Non-invasive vagal nerve stimulation decreases brain activity during trauma scripts

Matthew T Wittbrodt, Nil Z Gurel, Jonathon A Nye, Stacy Ladd, Md Mobashir H Shandhi, Minxuan Huang, Amit J Shah, Bradley D Pearce, Zuhayr S Alam, Mark H Rapaport, Nancy Murrah, Yi-An Ko, Ammer A Haffer, Lucy H Shallenberger, Viola Vaccarino, Omer T Inan, J Douglas Bremner, Matthew T Wittbrodt, Nil Z Gurel, Jonathon A Nye, Stacy Ladd, Md Mobashir H Shandhi, Minxuan Huang, Amit J Shah, Bradley D Pearce, Zuhayr S Alam, Mark H Rapaport, Nancy Murrah, Yi-An Ko, Ammer A Haffer, Lucy H Shallenberger, Viola Vaccarino, Omer T Inan, J Douglas Bremner

Abstract

Background: Traumatic stress can have lasting effects on neurobiology and result in psychiatric conditions such as posttraumatic stress disorder (PTSD). We hypothesize that non-invasive cervical vagal nerve stimulation (nVNS) may alleviate trauma symptoms by reducing stress sympathetic reactivity. This study examined how nVNS alters neural responses to personalized traumatic scripts.

Methods: Nineteen participants who had experienced trauma but did not have the diagnosis of PTSD completed this double-blind sham-controlled study. In three sequential time blocks, personalized traumatic scripts were presented to participants immediately followed by either sham stimulation (n = 8; 0-14 V, 0.2 Hz, pulse width = 5s) or active nVNS (n = 11; 0-30 V, 25 Hz, pulse width = 40 ms). Brain activity during traumatic scripts was assessed using High Resolution Positron Emission Tomography (HR-PET) with radiolabeled water to measure brain blood flow.

Results: Traumatic scripts resulted in significant activations within the bilateral medial and orbital prefrontal cortex, premotor cortex, anterior cingulate, thalamus, insula, hippocampus, right amygdala, and right putamen. Greater activation was observed during sham stimulation compared to nVNS within the bilateral prefrontal and orbitofrontal cortex, premotor cortex, temporal lobe, parahippocampal gyrus, insula, and left anterior cingulate. During the first exposure to the trauma scripts, greater activations were found in the motor cortices and ventral visual stream whereas prefrontal cortex and anterior cingulate activations were more predominant with later script presentations for those subjects receiving sham stimulation.

Conclusion: nVNS decreases neural reactivity to an emotional stressor in limbic and other brain areas involved in stress, with changes over repeated exposures suggesting a shift from scene appraisal to cognitively processing the emotional event.

Keywords: Insula; PTSD; Prefrontal cortex; Stress; Trauma scripts; Vagal nerve stimulation.

Conflict of interest statement

Declaration of competing interest Dr. Bremner reported having funding support from ElectroCore LLC. No other authors report potential conflicts of interests.

Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.

Figures

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Fig. 1.
Participant recruitment and study timeline. A: Consolidated Standards of Reporting Trials (CONSORT) diagram of the study. HR-PET = High Resolution Positron Emission Tomography; nVNS = non-invasive vagal nerve stimulation. B: Protocol timeline for the High-Resolution Positron Emission Tomography (HR-PET) scanning session. All trauma scripts were delivered via headphones with non-invasive cervical vagal nerve stimulation (nVNS) or sham stimulation occurring after script completion. Total scanning session length was 5 h, with each trauma script/HR-PET scan lasting 2 min and stimulation lasting 2 min. The rest period lasted for 90 min and time between scans was approximately 5 min.
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References
    1. Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ. Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans. J Physiol 2000;523(Pt 1):259–70. - PMC - PubMed
    1. Akiki TJ, Averill CL, Abdallah CG. A network-based neurobiological model of PTSD: evidence from structural and functional neuroimaging studies. Curr Psychiatr Rep 2017;19(11):81. - PMC - PubMed
    1. Merz CJ, Elzinga BM, Schwabe L. Stress, fear, and memory in healthy individuals. Posttraumatic Stress Disorder John Wiley & Sons, Inc; 2016. p. 159–78.
    1. Anda RF, Brown DW, Felitti VJ, Bremner JD, Dube SR, Giles WH. Adverse childhood experiences and prescribed psychotropic medications in adults. Am J Prev Med 2007;32(5):389–94. - PMC - PubMed
    1. Gurel NZ, Huang M, Wittbrodt MT, Jung H, Ladd SL, Shandhi MMH, et al. Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress. Brain Stimul 2020;13(1):47–59. - PubMed
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Fig. 3.
Fig. 3.
Sagittal slices presenting significant (p

Fig. 4.

Coronal slices of significant (p…

Fig. 4.

Coronal slices of significant (p

Fig. 4.
Coronal slices of significant (p

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Sagittal slices presenting significant (p…

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Sagittal slices presenting significant (p…

Fig. 7.

Sagittal slices presenting significant (p

Fig. 7.
Sagittal slices presenting significant (p
All figures (7)
Similar articles
Cited by
References
    1. Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ. Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans. J Physiol 2000;523(Pt 1):259–70. - PMC - PubMed
    1. Akiki TJ, Averill CL, Abdallah CG. A network-based neurobiological model of PTSD: evidence from structural and functional neuroimaging studies. Curr Psychiatr Rep 2017;19(11):81. - PMC - PubMed
    1. Merz CJ, Elzinga BM, Schwabe L. Stress, fear, and memory in healthy individuals. Posttraumatic Stress Disorder John Wiley & Sons, Inc; 2016. p. 159–78.
    1. Anda RF, Brown DW, Felitti VJ, Bremner JD, Dube SR, Giles WH. Adverse childhood experiences and prescribed psychotropic medications in adults. Am J Prev Med 2007;32(5):389–94. - PMC - PubMed
    1. Gurel NZ, Huang M, Wittbrodt MT, Jung H, Ladd SL, Shandhi MMH, et al. Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress. Brain Stimul 2020;13(1):47–59. - PubMed
Show all 101 references
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Fig. 4.
Fig. 4.
Coronal slices of significant (p

Fig. 5.

Sagittal slices presenting significant (p…

Fig. 5.

Sagittal slices presenting significant (p

Fig. 5.
Sagittal slices presenting significant (p

Fig. 6.

Sagittal slices presenting significant (p…

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Sagittal slices presenting significant (p

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Sagittal slices presenting significant (p

Fig. 7.

Sagittal slices presenting significant (p…

Fig. 7.

Sagittal slices presenting significant (p

Fig. 7.
Sagittal slices presenting significant (p
All figures (7)
Similar articles
Cited by
References
    1. Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ. Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans. J Physiol 2000;523(Pt 1):259–70. - PMC - PubMed
    1. Akiki TJ, Averill CL, Abdallah CG. A network-based neurobiological model of PTSD: evidence from structural and functional neuroimaging studies. Curr Psychiatr Rep 2017;19(11):81. - PMC - PubMed
    1. Merz CJ, Elzinga BM, Schwabe L. Stress, fear, and memory in healthy individuals. Posttraumatic Stress Disorder John Wiley & Sons, Inc; 2016. p. 159–78.
    1. Anda RF, Brown DW, Felitti VJ, Bremner JD, Dube SR, Giles WH. Adverse childhood experiences and prescribed psychotropic medications in adults. Am J Prev Med 2007;32(5):389–94. - PMC - PubMed
    1. Gurel NZ, Huang M, Wittbrodt MT, Jung H, Ladd SL, Shandhi MMH, et al. Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress. Brain Stimul 2020;13(1):47–59. - PubMed
Show all 101 references
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Cite
Copy Download .nbib
Format: AMA APA MLA NLM

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Fig. 5.
Fig. 5.
Sagittal slices presenting significant (p

Fig. 6.

Sagittal slices presenting significant (p…

Fig. 6.

Sagittal slices presenting significant (p

Fig. 6.
Sagittal slices presenting significant (p

Fig. 7.

Sagittal slices presenting significant (p…

Fig. 7.

Sagittal slices presenting significant (p

Fig. 7.
Sagittal slices presenting significant (p
All figures (7)
Similar articles
Cited by
References
    1. Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ. Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans. J Physiol 2000;523(Pt 1):259–70. - PMC - PubMed
    1. Akiki TJ, Averill CL, Abdallah CG. A network-based neurobiological model of PTSD: evidence from structural and functional neuroimaging studies. Curr Psychiatr Rep 2017;19(11):81. - PMC - PubMed
    1. Merz CJ, Elzinga BM, Schwabe L. Stress, fear, and memory in healthy individuals. Posttraumatic Stress Disorder John Wiley & Sons, Inc; 2016. p. 159–78.
    1. Anda RF, Brown DW, Felitti VJ, Bremner JD, Dube SR, Giles WH. Adverse childhood experiences and prescribed psychotropic medications in adults. Am J Prev Med 2007;32(5):389–94. - PMC - PubMed
    1. Gurel NZ, Huang M, Wittbrodt MT, Jung H, Ladd SL, Shandhi MMH, et al. Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress. Brain Stimul 2020;13(1):47–59. - PubMed
Show all 101 references
Publication types
MeSH terms
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM

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The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

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Fig. 6.
Fig. 6.
Sagittal slices presenting significant (p

Fig. 7.

Sagittal slices presenting significant (p…

Fig. 7.

Sagittal slices presenting significant (p

Fig. 7.
Sagittal slices presenting significant (p
All figures (7)
Similar articles
Cited by
References
    1. Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ. Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans. J Physiol 2000;523(Pt 1):259–70. - PMC - PubMed
    1. Akiki TJ, Averill CL, Abdallah CG. A network-based neurobiological model of PTSD: evidence from structural and functional neuroimaging studies. Curr Psychiatr Rep 2017;19(11):81. - PMC - PubMed
    1. Merz CJ, Elzinga BM, Schwabe L. Stress, fear, and memory in healthy individuals. Posttraumatic Stress Disorder John Wiley & Sons, Inc; 2016. p. 159–78.
    1. Anda RF, Brown DW, Felitti VJ, Bremner JD, Dube SR, Giles WH. Adverse childhood experiences and prescribed psychotropic medications in adults. Am J Prev Med 2007;32(5):389–94. - PMC - PubMed
    1. Gurel NZ, Huang M, Wittbrodt MT, Jung H, Ladd SL, Shandhi MMH, et al. Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress. Brain Stimul 2020;13(1):47–59. - PubMed
Show all 101 references
Publication types
MeSH terms
[x]
Cite
Copy Download .nbib
Format: AMA APA MLA NLM
Fig. 7.
Fig. 7.
Sagittal slices presenting significant (p
All figures (7)

