Effects of Repetitive Transcranial Magnetic Stimulation on Pain Thresholds in Patients With Chronic Low Back Pain
Effects of Repetitive Transcranial Magnetic Stimulation on Pain Thresholds in Patients With Chronic Low Back Pain
Chronic low back pain (CLBP) is a common reason for which patients are treated with opioids.
 Because the misuse of prescription opioids has become a serious problem in the Uinted States,
 finding effective alternative non-pharmaceutical interventions for chronic pain management
 has become an urgent matter. A phenomenon termed central sensitization (i.e. mal-adaption of
 the brain) has been hypothesized to be an underlying mechanism for the development of chronic
 pain, leading to sensory hypersensitivity to extremal stimuli. Therefore, non-invasive brain
 stimulation, such as repetitive transcranial magnetic stimulation (rTMS) may be an effective
 intervention to regulate brain excitability, thus reducing chronic pain. However, research
 has shown inconclusive evidence regarding the rTMS effects on chronic pain reduction, partly
 due to the heterogeneity of participants in studies to date. Therefore, the primary purpose
 of this study is to investigate the immediate and short-term effects of rTMS on neurosensory
 changes (i.e., pain thresholds) in patients with CLBP. The secondary purpuse of the study is
 to explore the relationship between changes of cortical excitability (TMS parameters) and
 changes of pain thresholds after the rTMS intervention in patients with CLBP.
Research Design

 A pre- and post-test research design will be used to examine the immediate and one-week
 carry-over effects of a single-session of rTMS intervention on individuals with CLBP. The
 primary outcome measures, including PPT, cold pain threshold (CPT), heat pain threshold
 (HPT), and heat-generated temporal summation (TS), will be collected three times: before the
 rTMS intervention, immediately after the intervention, and one week after the intervention.

 Participants

 Eligible participants are adults 18 years of age or older and who have had LBP for more than
 6 months. According to the Centers for Disease Control and Prevention, chronic pain is
 defined as pain lasts more than 3 months or past the time of normal tissue healing. In order
 to ensure the development of central sensitization in the investigator's participants, only
 individuals with LBP for more than 6 months will be enrolled in this study.

 Participants will be excluded from the study if they have previous low back surgery, systemic
 joint disease (e.g. rheumatoid arthritis), evidence of red flags (e.g. fracture, infection,
 tumor, cauda equina syndrome), cancer, neurological disorders, neuropathy, Raynaud's Disease
 or pregnancy, and inability to maintain the testing and treatment positions (i.e. sitting,
 supine hook-lying and prone-lying) for 15 minutes at a time. Additional exclusion criteria
 for the rTMS intervention include: 1) history of significant head trauma, 2) electrical,
 magnetic, or mechanical implantation (e.g. cardiac pacemakers or intracerebral vascular
 clip), 3) metal implantation in the head and neck areas, 4) history of seizures or
 unexplained loss of consciousness, 5) immediate family member with epilepsy, 6) use of
 seizure threshold lowering medicine, 7) current abuse of alcohol or drugs, and 8) history of
 psychiatric illness requiring medication controls.

 Procedure

 After the participant is enrolled the study, the participant will be asked to complete an
 intake form, collecting their demographic data (age, gender, height, weight, occupation, hand
 dominance), past medical history, and questions related to their low back pain (onset, injury
 mechanism if any, location, duration, type, and nature). In addition, 4 self-reported
 questionnaires will be collected from all of the participants before the rTMS treatment,
 including pain intensity determined using the NPRS, disability determined using the Modified
 Oswestry Low Back Pain Disability Questionnaire quality of life determined by the
 Patient-Reported Outcomes Measurement Information System® - short form (PROMIS-29), and
 severity of central sensitization determined by the Central Sensitization Inventory (CSI ).
 These questionnaires are commonly used in research studies of chronic pain or CLBP.

 1. Pain Threshold Tests:

 All participants will undergo a battery of tests to determine their sensory thresholds,
 including pressure, cold and heat pain thresholds and heat-generated temporal summation
 (TS). The pain thresholds and TS will be measured from three sites: the most painful
 point of low back, as well as the web space (WS) and the tibialis anterior (TA) of the
 painful side. Those who report no pain difference between the right and left low back,
 pain thresholds will be measured from the right side. The TA testing site will be in the
 muscle belly of the TA, approximately 2.5 cm lateral and 5 cm inferior to the tibial
 tubercle. The WS and TA sites were chosen because they are the most commonly selected
 sites in research studies for chronic pain. In addition, the first interosseous index
 (FDI) is located in the WS, where is the target site for the TMS assessment and
 intervention.

 Pressure pain threshold (PPT) testing: A hand-held computerized pressure algometer
 (Medoc ltd., Ramat Yishai, Israel) will be used to measure the PPTs. The algometer
 consists of a 1-sqaure centermeter round tip which will be pressed vertically on the
 target location of the muscle. To provoke the patient's pain or discomfort, pressure
 will be increased at a rate of 40 kPa/sec until the participant feels pain as indicated
 by pressing a patient safety unit. The limit of pressure threshold will be set at 800
 kPa, meaning that a pressure exceeding 800 kPa will be cut off to minimize tissue
 damage. If the participant does not push the button at 800 kPa, a value of 800 is used
 as the threshold value. Three trials of PPT testing will be administered to each testing
 site, and the average of the three trials will be used for data analysis.

