Does a Periaqueductal Gray-vagus Nerve Interface Malfunction Explain the Nat hx With Its Numerous Co-morbidities?

(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?

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.

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.

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