Neuroscience of fear extinction: Implications for assessment and treatment of fear-based and anxiety related disorders
Section snippets
Why fear extinction?
From the viewpoint of basic neuroscience, understanding how our brains learn to fear and how not to fear is an intriguing question. While such a fascination may have been the impetus for the initial wave of preclinical studies conducted in this domain, the rapid advancement of neuroimaging tools and their implementation in studying the psychopathology of anxiety disorders has generated a new translational research approach that merges basic neuroscience and clinical data. This merger has been a
Neural circuits mediating fear acquisition and its extinction
The neurobiology of fear acquisition is well characterized in rodents and humans (Maren & Quirk, 2004). Briefly, it is widely accepted that the basolateral complex of the amygdala is the main neural structure in which information about the conditioned and unconditioned stimuli converge (Ledoux, 2000). There is also evidence from rodent studies that the prelimbic division of the medial prefrontal cortex is involved in regulating the expression of learned fear (Burgos-Robles et al., 2009,
Is the functional integrity of the fear extinction network impaired across the anxiety disorders?
Structural and functional abnormalities of the brain regions mediating fear extinction has been reported across the anxiety disorders using an ample array of tasks. For example, in symptom provocation studies, it has been shown that blood flow in the medial frontal gyrus is reduced in PTSD participants compared to trauma-exposed controls when exposed to trauma reminders, and medial frontal gyrus blood flow was inversely correlated with changes in amygdala blood flow (Shin et al., 2004).
Is fear extinction impaired across the anxiety disorders?
Thus far, the vast majority of research efforts have focused on fear extinction in patients with PTSD, while other anxiety disorders remain relatively unstudied. It has been consistently shown that patients with PTSD exhibit an enhanced resistance to extinction (Blechert et al., 2007, Jovanovic et al., 2010, Jovanovic et al., 2009, Norrholm et al., 2011, Orr et al., 2000, Peri et al., 2000). Similarly, we have reported that individuals with PTSD exhibit deficits in extinction recall, despite
Does the functional integrity of this circuit change with treatment?
There are several key questions that cognitive and basic neuroscience strives to answer. For example, to what degree do current therapeutic approaches (pharmacological or behavioral) restore functional activity within affected brain regions in patients to levels that are comparable to normal controls? Are there differences in the functional activation of nodes specifically involved in fear extinction and emotion regulation in general after pharmacotherapy versus behavioral therapy? Could
How this line of research has been translated to the clinic?
In addition to predicting treatment outcomes and examining the mechanism of change induced by exposure- and behavioral-based therapies, understanding the mechanisms of fear extinction could help develop novel therapeutic approaches to treat anxiety disorders. Based on the understanding that extinction learning induces a new form of memory (CS- No-US association) (Bouton, 2002, Bouton and Moody, 2004, Milad et al., 2006), and that exposure-based therapy may rely on mechanisms that are shared
What's around the corner?
Many investigators have begun to explore other pharmacological agents that could facilitate fear extinction in rodents, and that could potentially be used in humans with minimal to no side effects. Some of these agents have already begun being tested in clinical trials including methylene blue and yohimbine, both of which have been shown to facilitate fear extinction in rodents (Gonzalez-Lima and Bruchey, 2004, Holmes and Quirk, 2010). Methylene blue is thought to improve extinction memory
Conclusion
Data gathered from basic and translational studies in the neuroscience of fear extinction have only recently begun to influence how these disorders are identified, understood, and treated. While early challenges and questions about the validity of the model may have delayed translation to clinical applications, it is becoming increasingly clear that developments in pharmaceutical and device-based therapies that target the fear extinction network may be very useful for breaking the impasse we
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