Osteoarthritis, Knee
Conditions
Keywords
TMS, rTMS, corticospinal, quadriceps
Brief summary
The purpose of the study is to identify things that influence the ability to turn on the thigh muscle (quadriceps). The thigh muscle tends to be under active with knee osteoarthritis, which may make it difficult to strengthen the muscle. The investigators are also testing a new technology called repetitive transcranial magnetic stimulation (rTMS) to determine whether it may help turn up activity in the under active thigh muscle immediately after its application. rTMS uses a targeted pulsed magnetic field, similar to what is used in an MRI (magnetic resonance imaging) machine to send an electrical signal from the brain to the thigh muscle.
Detailed description
The investigators will recruit up to 20 people with symptomatic knee osteoarthritis. The 20 eligible participants will attend 3 sessions in the laboratory. Session 1 is to collect data for Aim 1. Sessions 2 and 3 will include the rTMS interventions and data collection for Aim 2. Aim 1 is a descriptive study to compare the neural (cortical and corticospinal) excitability of the quadriceps in the symptomatic knee to the asymptomatic knee in participants with knee osteoarthritis. The investigators will examine the associations between neural excitability and clinical measures of pain, strength, function, and coping styles. Aim 2 is a double blind, crossover study design. Each participant will partake in two testing sessions, spaced 1 week apart. The investigators will evaluate outcome measures prior to and following the true intervention versus the sham intervention. The true intervention is rTMS + exercise. The sham is sham rTMS + exercise. The primary outcome measures are quadriceps strength, as measured from a maximal isometric voluntary contraction, and quadriceps central activation ratio (CAR), as calculated from the torque values from the voluntary strength measurement and a brief, intense electrical stimulus. Secondary measures evaluate effects of the intervention on 1) clinical measures of pain and functional performance, 2) corticospinal excitability, and 3) intracortical inhibition and facilitation.
Interventions
DEVICErTMS and exercise
rTMS at 10 Hz (5 sec on, 55 sec off) and light quadriceps isometric exercise (5% MVIC)
DEVICESham rTMS and exercise
rTMS unit is on and running but mu metal is placed between the coil and the skull
Sponsors
North Carolina Translational and Clinical Sciences Institute
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
40 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* symptomatic knee osteoarthritis primarily involving one leg based on Western Ontario and McMaster Universities Arthritis Index (WOMAC) function subscale score \> 10 (out of 100 points, indicating most dysfunction) * diagnosis of knee osteoarthritis * opposite knee with WOMAC pain score ≤ 5. * opposite knee does not have a diagnosis of knee osteoarthritis
Exclusion criteria
* conditions affecting the leg other than osteoarthritis * low blood pressure (\< 90 systolic, 60 diastolic) or heart rate (\< 60 beats per minute) * conditions that limit exercise tolerance such as a heart condition * pregnant or planning to become pregnant in the next 3 months * conditions that alter sensation and pain processing * BMI \> 35 * severe arthritis in both knees * history of leg or back surgery in the past year or knee replacement surgery; * injection in the knee joint in the past 4 weeks * requires an assistive device to walk * any contraindications for TMS or rTMS (seizures, metal implants in head, brain related conditions, brain injury, drug or alcohol withdrawal) * medications that lower seizure threshold * history of fainting spells (syncope) or low blood pressure * sleep deprived * inability to understand and repeat back directions regarding the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Quadriceps Central Activation Ratio (CAR) | Within 1 hour post intervention | Quadriceps Central Activation Ratio (CAR) is a percentage of the amount of torque produced during the superimposed burst technique using maximal voluntary isometric contraction (MVIC) and superimposed burst torque. It is reported on a scale of 0 (worst) to 100% (best) activation. |
