Transcutaneous vagal nerve stimulation blocks stress-induced activation of Interleukin-6 and interferon-γ in posttraumatic stress disorder: A double-blind, randomized, sham-controlled trial

Bremner, J. Douglas; Gurel, Nil Z.; Jiao, Yunshen; Wittbrodt, Matthew T.; Levantsevych, Oleksiy; Huang, Minxuan; Jung, Hewon; Shandhi, MdMobashir H.; Beckwith, Joy; Herring, Isaias; Rapaport, Mark Hyman; Murrah, Nancy; Driggers, Emily; Ko, Yi‐An; Alkhalaf, Mhmtjamil; Soudan, Majd; Song, Jin H.; Ku, Benson S.; Shallenberger, Lucy; Hankus, Allison; Nye, Jonathon A.; Park, Jeanie; Vaccarino, Viola; Shah, Amit; Inan, Omer T.; Pearce, Bradley D.

doi:10.1016/j.bbih.2020.100138

Cited by 21 publications

(18 citation statements)

References 183 publications

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“…Recent work has shown that effects of auricular stimulation on cardiac function do not outlast the stimulation epoch [61]. The short-duration (<1 s), discrete pulse trains used in the present study are less likely to elicit carryover effects observed with continuous, 2-min bouts of stimulation used in previous studies examining inflammatory and neuropeptide responses [62,63]. To minimize the potential for carryover, 10 min elapsed between sets of trials at each stimulation frequency; location and frequency conditions were also counterbalanced.…”

Section: Eye Tracking Configurationmentioning

confidence: 56%

Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans

et al. 2021

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Background: Transcutaneous stimulation of the external ear is thought to recruit afferents of the auricular vagus nerve, providing a means to activate noradrenergic pathways in the central nervous system. Findings from human studies examining the effects of auricular stimulation on noradrenergic biomarkers have been mixed, possibly relating to the limited and variable parameter space explored to date. Objective: We tested the extent to which brief pulse trains applied to locations of auricular innervation (canal and concha) elicit acute pupillary responses (PRs) compared to a sham location (lobe). Pulse amplitude and frequency were varied systematically to examine effects on PR features. Methods: Participants (n ¼ 19) underwent testing in three separate experiments, each with stimulation applied to a different external ear location. Perceptual threshold (PT) was measured at the beginning of each experiment. Pulse trains (~600 ms) consisting of different amplitude (0.0xPT, 0.8xPT, 1.0xPT, 1.5xPT, 2.0xPT) and frequency (25 Hz, 300 Hz) combinations were administered during eye tracking procedures. Results: Stimulation to all locations elicited PRs which began approximately halfway through the pulse train and peaked shortly after the final pulse ( 1 s). PR size and incidence increased with pulse amplitude and tended to be greatest with canal stimulation. Higher pulse frequency shortened the latency of PR onset and peak dilation. Changes in pupil diameter elicited by pulse trains were weakly associated with baseline pupil diameter. Conclusion: (s): Auricular stimulation elicits acute PRs, providing a basis to synchronize neuromodulator release with task-related neural spiking which preclinical studies show is a critical determinant of therapeutic effects. Further work is needed to dissociate contributions from vagal and non-vagal afferents mediating activation of the biomarker.

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Section: Eye Tracking Configurationmentioning

confidence: 56%

Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans

et al. 2021

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“…Research into MDMA-assisted psychotherapy, as well as other nontraditional treatment options for PTSD (e.g., vagal nerve stimulation, stellate ganglion blockade), has occurred because of the non-response rates that were observed with traditional therapies [ 35 ]. While CBT with prolonged exposure therapy is effective in some patients, it takes time and considerable expertise [ 36 ], and the efficacy of SSRIs in the treatment of PTSD has recently come into question [ 37 , 38 ]. Furthermore, less than half of patients with PTSD either seek or receive treatment, and for those that do, the dropout rate is approximately 24% [ 36 ].…”

