Neurobiological Mechanisms of Stress in Youth With Chronic Widespread Pain

Pediatric chronic widespread pain (CWP) is a serious public health problem resulting in high levels of healthcare utilization and disability. Youth with CWP also frequently report exposure to adverse childhood experiences (ACEs; abuse/neglect, violent/conflictual home environment, etc.) and a significant subset continue to experience physical and psychosocial impairment long-term. Certain mind-body interventions such as mindfulness-based stress reduction (MBSR) or meditation may be particularly appropriate for youth with CWP as they have been shown to modulate stress-induced maladaptation of the HPA-axis, autonomic nervous system, cardiovascular system, and brain structure (e.g., hippocampus). However, it is currently unknown if these targets are affected in youth with CWP. Preliminary research indicates that allostatic load (AL), or "wear and tear" on the nervous system due to stress, may contribute to pain chronicity. Similarly, evidence suggests that the hippocampus, a brain structure that is among the most deleteriously affected by stress, plays a role in pain perception. However, no study to-date has examined AL and hippocampal functioning in relation to stress exposure in youth with CWP. Mind-body interventions such as MBSR or meditation are an important and safe therapy option for both pain and stress reduction in youth with CWP and may modulate the negative impact of ACEs, so there is a critical need to know if these mechanisms are engaged in this population. The current study utilizes multifactorial physiological and neuroimaging measurement techniques to enhance our understanding of the potential role of these mechanisms in pain-related impairment and responsiveness to mind-body interventions over time. The aims of this study are to better characterize AL, assessed via a multifactorial composite, and hippocampal functioning via fMRI in pediatric CWP as specific targets for mind-body interventions that can lead to treatment optimization and improved compliance.

• functional Magnetic Resonance Imaging (fMRI) (Diagnostic test): Participants will undergo a one hour fMRI scan with pain-induction using heat-based QST protocol.
• Allostatic Load Composite (Other): All participants will be asked to provide saliva samples to measure cortisol response over time and dehydroepiandrosterone (DHEA) in addition to physiological measurements such as blood pressure/pulse, height/weight, and waist-hip ratio. Measurements will be taken at baseline and 4-month follow-up.

Primary outcomes

• Hippocampal Functioning [baseline]: measured via fMRI
• Change in Morning Cortisol [baseline and 4-month follow-up]: measured via 2 samples of saliva taken via passive drool over the course of two days. After analysis, morning cortisol will be dichotomously coded with participants receiving a "1" if they score over one standard deviation above the mean. Coding will them be combined to formulate an allostatic load risk ratio, with higher scores indicating greater risk for allostatic load.
• Change in Dehydroepiandrosterone (DHEA) [baseline and 4-month follow-up]: measured via 2 samples of saliva taken via passive drool over the course of two days. After analysis, DHEA will be dichotomously coded with participants receiving a "1" if they score over one standard deviation above the mean. Coding will them be combined to formulate an allostatic load risk ratio, with higher scores indicating greater risk for allostatic load.
• Change in Flattened Cortisol [baseline and 4-month follow-up]: measured via 10 samples of saliva taken via passive drool over the course of two days. After analysis, the presence of cortisol will be dichotomously coded with participants receiving a "1" if the change in cortisol levels across the day fell at or below one standard deviation below the mean. Coding will them be combined to formulate an allostatic load risk ratio, with higher scores indicating greater risk for allostatic load.
• Change in Blood Pressure [baseline and 4-month follow-up]: measured via blood pressure cuff by trained nurse. Results will be coded to capture levels that fall in the "normal", "prehypertension" and "hypertension" range with individuals scoring in the latter two ranges receiving a coding of "1" to be included in the allostatic load risk composite measure. Scoring of blood pressure ranges will be done using ezbmi- calculates deviation from expected BP/BMI by age/gender.
• Change in Body-Mass Index (BMI) [baseline and 4-month follow-up]: measured via height and weight (in cm and kg) by a trained nurse. Results will be coded to capture individuals that score in the "underweight", "normal", "overweight" and "obese" ranges with individuals falling in all categories but "normal" receiving a coding of "1" to be included in the allostatic load risk ratio. Scoring of BMI ranges will be done using ezbmi- calculates deviation from expected BP/BMI by age/gender.
• Change in Waist-Hip Ratio (WHR) [baseline and 4-month follow-up]: measured via tape measure around the smallest part of the waist and the widest part of the hips by a trained research coordinator. Results (waist measurement/hip measurement) will be coded dichotomously with individuals scoring a "1" whose WHR falls greater than or equal to one standard deviation above the mean of the sample. This scoring will also be included in the larger allostatic load risk ratio.
• Change in Heart Rate (HR) [baseline and 4-month follow-up]: measured via pulse taken by a trained nurse. Results will be coded dichotomously with individuals scoring a "1" whose HR falls greater than or equal to one standard deviation above the mean of the sample. This scoring will also be included in the larger allostatic load risk ratio.

