Next Article in Journal / Special Issue
Deep Brain Stimulation—Possible Treatment Strategy for Pathologically Altered Body Weight?
Previous Article in Journal / Special Issue
Awake versus Asleep Deep Brain Stimulation Surgery: Technical Considerations and Critical Review of the Literature

Brain Sci. 2018, 8(1), 18;

DBS in Treatment of Post-Traumatic Stress Disorder
Unit of Functional and Stereotactic Neurosurgery/Operative Unit of Neurosurgery, Department of Medical and Surgical Sciences, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
Department of Health Science, University Magna Graecia of Catanzaro, Catanzaro 88100, Italy
Author to whom correspondence should be addressed.
Received: 6 December 2017 / Accepted: 17 January 2018 / Published: 20 January 2018


Post-traumatic stress disorder (PTSD) is a debilitating psychiatric condition for which pharmacological therapy is not always solvable. Various treatments have been suggested and deep brain stimulation (DBS) is currently under investigation for patients affected by PTSD. We review the neurocircuitry and up-to-date clinical concepts which are behind the use of DBS in posttraumatic stress disorder (PTSD). The role of DBS in treatment-refractory PTSD patients has been investigated relying on both preclinical and clinical studies. DBS for PTSD is in its preliminary phases and likely to provide hope for patients with medical refractory PTSD following the results of randomized controlled studies.
posttraumatic stress disorder; deep brain stimulation; fear extinction; amygdala; prefrontal cortex

1. Introduction

In the Diagnostic and Statistical Manual of Mental Disorder–V (DSM-V) post-traumatic stress disorder (PTSD) is described not only as a feeling of fear and helplessness, as it was classified in the DSM-III, but also as a disorder including negative cognitions, negative emotional states, and reactivity symptoms [1]. Victims of sexual assault, serious accidents, sudden death of a loved one, or soldiers employed in war are exposed to various traumatic events with serious risk of developing PTSD, especially in the presence of comorbidity such as depression and substance abuse [2]. To make a diagnosis of PTSD, the patient must report the symptoms mentioned above for over 30 days following the traumatic event to an extent that it is an impairment in the quality of daily life. PTSD has significant economic and health repercussions; it is estimated prevalence in the United States is around 5–8% with a greater tendency in the female sex [3]. The risk of suicide attempt or ideation is also associated to PTSD [4]. Other risk factors involved in the pathophysiology of PTSD are genetic polymorphism [5], endocrine dysregulation [6], reduction of neurotrophic factors levels [7], as well as abnormal monoamine [8] and neuropeptide levels [9].

2. Materials and Methods

The anatomical structures involved in the neurocircuitry of fear conditioning are amygdala, prefrontal cortex, and hippocampus. Basolateral complex (BLA) of amygdala, consisting of the lateral nucleus (LA), the basal nucleus (BA), and the accessory basal nucleus, is the main receiver of the sensory afferences coming from two sources: the thalamus sensory nuclei and the primary sensory areas of the cerebral cortex. For many types of emotions, and especially for fear, the amygdala is of great importance, and valuable information retransmitted through this path reaches the amygdala more rapidly than sensory information retransmitted by the cortex. For example, lesions of the basolateral complex abolish classic fear conditioning [10]. Other nuclei of amygdala are the cortical nucleus, the central nucleus (CE), and intercalated cell clusters (ITC). The LA receives somatic, visual, and auditory sensory fibers, conveying a fast signal for danger [11,12] and it transmits the stimulus to the CE that is in connection with different hypothalamic and brainstem areas responsible for autonomic responses associated with fear [13]. Neurocircuitry of fear extinction differs from that of fear conditioning and it involves the ventromedial prefrontal cortex (vmPFC), the basolateral complex (BLA), the intercalated cell cluster (ITC) of the amygdala, and the hippocampus. The infralimbic (IL) subregion of medial prefrontal cortex (mPFC) is necessary for the inhibition of conditioned fear following extinction [14] and it drives extinction-related plasticity in the amygdala [15]. The BLA of amygdala is involved in extinction learning while vmPFC allows inhibition of fear during extinction recall [16]. In animal models, extinction may be due to an increased inhibition of fear output CE neurons related to an enhanced recruitment of GABAergic ITC cells by BLA inputs. It is likely that ITC neurons constitute mediators of extinction because they receive information about the conditioned stimulus from the basolateral amygdala (BLA), and contribute inhibitory projections to the CE, the main output station of the amygdala for conditioned fear responses [17]. Functional neuroimaging studies, based on single-photon emission tomography (SPECT), positron emission tomography (PET), and functional magnetic resonance imaging (fMRI) showed functional changes in the amygdala, hippocampus, and prefrontal cortex during emotional processing tasks and at rest in PTSD patients, consisting of increase of cerebral blood perfusion in the amygdala and decrease of perfusion in the superior frontal gyrus and parietal and temporal regions [18,19,20]. The dorsal anterior cingulate cortex, hippocampus, and insula appeared hyperactive [21] while simultaneous hypo-activity in the inferior occipital gyrus, ventromedial prefrontal cortex, rostral anterior cingulate cortex, para-hippocampal gyrus, lingual gyrus, dorsal amygdala and anterior hippocampus, orbitofrontal cortex, putamen, middle occipital gyrus, dorsomedial prefrontal cortex, dorsal anterior cingulate cortex and mid-cingulate appeared to be related to a greater symptom severity [22].

