Optimization of NIBS for Diabetic Neuropathy Neuropathic Pain

Study Overview
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Brief Summary
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The purpose of this study is to assess the effects of Transcranial Direct Current Stimulation (tDCS) in combination with Transcranial ultrasound (TUS) for the treatment of pain and functional limitations in subjects with Diabetic Neuropathic Pain.

Detailed Description
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Active stimulation will be compared with compared to SHAM stimulation in DNP patients. 20 DNP patients, 10 per group, receive stimulation or sham for 5 consecutive days, 20 min/day, followed by 2, 4, and 6 weeks post-therapy. 9 visits plus screening/baseline (total 10 visits). Subsequently, 40 DNP patients will be enrolled, 20 per group, giving 5 consecutive days, 20 min/day, followed by 2 weeks of bi-weekly stimulation or sham for 20 min/day (total stimulations n=9) and follow-ups at 2, 4, 6, & 8 weeks post-stim): 13 visits plus screening/ baseline (total 14 visits).

Official Title
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Optimization of Non-Invasive Brain Stimulation for Diabetic Neuropathy

Conditions
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Diabetic Neuropathies, Chronic Pain

Intervention / Treatment
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* Device: Active Comparator: Active tDCS + Active TUS
* Device: Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to provide informed consent to participate in the study. Subjects between 40 to 80 years old. Having diabetic neuropathic pain, involving at least 1 foot, with existing pain for at least 6 months, and having pain on at least half the days in the past 6 months with an average of at least a 4 on a 0-10 VAS scale). Having pain resistant to common analgesics and medications for first-line therapy of chronic pain such as Tylenol, Aspirin, Ibuprofen, Soma, Parafon Forte DCS, Zanaflex, Codeine, etc. Must have the ability to feel pain as self-reported. Exclusion Criteria: Subject is pregnant. Contraindications to tDCS in conjunction with TUS, i.e. metallic implant in the brain or implanted brain medical devices History of alcohol or drug abuse within the past 6 months as self-reported. Use of carbamazepine within the past 6 months as self-reported. Suffering from severe depression (with a PHQ 9 score of ≥ 10). History of neurological disorders as self-reported. History of unexplained fainting spells as self-reported. History of severe head injury resulting in more than a momentary loss of consciousness as self-reported. History of neurosurgery as self-reported. Unstable pain (defined as pain intensities that vary by more than 4 points on 0-10 VAS scale over the 1-week period of trial run-in).