| Quadriceps Maximal Voluntary Isometric Contraction (MVIC) | Within 1 hour post intervention | HUMAC NORM electromechanical dynamometer is used to measure isometric torque generation in quadriceps muscle stabilized with 70 degrees of knee flexion. Units of measure are in Newton meters (Nm). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Numeric Pain Rating Scale (NPRS) Score | Within 1 hour post intervention | Pain intensity is rated on a visual analog scale of 0-10 where 0 is no pain and 10 is maximum pain |
| Pressure Pain Threshold (PPT) - Medial Knee | Within 1 hour post intervention | Using the AlgoMed algometer, pressure at a rate of 35 kPA/second is applied to the medial knee to the level that subject indicates is painful. Units of measure are kilopascal (kPa) |
| Timed Up & Go (TUG) | Within 1 hour post intervention | Time in seconds to rise from a chair, walk 3 m, return and sit down |
| Active Motor Threshold Motor Evoked Potential (AMT-MEP) | Within 1 hour post intervention | The quadriceps active muscle responses (motor evoked potentials) that result from the single-pulse transcranial magnetic stimulation (TMS) pulses over the motor cortex. These AMT-MEP are measured peak-to-peak in microvolts (uV ). 10 AMT-MEP values were collected and averaged. |
| Short Interval Cortical Inhibition (SICI) | Within 1 hour post intervention | Transcranial magnetic stimulation (TMS), using the conditioning-test paired-pulse paradigm with a 3 ms interval, will be used. SICI is the ratio of the conditioning stimulus relative to the test stimulus. A ratio \< 1.0 indicates inhibition. |
| Intra Cortical Facilitation (ICF) | Within 1 hour post intervention | Transcranial magnetic stimulation (TMS), using the conditioning-test paired-pulse paradigm with a 15 ms interval, will be used. ICF is the ratio of the conditioning stimulus relative to the test stimulus. A ratio \> 1.0 indicates facilitation. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| All Study Participants Participants who were randomized to receive either rTMS and exercise or sham rTMS and exercise. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants |
| Age, Continuous | 63 years STANDARD_DEVIATION 6.5 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 19 Participants |
| Region of Enrollment United States | 20 Participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 |
Outcome results
Primary
Quadriceps Central Activation Ratio (CAR)
Quadriceps Central Activation Ratio (CAR) is a percentage of the amount of torque produced during the superimposed burst technique using maximal voluntary isometric contraction (MVIC) and superimposed burst torque. It is reported on a scale of 0 (worst) to 100% (best) activation.
Time frame: Within 1 hour post intervention
Population: 4 subjects withdrew from the study after the baseline measures. This left 16 subjects for the intervention arm of the study. Four subjects declined to perform the test after the experience with the electrical stimulus in the baseline session.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS and Exercise | Quadriceps Central Activation Ratio (CAR) | CAR Baseline (BL) | 86.3554 % activation | Standard Error 3.2921 |
| rTMS and Exercise | Quadriceps Central Activation Ratio (CAR) | CAR BL Change | -1.2496 % activation | Standard Error 2.1397 |
| Sham rTMS and Exercise | Quadriceps Central Activation Ratio (CAR) | CAR Baseline (BL) | 86.1983 % activation | Standard Error 3.2921 |
| Sham rTMS and Exercise | Quadriceps Central Activation Ratio (CAR) | CAR BL Change | -1.2670 % activation | Standard Error 2.1397 |
Comparison: Comparison of CAR BL Change (treatment by time)p-value: 0.9994ANOVA
Primary
Quadriceps Maximal Voluntary Isometric Contraction (MVIC)
HUMAC NORM electromechanical dynamometer is used to measure isometric torque generation in quadriceps muscle stabilized with 70 degrees of knee flexion. Units of measure are in Newton meters (Nm).
