F. Caroline Davis

Anxiety Dissociates Dorsal and Ventral Medial Prefrontal Cortex Functional Connectivity with the Amygdala at Rest

Anxiety is linked to compromised interactions between the amygdala and the dorsal and ventral medial prefrontal cortex (mPFC). While numerous task-based neuroimaging studies show that anxiety levels predict amygdala-mPFC connectivity and response magnitude, here we tested the hypothesis that anxiety would predict functional connectivity between these brain regions even during rest. Resting-state functional magnetic resonance imaging scans and self-reported measures of anxiety were acquired from healthy subjects. At rest, individuals with high anxiety were characterized by negatively correlated amygdala-ventral mPFC functional connectivity, while low anxious subjects showed positively correlated activity. Further, high anxious subjects showed amygdala-dorsal mPFC activity that was uncorrelated, while low anxious subjects showed negatively correlated activity. These data show that amygdala-mPFC connectivity at rest indexes normal individual differences in anxiety.

From Pavlov to PTSD: the extinction of conditioned fear in rodents, humans, and anxiety disorders.

Nearly 100 years ago, Ivan Pavlov demonstrated that dogs could learn to use a neutral cue to predict a biologically relevant event: after repeated predictive pairings, Pavlovs dogs were conditioned to anticipate food at the sound of a bell, which caused them to salivate. Like sustenance, danger is biologically relevant, and neutral cues can take on great salience when they predict a threat to survival. In anxiety disorders such as posttraumatic stress disorder (PTSD), this type of conditioned fear fails to extinguish, and reminders of traumatic events can cause pathological conditioned fear responses for decades after danger has passed. In this review, we use fear conditioning and extinction studies to draw a direct line from Pavlov to PTSD and other anxiety disorders. We explain how rodent studies have informed neuroimaging studies of healthy humans and humans with PTSD. We describe several genes that have been linked to both PTSD and fear conditioning and extinction and explain how abnormalities in fear conditioning or extinction may reflect a general biomarker of anxiety disorders. Finally, we explore drug and neuromodulation treatments that may enhance therapeutic extinction in anxiety disorders.

Behind the mask: the influence of mask-type on amygdala response to fearful faces

In this study, we compared the effects of using neutral face masks vs non-face pattern masks on amygdala activity to masked fearful faces. Twenty-seven subjects viewed 18 s blocks of either fearful or happy faces masked with either neutral faces or patterns, while their brain activity was measured using functional magnetic resonance imaging. Results replicated increased amygdala activation to face-masked fearful vs happy faces. In the pattern mask condition, the amygdala discriminated between masked fearful and happy faces, but this effect manifested as a decrease in activation to fearful faces compared to happy faces. This interactive effect between facial expression and mask stimulus shows that amygdala responses to masked fearful faces are influenced by the fearful stimuli per se as well as their interaction with the mask stimulus.

Neuroimaging predictors of treatment response in anxiety disorders

Although several psychological and pharmacological treatment options are available for anxiety disorders, not all patients respond well to each option. Furthermore, given the relatively long duration of adequate treatment trials, finding a good treatment fit can take many months or longer. Thus, both clinicians and patients would benefit from the identification of objective pre-treatment measures that predict which patients will best respond to a given treatment. Recent studies have begun to use biological measures to help predict symptomatic change after treatment in anxiety disorders. In this review, we summarize studies that have used structural and functional neuroimaging measures to predict treatment response in obsessive-compulsive disorder (OCD), posttraumatic stress disorder (PTSD), generalized anxiety disorder (GAD), and social anxiety disorder (SAD). We note the limitations of the current studies and offer suggestions for future research. Although the literature is currently small, we conclude that pre-treatment neuroimaging measures do appear to predict treatment response in anxiety disorders, and future research will be needed to determine the relative predictive power of neuroimaging measures as compared to clinical and demographic measures.

