Distributed and Multifaceted Effects of Threat and Safety

In the present fMRI study, we examined how anxious apprehension is processed in the human brain. A central goal of the study was to test the prediction that a subset of brain regions would exhibit sustained response profiles during threat periods, including the anterior insula, a region implicated in anxiety disorders. A second important goal was to evaluate the responses in the amygdala and the bed nucleus of the stria terminals, regions that have been suggested to be involved in more transient and sustained threat, respectively. A total of 109 participants performed an experiment in which they encountered “threat” or “safe” trials lasting approximately 16 sec. During the former, they experienced zero to three highly unpleasant electrical stimulations, whereas in the latter, they experienced zero to three benign electrical stimulations (not perceived as unpleasant). The timing of the stimulation during trials was randomized, and as some trials contained no stimulation, stimulation delivery was uncertain. We contrasted responses during threat and safe trials that did not contain electrical stimulation, but only the potential that unpleasant (threat) or benign (safe) stimulation could occur. We employed Bayesian multilevel analysis to contrast responses to threat and safe trials in 85 brain regions implicated in threat processing. Our results revealed that the effect of anxious apprehension is distributed across the brain and that the temporal evolution of the responses is quite varied, including more transient and more sustained profiles, as well as signal increases and decreases with threat.

Callous-Unemotional Traits Moderate the Relationship Between Irritability and Threatening Responding

Background: Irritability and callous-unemotional (CU; reduced guilt/empathy) traits vary dimensionally in the typically developing population but may be particularly marked in youth with conduct disorder (CD). While these dimensional traits are positively correlated, they have been associated with divergent forms of dysfunction, particularly with respect to threat processing (i.e., irritability with increased, and CU traits with decreased, threat responsiveness). This suggests that interactions between these two dimensions may be complex at the neurobiological level. However, this issue has received minimal empirical attention.Methods: The study included 105 adolescents (typically developing and cases with CD; N = 59). They were scanned with fMRI during a looming threat task that involved images of threatening and neutral human faces or animals that appeared to be either looming or receding.Results: Significant irritability-by-CU traits-by-Direction-by-Emotion interactions were seen within right thalamus/PAG, left lingual gyrus and right fusiform gyrus; irritability was positively associated with the BOLD response for Looming Threatening vs. Receding Threatening trials, particularly for youth with low CU traits. In contrast, CU traits were negatively associated with the same differential BOLD response but particularly for youth showing higher levels of irritability. Similar findings were seen within left ventral anterior and posterior cingulate cortices, though the addition of the interaction with CU traits was only seen at slightly more lenient thresholds.Conclusions: The results support previous work linking irritability to increased, and CU traits to reduced, threat responsiveness. However, for adolescents with high irritability, if CU traits are also high, the underlying neuropathology appears to relate to reduced, rather than increased, threat responsiveness.

How Multi-Sensory Animal Embodiment in Virtual Reality Influences Environmental Threat Processing and Conservation Behaviors

Efforts to mitigate environmental threats are often inversely related to the magnitude of casualty, human or otherwise1–3. This “compassion fade” can be explained, in part, by differential processing of large- versus small-scale threats: it is difficult to form empathic connections with unfamiliar masses versus singular victims4. Despite robust findings, little is known about how non-human casualty is processed, and what strategies override this bias. Over four experiments, we show how embodying threatened megafauna – Loggerhead sea turtles (Caretta Caretta) – in virtual reality can offset and reverse compassion fade. After observing compassion fade during exposure to mass non-human casualty in virtual reality (Study 1; N=60), we then tested a custom multi-sensory virtual reality simulation facilitating embodiment of a threatened Loggerhead (Study 2; N=98). Afterwards, a field experiment (Study 3; N=90) testing the simulation with varied number of victims showed embodiment offset compassion fade. Lastly, a fourth study (N=25) found that charitable giving among users embodying threatened wildlife was highest when exposed to one versus many victims, though this effect was reversed if victims were of a different species (Dolphins). The findings demonstrate how animal embodiment in virtual reality alters processing of environmental threats and non-human casualty, thereby influencing biodiversity conservation outcomes.

Distinctive Regulation of Emotional Behaviors and Fear-Related Gene Expression Responses in Two Extended Amygdala Subnuclei With Similar Molecular Profiles

The central nucleus of the amygdala (CeA) and the lateral division of the bed nucleus of the stria terminalis (BNST) are the two major nuclei of the central extended amygdala that plays essential roles in threat processing, responsible for emotional states such as fear and anxiety. While some studies suggested functional differences between these nuclei, others showed anatomical and neurochemical similarities. Despite their complex subnuclear organization, subnuclei-specific functional impact on behavior and their underlying molecular profiles remain obscure. We here constitutively inhibited neurotransmission of protein kinase C-δ-positive (PKCδ+) neurons—a major cell type of the lateral subdivision of the CeA (CeL) and the oval nucleus of the BNST (BNSTov)—and found striking subnuclei-specific effects on fear- and anxiety-related behaviors, respectively. To obtain molecular clues for this dissociation, we conducted RNA sequencing in subnuclei-targeted micropunch samples. The CeL and the BNSTov displayed similar gene expression profiles at the basal level; however, both displayed differential gene expression when animals were exposed to fear-related stimuli, with a more robust expression change in the CeL. These findings provide novel insights into the molecular makeup and differential engagement of distinct subnuclei of the extended amygdala, critical for regulation of threat processing.

Social Housing Status Impacts Rhesus Monkeys' Affective Responding in Classic Threat Processing Tasks

The established literature clearly demonstrates that whether or not monkeys are socially reared has long term consequences for their affective behavior. Yet, in the context of behavioral neuroscience and pharmacological studies, social context of adult animals is often ignored. When social context has been studied in adult monkeys, such studies have typically focused on welfare-related issues, as social isolation often leads to the development of abnormal behavior, rather than the impact on outcomes in behavioral neuroscience studies. Variation in social housing conditions for adult animals could have an impact on affective responding and may have significant implications for the interpretation of data from biopsychiatry and behavioral neuroscience studies. We evaluated the affective reactivity of rhesus monkeys (Macaca mulatta) maintained in one of four housing conditions (individually-housed, grate-paired, intermittently-paired, and continuously-paired) using two classic threat processing tasks: a test of responsivity to objects and the Human Intruder Test. Individually-housed monkeys exhibited consistently blunted sensitivity to ostensibly threatening stimuli as compared to socially-housed monkeys. Within the three socially-housed conditions, intermittently- and continuously-paired monkeys behaved similarly to each other and grate-paired monkeys exhibited relatively enhanced sensitivity to threatening stimuli. These findings suggest that the adult housing conditions of monkeys can robustly modulate affective responding in a way that may be consistent with behavioral phenotypes observed in human psychiatric conditions. Results are considered in the context of the broad behavioral and psychiatric neuroscience literatures, which have historically used individually-housed animals, pointing to the potential need to reconsider inferences drawn from those studies.

041 Alteration of Threat-Related Information Processing During Extended Sleep Deprivation

Introduction Threat-related information is preferentially processed, facilitating quick and efficient responses. However, the impact of extended sleep deprivation on perception of and response to threatening information is not well known. Sleep loss may increase amygdalar activity and negative mood, potentially facilitating threat processing. However, it also reduces cognitive function, possibly impairing ability to respond. The present study assessed the extent to which extended sleep deprivation modulates threat processing using a threat expectation paradigm. Methods Twenty-one participants underwent one baseline night of sleep followed by 62hrs total sleep deprivation (TSD) and one recovery night of sleep (12hrs). Threat expectation task performance was assessed at baseline, at multiple time points during TSD, and following recovery sleep. To control for circadian influence, performance at three 1100 sessions (baseline, 52hrs into TSD, and recovery) were compared. The threat expectation task involved determining whether a presented face was fearful (i.e., signaled threat) or neutral. Faces were presented at three expectation levels: 80%, 50%, and 20% chance of viewing a fearful face. Results Overall, responses were faster (F=9.77, p=0.001) and more accurate (F=11.48, p=0.001) when the type of face (fearful or neutral) was expected. Accuracy significantly decreased over TSD (t=7.71, p<0.001) and recovered following subsequent sleep. Fear bias was calculated for accuracy (accuracy for fearful face minus neutral face). Under conditions of high expectation (80%) of viewing a fearful face, fear bias increased across TSD (t=-1.95, p=0.07). Although accuracy to both fearful and neutral faces significantly declined across TSD (both p<0.001), decline for neutral faces was greater, thus increasing fear bias. Importantly, the increased bias toward fear was still evident compared to baseline following a 12-hour recovery sleep opportunity, (t=-1.93, p=0.07). Conclusion Extended sleep deprivation, common in operational environments where there is also high expectation of encountering threat, impairs cognitive control and is thought to enhance amygdala activity. These data show that, consequently, cognitive resources become biased toward biologically adaptive behaviors (i.e., threat processing) at the expense of attending and responding more broadly to all stimuli. This behavior is not reversed with a single extended sleep opportunity. Support (if any) Department of Defense Military Operational Medicine Research Program (MOMRP)