Neurostimulation for Autonomic Dysfunction

Overseen By Mychoua Vang, BS

Age: < 65

Sex: Female

Trial Phase: Academic

Sponsor: Medical College of Wisconsin

Must not be taking: Antidepressants

Disqualifiers: Organic disease, Parenteral nutrition, Developmental delays, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 6

Duration: 6 weeks

120 Participants Needed

Trial Summary

What is the purpose of this trial?

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). Unfortunately, due to common features of anxiety and visceral hyperreactivity and lack of obvious pathology, children with DGBI 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. As the team's prior research has shown, ANS regulation can be non-invasively measured via several validated indices of cardiac vagal tone. Using the novel vagal efficiency (VE) metric, the investigators have demonstrated inefficient vagal regulation in cyclic vomiting syndrome and pain-related DGBI and that low VE predicts response to non-invasive, 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 currently 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 an ANS tracking software in assessing real-time, autonomic regulation and providing individualized neurostimulation in children with nausea/vomiting and ANS imbalance.

Do I need to stop my current medications for the trial?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the trial coordinators.

What data supports the effectiveness of the treatment Hypnotherapy and Percutaneous electrical nerve field stimulation for autonomic dysfunction?

Research shows that hypnosis can reduce activity in the sympathetic nervous system (which controls the 'fight or flight' response), which may help treat conditions with strong sympathetic involvement like hypertension and chronic pain. Additionally, neuromodulation therapies have shown promise in restoring autonomic balance in heart failure, suggesting potential benefits for autonomic dysfunction. ^{1 2 3 4 5}

Is neurostimulation generally safe for humans?

Research on neuromodulation treatments like vagus nerve stimulation and other device-based therapies has shown them to be generally safe in humans, although side effects can occur and may be severe in some cases. ^{1 6 7 8 9}

How does hypnotherapy differ from other treatments for autonomic dysfunction?

Hypnotherapy is unique because it uses guided relaxation and focused attention to influence the autonomic nervous system, which is different from other treatments that may involve medications or devices to directly stimulate nerves. This approach is non-invasive and relies on the mind-body connection to potentially improve symptoms. ^{1 2 10 11 12}

Research Team

Katja Karrento, MD

Principal Investigator

Medical College of Wisconsin

Eligibility Criteria

This trial is for children with gut-brain interaction disorders like cyclic vomiting, dyspepsia, and irritable bowel syndrome. These conditions often come with other issues such as sleep disturbances, fatigue, and anxiety due to autonomic nervous system (ANS) dysregulation. Children who are frequently misdiagnosed or treated with antidepressants without clear benefits may benefit from this study.

Inclusion Criteria

English speaking

I have been diagnosed with cyclic vomiting syndrome or functional dyspepsia and agree to join the study.

I have had symptoms like dizziness, fainting, and fatigue for at least 3 months.

Exclusion Criteria

My severe mental health condition is not well-controlled.

I have a diagnosed condition that explains my symptoms.

Implanted electrical device

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive personalized PENFS therapy for 6 weeks, with weekly autonomic nervous system assessments. Some participants also receive adjunctive hypnotherapy.

6 weeks

6 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Hypnotherapy
• Percutaneous electrical nerve field stimulation

Trial Overview The trial is testing the use of hypnotherapy and percutaneous electrical nerve field stimulation (PENFS) to treat disorders related to gut-brain interactions in children. It aims to personalize neurostimulation based on individual sensory thresholds while tracking real-time ANS reactivity using new software.

Participant Groups

Group I: PENFS (percutaneous electrical nerve field stimulation) therapy Experimental Treatment 1 Intervention

Personalized PENFS therapy x 6 weeks based on weekly autonomic nervous system assessments

Group II: PENFS (percutaneous electrical nerve field stimulation) therapy + Hypnotherapy Active Control 2 Interventions

Personalized PENFS therapy x 6 weeks based on weekly autonomic nervous system assessments + adjuntive hypnotherapy

Who Is Running the Clinical Trial?