Section: Reviewmentioning

confidence: 99%

“…While CBT with prolonged exposure therapy is effective in some patients, it takes time and considerable expertise [ 36 ], and the efficacy of SSRIs in the treatment of PTSD has recently come into question [ 37 , 38 ]. Furthermore, less than half of patients with PTSD either seek or receive treatment, and for those that do, the dropout rate is approximately 24% [ 36 ]. Feduccia et al [ 32 ] compared data that was used for the approval of the only two FDA-approved oral medications for the treatment of PTSD, sertraline and paroxetine, with the data for MDMA-assisted psychotherapy that was submitted for its successful breakthrough therapy application.…”

Section: Reviewmentioning

confidence: 99%

The Efficacy of MDMA (3,4-Methylenedioxymethamphetamine) for Post-traumatic Stress Disorder in Humans: A Systematic Review and Meta-Analysis

Tedesco

Gajaram

Chida

et al. 2021

Cureus

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Background : 3,4-methylenedioxymethamphetamine (MDMA), known recreationally as “Molly” or “Ecstasy”, is a triple monoamine reuptake inhibitor. MDMA specifically acts as a weak 5-HT1 and 5-HT2 receptor agonist, targeting 5-HT 2A , 5-HT 2B , and 5-HT 2C receptors. Its potential use for therapeutic purposes with these pharmacological profiles remains a controversial subject. Studies have shown the potential benefits in clinical trials for post-traumatic stress disorder (PTSD). A larger amount of data has been provided for the push in support of MDMA-assisted psychotherapy in these patients. Objective : The aim of this article is to compute a meta-analysis and conduct a systematic review of the effects of MDMA on PTSD, discussing the potential benefits and adverse events relative to dosing and stability of treatment. Methods : Articles were collected and analyzed for systematic review: 16 articles were included in the systematic review that met the criteria for the use of MDMA in the treatment of PTSD as well as assessing the safety and efficacy of the drug in human participants. Ten studies were used for the meta-analysis, with a cumulative sample size of 168 patients. The significance of the findings on dosing and efficacy of MDMA in healthy human participants was quantified based on the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and PTSD symptom scores. Results : The disorders for which MDMA demonstrated a net positive or net negative effect on symptoms are presented separately. Adverse events in patients across all disease classes are presented. The therapeutic index for patients who demonstrated a benefit is also presented. An odds ratio for beneficial and adverse events is used to determine treatment-resistant patients who may benefit from clinical trials of MDMA. Discussion : Findings show promising evidence for the potential therapeutic use of MDMA alongside psychotherapy in the treatment of PTSD. The pharmacological profile of MDMA may provide direction for future drug developments to treat patients with treatment-resistant psychiatric disorders.

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“…VNS can be applied to branches of the vagus nerve in the ear (transcutaneous auricular VNS, or taVNS) or in the neck, where it travels through the carotid sheath (transcutaneous cervical VNS, or tcVNS) ( Adair et al, 2020 ; Badran et al, 2019 ; Bremner et al, 2020b ). PTSD is associated with an increase in the blood concentrations of the inflammatory marker interleukin (IL)-6 at baseline ( Gill et al, 2010 ; Gill et al, 2008 ; ( Guo et al, 2012 ); Li et al, 2014 ; Lindqvist et al, 2017 ; Miller et al, 2001 ; Passos et al, 2015 ; Sutherland et al, 2003 ; Tucker et al, 2010 ; Vidovic et al, 2011 ; von Kanel et al, 2010 ) and in response to mental stress such as public speaking ( Lima et al, 2019 ) or exposure to personalized traumatic scripts ( Bremner et al, 2020a ) as well as in diurnal cerebrospinal fluid (CSF) ( Baker et al, 2001 ). Studies have shown increased blood concentrations of interferonγ (IFNγ) at baseline ( Guo et al, 2012 ; Hoge et al, 2009 ; Lindqvist et al, 2014 ; Passos et al, 2015 ; Woods et al, 2005 ; Zhou et al, 2014 ) and in response to traumatic script stress in PTSD ( Bremner et al, 2020a ).…”