References

    1. Critchley HD, Corfield DR, Chandler MP, Mathias CJ, Dolan RJ. Cerebral correlates of autonomic cardiovascular arousal: a functional neuroimaging investigation in humans. J Physiol 2000;523(Pt 1):259–70.
    1. Akiki TJ, Averill CL, Abdallah CG. A network-based neurobiological model of PTSD: evidence from structural and functional neuroimaging studies. Curr Psychiatr Rep 2017;19(11):81.
    1. Merz CJ, Elzinga BM, Schwabe L. Stress, fear, and memory in healthy individuals. Posttraumatic Stress Disorder John Wiley & Sons, Inc; 2016. p. 159–78.
    1. Anda RF, Brown DW, Felitti VJ, Bremner JD, Dube SR, Giles WH. Adverse childhood experiences and prescribed psychotropic medications in adults. Am J Prev Med 2007;32(5):389–94.
    1. Gurel NZ, Huang M, Wittbrodt MT, Jung H, Ladd SL, Shandhi MMH, et al. Quantifying acute physiological biomarkers of transcutaneous cervical vagal nerve stimulation in the context of psychological stress. Brain Stimul 2020;13(1):47–59.
    1. Pitman RK, Rasmusson AM, Koenen KC, Shin LM, Orr SP, Gilbertson MW, et al. Biological studies of post-traumatic stress disorder. Nat Rev Neurosci 2012;13(11):769–87.
    1. Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci 2009;10(6): 434–45.
    1. Bremner JD, Randall P, Vermetten E, Staib L, Bronen RA, Mazure C, et al. Magnetic resonance imaging-based measurement of hippocampal volume in posttraumatic stress disorder related to childhood physical and sexual abuse–a preliminary report. Biol Psychiatr 1997;41(1):23–32.
    1. Lerman I, Davis B, Huang M, Huang C, Sorkin L, Proudfoot J, et al. Noninvasive vagus nerve stimulation alters neural response and physiological autonomic tone to noxious thermal challenge. PloS One 2019;14(2):e0201212.
    1. Lerman I, Hauger R, Sorkin L, Proudfoot J, Davis B, Huang A, et al. Noninvasive transcutaneous vagus nerve stimulation decreases whole blood culture-derived cytokines and chemokines: a randomized, blinded, healthy control pilot trial. Neuromodulation: Technol. Neural Inter 2016;19(3):283–90.
    1. Zhou L, Lin J, Lin J, Kui G, Zhang J, Yu Y. Neuroprotective effects of vagus nerve stimulation on traumatic brain injury. Neural Regen Res 2014;9(17): 1585–91.
    1. George MS, Rush AJ, Marangell LB, Sackeim HA, Brannan SK, Davis SM, et al. A one-year comparison of vagus nerve stimulation with treatment as usual for treatment-resistant depression. Biol Psychiatr 2005;58(5):364–73.
    1. Sackeim HA, Brannan SK, Rush AJ, George MS, Marangell LB, Allen J. Durability of antidepressant response to vagus nerve stimulation (VNS). Int J Neuropsychopharmacol 2007;10(6):817–26.
    1. Rong P, Liu J, Wang L, Liu R, Fang J, Zhao J, et al. Effect of transcutaneous auricular vagus nerve stimulation on major depressive disorder: a nonrandomized controlled pilot study. J Affect Disord 2016;195:172–9.
    1. Fang J, Rong P, Hong Y, Fan Y, Liu J, Wang H, et al. Transcutaneous vagus nerve stimulation modulates default mode network in major depressive disorder. Biol Psychiatr 2016;79(4):266–73.
    1. Pruitt DT, Schmid AN, Kim LJ, Abe CM, Trieu JL, Choua C, et al. Vagus nerve stimulation delivered with motor training enhances recovery of function after traumatic brain injury. J Neurotrauma 2016;33(9):871–9.
    1. Smith DC, Modglin AA, Roosevelt RW, Neese SL, Jensen RA, Browning RA, et al. Electrical stimulation of the vagus nerve enhances cognitive and motor recovery following moderate fluid percussion injury in the rat. J Neurotrauma 2005;22(12):1485–502.
    1. Noble LJ, Meruva VB, Hays SA, Rennaker RL, Kilgard MP, McIntyre CK. Vagus nerve stimulation promotes generalization of conditioned fear extinction and reduces anxiety in rats. Brain Stimul 2019;12(1):9–18.
    1. Clark KB, Krahl SE, Smith DC, Jensen RA. Post-training unilateral vagal stimulation enhances retention performance in the rat. Neurobiol Learn Mem 1995;63(3):213–6.
    1. Clark KB, Smith DC, Hassert DL, Browning RA, Naritoku DK, Jensen RA. Posttraining electrical stimulation of vagal afferents with concomitant vagal efferent inactivation enhances memory storage processes in the rat. Neurobiol Learn Mem 1998;70(3):364–73.
