The goal of this observational study is to investigate how adverse experiences during childhood are linked to people experiencing persistent pain and fatigue in adulthood. The questions the investigators aim to answer are: 1. Does participant-reported childhood adversity predict levels of IL-6 and TNF-α after in vitro provocation of whole blood using endotoxin? 2. Do levels of IL-6 and TNF-α after in vitro immune provocation using endotoxin predict vulnerability to persistent pain and fatigue after in vivo immune provocation (tetravalent influenza vaccine)? 3. Do levels of IL-6 and TNF-α after in vitro immune provocation using endotoxin predict vulnerability to persistent pain and fatigue after in vivo neural provocation? For this study, the investigators will recruit and enrol 96 healthy human adults (18 - 65 years old) with a range of adverse experiences during childhood. Participants will attend 2 study sessions during which the investigators will take a sample of blood, assess pressure pain threshold before and after cold water immersion, assess heart rate variability, and assess the surface area of secondary skin hypersensitivity after electrical stimulation. At the end of the first session, participants will receive the influenza vaccination.
Background Adverse experiences during childhood (childhood adversity) are associated with an increased risk of persistent pain and fatigue in adulthood. While the physiological relationships that link childhood adversity, persistent pain, and fatigue are unclear, all three factors are each associated with heightened innate immune and neural responses in adulthood. As such, neuroimmune interactions could underlie the relationship between childhood adversity, persistent pain, and fatigue, although the balance between the immune and neural influences likely varies across individuals.The investigators hypothesise that childhood adversity influences persistent pain and fatigue by priming: 1) immune, 2) neural, or 3) both systems, within an individual. Although previous studies have examined either immune or neural processes representing vulnerability to persistent pain and fatigue, the investigators are not aware of any study that has investigated both systems in the same cohort. Methods 96 healthy adult humans with a range of childhood adversity history will undergo psychophysical testing before and after in vivo neural provocation (high frequency electrical stimulation) and, separately, immune provocation (influenza vaccine). Study proxies for vulnerability to persistent pain are surface area of secondary skin hypersensitivity induced by neural provocation and change in conditioned pain modulation after immune provocation; the proxy for vulnerability to fatigue is heart rate variability 24h after immune provocation. Immune responsiveness is represented by IL-6 and TNF-α levels in supernatant after in vitro lipopolysaccharide provocation of whole blood. The investigators hypothesise that levels of IL-6 and TNF-α after in vitro immune provocation will be positively associated with the area of secondary skin hypersensitivity after in vivo neural provocation, and negatively associated with conditioned pain modulation after in vivo immune provocation.
Study Type
OBSERVATIONAL
Enrollment
101
All participants will receive the tetravalent influenza vaccine
All participants will receive High-frequency electrical stimulation
University of Cape Town
Cape Town, Western Cape, South Africa
Childhood Trauma Questionnaire-Short form
The Childhood Trauma Questionnaire-Short form uses 28 statements to probe five domains: emotional abuse, physical abuse, sexual abuse, emotional neglect, and physical neglect. Participants rate the extent to which each of the 28 possible situations was true during their childhood and adolescence, on a 5-point Likert scale ranging from "never true" to "very often true". The total score is computed by summing scores across forward- and reverse-coded items and a separate denial score that is obtained using three of the items. A higher score indicates more childhood adversities (i.e. worse outcome). The investigators will use the total score on the Childhood Trauma Questionnaire-Short to recruit specifically for a varied range in childhood adversity history and enrol participants into three similarly sized groups: 1) minimal childhood adversity (control) (score 25-36), 2) moderate childhood adversity (score 37-67), and 3) severe childhood adversity (score \> 67).
Time frame: Baseline
Provoked inflammatory response
Mean z-scores of IL-6 and TNF-alpha levels
Time frame: Baseline
Secondary hypersensitivity (surface area)
Surface area of secondary hypersensitivity induced by high-frequency electrical stimulation
Time frame: 30 minutes, 45 minutes and 60 minutes after the high-frequency electrical stimulation (neural provocation)
Conditioned pain modulation
Change in pressure pain threshold (test stimulus) after cold water immersion (conditioning stimulus)
Time frame: Baseline and 24 hours after the influenza vaccine (immune provocation).
Temporal summation
Mechanical stimuli will be provided from a 256mN von Frey Filament. Participants will provide ratings to mechanical stimuli using the Sensation and Pain Rating Scale. The Sensation and Pain Rating Scale has a 'non-painful' range, on the left of the scale, ranging from -50 - "no sensation" to 0 - "the exact point at which what you feel transitions to pain". The 'painful' range, on the right of the scale, ranges from 0 to +50 - "most intense pain you can imagine". A lower score means less intense sensation/pain (i.e. better outcome) and a higher score means more intense sensation/pain (i.e. worse outcome).
Time frame: Baseline and 24 hours after the influenza vaccine (immune provocation).
Heart rate variability
Using 3-lead ECG and Biopac System
Time frame: Baseline, 40 minutes after the high-frequency electrical stimulation (neural provocation), and 24 hours after the influenza vaccine (immune provocation).
N-back test
Assessing working memory
Time frame: Baseline and 24 hours after the influenza vaccine (immune provocation).
6-minute walk test
Assessing physical exertion and recovery
Time frame: Baseline and 24 hours after the influenza vaccine (immune provocation).
Secondary hypersensitivity (magnitude)
Change in ratings on the Sensation and Pain Rating Scale to punctate mechanical stimulation. The Sensation and Pain Rating Scale has a 'non-painful' range, on the left of the scale, ranging from -50 - "no sensation" to 0 - "the exact point at which what you feel transitions to pain". The 'painful' range, on the right of the scale, ranges from 0 to +50 - "most intense pain you can imagine". A lower score means less intense sensation/pain (i.e. better outcome) and a higher score means more intense sensation/pain (i.e. worse outcome).
Time frame: Baseline, and 35 minutes, 50 minutes and 65 minutes after the high-frequency electrical stimulation (neural provocation).
Static and dynamic light touch, and single electrical stimulation
Change in ratings on the Sensation and Pain Rating Scale to punctate mechanical stimulation. The Sensation and Pain Rating Scale has a 'non-painful' range, on the left of the scale, ranging from -50 - "no sensation" to 0 - "the exact point at which what you feel transitions to pain". The 'painful' range, on the right of the scale, ranges from 0 to +50 - "most intense pain you can imagine". A lower score means less intense sensation/pain (i.e. better outcome) and a higher score means more intense sensation/pain (i.e. worse outcome).
Time frame: Baseline, and 35 minutes, 50 minutes and 65 minutes after the high-frequency electrical stimulation (neural provocation)
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.