Effects of Vagus Nerve Stimulation on Central Pain Sensitivity & Parasympathetic Function in Knee Osteoarthritis

Pressure pain thresholds (PPT) will be assessed at the wrist and patellae. PPT being assessed at a remote body site (e.g., wrist) is to measure central pain sensitivity while PPT being assessed at the location of pain (i.e., knee, patellae) is to assess peripheral pain sensitivity with or without central pain sensitivity. PPT will be assessed using a handheld pressure algometer with 1 cm2 rubber tip. PPT will be defined as the point at which the participant verbally indicated that the pressure first changed to slight pain. A lower PPT value (Kgf) represents greater pain sensitivity. PPT will be assessed 3 times at each location and averaged. Changes in PPT between immediately after tVNS and baseline and between 15 minutes after tVNS intervention and baseline will be used for analysis.

Conditioned pain modulation (CPM) evaluates the adequacy of the descending pain modulatory pathways, which contributes to central pain sensitivity. Investigators will assess CPM using PPT as the test stimulus (PPT1) at the wrist as described above, with forearm ischemia using a blood pressure cuff as the conditioning stimulus. Briefly, the blood pressure cuff applied to the contralateral arm will be inflated to 10mm Hg above systolic pressure. The participant will be then instructed to perform hand grip squeezes until pain of at least 4/10 occurs in the contralateral arm. PPT will be then reassessed at the wrist 3 times and averaged (PPT2). Percent efficiency of CPM (%CPM) was computed as PPT2/PPT1, multiplied by 100; %CPM ≤ 100 indicates inefficient CPM. Changes in %CPM between immediately after tVNS intervention and baseline and between 15 minutes after tVNS intervention and baseline will be used for analysis.

Temporal summation (TS) is a sensitive measurement of central pain sensitivity. Investigators will assess TS using a standard set of weighted probes from 64-512 mN. Participants will rate the pain experienced by each successive weighted probe being touched on the skin of the wrist until a pain rating of ≥ 4/10 is achieved. The selected probe will be then applied at a frequency of 1 Hz for 10 seconds on the wrist. Participants will provide a pain rating at the completion of the train of 10 stimulations and 15 seconds post-stimulation. TS will be defined as the difference between the highest post-stimulation pain rating and the initial pain rating. A post-stimulation pain rating greater than the initial pain rating will be considered to be reflective of an increase in central pain sensitivity. Changes in TS between immediately after tVNS intervention and baseline and between 15 minutes after tVNS intervention and baseline will be used for analysis.

Investigators will assess changes in parasympathetic function before and immediately after- and 15 minutes after tVNS intervention. Heart rate variability (HRV), a measurement of autonomic function, will be assessed at baseline and after tVNS intervention using a wearable and wireless heart rate monitor. Investigators will have participants lie supine for 5 mins in each assessment to collect heart rate variability parameters such as high frequency and high-frequency/low-frequency ratio that is specific to activity in parasympathetic nervous system function.

Investigators will assess changes in knee pain before (baseline), immediately after- and 15 minutes after tVNS intervention using a 0-10 numeric rating scale where 0 indicates no knee pain and 10 indicates the worst knee pain. Changes in knee pain between immediately after tVNS intervention and baseline and between 15 minutes after tVNS intervention and baseline will be used for analysis.

Investigators will assess changes in knee pain before (baseline), immediately after- and 15 minutes after tVNS intervention using The Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). WOMAC knee pain scale ranges 0-20 with 5 questions assessing knee pain in different contexts such as knee pain during walking and pain during standing. Each question has a score of 0-4. A greater WOMAC score represents greater knee pain. Change in WOMAC score between immediately after tVNS intervention and baseline and between 15 minutes after tVNS intervention and baseline will be used for analysis.

Investigators will assess safety by evaluating the intervention completion rate, determined by the number of participants who completed the intervention divided by the number of participants enrolled. If there is any adverse/side effect, the types of such events will be documented.

At the end of the study visit, investigators will assess the satisfaction level with tVNS intervention using the 8-item Client Satisfaction Questionnaire. The questionnaire asks about the satisfaction level regarding the new intervention using 8 questions. Each question has a 1-4 score where 1 indicates poor, and 4 indicates high satisfaction level.

The Pain Catastrophizing Scale is a validated 13-item scale with questions related to catastrophizing behavior. The total score is 52 with higher scores indicating greater catastrophic thoughts.

The Fear-Avoidance Belief Questionnaire categorizes these traits using items related to fear about physical and work activities. A total score is 96 with 16 questions. Each item is scored from 0 to 6 with a higher number indicating increased fear of activity or work.

The Pittsburgh Sleep Quality Index (PSQI) is a self-reported questionnaire. PSQI contains 19 individual items, creating seven components that produce one global score, ranging from 0 to 21. A score of 0-4 indicates the absence of sleep problems, while scores 5 and higher indicate poor sleep quality.

HADS contains seven questions about anxiety and seven questions about depression, with a 0-3 score for each question. Higher scores indicate greater anxiety and depression.

MEIM contains 12 questions to assess the extent to which individuals have an ethnic identity. Each question has a 1-4 score where 1 indicates poor ethnic identity and 4 indicates strong ethnic identity. Higher scores indicate that the individual has stronger feelings of belonging to the ethnic group with which he/she identified.