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

Abstract

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.

Figure 1.

CONSORT diagram showing flow of study participants screened, enrolled, and completing the protocol.

Figure 2.

Diagram of the baseline study protocol. PTSD patients underwent three days of stress, one day (Day 1) with neutral scripts (NS) and personalized traumatic scripts (TS), and two days (Days 2 and 3) with mental stress (MS) involving public speaking and mental arithmetic tasks. Participants underwent randomized, double-blind assignment to tcVNS or sham stimulation which was paired with stress tasks (or no task) on Days 1, 2 and 3. On Day 1 neutral and traumatic scripts lasted about one minute and occurred in pairs with 10 minutes in between. Stress tasks were paired with stimulation with tcVNS or sham which began immediately after termination of the task and continued for two minutes followed by a blood draw (purple/blue boxes signify pairing of task/stimulation/blood draw but blood draw actually occurred at the termination of stimulation). On Day 1 participants also underwent stimulation with tcVNS or sham for two minutes in the absence of a task (N) repeated twice with 10 minutes in between followed by a blood draw. Neutral and traumatic script pairs were repeated followed by a 60 minute rest and lunch break, with a repeat of neutral and traumatic script pairs in the afternoon each paired with blood draws. The neutral scripts tasks #11 and #12 were followed by a blood draw (which was about 110 minutes after the first trauma script pairs at tasks #3 and #4) and the trauma scripts tasks #13 and #14 paired with tcVNS or sham were followed by the final blood draw at 210 minutes into Day 1 (Traumatic Stress). On Day 2 after a baseline blood draw at rest (task #15) participants underwent mental stress (MS) involving five minutes of public speaking (task #16) with tcVNS or sham at the end, followed by an eight minute rest period, and another five minutes of mental arithmetic (task #17) followed by tcVNS or sham. After a 90 minute rest period participants underwent a blood draw at rest (task#18). This was repeated for Day 3 with baseline (task #19, public speaking (task #20), mental arithmetic (task #21) and a blood draw post-task at rest (task #22). The blood draws for all three days were timed to coincide with the roughly 90 minute time course of interleukin-6 (IL-6) response to stress based on prior studies. Patients then underwent three months of tcVNS/sham followed by a repeat of Day 1 only.

Figure 3.

Diagram showing placement of tcVNS device on the neck to target the vagus nerve as it travels through the carotid sheath.

Figure 4.

Effects of up to three months of twice daily transcutaneous cervical Vagal Nerve Stimulation (tcVNS) (on the left, red lines) or sham stimulation (on the right, blue lines) on symptoms of PTSD as measured with the PTSD Checklist (PCL). Individual participants are shown with lines separating pre- and post-treatment; lines with bars represent means and SD before and after treatment for both groups. Active tcVNS resulted in a 17% reduction in PTSD symptoms (p=.013) and sham stimulation a 13% reduction in PTSD symptoms after treatment (p=.15) (*p<.05 from pretreatment).

Figure 5.

Effects of up to three months of twice daily tcVNS (on the left, red lines) or sham stimulation (on the right, blue lines) on symptoms of PTSD as measured with the PTSD Checklist (PCL). Individual participants are shown with lines separating pre- and post-treatment; lines with bars represent means and SD before and after treatment for both groups. Active tcVNS resulted in a 21% reduction in hyperarousal symptoms (p=.008) while sham stimulation resulted in a 17% decrease (p=.06) (*p<.05 from pretreatment).

Figure 6.

Effects of tcVNS and sham on autonomic anxiety as measured with the Hamilton Anxiety Scale (Ham-A). Scores represent the sum of items for gastrointestinal and autonomic somatic anxiety (see text) at baseline and with three months of twice daily tcVNS (on the left, red lines) or sham stimulation (on the right, blue lines) on autonomic anxiety as measured with the Ham-A. Individual participants are shown with lines separating pre- and post-treatment; lines with bars represent means and SD before and after treatment for both groups. There was a −46% decrease in Ham-A somatic anxiety in the tcVNS group (p=.036) versus a −35% change in the sham stimulation group (p=.22) (*p<.05 from pretreatment).

Figure 7.

Effects of tcVNS and sham on clinical improvement as measured with the Clinical Global Impressions scale-improvements (CGI-I) in active tcVNS (red) and sham (blue) stimulation groups at baseline and 30 and 90 days after start of double-blind active (N=9) versus sham (N=11) treatment in patients with PTSD. The final measurement at 124 days (34 days after start of open label treatment) showed a significant improvement compared to after three months of sham stimulation (2.75 (0.71) versus 4.00 (0.82 SD) (*p=0.003). This score is intermediated between much improved (2) and minimally improved (3) compared to no improvement (4).

Figure 8.

Effects of tcVNS (red lines, right side) or sham (blue lines, left side) on interleukin-6 (IL-6) at baseline (base) and following repeated exposure to traumatic script stress (post) in patients with PTSD. Lines connect pre and post stress in individual patients and bars represent the means for each group. There was a significant increase in IL-6 in the sham group (*p<0.05) not seen in the PTSD group.

Figure 9.

Effects of tcVNS (red lines, right side) or sham (blue lines, left side) on interleukin-6 (IL-6) at baseline (base) and following three months of double blind active tcVNS or sham treatment in patients with PTSD. Lines connect baseline to post-treatment and post traumatic script stress in 5/9 patients and bars represent the means for each group. There was a significant increase in IL-6 in the sham group (*p<0.05) not seen in the PTSD group.