Hypermobile Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder characterized by hyperextensible skin, joint hypermobility and additional connective tissue manifestations. For unclear reasons, hEDS is associated with many gastrointestinal (GI) and autonomic nervous system (ANS) complaints such as postural orthostatic tachycardia syndrome (POTS). This study will address the clinical relationship between hEDS/Hypermobile Spectrum Disorders and autonomic regulation and see if there is a benefit of two forms of non-invasive vagal nerve stimulation therapies to reduce GI symptoms in hEDS and POTS. The study will also investigate plausible effects of these nerve stimulation therapies on gastric function and autonomic signaling.

Hypermobile Ehlers-Danlos Syndrome (hEDS) is a connective tissue disorder characterized by hyperextensible skin, joint hypermobility and additional connective tissue manifestations. For unclear reasons, hEDS and Hypermobile Spectrum Disorders are associated with many gastrointestinal (GI) and autonomic nervous system (ANS) complaints such as postural orthostatic tachycardia syndrome (POTS). Symptoms are often disabling and associated with poor quality of life and high health care costs. The proposed research will address the following understudied areas: 1) the clinical relationship between hEDS and autonomic regulation, 2) the potential benefit of two forms of non-invasive vagal nerve stimulation (VNS) therapies in reducing functional GI symptoms in hEDS and POTS, and 3) plausible effects of these VNS therapies on gastric motor function and neurohormonal signaling.

Clinical reports document a high co-morbidity between autonomic disorders and hEDS. This prospective study will focus on three major clinical questions: 1) Are there reliable neurophysiological markers associated with hEDS that can provide insights into the 'neural mechanisms' resulting in multisystem co-morbidities? 2) Will innovative intervention techniques designed to enhance autonomic regulation via two non-invasive vagal nerve stimulation techniques (e.g., auricular and acoustic VNS) provide substantial symptom reduction and improve the hEDS patients' quality of life? 3) Can a novel gastric MRI technique capture gastric motor function abnormalities in adolescents with hEDS?

Inclusion Criteria:

• Children aged 10-18 years old
• Children with functional upper GI complaints and clinical suspicion for hEDS or HSD as well as a Beighton score of at least 4/9
• Children with functional upper GI complaints and clinical suspicion for ANS dysfunction
• De-identified data from our prior studies (IRB #689519 and IRB #1064187) of patients with functional GI disorders who do NOT meet criteria for hEDS will be used as a comparison group
• Children who are English-speaking and lack other explanation for symptoms
• Children willing to participate and consent to this study (for children, have a parent willing to participate)

Exclusion Criteria:

A) Exclusion Criteria applying to all participants:

• Medically complex children or those who take a medication or suffer from a disease that can explain symptoms will be excluded from participation in the study.
• Adult subjects, children or their parents who have significant developmental delay (will be excluded due to difficulties in accurately completing the questionnaires and assessing symptoms)
• Patients with findings of organic disease such as peptic ulcer disease, H.pylori gastritis, celiac disease, inflammatory bowel disease, allergic disorders, metabolic disorder or any other chronic condition or medication that may cause chronic GI symptoms will be excluded from the study.
• Patients who are treated with a new drug affecting the central nervous system in the two weeks prior to enrollment will also be excluded.
• Pregnancy (evaluating MD screens patients as they normally would during a clinic visit (by questioning) and would only perform urine pregnancy test if clinically indicated (absence of menstrual period or other symptoms concerning for pregnancy)
• Chronic alcohol/illicit drug use and/or smoking.

B) Exclusion Criteria for subjects undergoing pVNS therapy:

• Severe dermatological condition or active infection of external or middle ear
• Implanted electrical device

C) Exclusion Criteria for subjects undergoing aVNS therapy:

• Hearing impaired
• Sight impaired without correction
• Seizure disorder

D) Exclusion Criteria for subjects undergoing gastric motor function sub-study:

• Patients with pacemakers, metal clips used in previous surgery or other device which are not compatible with MRI scanning
• Claustrophobia or inability to lie still in the scanner
• Orthodontic braces or permanent retainers
• Patients who are unable to tolerate noise produced by the MRI
• Egg allergy or anticipated inability to complete a standardized egg meal

E) Exclusion Criteria for subjects undergoing HepGI Biobank specimen collection sub-study:

• Bleeding disorder for the specific biopsies
• Recent antibiotic usage for fecal sample
• Significant anemia or clinical status which will not allow safe blood draw required for blood collection
• Refusal of blood collection or to provide DNA sample
• Inability or unwillingness on the individual (or parent/legal guardian) to provide clinical or family history.

Treatment Arm A is masked (double-blinded). Treatment Arm B is not masked.