Theta Burst Brain Stimulation in Diabetic Neuropathy Patients With Neuropathic Pain: Investigating Neural Mechanisms

Study Overview
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Brief Summary
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The purpose of the study is to determine the effects of a newer form of non-invasive brain stimulation (called transcranial magnetic stimulation or TMS) as a treatment in patients with painful diabetic neuropathy to examine its effects on their understanding of their pain experience.

Detailed Description
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The proposed brain stimulation technique in this study is an investigational procedure that has not been approved by the U.S. FDA for treating pain linked to diabetic neuropathy, but it has been approved to treat depression. The study will use surveys to monitor how participant's body changes as their understanding of their pain experience changes. Participants will be randomized (like the flip of a coin) to receive brain stimulation at one of two brain regions which are involved in the processing and understanding of the pain experience.

Official Title
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Theta Burst Brain Stimulation in Diabetic Neuropathy Patients With Neuropathic Pain: Investigating Neural Mechanisms

Conditions
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Diabetic Neuropathy, Painful

Intervention / Treatment
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* Procedure: Prolonged continuous theta burst stimulation (pcTBS)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with type II Diabetes Mellitus. Age 18-75 years. Diagnosed by a Physician with diabetic neuropathy/ distal symmetric polyneuropathy/ diabetic polyneuropathy. Patients under physician care at Virginia Commonwealth University Health Systems in the Neurology Clinic/ Neurology Department and the Endocrinology Clinic Neuropathic pain for at least 3 months. Neuropathic pain signs and symptoms identified using Pain DETECT questionnaire. Current pain score ≥3 or higher (0='no pain' and 10='worst possible pain'). Pain Medication dosage stable for at least 4 weeks Exclusion Criteria: Non-neuropathic chronic pain Another concurrent cause of neuropathic pain Any history of epilepsy, drug-resistant migraine, and/or any presence of ferromagnetic implant, cardiac pacemakers, implanted insulin pumps, neurostimulators, cochlear implants and surgical clips or medical pumps. Limited English proficiency Pregnant patients

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Primary motor cortex (M1)<br>Stimulation of the M1 | Procedure: Prolonged continuous theta burst stimulation (pcTBS)<br>* Non-invasive brain stimulation (transcranial magnetic stimulation or TMS) which consists of a stimulating coil being held over the head. When this coil delivers a painless magnetic pulse, it feels like a quick, light tap on the head. Two different coils will be used to perform TMS. One coil will be used to determine stimulation parameters for the pcTBS protocol. The second coil will be used to implement pcTBS, which is a repetitive non-invasive brain stimulation protocol which feels like many quick, light taps on the head. Participants will receive two procedures during one session, one with active stimulation and one with inactive stimulation.<br>|
| Active Comparator: Dorsolateral prefrontal cortex (DLPFC)<br>Stimulation of the DLPFC | Procedure: Prolonged continuous theta burst stimulation (pcTBS)<br>* Non-invasive brain stimulation (transcranial magnetic stimulation or TMS) which consists of a stimulating coil being held over the head. When this coil delivers a painless magnetic pulse, it feels like a quick, light tap on the head. Two different coils will be used to perform TMS. One coil will be used to determine stimulation parameters for the pcTBS protocol. The second coil will be used to implement pcTBS, which is a repetitive non-invasive brain stimulation protocol which feels like many quick, light taps on the head. Participants will receive two procedures during one session, one with active stimulation and one with inactive stimulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score | The QOL-DN is questionnaire is an instrument to assess quality of life in patients with diabetic polyneuropathy. It is comprised of 35 items and yields a Total QOL score. | Baseline to the end of the procedure, about 2.25 hours | 
| Change in bodily and emotional perception of pain (BEEP) score | The BEEP questionnaire is a self-report questionnaire measuring the impact of chronic pain on daily life. It has 23 items on a 0-5 Likert scale that assesses three pain dimensions, namely the emotional reaction to pain, the limitations to daily life caused by pain and the interference caused by pain in personal and social functioning. Responses are summed to yield a single BEEP score. | Baseline to the end of the procedure, about 2.25 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in pain threshold - conditioned pain modulation (CPM) | To measure CPM, brief amounts of slight pressure using a handheld pressure device will be applied to a location either on the forearm or leg where the patient reports a current absence of pain. An average index percent ratio will be calculated from the pressure device in kilopascals at which participants report the pressure was first perceived as painful during a baseline assessment and during an assessment when the participant's contralateral hand was placed in cold water. Change will be measured by subtracting CPM scores before and after the active procedure. | Baseline to the end of the procedure, about 2.25 hours | 
| Change in pain threshold - Temporal Summation of Pain (TSP) | To measure TSP, the same pressure using a handheld pressure device that was perceived as first painful will be applied to a location either on the forearm or leg where the patient reports a current absence of pain. This pressure will be applied repeatedly applied 10 times and participants will be asked to report their pain on a 0-10 scale where 0 is no pain and 10 is worst pain imaginable. Change will be measured by subtracting TSP scores before and after the active procedure. | Baseline to the end of the procedure, about 2.25 hours | 
| Change in pain threshold - Offset Analgesia (OA) | A Velcro strap tied to participants forearm connected to a device that transmits heat will be used to measure OA. Three different temperatures of mild heat will be applied. Participants will use a visual analog scale (VAS, no heat 0- extreme heat 10) to rate the intensity of the heat stimulus at each temperature. Minimal VAS ratings at the highest temperature will be subtracted from maximal VAS ratings at the lowest temperature to yield OA value. Change will be measured by subtracting OA values before and after the active procedure. | Baseline to the end of the procedure, about 2.25 hours | 
| Change in cortical inhibition (CI) | The amplitude the motor evoked potentials (MEPS) from two simultaneous pulses will be used to determine level of cortical inhibition. | Baseline to the end of the procedure, about 2.25 hours | 
| Change in corticospinal excitability (CE) | The amplitude the motor evoked potentials (MEPS) from a single pulse will be used to determine level of corticomotor excitability | Baseline to the end of the procedure, about 2.25 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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transcranial magnetic stimulation, non-invasive brain stimulation