How do Alpha Oscillations Shape the Perception of Pain? - An EEG-based Neurofeedback Study

Study Overview
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Brief Summary
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Pain is closely linked to alpha oscillations (8 -13 Hz) which are thought to represent a supra-modal, top-down mediated gating mechanism that shapes sensory processing. Consequently, alpha oscillations might also shape the cerebral processing of nociceptive input and eventually the perception of pain. To test this mechanistic hypothesis, the investigators designed a sham-controlled and double-blind electroencephalography (EEG)-based neurofeedback study. In a short-term neurofeedback training protocol, healthy participants will learn to up- and downregulate somatosensory alpha oscillations using attention. Subsequently, the investigators will investigate how this manipulation impacts experimental pain applied during neurofeedback. Using Bayesian statistics and mediation analysis, the investigators will test whether alpha oscillations mediate attention effects on pain perception. This approach promises causal insights into the role of alpha oscillations in shaping pain, and thereby extends previous correlative evidence. Beyond, it can aid the development of novel, non-invasive modulatory treatment approaches for chronic pain, which are urgently needed. The prosed study protocol has been granted in-principle acceptance from PLOS Biology and the corresponding registration can be found at the OSF online repository [www.osf.io/qbkj2].

Official Title
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How do Alpha Oscillations Shape the Perception of Pain? - An EEG-based Neurofeedback Study

Conditions
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Experimental Pain in Healthy Human Subjects

Intervention / Treatment
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* Behavioral: attention right training, ARTNF
* Behavioral: attention left training, ALTNF
* Behavioral: sham attention right training, ARTsham
* Behavioral: sham attention left training, ALTsham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: aged 18-45 years right-handedness (laterality quotient > 60 on the Edinburgh handedness inventory) good command of German written informed consent attendance at both sessions and compliance with instructions throughout the experiment Exclusion Criteria: pregnancy neurological or psychiatric diseases (e.g., epilepsy, stroke, depression, anxiety disorders) severe general illnesses (e.g., tumors, diabetes) skin diseases (e.g., dermatitis, psoriasis or eczema) current or recurrent pain regular intake of medication (aside from contraception, thyroidal, and antiallergic medication) surgical procedures involving the head or spinal cord side-effects following previous thermal stimulation contact to a person with a SARS-CoV-2 infection within the last 2 weeks current symptoms of a cold or flu

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Interventional Model Description: Each participant will participate in 4 experimental conditions differing with respect to the administered neurofeedback training: (1) attention right training, ARTNF; (2) attention left training, ALTNF; (3) sham attention right training, ARTsham; (4) sham attention left training, ALTsham. During neurofeedback, noxious stimuli will be applied to the dorsum of the left hand using cutaneous laser stimulation (Nd:YAP laser, Stimul 1340, DEKA M.E.L.A. srl, Calenzano, Italy; stimulation settings: 4 ms duration, 7 mm stimulus diameter, 3.5 J laser intensity) while pain ratings will be recorded.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: neurofeedback<br>Modulation of brain activity using verum and sham neurofeedback. | Behavioral: attention right training, ARTNF<br>* In a first verum neurofeedback condition, participants will be instructed to focus attention on their right hand and the up-regulation of alpha oscillations in the right hemisphere relative to alpha oscillations in the left hemisphere will be incentivized through neurofeedback.<br>Behavioral: attention left training, ALTNF<br>* In a second verum neurofeedback condition, participants will be instructed to focus attention on their left hand and the down-regulation of right relative to left alpha oscillations will be incentivized.<br>Behavioral: sham attention right training, ARTsham<br>* During the first sham neurofeedback condition, participants will be instructed to focus attention on their right hand. However, the feedback signal will not mirror their brain activity. Instead, the feedback signal and the corresponding reward of the last matching verum condition completed by a previous participant, i.e., ARTNF for ARTsham, will be replayed (yoked feedback).<br>Behavioral: sham attention left training, ALTsham<br>* During the second sham neurofeedback condition, participants will be instructed to focus attention on their left hand. However, the feedback signal will not mirror their brain activity. Instead, the feedback signal and the corresponding reward of the last matching verum condition completed by a previous participant, i.e., ALTNF for ALTsham, will be replayed (yoked feedback).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alpha asymmetry index (AAI) during neurofeedback | During neurofeedback, brain activity will be recorded continuously and the AAI will be extracted. Subsequently, AAIs will be compared between neurofeedback conditions. Details regarding the complete analysis pipeline can be found at the OSF online repository [www.osf.io/qbkj2]. | During procedure (neurofeedback) | 
| Pain ratings during neurofeedback (NRS; 1: 'no pain' to 100: 'worst tolerable pain') | At the end of each neurofeedback trial, participants will verbally rate the perceived intensity of a cutaneous laser stimulus. Subsequently, pain ratings will be compared between neurofeedback conditions. Details regarding the complete analysis pipeline can be found at the OSF online repository [www.osf.io/qbkj2]. | During procedure (neurofeedback) | 
| Pain-related brain responses during neurofeedback | During neurofeedback, brain activity will be recorded continuously, and the pain-related brain responses will be extracted. Subsequently, pain-related brain responses will be compared between neurofeedback conditions. Details regarding the complete analysis pipeline can be found at the OSF online repository [www.osf.io/qbkj2]. | During procedure (neurofeedback) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Motivation to participate in the training measured by a numerical rating scale (NRS; 1: 'very low' to 7: 'very high') | The motivation to participate in the training will be assessed using a self-report measure. | Before each session | 
| General self-efficacy (German version of the General Self-Efficacy Scale, GSE, minimum score: 10, maximum score: 40) | General self-efficacy will be assessed using the German version of the General Self-efficacy Scale. | Before each session | 
| Health-related locus of control (Multidimensional Health Locus of Control Scales, MHLC, minimum score: 3, maximum score: 15) | The health-related locus of control will be assessed using Multidimensional Health Locus of Control Scales. | Before each session | 
| Current positive or negative affect (Positive and Negative Affect Schedule, PNAS, minimum score: 10, maximum score: 50) | The current positive or negative affect will be assessed using the Positive and Negative Affect Schedule. | Before each session | 
| Perceived task demand (NRS; 1: 'very low' to 7: 'very high') | The perceived task demand will be assessed using a self-report measure. | After each condition | 
| Effort exerted (NRS; 1: 'very low' to 7: 'very high') | The effort exerted will be assessed using a self-report measure. | After each condition | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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pain, neurofeedback, alpha, neural oscillations, attention, brain, registered report