    1. Bansal V, Ryu SY, Lopez N, Allexan S, Krzyzaniak M, Eliceiri B, et al. Vagal stimulation modulates inflammation through a ghrelin mediated mechanism in traumatic brain injury. Inflammation 2012;35(1):214–20.
    1. Lamb DG, Porges EC, Lewis GF, Williamson JB. Non-invasive vagal nerve stimulation effects on hyperarousal and autonomic state in patients with posttraumatic stress disorder and history of mild traumatic brain injury: preliminary evidence. Front Med (Lausanne) 2017;4:124.
    1. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405(6785):458–62.
    1. Noble LJ, Souza RR, McIntyre CK. Vagus nerve stimulation as a tool for enhancing extinction in exposure-based therapies. Psychopharmacology 2019;236(1):355–67.
    1. Manta S, Dong J, Debonnel G, Blier P. Enhancement of the function of rat serotonin and norepinephrine neurons by sustained vagus nerve stimulation. J Psychiatry Neurosci 2009;34(4):272–80.
    1. Manta S, El Mansari M, Debonnel G, Blier P. Electrophysiological and neurochemical effects of long-term vagus nerve stimulation on the rat monoaminergic systems. Int J Neuropsychopharmacol 2013;16(2):459–70.
    1. Groves DA, Bowman EM, Brown VJ. Recordings from the rat locus coeruleus during acute vagal nerve stimulation in the anaesthetised rat. Neurosci Lett 2005;379(3):174–9.
    1. Kraus T, Hosl K, Kiess O, Schanze A, Kornhuber J, Forster C. BOLD fMRI deactivation of limbic and temporal brain structures and mood enhancing effect by transcutaneous vagus nerve stimulation. J Neural Transm (Vienna) 2007;114(11):1485–93.
    1. Morilak DA, Barrera G, Echevarria DJ, Garcia AS, Hernandez A, Ma S, et al. Role of brain norepinephrine in the behavioral response to stress. Prog Neuro-Psychopharmacol Biol Psychiatry 2005;29(8):1214–24.
    1. Krahl SE, Clark KB, Smith DC, Browning RA. Locus coeruleus lesions suppress the seizure-attenuating effects of vagus nerve stimulation. Epilepsia 1998;39(7):709–14.
    1. Lerman I, Hauger R, Sorkin L, Proudfoot J, Davis B, Huang A, et al. Noninvasive transcutaneous vagus nerve stimulation decreases whole blood culture-derived cytokines and chemokines: a randomized, blinded, healthy control pilot trial. Neuromodulation 2016;19(3):283–90.
    1. Clark KB, Naritoku DK, Smith DC, Browning RA, Jensen RA. Enhanced recognition memory following vagus nerve stimulation in human subjects. Nat Neurosci 1999;2(1):94–8.
    1. Sackeim HA, Keilp JG, Rush AJ, George MS, Marangell LB, Dormer JS, et al. The effects of vagus nerve stimulation on cognitive performance in patients with treatment-resistant depression. Neuropsys. Neuropsychol. Behav Neuro 2001;14:53–62.
    1. Suthana N, Fried I. Deep brain stimulation for enhancement of learning and memory. Neuroimage 2014;85:996–1002.
    1. Lewine JD, Paulson K, Bangera N, Simon BJ. Exploration of the impact of brief noninvasive vagal nerve stimulation on EEG and event-related potentials. Neuromodulation 2018;22(5):564–72. 10.1111/ner.12864.
    1. Bremner JD, Rapaport MH. Vagus nerve stimulation: back to the future. Am J Psychiatr 2017;174(7):609–10.
    1. Neren D, Johnson MD, Legon W, Bachour SP, Ling G, Divani AA. Vagus nerve stimulation and other neuromodulation methods for treatment of traumatic brain injury. Neurocritical Care 2016;24(2):308–19.
    1. Mourdoukoutas AP, Truong DQ, Adair DK, Simon BJ, Bikson M. High-resolution multi-scale computational model for non-invasive cervical vagus nerve stimulation. Neuromodulation 2018;21(3):261–8.
    1. Nonis R, D’Ostilio K, Schoenen J, Magis D. Evidence of activation of vagal afferents by non-invasive vagus nerve stimulation: an electrophysiological study in healthy volunteers. Cephalalgia 2017;37(13):1285–93.
    1. Usami K, Kawai K, Sonoo M, Saito N. Scalp-recorded evoked potentials as a marker for afferent nerve impulse in clinical vagus nerve stimulation. Brain Stimul 2013;6(4):615–23.
    1. Frangos E, Komisaruk BR. Access to vagal projections via cutaneous electrixal stimulation of the neck: fMRI evidence in healthy humans. Brain Stimulation 2017;10:19–27.
    1. Frangos E, Ellrich E, Komisaruk BR. Non-invasive access to the vagus nerve central projections via electrical stimulation of the external ear: fMRI evidence in humans. Brain Stimulation 2015;8:624–36.
    1. Yakunina N, Kim SS, Nam EC. Optimization of transcutaneous vagus nerve stimulation using functional MRI. Neuromodulation 2017;20(3):290–300.
    1. Badran BW, Dowdle LT, Mithoefer OJ, LaBate NT, Coatsworth J, Brown JC, et al. Neurophysiologic effects of transcutaneous auricular vagus nerve stimulation (taVNS) via electrical stimulation of the tragus: a concurrent taVNS/fMRI study and review. Brain Stimul 2018;11(3):492–500.
    1. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T, Charney DS. Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am J Psychiatr 1999;156(11): 1787–95.
    1. Liberzon I, Britton JC, Phan KL. Neural correlates of traumatic recall in posttraumatic stress disorder. Stress 2003;6(3):151–6.
    1. Lanius RA, Williamson PC, Densmore M, Boksman K, Gupta MA, Neufeld RW, et al. Neural correlates of traumatic memories in posttraumatic stress disorder: a functional MRI investigation. Am J Psychiatr 2001;158(11):1920–2.
    1. Lindauer RJ, Booij J, Habraken JB, van Meijel EP, Uylings HB, Olff M, et al. Effects of psychotherapy on regional cerebral blood flow during trauma imagery in patients with post-traumatic stress disorder: a randomized clinical trial. Psychol Med 2008;38(4):543–54.
    1. Etkin A, Wager T. Functional neuroimaging of anxiety: a meta-analysis of emotional processing in PTSD, social anxiety disorder, and specific phobia. Am J Psychiatr 2007;164(10).
    1. American Psychiatric Association. In: The diagnostic and statistical manual of mental disorders. fifth ed. Washington, D.C.: American Psychiatric Association; 2013. (DSM-5). 5 ed.
    1. Weathers FW, Bovin MJ, Lee DJ, Sloan DM, Schnurr PP, Kaloupek DG, et al. The Clinician-Administered PTSD Scale for DSM-5 (CAPS-5): development and initial psychometric evaluation in military veterans. Psychol Assess 2018;30(3):383–95.
    1. Bremner JD, Bolus R, Mayer EA. Psychometric properties of the early trauma inventory-self report. J Nerv Ment Dis 2007;195(3):211–8.
    1. Bremner JD, Vermetten E, Mazure CM. Development and preliminary psychometric properties of an instrument for the measurement of childhood trauma: the Early Trauma Inventory. Depress Anxiety 2000;12(1):1–12.
    1. Wittbrodt MT, Vaccarino V, Shah AJ, Mayer EA, Bremner JD. Psychometric properties of the adulthood trauma inventory. Health Psychol 2020. 10.1037/hea0000856. In press.
    1. First MB, Gibbon M. The structured clinical interview for DSM-IV Axis I disorders (SCID-I) and the structured clinical interview for DSM-IV Axis II disorders (SCID-II). In: Segal MJHDL, editor Comprehensive handbook of psychological assessment. Hoboken, NJ, US: John Wiley & Sons Inc.; 2004. p. 134–43.
    1. Schmand M, Wienhard K, Casey M, Eriksson L, Jones W, Reed J, et al. Performance evaluation of a new LSO high resolution research tomograph-HRRT. In: Nuclear science symposium, 1999. Conference record. 1999 IEEE, vol. 2. IEEE; 1999. p. 1067–71.
    1. Bremner JD, Campanella C, Khan Z, Shah M, Hammadah M, Wilmot K, et al. Brain correlates of mental stress-induced myocardial ischemia. Psychosom Med 2018;80(6):515–25. 10.1097/PSY.0000000000000597.
    1. Gläscher J, Gitelman D. Contrast weights in flexible factorial design with multiple groups of subjects. Sml. SPM@ JISCMAIL AC UK; 2008. p. 1–12.
    1. Lane RD, Reiman EM, Ahern GL, Schwartz GE, Davidson RJ. Neuroanatomical correlates of happiness, sadness, and disgust. Am J Psychiatr 1997;154(7): 926–33.
    1. Reiman EM, Lane RD, Ahern GL, Schwartz GE, Davidson RJ, Friston KJ, et al. Neuroanatomical correlates of externally and internally generated human emotion. Am J Psychiatr 1997;154(7):918–25.
    1. Talairach J, Tournoux P. Co-planar stereotaxic atlas of the human brain: 3-dimensional proportional system: an approach to cerebral imaging. 1988.
    1. Lanius RA, Williamson PC, Densmore M, Boksman K, Neufeld RW, Gati JS, et al. The nature of traumatic memories: a 4-T FMRI functional connectivity analysis. Am J Psychiatr 2004;161(1):36–44.