Secondary outcomes

• Change in Pain Intensity [baseline and 4-month follow-up]: measured via numeric rating scale (range: 0-10). Higher rating indicates more intense pain.
• Change in Functional Disability [baseline and 4-month follow-up]: measured via self-report Functional Disability Inventory (range: 0-60). Higher rating indicates greater functional disability.
• Change in Sleep [baseline and 4-month follow-up]: measured via Patient Reported Outcome Measurement Information System (PROMIS) sleep disturbance scale short-form (8a). Raw scores are converted to T-scores (range: 0-100). Higher rating indicates greater impairment in sleep.

Other outcomes

• Change in Treatment Engagement [baseline and 4-month follow-up]: measured via participant self-report of treatment as usual (e.g., engagement in physical therapy, cognitive-behavioral therapy, acupuncture, etc.). Observational measure without metrics for risk or impairment.
• Change in Adverse Childhood Experiences (ACEs) exposure [baseline and 4-month follow-up]: measured via Childhood Trust Events Scale (CTES). Items on this measure are coded dichotomously (0 = no; 1 = yes) and will be summed to provide a total metric of ACEs exposure (range: 0-26).
• Change in Psychological Stress [baseline and 4-month follow-up]: measured via Patient Reported Outcome Measurement Information System (PROMIS) psychological stress scale short-form (8a). Raw scores are converted to T-scores (range: 0-100). Higher rating indicates greater amounts of psychological stress.
• Change in Anxiety [baseline and 4-month follow-up]: measured via Patient Reported Outcome Measurement Information System (PROMIS) anxiety scale short-form (8a). Raw scores are converted to T-scores (range: 0-100). Higher rating indicates greater amounts of anxiety.
• Change in Depression [baseline and 4-month follow-up]: measured via Patient Reported Outcome Measurement Information System (PROMIS) depression scale short-form (8a). Raw scores are converted to T-scores (range: 0-100). Higher rating indicates greater amounts of depressive symptoms.

Sex: All, ages: 11 Years to 17 Years, accepts healthy volunteers

Chronic Widespread Pain (CWP) group:

Inclusion Criteria:

* Between ages 11-17 years
* Referred to the Boston Children's Hospital Pain Treatment Service for evaluation of a CWP condition with duration > 3 months
* Right-handed

Exclusion Criteria:

* Inability to speak sufficient English to complete questionnaires
* Severe cognitive impairment
* Prescription steroidal (interference with cortisol measures) or psychotropic medication
* Any other chronic pain diagnosis (e.g., migraines, abdominal pain, CRPS)
* fMRI contraindications (e.g., dental appliances)

Healthy Control (HC) group:

Inclusion Criteria:

* Between ages 11-17 years
* Right-handed

Exclusion Criteria:

* Inability to speak sufficient English to complete questionnaires
* Severe cognitive impairment
* Prescription steroidal (interference with cortisol measures) or psychotropic medication
* Any chronic pain diagnosis
* Presence of documented chronic (> 3 months) medical condition with an identifiable, organic cause (e.g., diabetes, cystic fibrosis)
* fMRI contraindications (e.g., dental appliances)

• Sarah Nelson, Principal investigator, Boston Children's Hospital/Harvard Medical School

NIH grants: K23AT010643