Time frame: Within 1 hour post intervention
Population: 4 subjects withdrew from the study after the baseline measures. This left 16 subjects for the intervention arm of the study.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS and Exercise | Quadriceps Maximal Voluntary Isometric Contraction (MVIC) | MVIC Baseline | 129.46 Nm | Standard Error 11.8464 |
| rTMS and Exercise | Quadriceps Maximal Voluntary Isometric Contraction (MVIC) | MVIC BL Change | -6.3473 Nm | Standard Error 4.4266 |
| Sham rTMS and Exercise | Quadriceps Maximal Voluntary Isometric Contraction (MVIC) | MVIC Baseline | 129.09 Nm | Standard Error 11.8464 |
| Sham rTMS and Exercise | Quadriceps Maximal Voluntary Isometric Contraction (MVIC) | MVIC BL Change | -6.1643 Nm | Standard Error 4.4266 |
Comparison: Comparison of MVIC BL Change (treatment by time)p-value: 0.9768ANOVA
Secondary
Active Motor Threshold Motor Evoked Potential (AMT-MEP)
The quadriceps active muscle responses (motor evoked potentials) that result from the single-pulse transcranial magnetic stimulation (TMS) pulses over the motor cortex. These AMT-MEP are measured peak-to-peak in microvolts (uV ). 10 AMT-MEP values were collected and averaged.
Time frame: Within 1 hour post intervention
Population: 4 subjects withdrew from the study after the baseline measures. This left 16 subjects for the intervention arm of the study. A technical issue in how the TMS unit worked was discovered after collecting the first 4 subjects in the intervention part of the study. This impacted their AMT-MEP, ICF, and SICI data which were excluded from the analyses.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS and Exercise | Active Motor Threshold Motor Evoked Potential (AMT-MEP) | AMT-MEP Baseline | .1387 uV | Standard Error 0.009634 |
| rTMS and Exercise | Active Motor Threshold Motor Evoked Potential (AMT-MEP) | AMT-MEP BL Change | -.00007 uV | Standard Error 0.01107 |
| Sham rTMS and Exercise | Active Motor Threshold Motor Evoked Potential (AMT-MEP) | AMT-MEP Baseline | .1434 uV | Standard Error 0.009634 |
| Sham rTMS and Exercise | Active Motor Threshold Motor Evoked Potential (AMT-MEP) | AMT-MEP BL Change | -.01441 uV | Standard Error 0.01107 |
Comparison: Comparison of AMT-MEP BL Change (treatment by time)p-value: 0.3665ANOVA
Secondary
Intra Cortical Facilitation (ICF)
Transcranial magnetic stimulation (TMS), using the conditioning-test paired-pulse paradigm with a 15 ms interval, will be used. ICF is the ratio of the conditioning stimulus relative to the test stimulus. A ratio \> 1.0 indicates facilitation.
Time frame: Within 1 hour post intervention
Population: 4 subjects withdrew from the study after the baseline measures. This left 16 subjects for the intervention arm of the study. A technical issue in how the TMS unit worked was discovered after collecting the first 4 subjects in the intervention part of the study. This impacted their AMT-MEP, ICF, and SICI data which were excluded from the analyses.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS and Exercise | Intra Cortical Facilitation (ICF) | ICF Baseline | 1.193 ratio | Standard Error 0.903 |
| rTMS and Exercise | Intra Cortical Facilitation (ICF) | ICF BL Change | -.0354 ratio | Standard Error 0.1896 |
| Sham rTMS and Exercise | Intra Cortical Facilitation (ICF) | ICF Baseline | .904 ratio | Standard Error 0.903 |
| Sham rTMS and Exercise | Intra Cortical Facilitation (ICF) | ICF BL Change | .03042 ratio | Standard Error 0.1896 |
Comparison: Comparison of ICF BL Change (treatment by time)p-value: 0.2192ANOVA
Secondary
Numeric Pain Rating Scale (NPRS) Score
Pain intensity is rated on a visual analog scale of 0-10 where 0 is no pain and 10 is maximum pain
Time frame: Within 1 hour post intervention