 Cold and heat pain threshold testing: A Medoc TSA II Neurosensory Analyzer (Medoc ltd.,
 Ramat Yishai, Israel) will be used to measure heat and cold pain thresholds. All thermal
 pain threshold tests will be obtained with ramped stimuli (0°5 C/s) which can be
 terminated when the participant presses a safety button. Cut-off temperatures will be
 set 0 and 52°C, and the baseline temperature will be set at 32°C (i.e., average skin
 temperature). The contact area of the thermode is 23mmx30mm. All thermal pain threshold
 tests will be demonstrated first at an area somewhere other than the three testing
 sites. Three trials of thermal pain threshold tests will be administered per testing
 site and the average of the three trials will be used for statistical analysis.

 Heat-generated temporal summation (TS) testing: The instrument used for measuring cold
 and heat pain thresholds will be used for the heat-generated TS test. During TS testing,
 10 consecutive heat pulses of 0.5 sec duration will be delivered at an inter-stimulus
 interval of 2.5 sec. The temperature of the heat stimuli will increase from 40°C as a
 baseline temperature and inter-stimulus temperature, to 48°C at a rate of 8°C/sec.
 Participants will be asked to rate their pain intensity of each heat pulse on the NPRS
 of 0-100 (0 being no pain, 100 being unbearable pain). The TS score will be calculated
 by averaging the pain rating for the 10th stimulus and the 5th stimulus minus the 1st
 pain rating, with higher score indicating greater hypersensitivity of pain.

 2. Cortical Excitability Assessment

 A series of single pulse generated from a TMS machine (Rapid2, Magstim Co., UK) will be
 used to determine corticospinal excitability. Because the rTMS intervention will target
 the M1 area, specifically in the area corresponding to the FDI muscle, motor evoked
 potentials (MEPs), namely electromyographic (EMG) activity, will be recorded from the
 FDI muscle to determine the "hot spot" for the rTMS intervention. A hot spot is defined
 as the site at which the largest MEP amplitude is obtained at the lowest TMS stimulation
 intensity.

 First, a pair of surface EMG electrodes will be placed on the FDI muscle when the
 participant is seated on a reclining chair and wearing a pair of earplugs to reduce
 their awareness of noise from the rTMS equipment. Similar to the pain threshold testing
 on the low back, EMG activity will be measured from FDI muscle on the same side of the
 patient as the LBP. For those who report no difference in LBP between sides, EMG data
 will be recorded from the FDI of the right hand. The Mega 600 EMG machine (Mega
 Electronics Ltd., Finland) will be used to collect EMG data at a sampling rate of
 2,000Hz and bandpass-filtered at 15-500Hz. During the cortical excitability assessment,
 each participant will wear a Lycra swimming cap with a pre-marked grid. The intensity of
 TMS will begin at 40% of maximum stimulator output and then will be increased gradually
 to yield a MEP from the FDI until a 'hot spot' is observed. Next, the resting motor
 threshold (RMT) will be defined. RMT is the stimulation intensity which yields a
 peak-to-peak amplitude of MEP larger than 50 μV in 5 out of 10 consecutive trials. Once
 the RMT is determined, the stimulation intensity will be set at 120% of RMT and 10
 stimulations will be delivered to the hot-spot. The 10 supra-threshold MEP amplitudes
 recorded from the FDI will be averaged and the average will be used for the
 representation of corticospinal excitability.

 3. rTMS Intervention

 After the corticospinal excitability assessment, participants will receive 10Hz rTMS
 delivered to the hot-spot contralateral to the painful side in the form of twenty 10-second
 pulse trains (a total of 2,000 pulses) with a 50-second inter-train interval. The rTMS will
 be delivered via an air-filled coil (see figure to the right). The stimulation intensity will
 be set at 90% of RMT. After the rTMS intervention, the participant's corticospinal
 excitability will be re-assessed using the single-pulse TMS method as described earlier.
Inclusion Criteria:

 -  Adults 18 years of age or older

 -  Have LBP for more than 6 months

 Exclusion Criteria:

 -  Previous low back surgery, systemic joint disease (e.g. rheumatoid arthritis),

 -  Fracture,

 -  Infection

 -  Tumor or cancer

 -  Cauda equina syndrome

 -  neurological disorders

 -  Neuropathy

 -  Raynaud's Disease

 -  pregnancy,

 -  Inability to maintain the testing and treatment positions (i.e. sitting, supine
 hook-lying and prone-lying) for 15 minutes at a time.

 -  History of significant head trauma,

 -  Electrical, magnetic, or mechanical implantation (e.g. cardiac pacemakers or
 intracerebral vascular clip)

 -  Metal implantation in the head and neck areas

 -  History of seizures or unexplained loss of consciousness,

 -  Immediate family member with epilepsy

 -  Use of seizure threshold lowering medicine

 -  Current abuse of alcohol or drugs

 -  History of psychiatric illness requiring medication controls