Section: Introductionmentioning

confidence: 99%

“…PTSD is associated with an increase in the blood concentrations of the inflammatory marker interleukin (IL)-6 at baseline ( Gill et al, 2010 ; Gill et al, 2008 ; ( Guo et al, 2012 ); Li et al, 2014 ; Lindqvist et al, 2017 ; Miller et al, 2001 ; Passos et al, 2015 ; Sutherland et al, 2003 ; Tucker et al, 2010 ; Vidovic et al, 2011 ; von Kanel et al, 2010 ) and in response to mental stress such as public speaking ( Lima et al, 2019 ) or exposure to personalized traumatic scripts ( Bremner et al, 2020a ) as well as in diurnal cerebrospinal fluid (CSF) ( Baker et al, 2001 ). Studies have shown increased blood concentrations of interferonγ (IFNγ) at baseline ( Guo et al, 2012 ; Hoge et al, 2009 ; Lindqvist et al, 2014 ; Passos et al, 2015 ; Woods et al, 2005 ; Zhou et al, 2014 ) and in response to traumatic script stress in PTSD ( Bremner et al, 2020a ). Other studies showed increased baseline Tumor Necrosis Factor (TNF)-α blood concentrations in PTSD ( Gill et al, 2010 ; Lindqvist et al, 2017 ; Lindqvist et al, 2014 ; Passos et al, 2015 ; Sutherland et al, 2003 ; Vidovic et al, 2011 ; von Känel et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Transcutaneous Cervical Vagal Nerve Stimulation in Patients with Posttraumatic Stress Disorder (PTSD): A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 Response to Stress

Bremner

Wittbrodt

Gurel

et al. 2021

Journal of Affective Disorders Reports

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Background: Posttraumatic stress disorder (PTSD) is a highly disabling condition associated with alterations in multiple neurobiological systems, including increases in inflammatory and sympathetic function, responsible for maintenance of symptoms. Treatment options including medications and psychotherapies have limitations. We previously showed that transcutaneous Vagus Nerve Stimulation (tcVNS) blocks inflammatory (interleukin (IL)-6) responses to stress in PTSD. The purpose of this study was to assess the effects of tcVNS on PTSD symptoms and inflammatory responses to stress. Methods: Twenty patients with PTSD were randomized to double blind active tcVNS (N=9) or sham (N=11) stimulation in conjunction with exposure to personalized traumatic scripts immediately followed by active or sham tcVNS and measurement of IL-6 and other biomarkers of inflammation. Patients then self administered active or sham tcVNS twice daily for three months. PTSD symptoms were measured with the PTSD Checklist (PCL) and the Clinician Administered PTSD Scale (CAPS), clinical improvement with the Clinical Global Index (CGI) and anxiety with the Hamilton Anxiety Scale (Ham-A) at baseline and one-month intervals followed by a repeat of measurement of biomarkers with traumatic scripts. After three months patients self treated with twice daily open label active tcVNS for another three months followed by assessment with the CGI. Results: Traumatic scripts increased IL-6 in PTSD patients, an effect that was blocked by tcVNS (p<.05). Active tcVNS treatment for three months resulted in a 31% greater reduction in PTSD symptoms compared to sham treatment as measured by the PCL (p=0.013) as well as hyperarousal symptoms and somatic anxiety measured with the Ham-A p<0.05). IL-6 increased from baseline in sham but not tcVNS. Open label tcVNS resulted in improvements measured with the CGI compared to the sham treatment period p<0.05). Conclusions: These preliminary results suggest that tcVNS reduces inflammatory responses to stress, which may in part underlie beneficial effects on PTSD symptoms.

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Transcutaneous vagal nerve stimulation blocks stress-induced activation of Interleukin-6 and interferon-γ in posttraumatic stress disorder: A double-blind, randomized, sham-controlled trial

Cited by 21 publications

References 183 publications

Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans

Electrical stimulation of the external ear acutely activates noradrenergic mechanisms in humans

The Efficacy of MDMA (3,4-Methylenedioxymethamphetamine) for Post-traumatic Stress Disorder in Humans: A Systematic Review and Meta-Analysis

Transcutaneous Cervical Vagal Nerve Stimulation in Patients with Posttraumatic Stress Disorder (PTSD): A Pilot Study of Effects on PTSD Symptoms and Interleukin-6 Response to Stress

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