Neuropathy, Painful Diabetic
Conditions
Keywords
Neurofeedback, diabetic neuropathy, painful diabetic neuropathy, RCT, EEG-neurofeedback
Brief summary
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. This study aims to determine the short-term and long-term effects of EEG-based NF on self-reported pain intensity, neuropathic pain symptoms, daily functioning, QoL and neurophysiological activity in individuals with chronic P-DPN. The trial is designed as a superiority trial. The primary aim is to evaluate whether real EEG-NF compared with sham EEG-NF, leads to a greater reduction in self-reported pain intensity from T0 to T1, assessed using mean 7-day pain intensity derived from the electronic pain diary. Secondary aims are to examine whether EEG-NF improves neuropathic pain severity, pain interference, sleep, fatigue, mood and QoL, and promotes normalization of activity within predefined pain-related cortical networks assessed using z-score changes in standardized weighted low-resolution electromagnetic tomography (swLORETA)-derived regions.
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 blinded 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.
Interventions
BEHAVIORALEEG-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. NeuroGuide is used within the FDA 510(k)-cleared NeuroGuide Analysis System (K041263); clearance does not imply treatment validation.
Sponsors
University of Southern Denmark
European Foundation for the Study of Diabetes
Region of Southern Denmark
Vissing fonden
Steno Diabetes Center Odense
Aarhus University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Intervention model description
The project will investigate two randomized groups: a 'true' EEG-NF-group and 'sham' EEG-NF-group.
Eligibility
Sex/Gender
ALL
Age
18 Years to 82 Years
Healthy volunteers
No
Inclusion criteria
* Age ≥18 and ≤82 years * Diagnosed with 1) type 1 diabetes (for at least 5 years) or 2) type 2 diabetes * Confirmed diagnosis of at least "Probable Diabetic Polyneuropathy" as defined by Toronto Consensus Criteria (Presence of a combination of symptoms and signs of neuropathy including any two or more of the following: neuropathic symptoms, decreased distal sensation, or unequivocally decreased or absent ankle reflexes), and at least one of the following: * TCNS \> 5 * Abnormal DPNCheck results (amplitude \< 4µV and/or conduction velocity \< 40 m/s) * Abnormal NCS (Nerve Conduction Study) * Confirmed diagnosis of at least "Probable Neuropathic Pain" as defined by NeuPSIG guidelines (Pain distribution which makes neuropathic pain neuroanatomically plausible and history suggests relevant disease (e.g., symmetric pain in the feet/lower extremities and history of diabetes), and at least one of the following: * Negative or positive sensory signs, confined to innervation territory of the lesioned nervous structure (abnormal findings in at least one of: pinprick, temperature sensation, light touch (monofilament), vibration sense (biothesiometry or 128Hz tuning fork, position sense). * Abnormal DPNCheck results (amplitude \< 4µV and/or conduction velocity \< 40 m/s) * Abnormal NCS (Nerve Conduction Study) * 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
* 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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pain intensity | Seven consecutive days before baseline EEG assessment (T0; days -7 to -1) and seven consecutive days following the 10th and final neurofeedback session (T1; days +1 to +7). | The primary aim is to evaluate whether real EEG-NF compared with sham EEG-NF, leads to a greater reduction in self-reported pain intensity (NRS from 0-10) from T0 (baseline) to T1 (after 10th and final session), assessed using mean 7-day pain intensity derived from an electronic pain diary. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Neuropathic pain symptoms | Inclusion visit (pre-intervention), post-treatment assessment (after the 10th and final neurofeedback session), and 4 months after completion of the intervention. | Differences in neuropathic pain symptoms will be assessed using the Neuropathic pain scale (NPS). Changes from baseline will be evaluated following the intervention and at 4-month follow-up, and differences between the real EEG-NF and sham EEG-NF groups will be examined. |
| Pain interference | Inclusion visit (pre-intervention), post-treatment assessment (after the 10th and final neurofeedback session), and 4 months after completion of the intervention. | Pain interference will be assessed using the Brief Pain Inventory (BPI) interference scale. Changes from baseline will be evaluated following the intervention and at 4-month follow-up, and differences between the real EEG-NF and sham EEG-NF groups will be examined. |
| Sleep | Inclusion visit (pre-intervention), post-treatment assessment (after the 10th and final neurofeedback session), and 4 months after completion of the intervention. | Sleep disturbance will be assessed using the PROMIS sleep measure. Changes over time and between-group differences will be examined. |
| Pain network abnormality burden | Baseline EEG assessment and post-treatment EEG assessment after completion of the 10th and final neurofeedback session. | Neurophysiological outcomes will be assessed using normative z-scores within the predefined pain-related network. A composite pain-network abnormality burden will be derived across EEG features, with domain-specific measures for current source density (CSD), instantaneous coherence, and lagged coherence also examined. Changes from pre- to post-intervention will be compared between the real EEG-NF and sham EEG-NF groups. |
| Global impression of change | After completion of the 10th and final neurofeedback session (T1) and at 4-month follow-up (T2). | Participants' overall perceived change in their condition will be assessed using the Patient Global Impression of Change (PGIC). Ratings following treatment and at follow-up will be summarized and compared between the real EEG-NF and sham EEG-NF groups as a supportive secondary outcome. |
| Pain catastrophizing | Inclusion visit (pre-intervention), post-treatment assessment (after the 10th and final neurofeedback session), and 4 months after completion of the intervention. | Pain catastrophizing and coping will be assessed using the Pain Catastrophizing Scale (PCS). Changes from baseline will be evaluated following the intervention and at 4-month follow-up, and differences between the real EEG-NF and sham EEG-NF groups will be examined. |
| Quality of Life | Inclusion visit (pre-intervention), post-treatment assessment (after the 10th and final neurofeedback session), and 4 months after completion of the intervention. | Quality of life will be assessed using the World Health Organization Quality of Life-BREF (WHOQOL-BREF). Changes from baseline will be evaluated following the intervention and at 4-month follow-up, and differences between the real EEG-NF and sham EEG-NF groups will be examined. |
| Daily sleep interference | Seven consecutive days before baseline (T0; days -7 to -1) and seven consecutive days following the 10th and final neurofeedback session (T1; days +1 to +7). | Sleep interference will be assessed using daily self-reported ratings collected as part of the electronic diary. Mean ratings will be derived for the predefined baseline and post-intervention assessment periods. |
| Brief Pain Inventory (BPI) pain severity score | Inclusion visit (pre-intervention), post-treatment assessment (after the 10th and final neurofeedback session), and 4 months after completion of the intervention. | Pain severity will be assessed using the pain severity items of the Brief Pain Inventory (BPI). Changes over time and differences between the real EEG-NF and sham EEG-NF groups will be examined, with the 4-month follow-up used to assess durability of treatment effects. |
| Mood | Inclusion visit (pre-intervention), post-treatment assessment (after the 10th and final neurofeedback session), and 4 months after completion of the intervention. | Mood will be assessed using the PROMIS mood measure. Changes over time and between-group differences will be examined. |
| Fatigue | Inclusion visit (pre-intervention), post-treatment assessment (after the 10th and final neurofeedback session), and 4 months after completion of the intervention. | Fatigue will be assessed using the PROMIS fatigue measure. Changes over time and between-group differences will be examined. |
Countries
Denmark
Contacts
CONTACTFrancois Pouwer, Professor
CONTACTJohanne Axelsen, PhD-student
Outcome results
None listed