Diminished rostral anterior cingulate cortex activation during trauma-unrelated emotional interference in PTSD

BackgroundPrevious research suggests that individuals with posttraumatic stress disorder (PTSD) preferentially attend to trauma-related emotional stimuli and have difficulty completing unrelated concurrent tasks. Compared to trauma-exposed control groups, individuals with PTSD also exhibit lower rostral anterior cingulate cortex (rACC) activation during tasks involving interference from trauma-related stimuli. However, it is not clear whether relatively diminished rACC activation in PTSD also occurs during interference tasks involving trauma-unrelated emotional stimuli. The present study employed functional magnetic resonance imaging (fMRI) and an interference task that involves emotional facial expressions and elicits rACC activation in healthy participants.FindingsWhile performing a trauma-unrelated emotional interference task, participants with PTSD (n=17) showed less rACC activation than trauma-exposed non-PTSD (TENP; n=18) participants. In the PTSD group, rACC activation was negatively correlated with the severity of re-experiencing symptoms. The two groups did not significantly differ on behavioral measures (i.e., response times and error rates).ConclusionsThese findings suggest that relatively diminished rACC activation in PTSD can be observed in interference tasks involving trauma-unrelated emotional stimuli, indicating a more general functional brain abnormality in this disorder. Future neuroimaging studies need not employ trauma-related stimuli in order to detect rACC abnormalities in PTSD.

Interpreting ambiguous social cues in unpredictable contexts

Unpredictable environments can be anxiety-provoking and elicit exaggerated emotional responses to aversive stimuli. Even neutral stimuli, when presented in an unpredictable fashion, prime anxiety-like behavior and elicit heightened amygdala activity. The amygdala plays a key role in initiating responses to biologically relevant information, such as facial expressions of emotion. While some expressions clearly signal negative (anger) or positive (happy) events, other expressions (e.g. surprise) are more ambiguous in that they can predict either valence, depending on the context. Here, we sought to determine whether unpredictable presentations of ambiguous facial expressions would bias participants to interpret them more negatively. We used functional magnetic resonance imaging and facial electromyography (EMG) to characterize responses to predictable vs unpredictable presentations of surprised faces. We observed moderate but sustained increases in amygdala reactivity to predictable presentations of surprised faces, and relatively increased amygdala responses to unpredictable faces that then habituated, similar to previously observed responses to clearly negative (e.g. fearful) faces. We also observed decreased corrugator EMG responses to predictable surprised face presentations, similar to happy faces, and increased responses to unpredictable surprised face presentations, similar to angry faces. Taken together, these data suggest that unpredictability biases people to interpret ambiguous social cues negatively.

Botulinum toxin-induced facial muscle paralysis affects amygdala responses to the perception of emotional expressions: preliminary findings from an A-B-A design

BackgroundIt has long been suggested that feedback signals from facial muscles influence emotional experience. The recent surge in use of botulinum toxin (BTX) to induce temporary muscle paralysis offers a unique opportunity to directly test this “facial feedback hypothesis.” Previous research shows that the lack of facial muscle feedback due to BTX-induced paralysis influences subjective reports of emotional experience, as well as brain activity associated with the imitation of emotional facial expressions. However, it remains to be seen whether facial muscle paralysis affects brain activity, especially the amygdala, which is known to be responsive to the perception of emotion in others. Further, it is unknown whether these neural changes are permanent or whether they revert to their original state after the effects of BTX have subsided. The present study sought to address these questions by using functional magnetic resonance imaging to measure neural responses to angry and happy facial expressions in the presence or absence of facial paralysis.ResultsConsistent with previous research, amygdala activity was greater in response to angry compared to happy faces before BTX treatment. As predicted, amygdala activity in response to angry faces was attenuated when the corrugator/procerus muscles were paralyzed via BTX injection but then returned to its original state after the effects of BTX subsided. This preliminary study comprises a small sample size and no placebo condition; however, the A-B-A design affords the present sample to serve as its own control.ConclusionsThe current demonstration that amygdala responses to facial expressions were influenced by facial muscle paralysis offers direct neural support for the facial feedback hypothesis. Specifically, the present findings offer preliminary causal evidence that amygdala activity is sensitive to facial feedback during the perception of the facial expressions of others. More broadly, these data confirm the utility of using BTX to address the effect of facial feedback on neural responses associated with the perception, in addition to the experience or expression of emotion.

