Autonomic Reactivity to Restore a Dysregulated Brain-Gut Axis via Targeted Therapy

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.