Population: 4 subjects withdrew from the study after the baseline measures. This left 16 subjects for the intervention arm of the study. For two subjects, the research assistant missed obtaining the post-intervention pain rating.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS and Exercise | Numeric Pain Rating Scale (NPRS) Score | NPRS Baseline | 3.25 score on scale | Standard Error 0.5749 |
| rTMS and Exercise | Numeric Pain Rating Scale (NPRS) Score | NPRS BL Change | -.625 score on scale | Standard Error 0.4187 |
| Sham rTMS and Exercise | Numeric Pain Rating Scale (NPRS) Score | NPRS Baseline | 3.000 score on scale | Standard Error 0.5749 |
| Sham rTMS and Exercise | Numeric Pain Rating Scale (NPRS) Score | NPRS BL Change | -.1570 score on scale | Standard Error 0.4378 |
Comparison: Comparison of NPRS BL Change (treatment by time)p-value: 0.444ANOVA
Secondary
Pressure Pain Threshold (PPT) - Medial Knee
Using the AlgoMed algometer, pressure at a rate of 35 kPA/second is applied to the medial knee to the level that subject indicates is painful. Units of measure are kilopascal (kPa)
Time frame: Within 1 hour post intervention
Population: 4 subjects withdrew from the study after the baseline measures. This left 16 subjects for the intervention arm of the study.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS and Exercise | Pressure Pain Threshold (PPT) - Medial Knee | PPT Baseline | 402.41 kPa | Standard Error 60.178 |
| rTMS and Exercise | Pressure Pain Threshold (PPT) - Medial Knee | PPT BL Change | 21.8583 kPa | Standard Error 28.0167 |
| Sham rTMS and Exercise | Pressure Pain Threshold (PPT) - Medial Knee | PPT Baseline | 419.21 kPa | Standard Error 60.178 |
| Sham rTMS and Exercise | Pressure Pain Threshold (PPT) - Medial Knee | PPT BL Change | 4.3548 kPa | Standard Error 28.0167 |
Comparison: PPT BL Change (treatment by time)p-value: 0.6608ANOVA
Secondary
Short Interval Cortical Inhibition (SICI)
Transcranial magnetic stimulation (TMS), using the conditioning-test paired-pulse paradigm with a 3 ms interval, will be used. SICI is the ratio of the conditioning stimulus relative to the test stimulus. A ratio \< 1.0 indicates inhibition.
Time frame: Within 1 hour post intervention
Population: 4 subjects withdrew from the study after the baseline measures. This left 16 subjects for the intervention arm of the study. A technical issue in how the TMS unit worked was discovered after collecting the first 4 subjects in the intervention part of the study. This impacted their AMT-MEP, ICF, and SICI data which were excluded from the analyses.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS and Exercise | Short Interval Cortical Inhibition (SICI) | SICI Baseline | .5140 ratio | Standard Error 0.054 |
| rTMS and Exercise | Short Interval Cortical Inhibition (SICI) | SICI BL Change | -.02588 ratio | Standard Error 0.07227 |
| Sham rTMS and Exercise | Short Interval Cortical Inhibition (SICI) | SICI Baseline | .5996 ratio | Standard Error 0.1054 |
| Sham rTMS and Exercise | Short Interval Cortical Inhibition (SICI) | SICI BL Change | -.1151 ratio | Standard Error 0.07227 |
Comparison: Comparison of SICI BL Change (treatment by time)p-value: 0.3889ANOVA
Secondary
Timed Up & Go (TUG)
Time in seconds to rise from a chair, walk 3 m, return and sit down
Time frame: Within 1 hour post intervention
Population: 4 subjects withdrew from the study after the baseline measures. This left 16 subjects for the intervention arm of the study.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| rTMS and Exercise | Timed Up & Go (TUG) | TUG Baseline | 8.3919 seconds | Standard Error 0.4079 |
| rTMS and Exercise | Timed Up & Go (TUG) | TUG BL Change | -.08021 seconds | Standard Error 0.803 |
| Sham rTMS and Exercise | Timed Up & Go (TUG) | TUG Baseline | 8.3056 seconds | Standard Error 0.4079 |
| Sham rTMS and Exercise | Timed Up & Go (TUG) | TUG BL Change | -.00542 seconds | Standard Error 0.1803 |
Comparison: Comparison of TUG BL Change (treatment by time)p-value: 0.7706ANOVA