3. Results

Pharmacotherapy, based on paroxetine, sertraline, fluoxetine, risperidone, topiramate, and venlafaxine, associated with psychotherapy can be effective in PTSD [23]; however, many patients may be unresponsive or only partially responsive to medical treatment. It is unclear when a patient affected by PTSD can be considered treatment-resistant and if the coexistence of mental diseases or substance abuse are responsible for the refractoriness to conventional treatments [24]. The application of Deep Brain Stimulation (DBS) in PTSD is under investigation since the procedure has achieved promising results in the surgical treatment of other psychiatric disorders such as major depression and obsessive-compulsive disorder. The targets studied in preclinical models are the basolateral amygdala, ventral striatum, hippocampus, and prefrontal cortex.

3.1. Basolateral Amygdala

Langevin et al. demonstrated a therapeutic response and a decrease of amygdala hyperactivity after DBS stimulation of the BLA complex in PTSD model rats using 4 h/die stimulation with 160 Hz, 120 μs and 2.5 Volts in monopolar configuration [25,26]. Development of epileptiform after discharge may be a potential side effect when high current intensities are used [27]. Based on these observations in 2014, a study was started on human clinical use of BLA DBS in six combat veterans affected by PTSD and it is still actively recruiting patients [28] Eligible subjects signed informed consent and underwent baseline evaluations for six-weeks with Clinician Administered PTSD Rating Scale (CAPS), baseline 18-FluoroDeoxyGlucose (18FDG) PET scan and additional baseline clinical evaluation of an independent team of psychiatrists and neurosurgeons. Patients with total CAPS score ≥85 at the end of baseline period could be kept in the study. The leads (Model 3387, Medtronic Minneapolis, USA) were implanted bilaterally in the BLA with standard precoronal trajectory and stimulation started four weeks after the implant with progressive increase of stimulation parameters to a maximum of 7 V, 200 Hz, and 210 μs [29,30]. A positive clinical response is defined as a 30% reduction in CAPS [31] from baseline and a Clinical Global Impression-Improvement (CGI-I) [32] score of 1 (very much improved) or 2 (much improved).

3.2. Ventral Striatum

The effects of ventral striatum (VS) DBS (100–200 μA, 0.1-ms pulse duration, 130 Hz) have been tested in a rodent PTSD model. DBS of the VS (the VC/VS homolog in rats) during extinction training allowed reduction of fear expression and strength of extinction memory; stimulation of dorso-medial VS, just above the anterior commissure, allowed facilitation of extinction while stimulation of more ventro-lateral sites in VS impaired extinction [33].

3.3. Hippocampus and Prefrontal Cortex

Disruptions of fear extinction-related potentiation of synaptic efficacy in the connection between the hippocampus (HPC) and the medial prefrontal cortex (mPFC) have been shown to impair the recall of memory extinction in rats. Moreover, low-frequency hippocampal stimulation delivered after extinction impaired the extinction learning and the development of hippocampal-PFC plasticity [34]. Medial Prefrontal Cortex DBS mitigated conditioned fear, partially improved anxiety-like behavior, and reduced BLA cell firing in a preclinical model of PTSD [35].

4. Conclusions

Treatment-resistant PTSD is an important mental health issue in terms of the number of people affected and morbidity and functional impairment associated with the disorder.
Neuroimaging studies in humans support the hypothesis of the involvement of limbic regions in the pathophysiology of the disorder. The application of DBS for PTSD is still strictly investigational and animal models suggest that stimulation of the amygdala, ventral striatum, hippocampus, and prefrontal cortex may be effective in fear extinction and anxiety-like behavior. The limited data from humans support the potential safety and effectiveness of high frequency DBS of the basolateral amygdala (BLA) in treating PTSD.
Optimal targets and stimulation parameters, greater knowledge of the action mechanisms, and established criteria of inclusion/exclusion need to be characterized prior to the launch of multidisciplinary larger scale studies, always keeping in mind the risks associated with the surgical procedure and long-term neurostimulation.


We did not receive funds for covering the costs to publish in open access.

Author Contributions

A.L. and G.G. conceived and designed the work; SM.L. and R.T conducted the bibliographic research; A.DT. wrote the paper; G.V. supervised the manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.


