NEUROSURGICAL FOCUS Neurosurg Focus 45 (2):E17, 2018

EDITORIAL Deep brain stimulation for refractory posttraumatic stress disorder

Justin D. Hilliard, MD,1 and Kelly D. Foote, MD1,2

1Department of Neurosurgery, and 2Fixel Center for Neurological Disorders, University of Florida, Gainesville, Florida

osttraumatic stress disorder (PTSD) is an anxiety the BLn. When a sensory stimulus is applied, the relative disorder resulting in functional impairment as a re- activity of “fear” cells to “extinction” cells determines the sult of exposure to threatened or actual death, serious individual’s ultimate behavioral response.10 Modulating injury,P or sexual violence. The traumatic event is persis- the BLn to enhance extinction while mitigating fear could tently re-experienced with intrusions of thoughts, feelings, reduce the emotional arousal associated with stimuli con- or reminders, with associated excessive emotional arousal ditioned to the index traumatic event. Functional imaging including hypervigilance, difficulty concentrating, and ir- studies have demonstrated that individuals with PTSD ritability.8 Individuals affected with the disorder often so- have hyperactivity in the amygdala, particularly within the cially isolate themselves to avoid trauma-related stimuli, basal portion, compared to controls.5 The intensity of such and frequently have concomitant depression. Historically, hyperactivity appears linked to the magnitude of symp- PTSD treatments have consisted of cognitive behavioral toms.2 It is hypothesized that as with other psychiatric therapy, exposure therapy, and pharmacological treatment conditions characterized by hyperactive networks, such as with SSRIs (selective serotonin reuptake inhibitors) and depression and obsessive-compulsive disorder, DBS ap- SNRIs (serotonin–norepinephrine reuptake inhibitors). plied to the hyperactive amygdala could moderate func- Lifetime prevalence of the disorder is as high as 7% in tion in connected regions, thereby suppressing symptoms the United States.1 Combat veterans are classically at high of PTSD. risk for PTSD, with a 15% prevalence in male Vietnam- More refined neuromodulation with closed-loop DBS era veterans.10 Although significant advances have been could theoretically be used in a PTSD application, with made in the cognitive and pharmaceutical therapies for biomarkers reflecting sympathetic activation (skin con- PTSD, in a subset of the population the disorder remains ductance changes, pupillary dilation, piloerection). How- refractory to treatment. Refractory PTSD is probably par- ever, these peripheral cues inherently lack specificity, be- tially due to lack of fear extinction, rendering exposure cause normal emotional responses could trigger activation. therapy ineffective.11 Fear extinction is modulated by the Characteristic neuronal activity (e.g., local field potentials) basolateral nucleus (BLn) of the amygdala and the medial from the amygdala or medial prefrontal cortex itself may prefrontal cortex, the former of which demonstrates am- be a more specific and more easily integrated biomarker plified blood flow and metabolism on functional imaging into a closed-loop DBS system.3 in refractory PTSD.4,5 This poses a unique treatment chal- In their paper titled “Bilateral amygdala stimulation re- lenge for which electrical neuromodulation may be par- duces avoidance behavior in a predator scent posttraumat- ticularly well suited.12 ic stress disorder model,” Dengler et al. outline their trial The BLn of the amygdala is hypothesized to be an ef- of bilateral basolateral amygdala DBS in a rodent PTSD fective target for deep brain stimulation (DBS) for PTSD model.6 Previous DBS studies in animals with PTSD have because it serves as a mediator for emotional and auto- used an aversive conditioning model whereby a foot shock nomic responses to stimuli in the environment. The BLn is stimulus is paired with an object placed in the environ- a relay station within the amygdala, connecting the lateral mental chamber at the same time as the shock. The rats, nucleus with the central nucleus and ultimately forming when exposed again to the innocuous object, will bury it a feedback loop with the medial prefrontal cortex.7 Ex- in an attempt to avoid the shock stimulus. The study’s au- tinction cells and fear-encoding cells are located within thors argue that the predator scent model, in which the

ACCOMPANYING ARTICLE DOI: 10.3171/2018.5.FOCUS18166.

©AANS 2018, except where prohibited by US copyright law Neurosurg Focus Volume 45 • August 2018 1