A face versus non-face context influences amygdala responses to masked fearful eye whites

The structure of the mask stimulus is crucial in backward masking studies and we recently demonstrated such an effect when masking faces. Specifically, we showed that activity of the amygdala is increased to fearful facial expressions masked with neutral faces and decreased to fearful expressions masked with a pattern mask—but critically both masked conditions discriminated fearful expressions from happy expressions. Given this finding, we sought to test whether masked fearful eye whites would produce a similar profile of amygdala response in a face vs non-face context. During functional magnetic resonance imaging scanning sessions, 30 participants viewed fearful or happy eye whites masked with either neutral faces or pattern images. Results indicated amygdala activity was increased to fearful vs happy eye whites in the face mask condition, but decreased to fearful vs happy eye whites in the pattern mask condition—effectively replicating and expanding our previous report. Our data support the idea that the amygdala is responsive to fearful eye whites, but that the nature of this activity observed in a backward masking design depends on the mask stimulus.

The impact of uncertain threat on affective bias: Individual differences in response to ambiguity.

Individuals who operate under highly stressful conditions (e.g., military personnel and first responders) are often faced with the challenge of quickly interpreting ambiguous information in uncertain and threatening environments. When faced with ambiguity, it is likely adaptive to view potentially dangerous stimuli as threatening until contextual information proves otherwise. One laboratory-based paradigm that can be used to simulate uncertain threat is known as threat of shock (TOS), in which participants are told that they might receive mild but unpredictable electric shocks while performing an unrelated task. The uncertainty associated with this potential threat induces a state of emotional arousal that is not overwhelmingly stressful, but has widespread—both adaptive and maladaptive—effects on cognitive and affective function. For example, TOS is thought to enhance aversive processing and abolish positivity bias. Importantly, in certain situations (e.g., when walking home alone at night), this anxiety can promote an adaptive state of heightened vigilance and defense mobilization. In the present study, we used TOS to examine the effects of uncertain threat on valence bias, or the tendency to interpret ambiguous social cues as positive or negative. As predicted, we found that heightened emotional arousal elicited by TOS was associated with an increased tendency to interpret ambiguous cues negatively. Such negative interpretations are likely adaptive in situations in which threat detection is critical for survival and should override an individual’s tendency to interpret ambiguity positively in safe contexts.

Different profiles of decision making and physiology under varying levels of stress in trained military personnel

Decision making is one of the most vital processes we use every day, ranging from mundane decisions about what to eat to life-threatening choices such as how to avoid a car collision. Thus, the context in which our decisions are made is critical, and our physiology enables adaptive responses that account for how environmental stress influences our performance. The relationship between stress and decision making can additionally be affected by ones expertise in making decisions in high-threat environments, where experts can develop an adaptive response that mitigates the negative impacts of stress. In the present study, 26 male military personnel made friend/foe discriminations in an environment where we manipulated the level of stress. In the high-stress condition, participants received a shock when they incorrectly shot a friend or missed shooting a foe; in the low-stress condition, participants received a vibration for an incorrect decision. We characterized performance using signal detection theory to investigate whether a participant changed their decision criterion to avoid making an error. Results showed that under high-stress, participants made more false alarms, mistaking friends as foes, and this co-occurred with increased high frequency heart rate variability. Finally, we examined the relationship between decision making and physiology, and found that participants exhibited adaptive behavioral and physiological profiles under different stress levels. We interpret this adaptive profile as a marker of an experts ingrained training that does not require top down control, suggesting a way that expert training in high-stress environments helps to buffer negative impacts of stress on performance.