  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (DSM V), 4th ed.; America Psychiatric Association: Washington, DC, USA, 2013. [Google Scholar]
  2. Marmar, C.R.; Schlenger, W.; Henn-Haase, C.; Qian, M.; Purchia, E.; Li, M.; Corry, N.; Williams, C.S.; Ho, C.L.; Horesh, D.; et al. Course of Post-traumatic stress Disorder 40 Years After the Vietnam War: Findings Fron the National Vietnam Veterans Longitudinal Study. JAMA Psychiatry 2015, 72, 875–881. [Google Scholar] [CrossRef] [PubMed]
  3. Kessler, R.C.; Berglund, P.; Demler, 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. Arch. Gen. Psychiatry 2005, 62, 593–602. [Google Scholar] [CrossRef] [PubMed]
  4. Sareen, J.; Cox, B.J.; Afifi, T.O.; de Graaf, R.; Asmundson, G.J.; ten Have, M.; Stein, M.B. Anxiety disorders and risk for suicidal ideation and suicide attempts: A population-based longitudinal study of adults. Arch. Gen. Psychiatry 2005, 62, 1249–1257. [Google Scholar] [CrossRef] [PubMed]
  5. Broekman, B.F.; Olff, M.; Boer, F. The genetic background to PTSD. Neurosci. Biobehav. Rev. 2007, 31, 348–362. [Google Scholar] [CrossRef] [PubMed]
  6. Yehuda, R. Advances in understanding neuroendocrine alterations in PTSD and their therapeutic implications. Ann. N. Y. Acad. Sci. 2006, 1071, 137–166. [Google Scholar] [CrossRef] [PubMed]
  7. Angelucci, F.; Ricci, V.; Gelfo, F.; Martinotti, G.; Brunetti, M.; Sepede, G.; Signorelli, M.; Aguglia, E.; Pettorruso, M.; Vellante, F.; et al. BDNF serum levels in subjects developing or not post-traumatic stress disorder after trauma exposure. Brain Cogn. 2014, 84, 118–122. [Google Scholar] [CrossRef] [PubMed]
  8. Southwick, S.M.; Paige, S.; Morgan, C.A., 3rd; Bremner, J.D.; Krystal, J.H.; Charney, D.S. Neurotransmitter alterations in PTSD: Catecholamines and serotonin. Semin. Clin. Neuropsychiatry 1999, 4, 242–248. [Google Scholar] [CrossRef] [PubMed]
  9. Yehuda, R.; Brand, S.; Yang, R.K. Plasma neuropeptide Y concentrations in combat exposed veterans: relationship to trauma exposure, recovery from PTSD, and coping. Biol. Psychiatry 2006, 59, 660–663. [Google Scholar] [CrossRef] [PubMed]
  10. Rauch, S.L.; Shin, L.M.; Whalen, P.J.; Pitman, R.K. Neuroimaging and the neuroanatomy of P osttraumatic Stress Disorder. CNS Spectr. 1998, 3, S30–S41. [Google Scholar] [CrossRef]
  11. Romanski, L.M.; Clugnet, M.C.; Bordi, F.; LeDoux, J.E. Somatosensory and auditory convergence in the lateral nucleus of the amygdala. Behav. Neurosci. 1993, 107, 444–450. [Google Scholar] [CrossRef] [PubMed]
  12. LeDoux, J.E. Emotion circuits in the brain. Annu. Rev. Neurosci. 2000, 23, 155–184. [Google Scholar] [CrossRef] [PubMed]
  13. LeDoux, J.E.; Iwata, J.; Cicchetti, P.; Reis, D.J. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 1988, 8, 2517–2529. [Google Scholar] [PubMed]
  14. Vidal-Gonzalez, I.; Vidal-Gonzalez, B.; Rauch, S.L.; Quirk, G.J. Microstimulation reveals opposing influences of prelimbic and infralimbic cortex on the expression of conditioned fear. Learn. Mem. 2006, 13, 728–733. [Google Scholar] [CrossRef] [PubMed]
  15. Amano, T.; Unal, C.T.; Pare, D. Synaptic correlates of fear extinction in the amygdala. Nat. Neurosci. 2010, 13, 489–494. [Google Scholar] [CrossRef] [PubMed]
  16. Corcoran, K.A.; Quirk, G.J. Recalling safety: Cooperative functions of the ventromedial prefrontal cortex and the hippocampus in extinction. CNS Spectr. 2007, 12, 200–206. [Google Scholar] [CrossRef] [PubMed]
  17. Likhtik, E.; Popa, D.; Apergis-Schoute, J.; Fidacaro, G.A.; Pare, D. Amygdala intercalated neurons are required for expression of fear extinction. Nature 2008, 454, 642–645. [Google Scholar] [CrossRef] [PubMed]
  18. Liberzon, I.; Sripada, C.S. The functional neuroanatomy of PTSD: A critical review. Prog. Brain Res. 2008, 167, 151–169. [Google Scholar] [CrossRef] [PubMed]
  19. Rauch, S.L.; Whalen, P.J.; Shin, L.M.; McInerney, S.C.; Macklin, M.L.; Lasko, N.B.; Orr, S.P.; Pitman, R.K. Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: A functional MRI study. Biol. Psychiatry 2000, 47, 769–776. [Google Scholar] [CrossRef]
