H-coil TMS to Reduce Pain: A Pilot Study Evaluating Relative Efficacy of the H1 vs H7 Coil

Study Overview
=================
Brief Summary
-----------------
Chronic pain is a serious public health problem with estimates as high as nearly half of the adult population experiencing some form of pain that lasts for more than 6 months. Chronic use of opiates is a rapidly escalating crisis in the United States, with over 4.3 million Americans dependent on opiate analgesics, an escalating rate of opiate overdose deaths, and a resurgence of intravenous heroin use leading to total societal cost exceeding $55 billion. While opiates are effective at treating acute pain, tolerance to the analgesic effects develops quickly, leading to high abuse liability and dependence potential. Consequently, the development of a new, non-pharmacologic intervention to treat pain, such as repetitive transcranial magnetic stimulation (rTMS), which would provide analgesic benefit while also directly remodeling the neural circuitry responsible for cognitive control over opiate craving, would fill an increasingly urgent public health need.

Detailed Description
-----------------
Chronic pain is a serious public health problem with estimates as high as nearly half of the adult population experiencing some form of pain that lasts for more than 6 months. Chronic use of opiates is a rapidly escalating crisis in the United States, with over 4.3 million Americans dependent on opiate analgesics, an escalating rate of opiate overdose deaths, and a resurgence of intravenous heroin use leading to total societal cost exceeding $55 billion. While opiates are effective at treating acute pain, tolerance to the analgesic effects develops quickly, leading to high abuse liability and dependence potential. Consequently, the development of a new, non-pharmacologic intervention to treat pain, such as repetitive transcranial magnetic stimulation (rTMS), which would provide analgesic benefit while also directly remodeling the neural circuitry responsible for cognitive control over opiate craving, would fill an increasingly urgent public health need. Acute pain is associated with elevated magnetic resonance imaging (MRI) blood-oxygen-level-dependent (BOLD) signal in targets of ascending nociceptive fibers including the insula, dorsal anterior cingulate (dACC), thalamus and somatosensory cortex - the 'Pain Network'. Perceived pain, and corresponding BOLD signal in the Pain Network, is attenuated by 10 Hz rTMS (a form of brain stimulation that results in long term potentiation (LTP) to the left dorsolateral prefrontal cortex (dlPFC, a node of the Executive Control Network). Dr. Borckardt was the first person to demonstrate that when LTP-like dlPFC rTMS was delivered in the postoperative recovery room, patients used less morphine in the hospital and require less morphine long-term. These analgesic effects are now widely known, with over 33 clinical trials utilizing rTMS as a tool to decrease acute and chronic pain in various clinical populations. These data all suggest that LTP-like DLPFC rTMS is a very strong candidate alleviating chronic pain (LTP-like dlPFC rTMS (Strategy 1, Aim 1)). An alternative approach, however, *which may also target opiate craving*, is to attenuate the Pain Network (through long term depression (LTD) of the ventromedial PFC) (LTD-like mPFC rTMS, Strategy 2, Aim 1). In a cohort of 49 individuals with chronic pain, Dr. Hanlon (Primary Investigator) recently demonstrated that LTD-like mPFC rTMS reduced baseline BOLD signal in multiple regions of interest (ROIs) *involved in craving which also overlap with the Pain Network* (e.g. dACC and Insula). To parametrically evaluate these 2 promising treatment strategies, the investigator has developed a 1-visit cross-sectional design wherein a cohort of healthy control individuals will receive Quantitative Sensory Testing before and after rTMS with the H1 and H7-coil for dlPFC stimulation (Strategy 1) and mPFC depression (Strategy 2), respectively. The investigator aims to: Aim 1. Quantify the effects of LTP-like and LTD-like RTMS on Quantitative Sensory Testing Hypothesis: The pressure pain tolerance of individuals in these two groups will increase after one session of rTMS administered by the H1- and H7-coil design. Aim 2. Evaluate the effects of rTMS on subjective experience of discomfort. Hypothesis: Subjective experience of discomfort will decrease in individuals after one session of LTP-like or LTD-like rTMS administered to the dlPFC and mPFC, respectively. The relative efficacy of Strategy 1 vs 2 will directly translate to development of a large clinical trial of rTMS as an innovative, new treatment option for pain in opiate dependent individuals.

