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Deep Brain Stimulation of the Basolateral Amygdala for Treatment-Refractory Posttraumatic Stress Disorder

  • Jean-Philippe Langevin
    Correspondence
    Address correspondence to Jean-Philippe Langevin, M.D., Department of Veterans Affairs Greater Los Angeles Healthcare System, West Los Angeles Medical Center, Surgery and Perioperative Care, 11301 Wilshire Boulevard, Building 500 (10H2), Los Angeles, CA, 90073.
    Affiliations
    Neurosurgery Service, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

    David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
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  • Ralph J. Koek
    Affiliations
    Psychiatry and Mental Health Service, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

    David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
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  • Holly N. Schwartz
    Affiliations
    Psychiatry and Mental Health Service, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
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  • James W.Y. Chen
    Affiliations
    Neurology Service, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

    David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
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  • David L. Sultzer
    Affiliations
    Psychiatry and Mental Health Service, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

    David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
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  • Mark A. Mandelkern
    Affiliations
    Radiology Service, Nuclear Medicine, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

    David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
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  • Alexis D. Kulick
    Affiliations
    Psychiatry and Mental Health Service, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California
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  • Scott E. Krahl
    Affiliations
    Research and Development Service, Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, California

    David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California
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Published:September 10, 2015DOI:https://doi.org/10.1016/j.biopsych.2015.09.003
      Posttraumatic stress disorder (PTSD) affects approximately 6.8% of the U.S. population in their lifetime (
      • Kessler R.C.
      • Berglund P.
      • Delmer O.
      • Jin R.
      • Merikangas K.R.
      • Walters E.E.
      Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication.
      ). Current treatments include antidepressant medications and psychotherapy, but a significant number of patients remain refractory. Treatment-refractory PTSD is associated with substance use disorders (
      • Mills K.I.
      • Teesson M.
      • Ross J.
      • Peters L.
      Trauma, PTSD, and substance use disorders: Findings from the Australian National Survey of Mental Health and Well-Being.
      ), general medical illnesses (
      • Cohen B.E.
      • Marmar C.R.
      • Neylan T.C.
      • Schiller N.B.
      • Ali S.
      • Whooley M.A.
      Posttraumatic stress disorder and health-related quality of life in patients with coronary heart disease.
      ), and suicide (
      • Kang H.K.
      • Bullman T.A.
      Risk of suicide among US veterans after returning from Iraq or Afghanistan war zones.
      ). Treatment refractoriness is due at least in part to failure of fear extinction, rendering exposure therapy ineffective. Fear extinction is mediated by the interaction of the basolateral nucleus of the amygdala (BLn) and the medial prefrontal cortex (
      • Luthi A.
      • Luscher C.
      Pathological circuit function underlying addiction and anxiety disorders.
      ). The infralimbic part of the medial prefrontal cortex plays an integral role in extinction through inhibition of the amygdala (
      • Luthi A.
      • Luscher C.
      Pathological circuit function underlying addiction and anxiety disorders.
      ). In PTSD, this control mechanism is lacking, leading to unchecked activity of the amygdala and failure of extinction (
      • Koenigs M.
      • Grafman J.
      Posttraumatic stress disorder: The role of medial prefrontal cortex and amygdala.
      ). As a result, high levels of amygdala blood flow in response to fear-eliciting stimuli predict failure of exposure therapy (
      • Bryant R.A.
      • Felmingham K.
      • Kemp A.
      • Das P.
      • Hughes G.
      • Peduto A.
      • Williams L.
      Amygdala and ventral anterior cingulate activation predicts treatment response to cognitive behavior therapy for PTSD.
      ). The levels of amygdala blood flow and metabolism as seen on functional magnetic resonance imaging and positron emission tomography studies, respectively, correlate with the presence (
      • Etkin A.
      • Wager T.D.
      Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia.
      ) and severity (
      • Armony J.L.
      • Corbo V.
      • Clement M.H.
      • Brunet A.
      Amygdala response in patients with acute PTSD to masked and unmasked emotional facial expressions.
      ,
      • Shin L.M.
      • Orr S.P.
      • Carson M.A.
      • Rauch S.L.
      • Macklin M.L.
      • Lasko N.B.
      • et al.
      Regional cerebral blood flow in the amygdala and medial prefrontal cortex during traumatic imagery in male and female Vietnam veterans with PTSD.
      ) of PTSD symptoms.
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      References

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          The endogenous cannabinoid 2-arachidonoylglycerol (2-AG) is a lipid-signaling molecule synthesized in the central nervous system primarily by diacylglycerol lipase alpha (DAGLA) that exerts biological actions primarily via activation of CB1 type cannabinoid receptors. CB1 is the primary target of Δ9-tetrahydrocannabinol, and anxiety reduction and tension relief have been reported as primary motives for chronic cannabis use (1). Consistent with this, pharmacologic augmentation of 2-AG levels reduces anxiety-like and depressive behaviors, and 2-AG levels increase in the amygdala in response to repeated stress exposure, suggesting a physiologic role for this signaling system in buffering against the development of stress-induced pathology (2).
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