Vagal Nerve Stimulation to Probe Inflammation and Brain in Post-traumatic Stress

Rates of posttraumatic stress disorder (PTSD) are high among combat Veterans with estimates
of PTSD within Iraq and Afghanistan Veterans at nearly 17% of active duty and over 24% of
reserve service members that screen positive for PTSD. Studies from the current and prior
wars have demonstrated that mental disorders, in particular PTSD, are associated with higher
rates of: 1) physical symptoms, 2) chronic physical illness and 3) overall mortality. Rates
of comorbid PTSD and chronic pain are exceedingly high among Veterans with reports of 30%-50%
in both Vietnam and OEF/OIF Veterans, that suggest a shared pathophysiology. Excessive
release of peripheral pro-inflammatory cytokines has been implicated in the generation of: 1)
pathologic chronic pain states and 2) in PTSD. Perception of an aversive stimulus/threat
activates peripheral inflammatory cytokine release, while exogenous administration of an
inflammatory stimulus (that also cause release of peripheral inflammatory cytokines)
increases the limbic (insular cortex and amygdala) response to aversive/threat stimuli as
measured by functional Magnetic Resonance Imaging (fMRI). Work by the investigators' group
shows that PTSD influences the: 1) nociceptive response, 2) intrathecal cytokine release and
3) peripheral cytokine release in response to a painful stimulus when compared to responses
of Veteran combat controls (CC). Vagus nerve stimulation has been shown to decrease: 1)
peripheral inflammatory cytokine release, 2) pain, and 3) anxiety.

Recent work by the group has shown that non-invasive vagal nerve stimulation (nVNS; using
extradermal stimulation) decreases peripheral inflammation in healthy control subjects and
may similarly decrease hyperinflammation observed in PTSD. In pilot work, the investigators
have obtained initial fMRI evidence (preliminary data) suggests that in healthy controls,
nVNS decreases insular response to painful stimuli, which is known to be dysregulated in
PTSD.

The investigators plan to use nVNS as a probe in PTSD and CC to observe the effects of vagal
nerve modulation on: 1) CNS neural circuit function during pain and pain anticipation
stimuli, and 2) peripheral inflammatory biomarker measures. The long-term goal of this line
of research is to use nVNS as a probe to obtain pilot data of: 1) peripheral inflammatory
biomarkers and 2) fMRI derived brain imaging response to pain, to advance the understanding
of fundamental pathophysiology of co-morbid pain and PTSD and to ultimately provide, targeted
neuromodulation based interventions for Veterans with pain and PTSD. The investigators will
study two groups [(PTSD, CC), (both without chronic pain diagnosis)], under two conditions
(either nVNS or Sham stimulation), over three time points (pre-nVNS/Sham), (7 days
post-nVNS/Sham) and one month after treatment (one month post VNS/Sham). The first objective
of this proposal, is to measure peripheral inflammation in response to nVNS treatment in
order to delineate peripheral inflammation based biomarker profiles of treatment
responsiveness to nVNS in PTSD and CC. The second step is to measure brain region response to
a pain and pain anticipation stimuli task before and after nVNS treatment in order to
demonstrate: 1) a neural profile of treatment responsiveness to nVNS and 2) the neural
profile of nVNS effects on pain in PTSD and CC. Participants will receive a 7-day long
nVNS/Sham trial where inflammatory biomarkers, neuroimaging tools, PTSD symptom severity and
functional life quality will be assessed before and after the 7 days. Additionally, PTSD
symptom severity and functional life quality will be assessed one month after study onset.
The direct contrast of pre and post nVNS/Sham will provide an objective and sensitive
assessment of neuromodulation with nVNS and lay the groundwork for further neuromodulation
based study in PTSD. Such outcomes may provide additional evidence of potential treatment
efficacy, thus ultimately provide therapies that enhance VA clinical practice guidelines.

Inclusion Criteria:

- Male subjects between 21 and 65 years, any race or ethnicity.

- For PTSD: Previously deployed, experienced a traumatic event, and meets
Clinician-Administered PTSD Scale for DSM-5(CAPS-5) symptom cluster severity criteria
for PTSD diagnosis, as well as CAPS total cut-off score > 33. 3. For CC: Previously
deployed, experienced a traumatic event, and fails to meet CAPS-5 symptom cluster
severity criteria for PTSD diagnosis with CAPS total cut-off score < 20.

- Capable of complying with study schedule, procedures, and speaks English.

- Able to provide voluntary written informed consent prior to initiation of Visit 1; and
be able to commit to the return visit at the end of the study.

Exclusion Criteria:

- Rule out significant mental illness, e.g. psychosis, bipolar disorder as well as major
depression pre-dating PTSD, based on Structured Clinical Interview for DSM-5(SCID)
interview.

- At risk for suicide or homicide(based upon Columbia Suicide Risk Severity
Scale(C-SSRS) or BDI-2 screen and follow-up clinical interview).

- Any subject who has undergone evidence-based treatment(CPT or PE) within one month
prior to study enrollment or plans to undergo CPT or PE during the study.

- History of head trauma involving loss of consciousness>1 minute and post-concussive
symptoms(PCS).

- Chronic pain as defined by pain persisting beyond its ecological alerting function,
and clinically defined as lasting longer than 3 months, and/or currently under the
care of a chronic pain physician.

- Any condition or therapy that, in the opinion of the investigator and research team,
may be significantly worsened by the administration of study treatment or is likely to
interfere with the successful collection of the measures required.

- Clinically significant uncontrolled/unstable medical illness or clinically significant
surgery within 1 month of the screening visit.

- Evidence of a maladaptive pattern of alcohol use or abuse(based on AUDIT-C interview)
one month prior to the screening visit and or illicit drug use or abuse as measured by
urine screen positive for illicit substances at the screening Visit 1 or follow up
Visit 2.

- Participation in a pharmaceutical trial or exposure to investigational drugs within 1
month of the screening visit.

- Standard of care medications used to treat PTSD will be continued. Any subject that
takes anti-inflammatory medications for chronic medical conditions or takes other
medications for chronic pain will be excluded.

- MRI-related exclusion criteria: A cardiac pacemaker; metal fragments in
eyes/skin/body(shrapnel), subjects who have ever been metal workers/welders; history
of eye surgery/eyes washed out because of metal, aortic/aneurysm clips, prosthesis,
bypass surgery/coronary artery clips, hearing aid, heart-valve replacement, subjects
with an intrauterine device, a shunt(ventricular or spinal), electrodes, metal
plates/pins/screws/wires, or neuro/bio-stimulators; vision problems uncorrectable with
lenses; claustrophobia; inability to lie still on their backs for approximately 60
minutes; prior neurosurgery; or unwillingness or inability to remove nose, ear,
tongue, or face rings. Any implants will be reviewed for safety.

- Vagus nerve stimulation related criteria: history of carotid endarterectomy, severe
carotid artery disease[e.g. bruits on physical exam or history of transient ischemic
attack(TIA) or stroke], congestive heart failure(CHF), cardiac arrhythmia, known
severe coronary artery disease or recent myocardial infarction(within 5 years), or a
history or seizure or syncope(within the last 1 year), or prior neck surgery will be
excluded.