Non-Invasive Vagal Nerve Stimulation in Veterans with Mild Traumatic Brain Injury (mTBI)

Mild Traumatic Brain Injury (mTBI) is an important concern of the Veterans Administration that affects
many veterans who served in combat in Afghanistan and Iraq and is frequently associated with
Posttraumatic stress disorder (PTSD). When these conditions occur together they are associated with
considerable morbidity, increased healthcare costs and loss of economic productivity. Current treatments
for mTBI and PTSD have limitations, and in many veterans these become lifelong disorders. Electrical
treatments represent a new horizon in the approach to disorders related to neurotrauma. One type of
treatment is Vagal Nerve Stimulation (VNS), which shows promise for neurotrauma in that it promotes
neuroplasticity, enhances new learning, and blocks stress physiology both through effects on brain
regions involved in modulation of stress as well reduction of peripheral sympathetic and inflammatory and
enhancement of parasympathetic function. This is mediated through afferent and efferent branches of the
vagus nerve that project to both the brain and peripheral inflammatory and autonomic systems. Earlier
generations of VNS were limited by the need for complicated surgical and anesthetic procedures, high
cost, and lack of reimbursement by insurance for procedures or routine healthcare follow-up. This
prevented wide-spread implementation of these treatments. New non-invasive Vagal Nerve Stimulation
(nVNS) devices are more economical and do not require surgical implantation. Our preliminary data
shows that nVNS (but not sham stimulation) blocks effects of stress on peripheral vasoconstriction and
increased sympathetic tone as measured with direct cardiovascular measures (pre-ejection period, or
PEP), reduces inflammatory markers (interleukin-6, or IL-6), enhances anterior cingulate function, blocks
insula response to stress, promotes memory and reduces PTSD symptoms. This project will explore the
effects of nVNS or sham treatment on brain, cardiovascular / sympathetic and immune response to stress
in combat veterans with mTBI and PTSD. Subjects will undergo exposure to stress in conjunction with
High Resolution Positron Emission Tomography (HR-PET) and radiolabeled water measurement of brain
blood flow, and peripheral cardiovascular /sympathetic function and immune biomarkers in blood. We
hypothesize that nVNS but not sham stimulation will result in an increase in anterior cingulate and
reduced insula function with stress tasks and hippocampal function with memory tasks, and block
cardiovascular / sympathetic and immune response to stress in patients with mTBI and PTSD.
Furthermore we hypothesize that daily nVNS (but not sham) for three months will lead to an enhancement
in memory function, reduction in PTSD symptoms, and modulate brain and autonomic responses to
stress. This project will provide information about mechanisms of nVNS on the neurobiology and
physiology of mTBI with comorbid PTSD and ways in which it may ameliorate symptoms and enhance
cognition. This may be a promising future approach for rehabilitation of veterans with neurotrauma.

Grant Number: 5I01RX003418-06
NIH Institute/Center: VA
Principal Investigator: James Bremner