  20. Chung, Y.A.; Kim, S.H.; Chung, S.K.; Chae, J.H.; Yang, D.W.; Sohn, H.S.; Jeong, J. Alterations in cerebral perfusion in posttraumatic stress disorder patients without re-exposure to accident-related stimuli. Clin. Neurophysiol. 2006, 117, 637–642. [Google Scholar] [CrossRef] [PubMed]
  21. Hughes, K.C.; Shin, L.M. Functional neuroimaging studies of post-traumatic stress disorder. Expert Rev. Neurother. 2011, 11, 275–285. [Google Scholar] [CrossRef] [PubMed]
  22. Etkin, A.; Wager, T.D. Functional neuroimaging of anxiety: A meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am. J. Psychiatry 2007, 164, 1476–1488. [Google Scholar] [CrossRef] [PubMed]
  23. Watts, B.V.; Schnurr, P.P.; Mayo, L.; Young-Xu, Y.; Weeks, W.B.; Friedman, M.J. Meta-analysis of the efficacy of treatments for posttraumatic stress disorder. J. Clin. Psychiatry 2013, 74, e541–e550. [Google Scholar] [CrossRef] [PubMed]
  24. Hamner, M.B.; Robert, S.; Frueh, B.C. Treatment-resistant posttraumatic stress disorder: Strategies for intervention. CNS Spectr. 2004, 9, 740–752. [Google Scholar] [CrossRef] [PubMed]
  25. Langevin, J.P.; de Salles, A.A.; Kosoyan, H.P.; Krahl, S.E. Deep brain stimulation of the amygdala alleviates post-traumatic stress disorder symptoms in a rat model. J. Psychiatry Res. 2010, 44, 1241–1245. [Google Scholar] [CrossRef] [PubMed]
  26. Stidd, D.A.; Vogelsang, K.; Krahl, S.E.; Langevin, J.P.; Fellous, J.M. Amygdala deep brain stimulation is superior to paroxetine treatment in a rat model of posttraumatic stress disorder. Brain Stimul. 2013, 6, 837–844. [Google Scholar] [CrossRef] [PubMed]
  27. Saldivar-Gonzalez, J.A.; Posadas-Andrews, A.; Rodriguez, R.; Gómez, C.; Hernández-Manjarrez, M.E.; Ortiz-León, S.; Martínez-Pineda, A.; Gómez-Laguna, D.; Salgado, V.; Manjarrez, J. Effect of electrical stimulation of the baso-lateral amygdala nucleus on defensive burying shock probe test and elevated plus maze in rats. Life Sci. 2003, 72, 819–829. [Google Scholar] [CrossRef]
  28. Koek, R.J.; Langevin, J.P.; Krahl, S.E.; Kosoyan, H.J.; Schwartz, H.N.; Chen, J.W.; Melrose, R.; Mandelkern, M.J.; Sultzer, D. Deep brain stimulation of the basolateral amygdala for treatment-refractory combat post-traumatic stress disorder (PTSD): Study protocol for a pilot randomized controlled trial with blinded, staggered onset of stimulation. Trials 2014, 15, 356. [Google Scholar] [CrossRef] [PubMed]
  29. Reznikov, R.; Hamani, C. Posttraumatic Stress Disorder: Perspectives for the Use of Deep Brain Stimulation. Neuromodulation 2016. E-pub ahead of print. [Google Scholar] [CrossRef] [PubMed]
  30. Sharma, M.; Naik, V.; Deogaonkar, M. Emerging applications of deep brain stimulation. J. Neurosurg. Sci. 2016, 60, 242–255. [Google Scholar] [PubMed]
  31. Blake, D.D.; Weathers, F.W.; Nagy, L.M.; Kaloupek, D.G.; Charney, D.S.; Keana, T.M. Clinician-Administered PTSD Scale for DSM-IV; National Center for Posttraumatic Stress Disorder, Rev: Boston, MA, USA; New Haven, CT, USA, 1998. [Google Scholar]
  32. National Institute of Mental Health: Clinical Global Impressions. CGI: Manual for the ECDEU Assessment Battery, 2nd ed.; Guy, W., Bonato, R.R., Chevy, C.M., Chevy Chase, M.D., Eds.; National Institute of Mental Health: Bethesda, MD, USA, 1970; pp. 12-1–12-6. [Google Scholar]
  33. Rodriguez-Romaguera, J.; do Monte, F.H.; Quirk, G.J. Deep brain stimulation of the ventral striatum enhances extinction of conditioned fear. Proc. Natl. Acad. Sci. USA 2012, 109, 8764–8769. [Google Scholar] [CrossRef] [PubMed]
  34. Garcia, R.; Spennato, G.; Nilsson-Todd, L.; Moreau, J.L.; Deschaux, O. Hippocampal low frequency stimulation and chronic mild stress similarly disrupt fear extinction memory in rats. Neurobiol. Learn. Mem. 2008, 89, 560–566. [Google Scholar] [CrossRef] [PubMed]
  35. Milad, M.R.; Vidal-Gonzalez, I.; Quirk, G.J. Electrical stimulation of medial prefrontal cortex reduces conditioned fear in a temporally specific manner. Behav. Neurosci. 2004, 118, 389–394. [Google Scholar] [CrossRef] [PubMed]
Back to TopTop