    1. Bremner JD, Staib LH, Kaloupek D, Southwick SM, Soufer R, Charney DS. Neural correlates of exposure to traumatic pictures and sound in Vietnam combat veterans with and without posttraumatic stress disorder: a positron emission tomography study. Biol Psychiatr 1999;45(7):806–16.
    1. Bremner JD, Vythilingam M, Vermetten E, Southwick SM, McGlashan T, Nazeer A, et al. MRI and PET study of deficits in hippocampal structure and function in women with childhood sexual abuse and posttraumatic stress disorder (PTSD). Am J Psychiatr 2003;160(5):924–32.
    1. Britton JC, Phan KL, Taylor SF, Fig LM, Liberzon I. Corticolimbic blood flow in posttraumatic stress disorder during script-driven imagery. Biol Psychiatr 2005;57(8):832–40.
    1. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T, Charney DS. Neural correlates of memories of childhood sexual abuse in women with and without posttraumatic stress disorder. Am J Psychiatr 1999;156(11): 1787–95.
    1. Rauch SL, van der Kolk BA, Fisler RE, Alpert NM, Orr SP, Savage CR, et al. A symptom provocation study of posttraumatic stress disorder using positron emission tomography and script-driven imagery. Arch Gen Psychiatr 1996;53(5):380–7.
    1. Osuch EA, Benson B, Geraci M, Podell D, Herscovitch P, McCann UD, et al. Regional cerebral blood flow correlated with flashback intensity in patients with posttraumatic stress disorder. Biol Psychiatr 2001;50(4):246–53.
    1. Dixon ML, Thiruchselvam R, Todd R, Christoff K. Emotion and the prefrontal cortex: an integrative review. Psychol Bull 2017;143(10):1033–81.
    1. Gilboa A, Shalev AY, Laor L, Lester H, Louzoun Y, Chisin R, et al. Functional connectivity of the prefrontal cortex and the amygdala in posttraumatic stress disorder. Biol Psychiatr 2004;55(3):263–72.
    1. Lindquist KA, Satpute AB, Wager TD, Weber J, Barrett LF. The brain basis of positive and negative affect: evidence from a meta-analysis of the human neuroimaging literature. Cerebr Cortex 2016;26(5):1910–22.
    1. Kross E, Davidson M, Weber J, Ochsner K. Coping with emotions past: the neural bases of regulating affect associated with negative autobiographical memories. Biol Psychiatr 2009;65(5):361–6.
    1. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995;118(Pt 1):279–306.
    1. Bush G, Luu P, Posner MI. Cognitive and emotional influences in anterior cingulate cortex. Trends Cognit Sci 2000;4(6):215–22.
    1. Kraynak TE, Marsland AL, Gianaros PJ. Neural mechanisms linking emotion with cardiovascular disease. Curr Cardiol Rep 2018;20(12):128.
    1. Hays SA, Rennaker RL, Kilgard MP. Targeting plasticity with vagus nerve stimulation to treat neurological disease. Prog Brain Res 2013;207:275–99.
    1. Detari L, Juhasz G, Kukorelli T. Effect of stimulation of vagal and radial nerves on neuronal activity in the basal forebrain area of anaesthetized cats. Acta Physiol Hung 1983;61(3):147–54.
    1. Follesa P, Biggio F, Gorini G, Caria S, Talani G, Dazzi L, et al. Vagus nerve stimulation increases norepinephrine concentration and the gene expression of BDNF and bFGF in the rat brain. Brain Res 2007;1179:28–34.
    1. Gurel NZ, Wittbrodt MT, Jung H, Ladd SL, Shah AJ, Vaccarino V, et al. Automatic detection of target engagement in transcutaneous cervical vagal nerve stimulation for traumatic stress triggers. IEEE J Biomed Health Inform 2020;24(7):1917–25. 10.1109/JBHI.2020.2981116.
    1. Gurel NZ, Gazi AH, Scott KL, Wittbrodt MT, Shah AJ, Vaccarino V, et al. Timing considerations for noninvasive vagal nerve stimulation in clinical studies. AMIA Annu Symp Proc 2019;2019:1061–70.
    1. Shetake JA, Engineer ND, Vrana WA, Wolf JT, Kilgard MP. Pairing tone trains with vagus nerve stimulation induces temporal plasticity in auditory cortex. Exp Neurol 2012;233(1):342–9.
    1. Weiner KS, Zilles K. The anatomical and functional specialization of the fusiform gyrus. Neuropsychologia 2016;83:48–62.
    1. Goodale MA, Milner AD. Separate visual pathways for perception and action. Trends Neurosci 1992;15:20–5.
