Interoception, the ability to perceive, process and respond to signals originating from within the body, is crucial for maintaining healthy physiological ranges. Indeed, dysfunction in this ability has been associated with various mood and pain disorders. Based on the overlap between the anatomical pathway of this ability and the site of action of the tool, transauricular vagal nerve stimulation (taVNS) could modulate this interoception. However, little is known about the breadth, duration, and mechanism of interoception modulation by taVNS. The study (Ethics Region Nord Jylland Denmark, N-20230022) will address these limitations, with 2 experiments with a focus on three interoceptive channels: deep muscular pressure pain, heartbeat, and thermal perception.
The first experiment will aim to corroborate and extend the pain-modulating effect of taVNS to other interoceptive functions and to vagal-activation markers. For this, 30 healthy subjects will complete a randomized, active control, crossover study. The main intervention is left concha taVNS (NEMOS, CerboMed GmbH, Erlangen, Germany) for 20 minutes (200µs duration, 25Hz, at a personalized intensity). This will be compared to an active control of identical electrical stimulation to the left earlobe. A blinding assessment inquiring which stimulation is supposed to be therapeutic will be collected. Main outcomes are pressure pain thresholds and temporal summation of pain responses acquired via cuff-pressure algometer (Cortex Technology, Aalborg University, Denmark) placed at the calf. Heartbeat perception, assessed via the heartbeat counting task, and thermal perception, assessed using a QST thermal grid, are also primary outcomes. Secondary outcomes are conditioned pain modulation, resting state electroencephalography, electrocardiography, and pupillary light reflexes. To assess whether, and how, taVNS modulates deep muscular pressure pain, heartbeat, and thermal perception, primary and secondary measurements pre, post and 30min post stimulation will be collected and compared. To assess the duration of the potential effects, these outcomes will be collected, and compared, at 5min intervals until the primary measurements are within 20% of baseline values. Given baseline is recovered, the second stimulation session will take place. Given this has not occurred within 1.5h of the cessation of the stimulation in the first stimulation session, subjects will be asked to come back at their earliest convenience. The second experiment will additionally explore the effect of stimulation paradigm and intensity. For this, 20 healthy subjects will complete a randomized, active and sham control, crossover study. The main intervention is left concha taVNS (NEMOS, CerboMed GmbH, Erlangen, Germany) for 40 minutes (200µs duration, 25Hz). This will be compared to an active control of identical electrical stimulation to the left earlobe and sham stimulation. Stimulation intensity will be given at 2/3rd of perception to pain threshold and at pain thresholds. A burst and continuous paradigm will also be employed. A blinding assessment inquiring which stimulation is supposed to be therapeutic will be collected. Main outcomes are pressure pain thresholds acquired via cuff-pressure algometer (Cortex Technology, Aalborg University, Denmark) placed at the calf. Heartbeat perception, assessed via the heartbeat counting task is also primary outcomes. Secondary outcomes are conditioned pain modulation, resting state electroencephalography, electrocardiography, and pupillary light reflexes. Assessments will be acquire pre, during and post stimulation.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
OTHER
Masking
DOUBLE
Enrollment
50
transauricular vagal nerve stimulation electrodes (NEMOS, CerboMed GmbH, Erlangen, Germany), attached to a digitimer.
Standard electrodes (Ambu, Neuroline, Bordeaux, France) cut into 0.6cm circles, attached to a digitimer.
Center for Neuroplasticity and Pain
Gistrup, North Denmark, Denmark
Pain Perception Threshold
Pressure algometer cuffs, placed on the calf of participants, attached to an electronic visual analogue scale (VAS) measuring device will be employed. Per cuff, as it inflates, participants are asked to move the dial of the VAS when the pressure begins to be painful. The pressure at which this occurs is referred to as the pain perception threshold (PPT).
Time frame: This measurement will be taken pre-intervention, and directly post- and 30min post-intervention. It will also be taken in 5min intervals post-intervention until the PPT is back within 20% of the pre-intervention value.
Pain Tolerance Threshold
Pressure algometer cuffs, placed on the calf of participants, attached to a visual analogue scale (VAS) will be employed. Per cuff, as it inflates, participants are asked to move the dial of the VAS when the pressure begins to be painful. They are then tasked to accordingly move the dial as the pain increases. Importantly, when the pain becomes intolerable, participants are tasked to press the red button which releases all pressure. The pressure at which this occurs is referred to as the pain tolerance threshold (PTT).
Time frame: This measurement will be taken pre-intervention, and directly post- and 30min post-intervention.
Temporary Summation of Pain
The pressure algometer cuff will inflate on the dominant leg for 1second, with a 1second break, to the given PTT 10 times consecutively. Participants are asked to move the VAS dial to the pain level at each inflation, without returning to 0 on the scale. Nothing will be done with the cuff on the opposite leg.
Time frame: This measurement will be taken pre-intervention, and directly post- and 30min post-intervention.
Heartbeat Perception
Randomly interleaved and without manual help, subjects will be tasked to count their own heartbeat across 3 time-intervals (25, 35 and 45 seconds). The difference between the perceived and actual heartbeat count is defined herein as the heartbeat perception.
Time frame: This measurement will be taken pre-intervention, and directly post- and 30min post-intervention.
Thermal Perception
The QST.lab thermal stimulator contains 6 stimulation regions, which can individually be programmed. First, with all regions programmed identically, participants will be tasked to state when the stimulus is perceived as painfully cold and warm. These will respectively be the cold and warm thresholds. A thermal-grid illusion pattern will then be generated: this involves interleaving stimulation regions as cold (2deg above the cold threshold) and hot (2deg below the hot threshold). Participants will then be asked to rate the pain intensity of this stimulation (0=no pain, 10=worst pain imaginable).
Time frame: This measurement will be acquired pre-intervention, and directly post- and 30min post-intervention.
Conditioned Pain Modulation
The non-dominant leg will receive a continuous pressure of 70% of the PTT previously registered. The cuff on the dominant leg will gradually inflate. As this occurs, participants are once again asked to start moving the dial when the pressure begins to be painful, and to press the red button when this becomes intolerable.
Time frame: This measurement will be taken pre-intervention, and directly post- and 30min post-intervention.
Handheld Pain Perception Threshold
For each side separately, a handheld pressure algometer will be applied at a constant rate of 30kPa/s, perpendicularly to the belly of the musculus trapezius. Participants will be instructed to press a button when they first perceive the pressure to be painful. This is referred to as the handheld pain perception threshold.
Time frame: This measurement will be taken pre-intervention, and directly post- and 30min post-intervention.
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