Clinical trial NCT06616363: Does a Periaqueductal Gray-vagus Nerve Interface Malfunction Explain the Nat hx With Its Numerous Co-morbidities?
Official title: (PAG POTS - NIH) Pediatric Postural Orthostatic Tachycardia Syndrome (POTS) : Does a Periaqueductal Gray-vagus Nerve Interface Malfunction Explain the Natural History With Its Numerous Co-morbidities?
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: POTS - Postural Orthostatic Tachycardia Syndrome
Keywords: PAG activation
Cardiovagal Modulation
Lead sponsor: Virginia Commonwealth University
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
First posted: 2024-09-27
Enrollment: 120
Sex: FEMALE
Minimum age (years): 12
Maximum age (years): 21
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: The study aims to recruit only females aged 12-21. Females will be targeted specifically since POTS is more common in females than males and avoids creation of a subgroup too small to analyze.

Brief summary: Postural tachycardia syndrome (POTS) is a common and disabling disorder among adolescents. No epidemiologic data exist to support the often cited 0.5 to 2% prevalence. Case series suggest 3 to 5 times greater incidence in girls than boys. POTS is defined in children as daily chronic symptoms of orthostatic intolerance and a 40 bpm rise in heart rate in the first 10 minutes of a tilt study in the absence of orthostatic hypotension. POTS often develops after an acute event like an illness, infection, immunization, head trauma, psychological trauma or surgery. Natural history data are absent for POTS, though some outcome studies exist. Orthostatic symptoms improve in the majority and heart rate changes improve in 38% at 1 year. A 2-year follow up showed small improvement in comorbid symptoms of POTS in a 12 subject cohort followed yearly. In a pediatric 5-year outcome follow up questionnaire study, 86% of adolescents with POTS reported resolved, improved, or intermittent, symptoms, with primarily physical rather than mental health complaints.

Detailed description: The current definition of POTS highlights the peripheral mechanistic emphasis of 30 years of studies exploring cardio- and cerebro-vascular, immunologic, mast cell activation, connective tissue and other physiologic mechanisms. The classification of POTS itself also assumes a peripheral etiology, typically including neuropathic, hyperadrenergic, hypovolemic and sometimes immune POTS. However, a central nervous system (CNS) etiology might better account for what is knowns about POTS currently: (1) POTS often follows an infection, physical or psychological trauma. (2) POTS occurs most often in post-menarche adolescent girls volume redistribution differs across subjects (4) exercise, cognitive behavioral therapy provide best long-term outcomes (5) co-morbid disorders, typically overlapping pain conditions such as migraine headache, fibromyalgia, and most functional gastrointestinal disorders (FGID), often dominate the clinical picture. COPCs are typically considered to reflect a CNS etiology.

Because it coordinates the autonomic, motor and pain responses to an acute threat, the midbrain periaqueductal gray region (PAG) is an attractive candidate whose dysfunction could potentially explain all major features of POTS, including the frequent antecedent emotional or physical threat, the POTS core autonomic changes, and the co-morbid pain disorders. The PAG interprets threats as escapable or inescapable, specifically activating a different column for each response type.

Eligibility criteria: POTS sample

Inclusion Criteria:

* symptomatic ≥ 40 bpm rise in heart rate in the first 10 min of a tilt table study without a drop in blood pressure
* Clinical symptoms of orthostatic intolerance

Exclusion Criteria:

* Pregnant or breastfeeding
* Cognitive defects that preclude answering questionnaires or following assessment directions
* Other chronic diseases
* Unstable medical conditions
* Use of narcotics
* Limited English proficiency
* Investigator discretion that participant would not be suitable to participate
* A phone older than 5 years old or unable to support EMA software

POST INFECTION

Inclusion Criteria:

* acute upper respiratory or gastrointestinal infection that required admission to the acute care units but not requiring an ICU stay

Exclusion Criteria:

* Pregnant or breastfeeding
* Chronic prescriptions, history of POTS or orthostatic symptoms, recent inpatient psychiatric admissions, substance use disorder, trauma such as a motor vehicle accident, surgery, or other significant physical or emotional trauma in the last 5 years
* Cognitive defects that preclude answering questionnaires or following assessment directions
* Other unstable chronic diseases
* Unstable medical conditions
* Use of narcotics
* Severe depression or anxiety (untreated / unstable)
* Limited English proficiency
* Investigator discretion that participant would not be suitable to participate
* A phone older than 5 years old or unable to support EMA software

HEALTHY CONTROLS

Inclusion Criteria:

* Apparently healthy with no known chronic illnesses

Exclusion Criteria:

* Pregnant or breastfeeding
* History of POTS or orthostatic symptoms, migraines, fibromyalgia, chronic fatigue, PTSD. Functional gastrointestinal disorders, fainting, dysmenorrhea, or other chronic pain syndrome, inpatient psychiatric admissions, substance use disorder, trauma such as a motor vehicle accident, surgery, or other significant physical or emotional trauma in the last 5 years
* Cognitive defects that preclude answering questionnaires or following assessment directions
* Other chronic unstable diseases
* Unstable medical conditions
* Use of narcotics
* Severe depression or anxiety (untreated / unstable)
* Limited English proficiency
* Investigator discretion that participant would not be suitable to participate
* A phone older than 5 years old or unable to support EMA software

Primary outcomes:
measure: Functional Disability Inventory (FDI)
timeFrame: Experimental Cohort: Baseline and monthly for 24 months (3, 6, 12, 24 in-person study visits), the other months will be completed from home. The control cohort: months 0-12
measure: Pain Coping Questionnaire short form
timeFrame: Experimental Cohort: Baseline and monthly for 24 months (3, 6, 12, 24 in-person study visits), the other months will be completed from home. The control cohort: months 0-12
measure: Pain Catastrophizing Scale (PCS-C)
timeFrame: Experimental Cohort: Baseline and monthly for 24 months (3, 6, 12, 24 in-person study visits), the other months will be completed from home. The control cohort: months 0-12
measure: Functional MRI (fMRI) scan while completing a complete a looming animacy threat task; participants judge the valence of images via button press as they perceive the image.
timeFrame: Experimental cohort: Baseline, 3, 6, 12, 24 month in person visits. Control Cohort: Baseline, 3, 6, and 12 month in person visits.
measure: Bedside Tilt test
timeFrame: Experimental cohort: Baseline, 3, 6, 12, 24 month in person visits. Control Cohort: Baseline, 3, 6, and 12 month in person visits.
Secondary outcomes:
Other outcomes:
Locations:
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
Study officials:
affiliation: Virginia Commonwealth University
name: Gisela Chelimsky
role: PRINCIPAL_INVESTIGATOR
References: