Levels of pituitary adenylate cyclase-activating polypeptide (PACAP) in posttraumatic stress disorder (PTSD) and the modulatory effect of vagus nerve stimulation (VNS) Open Access

Jiao, Yunshen (Spring 2019)

Permanent URL: https://etd.library.emory.edu/concern/etds/q237ht16k?locale=en



Post-traumatic stress disorder (PTSD) is a mental disorder with 6.8% prevalence in the U.S. Evidence has shown that PACAP may be disturbed in PTSD. There is a lack of studies in humans examining longitudinal changes in PACAP in relation to experimentally-controlled trauma recall or other stressful paradigms. Vagus nerve stimulation is used experimentally in treating neuropsychiatric disorders. However, no study to date has examined whether VNS would improve the quality of life for patients with PTSD, or whether the up-regulation of PACAP found with PTSD can be decreased or modulated by VNS in humans.


This study is part of the project Closed Loop Vagal Stimulation in Patients with Posttraumatic Stress Disorder (Dr. JD Bremner, PI, BD Pearce, Co-I, Y Ko, Co-I). A total of 12 patients with PTSD and 24 healthy subjects had a baseline psychological and health assessment. Then, a procedure which elicits trauma-related stress responses was conducted. Patients were randomly assigned to VNS treatment or sham stimulation and blood was collected at baseline and during the procedure. Linear regression and mixed models were used to assess the association between PACAP and other biomarker blood levels, psychological tests scores, PTSD diagnosis, and VNS treatment.


Adjusted for age, sex, BMI, race, and education level, PACAP blood levels continuously increased during the procedure (1st day: 9%, 95%CI: (1.00, 1.18); 2nd day: 14%, 95%CI: (1.04, 1.25); 3rd day: 15%, 95%CI: (1.03, 1.28)). This increase was consistently lower in the VNS compared to the sham stimulated group. The log-transformed PACAP concentration was significantly, positively associated with the log-transformed concentration of IFN-γ (β=0.14, p=0.022) and Ghrelin (β=0.15, p=0.05), and significantly negatively correlated with IL6 (β=-0.13, p=0.048), IL13 (β=-0.25, p=0.006), and IL5 (β=-0.27, p=0.013).


This is the first report of PACAP in humans undergoing a trauma recalls paradigm. Trauma or stressful tasks were associated with increased PACAP blood levels. However, the association in VNS treatment to PACAP blood levels still needs to be established in a Phase 2 study. Combined with correlated inflammatory cytokines, PACAP may be a biomarker to show or predict the treatment effect of VNS to PTSD. 

Table of Contents

INTRODUCTION                              1

Neuroendocrine and immune connections to PTSD          2

VNS in the treatment of mental illness   3

METHODS          6

Overview           6

Eligibility Criteria             6

Exclusion Criteria             6

Recruitment      7

Baseline Assessments   7

VNS administration        8

Procedures        9

Biomarker Measurement            6

Statistical methods        11

RESULTS              13

Baseline Level Test         14

Longitudinal Analysis     15

Sex Differences in Trauma Procedure and VNS Treatment             17

Association with other biomarkers          18





Table 1. Demographic Characteristics by PTSD Diagnosis and Treatment Groups 29

Table 2. Description and Statistics of Psychological Scales Scores 30

Table 3. Ratio of PACAP concentration to the baseline PACAP concentration over time, grouped by treatment groups & PTSD diagnosis, measured from baseline to the end of Day 3.    35

Table 4. Ratio of PACAP concentration to the baseline PACAP concentration change over time, grouped by sex and PTSD diagnosis, measured from baseline to the end of Day 3.    36

Table 5. Ratio of PACAP concentration to the baseline PACAP concentration change over time, grouped by sex and treatment groups, measured from baseline to the end of Day 3.    37

Table 6. The Biomarker Statistics by PTSD Diagnosis and Treatment Groups          38

Table 7. Correlation of PACAP and Cytokines Concentration in Peripheral Blood (Over All Time Points)                     39


Figure 1. Timeline depiction of the study assessing the potency and kinetics of VNS treatment in the context of stressful scripts, speech task and math challenge.             40

Figure 2. The flow diagram of subjects’ eligibility and numbers including in the following analysis.              41

Figure 3. The association of log-transformed PACAP concentration with PTSD status at the baseline.         42

Figure 4. The association of log-transformed PACAP concentration with scores of psychological and functional scales at the baseline    43

Figure 5. The average blood levels of IFN-γ, IL-6, IL-13, IL-5 and Ghrelin at each time points.          44


Appendix Figure 1. The histograms of all psychological scores     45

Appendix Figure 2. The means and marginal means of log-transformed PACAP concentration change over time               48

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