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.

Inclusion Criteria:

• Between the ages of 18 and 65 years old.

Exclusion Criteria:

• Incompetence to consent and participate, e.g. acute psychosis or high suicide risk.
• Pregnancy,
• Electrical implants (e.g. pace-maker),
• Metal implants in the forearm,
• Tattoos on the forearm,
• Any visible injury or open wounds in the forearm,
• Known history of allergic reactions to vaccines,
• Has received the current season's influenza vaccine,
• Chronic pain (pain on most days for the past 3 months),
• Diabetes Mellitus,
• Peripheral vascular disease,
• Sensory impairment in the forearm, shoulder and lower back,
• Use of medication that could later skin sensitivity (e.g. analgesic medication, immune modulators, topical medical creams),
• Cardiovascular disorders,
• Medication that alters immune function (e.g. NSAIDs, steroids),
• Smoking habit,
• Febrile illness in the preceding 4 weeks.

The investigators will recruit healthy adult volunteers (≥18 and ≤ 65 years old) with a range of childhood trauma. All interested volunteers will complete the Childhood Trauma Questionnaire-Short form. The investigators will use the total score on the questionnaire 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) low-moderate childhood adversity (score 37-67), and 3) severe childhood adversity (score > 67). The investigators will enrol volunteers into each group using a 'first to qualify, book, and attend the testing sessions' approach, with the goal of achieving similar group sizes. Some groups may fill up faster than others.

The data management plan complies with the South African Protection of Personal Information Act (POPIA) of 2013. All coded data (from the screening, enrolment and data collection phases) will be stored in a password-protected Google Drive folder, under the governance of the PI. Additionally, the back-up external hard drives will be stored in a secure location.

In keeping with open science, and following a final assessment to eliminate the possibility of reverse identification of any participant, all coded data will be made publicly available via a public repository (e.g GitHub) at study completion.