Transcutaneous cervical vagal nerve stimulation reduces sympathetic responses to stress in posttraumatic stress disorder: A double-blind, randomized, sham controlled trial

Nil Z Gurel, Matthew T Wittbrodt, Hewon Jung, Md Mobashir H Shandhi, Emily G Driggers, Stacy L Ladd, Minxuan Huang, Yi-An Ko, Lucy Shallenberger, Joy Beckwith, Jonathon A Nye, Bradley D Pearce, Viola Vaccarino, Amit J Shah, Omer T Inan, J Douglas Bremner, Nil Z Gurel, Matthew T Wittbrodt, Hewon Jung, Md Mobashir H Shandhi, Emily G Driggers, Stacy L Ladd, Minxuan Huang, Yi-An Ko, Lucy Shallenberger, Joy Beckwith, Jonathon A Nye, Bradley D Pearce, Viola Vaccarino, Amit J Shah, Omer T Inan, J Douglas Bremner

Abstract

Objective: Exacerbated autonomic responses to acute stress are prevalent in posttraumatic stress disorder (PTSD). The purpose of this study was to assess the effects of transcutaneous cervical VNS (tcVNS) on autonomic responses to acute stress in patients with PTSD. The authors hypothesized tcVNS would reduce the sympathetic response to stress compared to a sham device.

Methods: Using a randomized double-blind approach, we studied the effects of tcVNS on physiological responses to stress in patients with PTSD (n = 25) using noninvasive sensing modalities. Participants received either sham (n = 12) or active tcVNS (n = 13) after exposure to acute personalized traumatic script stress and mental stress (public speech, mental arithmetic) over a three-day protocol. Physiological parameters related to sympathetic responses to stress were investigated.

Results: Relative to sham, tcVNS paired to traumatic script stress decreased sympathetic function as measured by: decreased heart rate (adjusted β = -5.7%; 95% CI: ±3.6%, effect size d = 0.43, p < 0.01), increased photoplethysmogram amplitude (peripheral vasodilation) (30.8%; ±28%, 0.29, p < 0.05), and increased pulse arrival time (vascular function) (6.3%; ±1.9%, 0.57, p < 0.0001). Similar (p < 0.05) autonomic, cardiovascular, and vascular effects were observed when tcVNS was applied after mental stress or without acute stress.

Conclusion: tcVNS attenuates sympathetic arousal associated with stress related to traumatic memories as well as mental stress in patients with PTSD, with effects persisting throughout multiple traumatic stress and stimulation testing days. These findings show that tcVNS has beneficial effects on the underlying neurophysiology of PTSD. Such autonomic metrics may also be evaluated in daily life settings in tandem with tcVNS therapy to provide closed-loop delivery and measure efficacy.ClinicalTrials.gov Registration # NCT02992899.

Keywords: Electroceuticals; Posttraumatic stress disorder; Stress; Transcutaneous cervical stimulation; Vagus nerve stimulation; Wearable bioelectronic medicine.

© 2020 The Authors.

Figures

Fig. 1
Fig. 1
tcVNS without acute stress: Outcomes for stimulation without acute stress, merged from all days. Bars represent the unadjusted mean changes from baseline, error bars: 95% confidence interval (CI), values calculated from raw data, * indicates p < 0.05. β coefficients, adjusted CI, effect sizes (d), and p-values were reported in β (±CI, d, p) format. Active tcVNS group experienced the following relative to sham after adjustments: (A) The ratio of short-term variability to long-term variability (SD1/SD2) increased following stimulation by 14.1% (±11.6%, d = 0.43, p = 0.019). (B) Heart rate (HR) decreased following stimulation by 2.7% (±2.0%, d = 0.21, p = 0.009). (C) Photoplethysmogram (PPG) amplitude increased during stimulation by 43.4% (±43.4%, d = 0.53, p = 0.049) and following stimulation by 73.1% (±63.2%, d = 0.67, p = 0.025). (D) Pulse arrival time (PAT) increased during stimulation by 2.5% (±2.2%, d = 0.26, p = 0.026).
Fig. 2
Fig. 2
tcVNS after traumatic stress: Outcomes for stimulation following traumatic stress (all six scripts). Bars represent the unadjusted mean changes from baseline, error bars: 95% confidence interval (CI), values calculated from raw data, * indicates p < 0.05. β coefficients, adjusted CI, effect sizes (d), and p-values were reported in β (±CI, d, p) format. Active tcVNS group experienced the following relative to sham after traumatic stress after adjustments: (A) Heart rate (HR) decreased during stimulation by 5.6% (±3.6%, d = 0.43, p = 0.003), and following stimulation by 3.9% (±3.0%, d = 0.29, p = 0.013). (B) Photoplethysmogram (PPG) amplitude increased during stimulation by 30.8% (±28.0%, d = 0.41, p = 0.032). (C) Pulse arrival time (PAT) decreased less during traumatic stress by 9.2% (±3.0%, d = 0.15, p < 0.0001), stimulation by 2.2% (±2.2%, d = 0.42, p = 0.045), and following stimulation by 6.2% (±1.9%, d = 0.57, p < 0.0001).
Fig. 3
Fig. 3
Change in long-term heart rate variability (SD2) for multiple stimulation protocol following traumatic stress (four traumatic stress and six stimulation administrations on the first day). Bars represent the unadjusted mean changes from baseline, error bars: 95% confidence interval (CI), values calculated from raw data, * indicates p 

Fig. 4

tcVNS after mental stress: Outcomes…

Fig. 4

tcVNS after mental stress: Outcomes for stimulation following two types of mental stress,…
Fig. 4
tcVNS after mental stress: Outcomes for stimulation following two types of mental stress, public speech and mental arithmetic. Bars represent the unadjusted mean changes from baseline, error bars: 95% confidence interval (CI), values calculated from raw data, * indicates p < 0.05. β coefficients, adjusted CI, effect sizes (d), and p-values were reported in β (±CI, d, p) format. Active tcVNS group experienced the following relative to sham after adjustments: (A) SD1/SD2 increased during stimulation right after speech task by 23.1% (±21.1%, d = 0.71, p = 0.033). (B) Similar to the speech task, SD1/SD2 increased by 41.2% (±22.5%, d = 0.44, p = 0.001). (C) Pre-ejection period (83) increased following stimulation after speech task by 6.8% (±5%, d = 0.16, p = 0.009). (D) Pulse pressure (PP) decreased following stimulation after mental arithmetic by 9.6% (±9.7%, d = 0.68, p = 0.049).
Fig. 4
Fig. 4
tcVNS after mental stress: Outcomes for stimulation following two types of mental stress, public speech and mental arithmetic. Bars represent the unadjusted mean changes from baseline, error bars: 95% confidence interval (CI), values calculated from raw data, * indicates p < 0.05. β coefficients, adjusted CI, effect sizes (d), and p-values were reported in β (±CI, d, p) format. Active tcVNS group experienced the following relative to sham after adjustments: (A) SD1/SD2 increased during stimulation right after speech task by 23.1% (±21.1%, d = 0.71, p = 0.033). (B) Similar to the speech task, SD1/SD2 increased by 41.2% (±22.5%, d = 0.44, p = 0.001). (C) Pre-ejection period (83) increased following stimulation after speech task by 6.8% (±5%, d = 0.16, p = 0.009). (D) Pulse pressure (PP) decreased following stimulation after mental arithmetic by 9.6% (±9.7%, d = 0.68, p = 0.049).

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Source: PubMed

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