PROJECT SUMMARY/ABSTRACT
Disorders of gut-brain interaction (DGBI) affect up to 25% of U.S. children. Patients often suffer from disabling,
multisystem comorbidities that suggest a common root (sleep disturbances, fatigue, anxiety, etc). Yet, DGBI are
defined and treated based on GI symptom origin (cyclic vomiting, dyspepsia, irritable bowel) rather than
underlying pathophysiology. Many patients manifest comorbidities suggesting an underlying autonomic nervous
system (ANS) dysregulation (palpitations, dizziness, cognitive dysfunction). Cyclic vomiting syndrome (CVS) is
a prototype DGBI with known ANS imbalance and episodic vomiting attacks. Many chronic nausea and vomiting
conditions, often termed ‘functional dyspepsia’, present with postprandial symptoms suggesting gastric
dysmotility. However, currently available tests do not capture the range of possible gastric motor disturbances.
These patients often have symptoms of ANS dysregulation. Unfortunately, due to common features of anxiety
and visceral hyperreactivity, children with CVS and functional dyspepsia are frequently diagnosed with
psychosomatic or ‘benign, functional disorders’ and treated with empiric antidepressants despite lack of scientific
support and risks of serious side effects. Little is known about the underlying brain-gut mechanisms linking these
comorbidities. A lack of targeted treatment options naturally follows the paucity of mechanistic data.
A dysregulated ANS response circuit via brainstem nuclei is linked to visceral hypersensitivity. ANS regulation
can be non-invasively measured via several validated indices of cardiac vagal tone. Using the novel vagal
efficiency (VE) metric, a dynamic measure of brainstem vagal afferent signaling, we have demonstrated
inefficient vagal regulation in CVS and pain-related DGBI and that low VE predicts response to auricular
percutaneous electrical nerve field stimulation (PENFS) therapy. PENFS targets brainstem vagal afferent
pathways and, along with brain-gut interventions such as hypnotherapy, are the only therapies proven effective
for pediatric DGBI. Individualizing neurostimulation based on sensory thresholds while assessing dynamic ANS
reactivity offers a path towards personalized medicine using the most effective therapies to date.
This proposal will test the feasibility of ANS-Sensing System (ANS-SS) software in assessing real-time,
autonomic regulation in children with nausea/vomiting and ANS imbalance. ANS-SS will measure VE output
(Aim 1) in response to PENFS using both standard and personalized neurostimulation parameters. Aim 2 will
investigate clinical efficacy and ANS changes of 6 weeks of personalized PENFS vs. personalized PENFS + gut-
directed hypnotherapy vs. standard of care pharmacotherapy. A subset will undergo multimodal assessment of
gastric physiology using real-time gastric MRI. Simultaneous pre- and post-meal ANS function measures will
attempt to correlate gastric and autonomic parameters and may further delineate brain-gut axis alterations.