Neural correlates of fear: insights from neuroimaging

Fear anticipates a challenge to one's well-being and is a reaction to the risk of harm. The expression of fear in the individual is a constellation of physiological, behavioral, cognitive, and experiential responses. Fear indicates risk and will guide adaptive behavior, yet fear is also fundamental to the symptomatology of most psychiatric disorders. Neuroimaging studies of normal and abnormal fear in humans extend knowledge gained from animal experiments. Neuroimaging permits the empirical evaluation of theory (emotions as response tendencies, mental states, and valence and arousal dimensions), and improves our understanding of the mechanisms of how fear is controlled by both cognitive processes and bodily states. Within the human brain, fear engages a set of regions that include insula and anterior cingulate cortices, the amygdala, and dorsal brain-stem centers, such as periaqueductal gray matter. This same fear matrix is also implicated in attentional orienting, mental planning, interoceptive mapping, bodily feelings, novelty and motivational learning, behavioral prioritization, and the control of autonomic arousal. The stereotyped expression of fear can thus be viewed as a special construction from combinations of these processes. An important motivator for understanding neural fear mechanisms is the debilitating clinical expression of anxiety. Neuroimaging studies of anxiety patients highlight the role of learning and memory in pathological fear. Posttraumatic stress disorder is further distinguished by impairment in cognitive control and contextual memory. These processes ultimately need to be targeted for symptomatic recovery. Neuroscientific knowledge of fear has broader relevance to understanding human and societal behavior. As yet, only some of the insights into fear, anxiety, and avoidance at the individual level extrapolate to groups and populations and can be meaningfully applied to economics, prejudice, and politics. Fear is ultimately a contagious social emotion

Neural mediators of subjective and autonomic responding during threat learning and regulation

Threat learning elicits robust changes across multiple affective domains, including changes in autonomic indices and subjective reports of fear and anxiety. It has been argued that the underlying causes of such changes may be dissociable at a neural level, but there is currently limited evidence to support this notion. To address this, we examined the neural mediators of trial-by-trial skin conductance responses (SCR), and subjective reports of anxious arousal and valence in participants (n = 27; 17 females) performing a threat reversal task during ultra-high field functional magnetic resonance imaging. This allowed us to identify brain mediators during initial threat learning and subsequent threat reversal. Significant neural mediators of anxious arousal during threat learning included the dorsal anterior cingulate, anterior insula cortex (AIC), and ventromedial prefrontal cortex (vmPFC), subcortical regions including the amygdala, ventral striatum, caudate and putamen, and brain-stem regions including the pons and midbrain. By comparison, autonomic changes (SCR) were mediated by a subset of regions embedded within this broader circuitry that included the caudate, putamen and thalamus, and two distinct clusters within the vmPFC. The neural mediators of subjective negative valence showed prominent effects in posterior cortical regions and, with the exception of the AIC, did not overlap with threat learning task effects. During threat reversal, positive mediators of both subjective anxious arousal and valence mapped to the default mode network; this included the vmPFC, posterior cingulate, temporoparietal junction, and angular gyrus. Decreased SCR during threat reversal was positively mediated by regions including the mid cingulate, AIC, two sub-regions of vmPFC, the thalamus, and the hippocampus. Our findings add novel evidence to support distinct underlying neural processes facilitating autonomic and subjective responding during threat learning and threat reversal. The results suggest that the brain systems engaged in threat learning mostly capture the subjective (anxious arousal) nature of the learning process, and that appropriate responding during threat reversal is facilitated by participants engaging self- and valence-based processes. Autonomic changes (SCR) appear to involve distinct facilitatory and regulatory contributions of vmPFC sub-regions

Adaptive contextualization: A new role for the default mode network in affective learning.

Safety learning describes the ability to learn that certain cues predict the absence of a dangerous or threatening event. Although incidental observations of activity within the default mode network (DMN) during the processing of safety cues have been reported previously, there is as yet no evidence demonstrating that the DMN plays a functional rather than a corollary role in safety learning. Using functional magnetic resonance imaging and a Pavlovian fear conditioning and extinction paradigm, we investigated the neural correlates of danger and safety learning. Our results provide evidence for a functional role of the DMN by showing that (i) the DMN is activated by safety but not danger cues, (ii) the DMN is anti-correlated with a fear-processing network, and (iii) DMN activation increases with safety learning. Based on our results, we formulate a novel proposal, arguing that activity within the DMN supports the contextualization of safety memories, constrains the generalization of fear, and supports adaptive fear learning. Our findings have important implications for our understanding of affective and stress disorders, which are characterized by aberrant DMN activity, as they suggest that therapies targeting the DMN through mindfulness practice or brain stimulation might help prevent pathological over-generalization of fear associations. Hum Brain Mapp 38:1082-1091, 2017. © 2016 Wiley Periodicals, Inc

Sleep-amount differentially affects fear-processing neural circuitry in pediatric anxiety: A preliminary fMRI investigation.

