Neurofeedback for the Management of Neuropathic Pain in People with Diabetes

We will conduct a high-quality, blinded, randomized controlled trial (RCT) to rigorously test the effectiveness of EEG-based NF in patients with diabetes-related neuropathic pain in: 1) reducing pain intensity and pain affect, and 2) improving daily functioning and QoL.

Study Overview

• Status: Recruiting
• Conditions: Neuropathy, Painful Diabetic
• Intervention / Treatment: Behavioral: EEG-neurofeedback

Detailed Description

20%-40% of people with diabetes develop diabetic polyneuropathy (DPN), which often manifests as a painful complication, strongly reducing quality of life. Current standard pharmacological treatments for neuropathic pain are often ineffective and have considerable side effects. Therefore, there is an urgent need for better treatment options. The way in which the brain interprets signals from the periphery can be modified through learning certain techniques, which can enable patients to modify signals related to painful DPN and consequently experience pain alleviation. Neurofeedback (NF) is a promising neuromodulatory therapy in which individuals receive real-time feedback about their brain's neurophysiological signals, thus increasing the volitional control of brain activity, reducing the experience of pain. Neurofeedback uses scalp EEG electrodes attached to a computer screen, which give real-time feedback to the individual. NF may offer symptom alleviation by teaching patients to regulate relevant activity patterns by themselves. By rewarding the person whenever the neural activity changes in a desired direction, the activity can be modulated. NF has not yet been investigated in an RCT in people with painful DPN. This proposed Danish-Brazilian project is the first triple blind RCT rigorously testing an EEG-NF intervention for neuropathic pain (NP) in diabetes. The treatment will be conducted over 10 sessions in two randomized groups: a real EEG-NF group and a sham (placebo) EEG-NF group. Brazilian participants will also undergo (functional) magnetic resonance imaging (fMRI) scanning to investigate how the NF-treatment targets and alters neural mechanisms. If found effective, the low-cost EEG-NF can be made available and implemented at large scale for people with diabetes and painful neuropathy, and will be in reach for low- to middle-income countries.

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Early Phase 1

Contacts and Locations

• Study Contact: Name: Francois Pouwer, Professor; Phone Number: +45 65 50 48 92; Email: fpouwer@health.sdu.dk
• Study Contact Backup: Name: Johanne Axelsen, PhD-student; Email: jlaxelsen@health.sdu.dk

Study Locations

• Denmark
  • Odense, Denmark, 5230
    • Recruiting
    • University of Southern Denmark
    • Contact: Johanne Axelsen, PhD-student; Phone Number: +45 65 50 48 94; Email: jlaxelsen@health.sdu.dk
    • Contact: Francois Pouwer, Professor

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Age ≥18 and ≤82 years

• Diagnosed with 1) type 1 diabetes (for at least 5 years) or 2) type 2 diabetes
• The Toronto consensus criteria will be used for a case definition of DPN where patients have to have at least probable DPN (31). Diagnosis of DPN is confirmed with abnormal DPN Check. Painful DPN will be defined using the grading system for neuropathic pain (50) and will be in line with IASP's definition of neuropathic pain, i.e., "pain caused by a lesion or disease of the somatosensory system" (The Toronto consensus criteria).
• TCNS score > 5
• Eligible patients with painful DPN must have a pain intensity of at least 4 on an 11-point numerical rating scale (NRS, 0-10) for at least 3 months on at least semi-daily basis and no severe pain other than pain due to neuropathy (the pain intensity will be based on the pain the patients experience while on current pain treatment, if any).
• Stable pain medication for > 1 month prior to inclusion. Exclusion criteria

Exclusion Criteria:

• Concomitant neurological (neurodegenerative disorders, migraine, epilepsy, stroke, tumor) or clinically significant psychiatric illness
• Neuropathy or neuropathic pain due to other causes than diabetes (vitamin B12 deficiency, prior treatment with neurotoxic chemotherapy, chronic alcohol abuse, spinal stenosis, etc.)
• Change in current pain treatment during treatment (paracetamol is allowed as rescue medicine)
• Prior or current excessive alcohol use (>14 or >21 units/week for women and men, respectively) or illegal substance abuse
• Positive urine hCG test result indicating pregnancy
• Morphine use >20mg/day
• Blindness or severely impaired vision
• The investigator finds the patient unfit for the study (e.g. due to use of alcohol or drugs, mental incapacity, unwillingness, or language barrier precluding adequate understanding or cooperation or presence of any condition that in the investigators' opinion may lead to poor adherence to study protocol).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Real EEG-neurofeedback; the NF intervention group will receive feedback based on the genuine real-time EEG activity	Behavioral: EEG-neurofeedback; Traditional neurofeedback uses one or two electrodes to modulate activity within a specific frequency band. Standardized Weighted Low Resolution Electromagnetic Tomography (swLORETA) analyzes the 3D distribution of intracortical brain electrical activity based on surface EEG recordings, enabling real-time brainwave imaging with a spatial resolution under one cubic centimeter. This divides the brain into over 12,000 voxels, offering localization similar to fMRI while maintaining EEG's faster temporal resolution. Source-localized NF can target specific, deeper brain regions, multiple Brodmann areas simultaneously, and provide feedback on connectivity between neural sources, enabling the training of specific neural networks. swLORETA metrics are compared to a normative database of neurotypical brains to produce z-scores for each area and metric. We will use the NeuroGuide normative database, FDA-approved and validated in peer-reviewed studies, widely used in clinical NF.
Sham Comparator: Sham EEG-neurofeedback; The sham-group will receive another participant's EEG-training protocol as a prerecorded signal. The feedback signal will consist of 15-25 rewards per minute. Meanwhile, the threshold for the sham group remains fixed, ensuring a consistent 70% positive feedback rate.	Behavioral: EEG-neurofeedback; Traditional neurofeedback uses one or two electrodes to modulate activity within a specific frequency band. Standardized Weighted Low Resolution Electromagnetic Tomography (swLORETA) analyzes the 3D distribution of intracortical brain electrical activity based on surface EEG recordings, enabling real-time brainwave imaging with a spatial resolution under one cubic centimeter. This divides the brain into over 12,000 voxels, offering localization similar to fMRI while maintaining EEG's faster temporal resolution. Source-localized NF can target specific, deeper brain regions, multiple Brodmann areas simultaneously, and provide feedback on connectivity between neural sources, enabling the training of specific neural networks. swLORETA metrics are compared to a normative database of neurotypical brains to produce z-scores for each area and metric. We will use the NeuroGuide normative database, FDA-approved and validated in peer-reviewed studies, widely used in clinical NF.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pain intensity and affect	Change in self-reported pain intensity and pain affect (an average over a daily measurement in a 7-day pain diary using a numeric rating scale (NRS) from 0-10)	Before and after the intervention (approx. 8 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neuropathic pain severity	Differences in neuropathic pain severity as measured by PROMIS. Both individually and between groups	Before and after the intervention (approx. 8 weeks) and at 4 months follow-up (approx. a half year from start until four months follow up)
Neuropathic pain severity	Differences in neuropathic pain severity as measured by the DN4. Both individually and between groups	Before and after the intervention (approx. 8 weeks) and at 4 months follow-up (approx. a half year from start until four months follow up)
Neuropathic pain severity	Differences in neuropathic pain severity as measured by the Neuropathic pain severity as measured by the Neuropathic Pain Scale (NPS). Both individually and between groups	Before and after the intervention (approx. 8 weeks) and at 4 months follow-up (approx. a half year from start until four months follow up)
Disability	Differences in disability as measured by the Brief Pain Inventory (BPI) (short form) and on the full BPI.	Before and after intervention (approx. 8 weeks). Between groups after intervention (approx. 8 weeks) and at 4 months follow-up (approx. a half year after baseline)
Sleep quality	Daily sleep interference scale	7 day diary before baseline and after intervention (approx. 8 weeks)
z-score normalization	Normalization of the z-score of the targeted neural networks described in the training protocol for the NF-treatment.	Before and after the intervention (approx. 8 weeks)
Loreta z-score responders versus non-responders	Investigate Loreta z-score responders versus non-responders. Responders will be a subgroup of participants who showed any amount of decrease from baseline to last visit in the total number of significant z-scores within the targeted networks. Responders, whose z-scores move toward neurotypical levels (i.e., toward z = 0) will be compared to non-responders whose z-scores will not move in this expected direction.	Before and after the intervention (approx. 8 weeks)

Collaborators and Investigators

• Sponsor: University of Southern Denmark
• Collaborators: Aarhus University Hospital; Region of Southern Denmark; European Foundation for the Study of Diabetes; Steno Diabetes Center Odense; Vissing fonden

Study record dates

Study Major Dates

• Study Start (Actual): September 1, 2024
• Primary Completion (Estimated): January 1, 2026
• Study Completion (Estimated): June 1, 2026

Study Registration Dates

• First Submitted: August 29, 2024
• First Submitted That Met QC Criteria: September 16, 2024
• First Posted (Estimated): September 19, 2024

Study Record Updates

• Last Update Posted (Estimated): September 19, 2024
• Last Update Submitted That Met QC Criteria: September 16, 2024
• Last Verified: May 1, 2024

More Information

Terms related to this study

• Keywords: RCT; Neurofeedback; diabetic neuropathy; painful diabetic neuropathy; EEG-neurofeedback
• Additional Relevant MeSH Terms: Nervous System Diseases; Pain; Neurologic Manifestations; Endocrine System Diseases; Diabetes Complications; Diabetes Mellitus; Neuromuscular Diseases; Peripheral Nervous System Diseases; Neuralgia; Diabetic Neuropathies
• Other Study ID Numbers: 11.719

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes