS) that declines with greater perceptual dissimilarity of generalization stimuli (GS) to the CS. In contrast, reactivity in the ventromedial prefrontal cortex (vmPFC), a region linked to fear inhibition, showed an opposite response pattern. The aim of the current study was to examine whether neural responses to fear generalization differ in generalized anxiety disorder (GAD). A second aim was to examine connectivity of primary regions engaged by the generalization task in the GAD group versus healthy group, using psychophysiological interaction analysis. METHODS: Thirty-two women diagnosed with GAD were scanned using the same generalization task as our healthy group. RESULTS: Individuals with GAD exhibited a less discriminant vmPFC response pattern suggestive of deficient recruitment of vmPFC during fear inhibition. Across participants, there was enhanced anterior insula (aINS) coupling with the posterior insula, ACC, SMA, and amygdala during presentation of the CS, consistent with a modulatory role for the aINS in the execution of fear responses. CONCLUSIONS: These findings suggest that deficits in fear regulation, rather than in the excitatory response itself, are more critical to the pathophysiology of GAD in the context of fear generalization.

The gray matter morphology associated with the electrophysiological response to errors in individuals with high trait anxiety.

Enhanced error monitoring has been associated with higher levels of anxiety. This has been consistently demonstrated in its most reliable electrophysiological index, the error-related negativity (ERN), such that increased ERN is related with elevated anxiety symptomology. However, it is still unclear whether the structural properties of the brain are associated with individual differences in ERN amplitude. Moreover, the relationship between ERN and anxiety has recently been suggested to be moderated by sex, but the degree to which sex moderates the association between brain structure and ERN amplitude is unknown. The present study investigated the association between gray matter volume (GMV) and ERN amplitude in individuals with high trait anxiety (N = 98) as well as the role of sex in moderating this association. The ERN was elicited from a flanker task, whereas structural MRI images were obtained from whole brain structural T1-weighted MRI scans. The results of voxel-based morphometry analyses showed that the relationship between ERN difference scores and GMV was moderated by sex in the dorsal anterior cingulate cortex (dACC). This sex difference was derived from a negative correlation between ERN difference scores and dACC GMV in females and a positive correlation in males. Our findings are in accordance with the critical role of the dACC serving as a neural substrate of error monitoring. It also provides further evidence for sex-specific associations with brain structures related to error monitoring.

Eye-size effects in the dot-probe task: Greater sclera exposure predicts delayed disengagement from fearful faces.

Fearful facial expressions are nonverbal and biologically salient signals of potential threat that automatically hold, capture, and direct observers' attention. They are characterized by enlarged eye whites and dilated pupils, and fearful eyes alone are sufficient to capture attention. The morphological properties of the eye region, such as sclera exposure, are thought to play an important role in nonverbal communication. Specifically, increased sclera exposure associated with fearful expressions has been shown to moderate how observers' shift their attention toward the direction of another's gaze. Yet, the extent to which variability in sclera exposure possibly impacts the capture and hold of attention by fearful faces is untested. To address this, a sample of 249 adults completed a dot-probe task of selective attention with fearful and neutral faces. The results suggested that (1) fearful faces were prioritized over neutral faces (i.e., they captured and held attention), (2) greater sclera exposure at target locations facilitated reaction times, and (3) attention was held by greater sclera exposure of fearful faces at task irrelevant locations resulting in delayed disengagement. Collectively, the results indicate that fearful facial expressions and sclera exposure modulate spatial attention through independent and interactive mechanisms. Sclera exposure appears to be an important facilitator of nonverbal communication and perhaps represents an understudied variable in social cognition more broadly.

Nonconscious attention bias to threat is correlated with anterior cingulate cortex gray matter volume: a voxel-based morphometry result and replication.

An important aspect of the fear response is the allocation of spatial attention toward threatening stimuli. This response is so powerful that modulations in spatial attention can occur automatically without conscious awareness. Functional neuroimaging research suggests that the amygdala and anterior cingulate cortex (ACC) form a network involved in the rapid orienting of attention to threat. A hyper-responsive attention bias to threat is a common component of anxiety disorders. Yet, little is known of how individual differences in underlying brain morphometry relate to variability in attention bias to threat. Here, we performed two experiments using dot-probe tasks that measured individuals' attention bias to backward masked fearful faces. We collected whole-brain structural magnetic resonance images and used voxel-based morphometry to measure brain morphometry. We tested the hypothesis that reduced gray matter within the amygdala and ACC would be associated with reduced attention bias to threat. In Experiment 1, we found that backward masked fearful faces captured spatial attention and that elevated attention bias to masked threat was associated with greater ACC gray matter volumes. In Experiment 2, this association was replicated in a separate sample. Thus, we provide initial and replicating evidence that ACC gray matter volume is correlated with biased attention to threat. Importantly, we demonstrate that variability in affective attention bias within the healthy population is associated with ACC morphometry. This result opens the door for future research into the underlying brain morphometry associated with attention bias in clinically anxious populations.