Medical College of Wisconsin

Lead Sponsor

Trials

645

Recruited

1,180,000+

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Collaborator

Trials

2,513

Recruited

4,366,000+

Findings from Research

Neuromodulation therapies, such as spinal cord stimulation and vagus nerve stimulation, have shown promise in restoring autonomic balance in heart failure patients, which is crucial given the disease's association with sympathetic hyperactivity and parasympathetic hypoactivity.

Preclinical studies and early clinical trials indicate that these neuromodulatory treatments are both safe and effective, offering new hope for managing heart failure, a condition with high mortality rates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Interventional and device-based autonomic modulation in heart failure. Shen, MJ., Zipes, DP.[2015]

Recent advancements in evaluating autonomic dysfunction and neurostimulation techniques have led to effective treatments for various conditions, including bladder control issues, sexual dysfunction, and angina.

Future therapies may enable targeted control of conditions like hypertension, pain, and cardiac arrhythmias, highlighting the potential for more precise autonomic nervous system interventions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autonomic stimulation. Upton, AR., White, AM.[2019]

Sleep disorders are not just about poor sleep quality; they are medical conditions that can significantly affect emotional, cognitive, and physical health, particularly in patients with autonomic dysfunction.

There is a bidirectional relationship between sleep architecture and autonomic regulation, meaning that issues in one can impact the other, which suggests that targeted neuromodulation could be an effective treatment strategy for various sleep disorders.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Autonomic Dysfunction in Sleep Disorders: From Neurobiological Basis to Potential Therapeutic Approaches. Kim, H., Jung, HR., Kim, JB., et al.[2022]

In a study of 121 young adults, hypnosis was found to significantly decrease skin conductance level (SCL), indicating reduced sympathetic nervous system activity compared to a control group listening to music.

These results suggest that hypnosis may be beneficial for treating conditions linked to high sympathetic activity, such as chronic pain and hypertension, although further research is needed to clarify the specific effects of hypnosis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Alterations in electrodermal activity and cardiac parasympathetic tone during hypnosis. Kekecs, Z., Szekely, A., Varga, K.[2017]

In a study of 12 healthy subjects, hypnosis significantly enhanced parasympathetic modulation of heart rate, indicated by increased high-frequency heart rate variability (HFnu) and decreased low-frequency heart rate variability (LFnu), suggesting improved autonomic cardiac control.

Despite these changes in autonomic modulation, the overall heart rate remained unchanged during hypnosis, indicating that hypnosis alters the balance of sympathetic and parasympathetic activity without affecting heart rate directly.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cardiac autonomic regulation under hypnosis assessed by heart rate variability: spectral analysis and fractal complexity. Aubert, AE., Verheyden, B., Beckers, F., et al.[2009]

In a study of 77 patients undergoing in-patient psychotherapy for psychosomatic disorders, significant symptom improvements were observed, but there was no change in autonomic regulation or hemodynamic responses during rest or mental stress tests.

The findings suggest that while psychotherapy may alleviate symptoms, its short-term effects do not translate to improved autonomic function, indicating that further research is needed to explore the long-term benefits of increased physical activity and relaxation following treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Stability of mental stress-induced hemodynamic and autonomic reaction despite successful treatment for psychosomatic disorder]. Lomb, J., Kleiber, C., Herrmann-Lingen, C.[2016]

Electroconvulsive therapy (ECT) is considered the gold standard for treating treatment-resistant depression (TRD), despite potential cognitive and cardiovascular side effects, and it remains stigmatized.

Transcranial magnetic stimulation (TMS) and vagus nerve stimulation (VNS) are effective for late-life depression, with TMS having fewer side effects, but VNS shows limited data in older patients; emerging treatments like magnetic seizure therapy and deep brain stimulation show promise but require more safety and efficacy evidence in older adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Efficacy and Safety of Neuromodulation Treatments in Late-Life Depression. van Rooij, SJH., Riva-Posse, P., McDonald, WM.[2022]

In a study of 11 patients with chronic treatment-resistant depression, vagus nerve stimulation therapy led to significant reductions in depression scores over one year, with response and remission rates of 55% and 27%, respectively.