    1. Silson EH, Gilmore AW, Kalinowski SE, Steel A, Kidder A, Martin A, et al. A posterior-anterior distinction between scene perception and scene construction in human medial parietal cortex. J Neurosci 2019;39(4):705–17.
    1. Svoboda E, McKinnon MC, Levine B. The functional neuroanatomy of autobiographical memory: a meta-analysis. Neuropsychologia 2006;44(12): 2189–208.
    1. Kulkarni B, Bentley DE, Elliott R, Youell P, Watson A, Derbyshire SW, et al. Attention to pain localization and unpleasantness discriminates the functions of the medial and lateral pain systems. Eur J Neurosci 2005;21(11): 3133–42.
    1. Goldin PR, McRae K, Ramel W, Gross JJ. The neural bases of emotion regulation: reappraisal and suppression of negative emotion. Biol Psychiatr 2008;63(6):577–86.
    1. Noble IJ, Gonzalez IJ, Meruva VB, Callahan KA, Belfort BD, Ramanathan KR, et al. Effects of vagus nerve stimulation on extinction of conditioned fear and post-traumatic stress disorder symptoms in rats. Transl Psychiatry 2017;7(e1217):1–8.
    1. Souza RR, Robertson NM, Pruitt DT, Gonzales PA, Hays SA, Rennaker RL, et al. Vagus nerve stimulation reverses the extinction impairments in a model of PTSD with prolonged and repeated trauma. Stress 2019;22(4):509–20.
    1. Burger AM, Van der Does W, Thayer JF, Brosschot JF, Verkuil B. Transcutaneous vagus nerve stimulation reduces spontaneous but not induced negative thought intrusions in high worriers. Biol Psychol 2019;142:80–9.
    1. Burger AM, Verkuil B, Fenlon H, Thijs L, Cools L, Miller HC, et al. Mixed evidence for the potential of non-invasive transcutaneous vagal nerve stimulation to improve the extinction and retention of fear. Behav Res Ther 2017;97:64–74.
    1. Burger AM, Verkuil B, Van Diest I, Van der Does W, Thayer JF, Brosschot JF. The effects of transcutaneous vagus nerve stimulation on conditioned fear extinction in humans. Neurobiol Learn Mem 2016;132:49–56.
    1. Burger AM, Van Diest I, van der Does W, Hysaj M, Thayer JF, Brosschot JF, et al. Transcutaneous vagus nerve stimulation and extinction of prepared fear: a conceptual non-replication. Sci Rep 2018;8(1):11471.
    1. Bremner JD, Mishra S, Campanella C, Shah M, Kasher N, Evans S, et al. A pilot study of the effects of mindfulness-based stress reduction on post-traumatic stress disorder symptoms and brain response to traumatic reminders of combat in operation enduring freedom/operation Iraqi freedom combat veterans with post-traumatic stress disorder. Front Psychiatr 2017;8:157.
    1. Campanella C, Bremner JD. Neuroimaging of PTSD. In: Bremner JD, editor. Posttraumatic stress disorder: from neurobiology to treatment. Hoboken, New Jersey: Wiley-Blackwell; 2016. p. 291–320.
    1. Cain C, Sullivan R. Amygdala contributions to fear and safety conditioning: insights into PTSD from an animal model across development. Posttraumatic Stress Disorder: From Neurobiology to Treatment 2016:81–104.
    1. Zoladz PR, Diamond D. Psychosocial predator stress model of PTSD based on clinically relevant risk factors for trauma-induced psychopathology. Posttraumatic Stress Disorder: From Neurobiology to Treatment 2016;125: 125–43.
    1. Kraus T, Kiess O, Hosl K, Terekhin P, Kornhuber J, Forster C. CNS BOLD fMRI effects of sham-controlled transcutaneous electrical nerve stimulation in the left outer auditory canal - a pilot study. Brain Stimul 2013;6(5):798–804.
    1. Fallgatter AJ, Neuhauser B, Herrmann MJ, Ehlis A-C, Wagener A, Scheuerpflug P, et al. Far field potentials from the brain stem after transcutaneous vagus nerve stimulation. J Neural Transm 2003;110:1437–43.
    1. Polak T, Markulin F, Ehlis A-C, Langer JBM, Ringel TM, Fallgatter AJ. Far field potentials from brain stem after transcutaneous vagus nerve stimulation: optimization of stimulation and recording parameters. J Neural Transm 2009;116:1237–42.
    1. Dimitrov B, Gatev P. Effects of acute transcutaneous vagal stimulation on the EEG power maps, EEG sources distribution and steadiness of quiet and sensory-conflicted stance. Balance Brain: Int Works Proc. 2015:45–54.

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