Official Title
-----------------
H-coil TMS to Reduce Pain: A Pilot Study Evaluating Relative Efficacy of the H1 vs H7 Coil

Conditions
-----------------
Healthy, Chronic Pain, Opioid Use, Pain, Chronic

Intervention / Treatment
-----------------
* Device: Real rTMS to the mPFC using H7 Coil
* Device: Real rTMS to the dlPFC using H1 Coil


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18 - 65 (to maximize participation). Does not have a history of and is currently not experiencing chronic pain. Able to read and understand questionnaires and informed consent. Lives within 50 miles of the study site. Is not at elevated risk of seizure (i.e., does not have a history of seizures, is not currently prescribed medications known to lower seizure threshold). Does not have a history of traumatic brain injury, including a head injury that resulted in hospitalization, loss of consciousness for more than 10 minutes, or having ever been informed that they have an epidural, subdural, or subarachnoid hemorrhage. Exclusion Criteria: Any psychoactive illicit substance use (except marijuana and nicotine) within the last 30 days by self-report and urine drug screen. For marijuana, no use within the last seven days by verbal report and negative (or decreasing) urine THC levels. Meets DSM-V criteria for moderate substance dependence, current axis I disorders of major depression, panic disorder, obsessive-compulsive disorder, post traumatic stress syndrome, bipolar affective disorder, schizophrenia, dissociate disorders, eating disorders, and any other psychotic disorder. Has current suicidal ideation or homicidal ideation. Has the need for maintenance or acute treatment with any psychoactive medication including anti-seizure medications and medications for ADHD. Females of childbearing potential who are pregnant (by urine HCG), nursing, or who are not using a reliable form of birth control. Has current charges pending for a violent crime (not including DUI related offenses). Suffers from chronic migraines.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: The proposed study will employ a 1-visit cross sectional, double-blind, placebo-controlled design to parametrically evaluate two promising treatment strategies of rTMS using the H1 and H7-coil for dlPFC stimulation (Strategy 1) or mPFC stimulation (Strategy 2), respectively. Participants will be randomized to receive TMS to the dlPFC or mPFC (50% at each site). This will be done in a cohort of healthy control individuals recruited from the local Wake Forest University (WFU) community. Quantitative Sensory Testing (QST) and subjective pain ratings will be measured before and after the rTMS session.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: First H1 coil, then H7 coil<br>There will be 1 screening and 2 TMS visits. The procedures will be identical for each TMS visit, except for the type of TMS delivered (H1 or H7 coil). Each participant will be assigned to both coils, with TMS type. Participants assigned to this arm will receive the H1 coil at TMS visit 1, H7 coil at TMS visit 2 | Device: Real rTMS to the mPFC using H7 Coil<br>* This will be delivered with the Brainsway H7 coil system; 1200 pulses with the H7 coil helmet. Blinded using active/sham operator cards.<br>Device: Real rTMS to the dlPFC using H1 Coil<br>* This will be delivered with the Brainsway H1 coil system; 3000 pulses with the H1 coil helmet. Blinded using active/sham operator cards.<br>|
| Experimental: First H7 coil, then H1 coil<br>There will be 1 screening and 2 TMS visits. The procedures will be identical for each TMS visit, except for the type of TMS delivered (H1 or H7 coil). Each participant will be assigned to both coils, with TMS type. Participants assigned to this arm will receive the H7 coil at TMS visit 1, H1 coil at TMS visit 2. | Device: Real rTMS to the mPFC using H7 Coil<br>* This will be delivered with the Brainsway H7 coil system; 1200 pulses with the H7 coil helmet. Blinded using active/sham operator cards.<br>Device: Real rTMS to the dlPFC using H1 Coil<br>* This will be delivered with the Brainsway H1 coil system; 3000 pulses with the H1 coil helmet. Blinded using active/sham operator cards.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Painfulness Thresholds Using the Quantitative Pain Testing (QST) Task, Which Utilizes Pressure From the Medoc Algomed Device (Measured in kiloPascals). | Based on pilot data, the investigators expect an interaction between treatment (DLPFC or MPFC TMS) and time (Before vs. After rTMS) on reported painfulness using a quantitative sensory testing technique which determines the sensation and pain thresholds of pressure. Painfulness ratings will be assessed and reported before and after rTMS. | rTMS treatment visit, an average of 2 and a half hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Pain Tolerance Thresholds Using the Quantitative Pain Testing (QST) Task, Which Utilizes Pressure From the Medoc Algomed Device (Measured in kiloPascals). | The investigators do not expect an interaction between treatment (DLPFC or MPFC TMS) and time (Before vs. After rTMS) on pain tolerance thresholds using a quantitative sensory testing technique which determines the sensation and pain thresholds of pressure. Pain tolerance ratings will be assessed and reported before and after rTMS. | rTMS treatment visit, an average of 2 and a half hours | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Transcranial Magnetic Stimulation, Brain Stimulation, Healthy controls, Treatment