While the therapy showed promise in improving mood, it was associated with common and sometimes severe side effects, highlighting the need for careful monitoring.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in chronic treatment-resistant depression: preliminary findings of an open-label study. Corcoran, CD., Thomas, P., Phillips, J., et al.[2019]

Veterans with post-traumatic stress disorder (PTSD) exhibit significantly heightened sympathetic nervous system activity and cardiovascular responses during mental stress, which may increase their risk for hypertension and cardiovascular disease.

The study found that PTSD patients have impaired baroreflex sensitivity and elevated inflammation levels, suggesting that these factors contribute to their increased cardiovascular risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Baroreflex dysfunction and augmented sympathetic nerve responses during mental stress in veterans with post-traumatic stress disorder. Park, J., Marvar, PJ., Liao, P., et al.[2021]

Bright white light therapy was effective in improving symptoms for 52% of the 51 patients with autonomic dysfunction, showing benefits across various symptoms including neuroendocrine and psychological aspects after 2 weeks of treatment.

The therapy led to significant changes in EEG activity and increased urinary excretion of catecholamine and serotonin metabolites in responders, indicating potential mechanisms of action related to brain activity and neurotransmitter regulation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The effect of phototherapy on psychoautonomic disorders of a neurotic nature]. Solov'eva, AD., Fishman, EIa.[2017]

Midodrine treatment, which targets the autonomic nervous system, successfully corrected dysautonomia in a patient with chronic fatigue syndrome (CFS), leading to significant improvement in fatigue levels.

These results support the idea that dysautonomia is a key factor in CFS and suggest that therapies aimed at the autonomic nervous system could be beneficial for treating this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midodrine treatment for chronic fatigue syndrome. Naschitz, J., Dreyfuss, D., Yeshurun, D., et al.[2019]

In a study involving 50 healthy subjects, including 21 older adults over 60, anodal transcranial direct current stimulation (tDCS) was found to significantly improve cardiovascular function by enhancing vagal activity and reducing sympathetic activity during stimulation.

The results indicate that tDCS can positively influence heart health in older adults by improving temporal ventricular repolarization dispersion and increasing baroreflex sensitivity, suggesting a potential therapeutic role for tDCS in managing autonomic nervous system responses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation improves the QT variability index and autonomic cardiac control in healthy subjects older than 60 years. Piccirillo, G., Ottaviani, C., Fiorucci, C., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Interventional and device-based autonomic modulation in heart failure. [2015]

2. United States pubmed.ncbi.nlm.nih.gov

Autonomic stimulation. [2019]

3. Korea (South) pubmed.ncbi.nlm.nih.gov

Autonomic Dysfunction in Sleep Disorders: From Neurobiological Basis to Potential Therapeutic Approaches. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Alterations in electrodermal activity and cardiac parasympathetic tone during hypnosis. [2017]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Cardiac autonomic regulation under hypnosis assessed by heart rate variability: spectral analysis and fractal complexity. [2009]

6. Germany pubmed.ncbi.nlm.nih.gov

[Stability of mental stress-induced hemodynamic and autonomic reaction despite successful treatment for psychosomatic disorder]. [2016]

7. Switzerland pubmed.ncbi.nlm.nih.gov

The Efficacy and Safety of Neuromodulation Treatments in Late-Life Depression. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Vagus nerve stimulation in chronic treatment-resistant depression: preliminary findings of an open-label study. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Baroreflex dysfunction and augmented sympathetic nerve responses during mental stress in veterans with post-traumatic stress disorder. [2021]

10. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[The effect of phototherapy on psychoautonomic disorders of a neurotic nature]. [2017]

11. England pubmed.ncbi.nlm.nih.gov

Midodrine treatment for chronic fatigue syndrome. [2019]

12. New Zealand pubmed.ncbi.nlm.nih.gov

Transcranial direct current stimulation improves the QT variability index and autonomic cardiac control in healthy subjects older than 60 years. [2022]