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Circuitry for Fearful Feelings, Behavior Untangled in Anxiety Disorders

"Two-system” theory bridges basic/clinical gap, may spur treatment advances

Science Update

An “incorrect” assumption that fear and anxiety are mediated in the brain by a single “fear circuit” has stalled progress in developing better treatments for anxiety disorders, argue two leading experts. Designing future research based on a “two-system” framework holds promise for improving treatment outcomes, say Daniel Pine, M.D., a clinical researcher in the NIMH Emotion and Development Branch, and Joseph LeDoux, Ph.D. , a basic scientist and NIMH grantee at New York University.

Pine, who conducts brain imaging studies of anxiety disorders in youth, and LeDoux, well-known for discovering circuitry underlying threat processing, offer their “conceptual reframing” September 9, 2016 in the American Journal of Psychiatry

Neuroscience advances in understanding how the brain detects and responds to threat have failed to translate into significantly improved treatments because the field has been led astray by a simplistic notion of a “fear system,” contend Pine and LeDoux. For example, hopes that medications that lessen rodents’ stress reactivity might help people feel less fearful or anxious often haven’t borne out.

Rather, the authors point to mounting evidence that such subjective feeling states are mediated via different circuitry than defensive behaviors. The former via higher order processing in the cortex – and the latter via the amygdala and related centers, mostly deeper in the brain.

For starters, Pine and LeDoux propose more precise use of terminology. Fear and anxiety describe conscious subjective feeling states; defensive reactions refer to rapidly-deployed behaviors or physiological responses. Fear denotes feelings associated with an imminent threat, anxiety feelings associated with an uncertain or more distant source of harm.

For example, the amygdala, often colloquially dubbed the brain’s “fear center,” in fact unconsciously detects and responds to imminent threats and contributes to fear only indirectly. States like fear and anxiety instead arise from areas of the cortex associated with higher order thinking processes and language in people, only some of which occur in other animals.

“If feelings of fear or anxiety are not products of circuits that control defensive behavior, studies of defensive behavior in animals will be of limited value in finding medications that can relieve feelings of fear and anxiety in people,” observe the authors, who note that making such distinctions will help in the design of more realistic translational studies.

Meanwhile, the distinctions may also temper expectations for development of specific-acting anti-anxiety agents. “Existing medications are blunt tools,” note Pine and LeDoux. If the experience of fear and anxiety is rooted in cortical changes in thinking, attention and memory, some “anxiolytic” effects might result from “general emotional blunting” or “impaired cognitive processing,” they add.

Improving treatments will require a more exact understanding of how treatments work. With this knowledge and the two-systems perspective, existing treatments might be adapted to work better. Brain imaging biomarkers might help tailor treatments to target circuit dysfunctions of specific patients. For example, anxious patients showing altered activity profiles in cortex circuitry underlying working memory might receive psychotherapies that teach them how to regulate emotion through reappraisal or other thinking strategies.

2-systems graph


Using Neuroscience to Help Understand Fear and Anxiety: A Two-System Framework.  LeDoux JE, Pine DS.Am J Psychiatry. 2016 Sep 9:appiajp201616030353. [Epub ahead of print] PMID: 27609244



For more information

See NYU Press Release
There Must be Some Misunderstanding: Researchers Outline Barriers to Treating Fear and Anxiety