Ages Eligible for Study
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Minimum Age: 40 Years
Maximum Age: 80 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: single-center, double-blinded, placebo controlled, randomized study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Comparator: Active tDCS + Active TUS<br>Subjects in the experimental group will undergo 20 minutes of active transcranial direct current stimulation (tDCS) and active transcranial ultrasound (TUS). | Device: Active Comparator: Active tDCS + Active TUS<br>* Device: transcranial Direct Current Stimulation (tDCS) Subjects will receive 20 minutes of either active or sham tDCS at intensity of 2mA. The anodal electrode will be placed over the primary motor cortex contralateral to the most painful side, and the cathodal electrode will be placed over the contralateral supraorbital area. In the sham group, the tDCS device will not be active for the full 20 minutes. Device: Transcranial Ultrasound (TUS) Subjects will receive 20 minutes of either active or sham TUS. During active stimulation the ultrasound will be active for the full 20 minutes- however, during sham stimulation the ultrasound will not be active for the full 20 minutes.<br>|
| Sham Comparator: Sham<br>Subjects in the sham group will undergo 20 minutes of sham transcranial direct current stimulation (tDCS) and sham transcranial ultrasound (TUS). | Device: Sham<br>* Device: SHAM Comparator Device: transcranial Direct Current Stimulation (tDCS) Subjects will receive 20 minutes of either active or sham tDCS at intensity of 2mA. The anodal electrode will be placed over the primary motor cortex contralateral to the most painful side, and the cathodal electrode will be placed over the contralateral supraorbital area. In the sham group, the tDCS device will not be active for the full 20 minutes. Device: Transcranial Ultrasound (TUS) Subjects will receive 20 minutes of either active or sham TUS. During active stimulation the ultrasound will be active for the full 20 minutes- however, during sham stimulation the ultrasound will not be active for the full 20 minutes.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in pain as measured by the Visual Analog Scale (VAS) | The scale will assess a patient's pain intensity on a scale from 0 (no pain) to 10 (worst pain imaginable). Changes in VAS for Pain will be measured to determine whether anodal transcranial direct current stimulation (tDCS) in conjunction with transcranial ultrasound (TUS) (applied in a diagnostic mode) is effective in reducing pain of subjects with diabetic neuropathic pain. | Measured for approximately 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in the Verbal Rating Scale (VRS) for Pain | The VRS for Pain is a categorical scale of pain with categories: none, mild, moderate, severe pain intensity. Changes in VRS for Pain will be measured in order to determine whether anodal transcranial direct current stimulation (tDCS) in conjunction. with transcranial ultrasound (TUS) (applied in a diagnostic mode) is effective in reducing pain of subjects with diabetic neuropathic pain. | Measured for approximately 3 months | 
| Changes in Conditional Pain Modulation | Changes in Conditional Pain Modulation (CPM) will be measured in order to determine whether anodal transcranial direct current stimulation (tDCS) in conjunction with transcranial ultrasound (TUS) (applied in a diagnostic mode) is effective in increasing the pain pressure threshold in subjects with diabetic neuropathic pain. | Measured for approximately 3 months | 
| Changes in Visual Analog Scalefor Mood (VAMS) | The VAS for Mood will investigate Anxiety, Depression, Stress, and Sleepiness. The Subscales are as follows: The anxiety scale will assess a patient's anxiety on a scale from 0 (not anxious) to 10 (very anxious). The depression scale will assess a patient's depression on a scale from 0 (not depressed) to 10 (very depressed). The stress scale will assess a patient's stress on a scale from 0 (not stressed) to 10 (very stressed). The sleepiness scale will assess a patient's depression on a scale from 0 (not sleepy) to 10 (very sleepy). | Measured for approximately 3 months | 
| Montreal Cognitive Assessment | The investigators will monitor the safety of tDCS and TUS in subjects by measuring any changes in cognition. Scores range from lowest being 0 to highest being 30. | Measured for approximately 3 months | 
| 4-choice reaction time | This is an attentional task that measures the time for a subject response to stimuli (in seconds) with shorter times being better. | Measured for approximately 3 months | 
| N-back tests | Assesses registration and immediate recall on a scale of the number of items correctly responded to | Measured for approximately 3 months | 
| Electroencephalography | Investigators will measure electroencephalogram (EEG) electrical activity (EEG amplitude and EEG frequency) as function of time. | Measured for approximately 3 months | 
| Walking test | The investigators will measure if there are changes in the walking speed, gait asymmetry, stride length, and walking smoothness of the subject from the beginning of the study to the end | Measured for approximately 3 months | 
| Functional reach test | The investigators will measure changes in subjects ability to complete the functional reach test across the duration of study. | Measured for approximately 3 months | 
| Study 36-Item Short Form (SF-36) | This is a health survey using a scale from 0 (worst) to 100 (best) | Measured for approximately 3 months | 
| Patient Health Questionnaire (PHQ-9) | This questionnaire screens for depression with a score of 0 (best) to 27 (worst) | Measured for approximately 3 months | 
| American Pain Foundation Pain and Medication Diary | The pain sub-scale measures pain intensity from 0 (best) to 10 (worst) | Measured for approximately 3 months | 
| Multidimensional Pain Inventory (MPI) | This pain scale measures aspects of pain from 0 (best) to 6 (worst) | Measured for approximately 3 months | 
| Brief Pain Inventory-DPN | This pain scale measures aspects of pain from 0 (no pain) to 10 (worst) | Measured for approximately 3 months | 
| Adverse events | At each session after stimulation begins, subjects will complete a questionnaire to evaluate potential adverse effects of stimulation (headache, neck pain, mood alterations, and seizures) on a 5-point scale (0 being best and 5 worst). The scale will also be administered at the follow-up. | Measured for approximately 3 months |