Insufficient sleep, as well as the incidence of anxiety disorders, both peak during adolescence. While both conditions present perturbations in fear-processing-related neurocircuitry, it is unknown whether these neurofunctional alterations directly link anxiety and compromised sleep in adolescents. Fourteen anxious adolescents (AAs) and 19 healthy adolescents (HAs) were compared on a measure of sleep amount and neural responses to negatively valenced faces during fMRI. Group differences in neural response to negative faces emerged in the dorsal anterior cingulate cortex (dACC) and the hippocampus. In both regions, correlation of sleep amount with BOLD activation was positive in AAs, but negative in HAs. Follow-up psychophysiological interaction (PPI) analyses indicated positive connectivity between dACC and dorsomedial prefrontal cortex, and between hippocampus and insula. This connectivity was correlated negatively with sleep amount in AAs, but positively in HAs. In conclusion, the presence of clinical anxiety modulated the effects of sleep-amount on neural reactivity to negative faces differently among this group of adolescents, which may contribute to different clinical significance and outcomes of sleep disturbances in healthy adolescents and patients with anxiety disorders

The uncertain brain: a co-ordinate based meta-analysis of the neural signatures supporting uncertainty during different contexts

Uncertainty is often inevitable in everyday life and can be both stressful and exciting. Given its relevance to psychopathology and wellbeing, recent research has begun to address the brain basis of uncertainty. In the current review we examined whether there are discrete and shared neural signatures for different uncertain contexts. From the literature we identified three broad categories of uncertainty currently empirically studied using functional MRI (fMRI): basic threat and reward uncertainty, decision-making under uncertainty, and associative learning under uncertainty. We examined the neural basis of each category by using a coordinate based metaanalysis, where brain activation foci from previously published fMRI experiments were drawn together (1998-2017; 87 studies). The analyses revealed shared and discrete patterns of neural activation for uncertainty, such as the insula and amygdala, depending on the category. Such findings will have relevance for researchers attempting to conceptualise uncertainty, as well as clinical researchers examining the neural basis of uncertainty in relation to psychopathology

Linked networks for learning and expressing location-specific threat

Learning locations of danger within our environment is a vital adaptive ability whose neural bases are only partially understood. We examined fMRI brain activity while participants navigated a virtual environment in which flowers appeared and were “picked.” Picking flowers in the danger zone (one-half of the environment) predicted an electric shock to the wrist (or “bee sting”); flowers in the safe zone never predicted shock; and household objects served as controls for neutral spatial memory. Participants demonstrated learning with shock expectancy ratings and skin conductance increases for flowers in the danger zone. Patterns of brain activity shifted between overlapping networks during different task stages. Learning about environmental threats, during flower approach in either zone, engaged the anterior hippocampus, amygdala, and ventromedial prefrontal cortex (vmPFC), with vmPFC–hippocampal functional connectivity increasing with experience. Threat appraisal, during approach in the danger zone, engaged the insula and dorsal anterior cingulate (dACC), with insula–hippocampal functional connectivity. During imminent threat, after picking a flower, this pattern was supplemented by activity in periaqueductal gray (PAG), insula–dACC coupling, and posterior hippocampal activity that increased with experience. We interpret these patterns in terms of multiple representations of spatial context (anterior hippocampus); specific locations (posterior hippocampus); stimuli (amygdala); value (vmPFC); threat, both visceral (insula) and cognitive (dACC); and defensive behaviors (PAG), interacting in different combinations to perform the functions required at each task stage. Our findings illuminate how we learn about location-specific threats and suggest how they might break down into overgeneralization or hypervigilance in anxiety disorders

The influence of social signals on the self-experience of pain: A neuroimaging review

Researchers in cognitive neuroscience have investigated extensively how psychological factors shape the processing and perception of pain using behavioral, physiological, and neuroimaging methods. However, social influences of pain, an essential part of biopsychosocial pain models, have received relatively little attention. This is particularly true for the neurobiological mechanisms underlying social modulations on pain. Therefore, this review discusses the findings of recent neuroimaging studies measuring the effects of social manipulations on pain perception (e.g., verbal and non-verbal social signals, social interaction style, conformity, social support, and sociocultural mediators). Finally, a schematic summary of the different social modulatory themes is presented