"Safety Signals" Help Reduce Fear and Anxiety

Learning about safety can successfully reduce fear, and does so by activating circuits in the brain that differ from those involved in typical treatment for anxiety.

A new study published in the Proceedings of the National Academy of Sciences (PNAS) shows that learning about safety can successfully reduce fear responding, with important implications for treating anxiety disorders.

A team of researchers at Weill Cornell Medicine and Yale University recently investigated the brain circuits through which “safety signals,” stimuli in the environment that signal an absence of threat, function to reduce fear. This work suggests that safety signals may be an effective way to boost current treatments for individuals with anxiety disorders or as an alternative for individuals who do not benefit sufficiently from typical interventions.

“Responding to a perceived threat can be adaptive, but when there is impairment in the ability to determine whether or not fear is appropriate, it can interfere with daily life and cause distress.” says co-first author Dr. Heidi Meyer from Weill Cornell Medicine.

This is a hallmark of stress-related and anxiety disorders, which are the most common psychiatric illnesses, affecting up to one-third of the population. A common way to treat anxiety is through exposure therapy, which is based on extinction. This is a learning process during which a fear-provoking stimulus is presented repeatedly to an individual, and they learn that the aversive outcome they are expecting does not occur. Thus over time, their level of fear and anxiety decreases. But for many individuals, this form of treatment is not sufficiently effective, and often fear returns over time. “Studies have shown that up to 50% of patients with anxiety disorders do not respond to current evidence-based treatment, suggesting a critical need for new interventions,” says co-senior author Dr. Francis Lee from Weill Cornell Medicine. This study was aimed at identifying alternative neurobiological pathways that may be targeted through novel treatment mechanisms.

Safety signal learning, in contrast to extinction, involves the ability to associate distinct stimuli in one’s environment with the absence of aversive events. Over time, these stimuli thus become “safety signals” that are capable of dampening down one's response to something threatening.

The researchers taught human participants and mice to associate safety with colored shapes, and simple tones, respectively. They found that the physiological and behavioral responses that normally arise when a threat is perceived were reduced when the “safety signal” was present in both mice and humans. This reduction was immediate, contrasting with the lengthy training procedures required for extinction-based therapies. “As a method of reducing fear that could provide initial relief, judicious use of safety signals may help patients to better engage with existing therapies that focus on exposure to the patient’s fears,” says co-senior author Dr. Dylan Gee from Yale University.

By using both mice and human participants, the authors were able to use brain imaging tools available for each species to better understand how the brain uses safety signals. The researchers identified a neural circuit that was specifically related to the reduction in fear during the safety signal. When a neuron is active (e.g., when it is communicating with other neurons), there is an elevation in intracellular calcium. Using a live imaging method called fiber photometry, the researchers were able to measure changes in calcium levels in neurons that are part of specific “circuits” (i.e., connections between one brain region and another). The researchers found that when the fearful behavior of the mice was reduced by the safety signal, there was an associated increase in activity in a specific portion of the hippocampus that supports emotional memory. Specifically, the increase presented in neurons that connect to the prelimbic prefrontal cortex, the frontmost part of the brain that is important for controlling complex thoughts and behaviors. In parallel, functional MRI recordings from human participants showed significant functional connectivity (i.e., correlation between brain regions’ blood oxygenation signal, which is used to interpret how strongly brain regions are communicating with each other) between the corresponding regions in the human brain.

Individuals with anxiety show weaker connectivity between the prefrontal cortex and the amygdala, a region of the brain linked to fear and other emotions, which may limit the ability to benefit from standard therapies that rely on extinction. “Importantly, the brain circuit highlighted by these findings is different from the circuitry that is involved in typical extinction learning,” says co-first author Paola Odriozola from Yale University. “This discovery of differential circuitry highlights the potential that safety signal learning could improve interventions for individuals with anxiety disorders by targeting an alternative neural circuit.” 



Co-first authors on the study were Dr. Heidi C. Meyer, Department of Psychiatry, Weill Cornell Medicine, and Paola Odriozola, Department of Psychology, Yale University. Co-senior authors were Dr. Francis S. Lee, Sackler Institute for Developmental Psychobiology and Department of Psychiatry, Weill Cornell Medicine, and Dr. Dylan G. Gee, Department of Psychology, Yale University. Co-authors were Emily M. Cohodes, Department of Psychology, Yale University, Jeffrey D. Mandell, Program in Computational Biology and Bioinformatics, Yale University, Anfei Li, Department of Psychiatry, Weill Cornell Medicine, Ruirong Yang, Department of Psychiatry, Weill Cornell Medicine, Dr. Baila S. Hall, Department of Psychology, Brain Research Institute, University of California Los Angeles, Jason T. Haberman, Department of Psychology, Yale University, Sadie J. Zacharek, Department of Psychology, Yale University, and Dr. Conor Liston, Sackler Institute for Developmental Psychobiology and Feil Family Brain & Mind Research Institute, Weill Cornell Medicine.

The research was supported by the National Institutes of Health (DP5OD021370; R01 NS052819; TL1 TR0002386, K99 MH119320), the Brain & Behavior Research Foundation, the Jacobs Foundation, the Pritzker Neuropsychiatric Disorders Research Consortium, the New York-Presbyterian Youth Anxiety Center, the Dr. Mortimer D. Sackler family, the DeWitt-Wallace Fund of the New York Community Trust, and the National Science Foundation (DGE1122492).

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