Unauthenticated | Downloaded 09/29/21 07:26 PM UTC Editorial rodent is exposed to a life-threatening, stress-inducing 2. Armony JL, Corbo V, Clément MH, Brunet A: Amygdala re- stimulus without direct physical repercussion, is perhaps sponse in patients with acute PTSD to masked and unmasked more in line with the types of cues that humans encounter emotional facial expressions. Am J Psychiatry 162:1961– 1963, 2005 in a situation leading to PTSD. The scent model produces 3. Bina RW, Langevin JP: Closed loop deep brain stimulation prolonged anxiety and avoidance behaviors, in contrast to for PTSD, addiction, and disorders of affective facial inter- the relatively short-acting effects of the aforementioned pretation: review and discussion of potential biomarkers and aversive conditioning model. stimulation paradigms. Front Neurosci 12:300, 2018 In the aforementioned study, rats were assigned to one 4. Bryant R, Felmingham K, Kemp A: Amygdala and ventral of four conditions: bilateral stimulation, unilateral stim- anterior cingulate activation predicts treatment response to ulation, no stimulation, and no stimulation/no exposure cognitive behaviour therapy for post-traumatic stress disor- to the predator scent. Stimulation was applied for 4 hours der. Psychol Med 38:555–561, 2008 5. Bryant RA, Felmingham KL, Kemp AH: Neural networks a day for 1 week prior to animals undergoing repeat be- of information processing in posttraumatic stress disorder: havioral testing. Electrode placement was validated with a functional magnetic resonance imaging study. Biolog Psy- postmortem histological investigation. The study demon- chiatry 58:111–118, 2005 strated that bilateral high-frequency stimulation resulted 6. Dengler BA, Hawksworth SA, Berardo L, McDougall I, in decreased avoidance behavior compared to the no-stim- Papanastassiou AM: Bilateral amygdala stimulation reduces ulation cohort. Interestingly, the stimulation cohort did not avoidance behavior in a predator scent posttraumatic stress demonstrate decreased anxiety, as measured by the lack disorder model. Neurosurg Focus 45(2):E16, 2018 7. Freese JL, Amaral DG: Neuroanatomy of the primate amyg- of a significant change in time spent on the open arm por- dala, in Whalen PJ, Phelps EA (eds): The Human Amyg- tion of the elevated plus maze. One shortcoming of the au- dala. New York: Guilford Press, 2009 thors’ study is the lack of control to negate the potential in- 8. Koek RJ, Langevin JP, Krahl SE: Deep brain stimulation of fluence of a lesion effect. A separate condition of predator the basolateral amygdala for treatment-refractory combat scent exposure without implantation should be tested. In post-traumatic stress disorder (PTSD): study protocol for human studies, damage to the amygdala has been shown a pilot randomized controlled trial with blinded, staggered to have a protective effect from PTSD, thereby highlight- onset of stimulation. Trials 15:356, 2014 ing the importance of ensuring that the effects noted in the 9. Langevin JP, Chen JW, Koek RJ: Deep brain stimulation of the basolateral amygdala: targeting technique and electrodi- study are not in part from implantation alone. agnostic findings. Brain Sci 6:E28, 2016 As DBS indications continue to mature beyond move- 10. Langevin JP, Koek RJ, Schwartz HN, Chen JWY, Sultzer ment disorders into the realm of psychiatric and cogni- DL, Mandelkern MA, et al: Deep brain stimulation of the tive disorders, the need for careful selection of anatomical basolateral amygdala for treatment-refractory posttraumatic targets, development of stringent implant criteria, and a stress disorder. Biol Psychiatry 79:e82–e84, 2016 consensus of ethical considerations will become critically 11. Laufer RS, Brett E, Gallops MS: Dimensions of posttrau- important. Well-designed preclinical studies are helpful matic stress disorder among Vietnam veterans. J Nerv Ment in narrowing the vast array of plausible anatomical tar- Dis 173:538–545, 1985 12. Marin MF, Camprodon JA, Dougherty DD, Milad MR: gets. Given the promising results, already there are groups Device-based brain stimulation to augment fear extinction: that have extended DBS for PTSD beyond animal models. implications for PTSD treatment and beyond. Depress Anxi- Langevin et al. implanted bilateral BLn DBS electrodes ety 31:269–278, 2014 in a 48-year-old combat veteran with severe, refractory PTSD.11 After 8 months of continuous stimulation, he had Disclosures experienced a 38% decrease in his clinician-administered Dr. Foote received support from Medtronic, Abbott/St. Jude, PTSD (CAPS) score, which is a measure of PTSD sever- Boston Scientific, and Functional Neuromodulation for non– ity. The results from this initial subject led to the launch of study-related clinical or research efforts that he oversaw. He is also a patent holder for DBS-related inventions, and receives fel- a Phase I pilot study investigating bilateral BLn DBS for lowship grant support from Medtronic. 6 combat veterans with refractory PTSD.8,9 For those with refractory PTSD, DBS may offer not only a life-modify- Correspondence ing therapy, but in fact a life-saving one. Kelly D. Foote: [email protected]. https://thejns.org/doi/abs/10.3171/2018.5.FOCUS18266 INCLUDE WHEN CITING References DOI: 10.3171/2018.5.FOCUS18266. 1. American Psychiatric Association: Diagnostic and Statisti- cal Manual of Mental Disorders, ed 5. Washington, DC: American Psychiatric Association, 2013

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