Stimulation of Peripheral Afferents to Reduce Muscle Inhibition at the Knee

Knee osteoarthritis affects more than 14 million adults in the United States and is a leading cause of disability. Its most disabling consequence is not joint degeneration alone but persistent quadriceps dysfunction. Afferent signals arising from the painful joint inhibit the descending motor drive that activates the muscle, so voluntary activation remains incomplete. Exercise therapy, the mainstay of care, therefore produces strength gains of only 10 to 20 percent against the 30 to 40 percent required for meaningful clinical benefit, and patients walk with rigid, co-contracted movement patterns that concentrate joint loading and accelerate degeneration. Existing interventions address either pain or motor retraining; none target the cortical circuits in which the two interact. This study tests whether paired-pulse electrical stimulation (ppES) of the tibial nerve can reduce that inhibition. ppES delivers two stimuli in rapid succession: the first activates sensory afferents projecting to the primary somatosensory cortex, and the second, delivered at a precisely timed interval, induces heterosynaptic depression of that transmission, in turn reducing sensory-driven inhibition of motor output. Applied at the tibial nerve, ppES acts on the sensorimotor integration that governs quadriceps activation during walking. Twenty adults with knee osteoarthritis will each complete two single-session visits separated by at least seven days, receiving active ppES at one visit and sham stimulation at the other in randomized order, with participants and outcome assessors blinded. At each visit, before intervention and again immediately and 30 minutes afterward, we will measure short-latency afferent inhibition of the quadriceps motor pathway and quadriceps-hamstrings co-contraction during treadmill walking, the two primary outcomes. Somatosensory evoked potentials and modular organization of gait will be measured as secondary outcomes. Aim 1 will determine whether ppES reduces sensorimotor inhibition and co-contraction relative to sham. Aim 2 will determine whether baseline pain sensitization, cortical sensory processing, and sensorimotor inhibition predict the magnitude and variability of individual response. Establishing that this circuit is modifiable would identify a rehabilitation target that current care does not address and would provide the mechanistic evidence and effect-size estimates required for a trial of ppES as an adjunct to exercise.

Inclusion criteria

• >45 years old
• Able to speak and understand English
• Unilateral or bilateral knee OA, per NICE criteria

• Age 45+ AND
• Have activity-related joint pain AND
• Have either no morning joint-related stiffness or morning stiffness that lasts no longer than 30 minutes
• Score > 3/20 on WOMAC pain scale
• If using pain medications, report >4 weeks of stable use without recent adjustments

Exclusion criteria

• History of lower extremity surgery.
• BMI > 40kg/m^2
• Received an intra-articular knee joint injection within the last 3 months.
• Currently pregnant.
• Currently experiencing heavy menstruation, within one month of an IUD contraceptive device (e.g. coil) being fitted or within 6 weeks after giving birth or at least three months after having a Caesarean.
• Suspected or diagnosed heart problems (e.g. arrhythmia, cardiac disturbances).
• Use of an implanted electronic device (e.g. a cardiac pacemaker or defibrillator).
• Insulin-dependent diabetes.
• Implants in the lower limb.
• Suspected or diagnosed epilepsy or a familial history of epilepsy.
• History of neurologic or psychiatric condition (e.g. Parkinson's disease, bipolar disorder, epilepsy, etc)
• Implanted cardiac pacemaker, cochlear implant, medication pump, surgical clips or other metal (dental implants excluded).
• Use of alcohol or recreational drugs in the prior 12 hours.
• Frequent or severe headaches.
• Prior adverse reaction to transcranial magnetic stimulation.
• Altered sensation (hypo or hypersensitivity) of the skin of the thigh.
• Swollen, infected, inflamed, or damaged skin of the thigh.
• Current Use of prescription and over the counter medications will be grounds for exclusion except for:

• Contraceptive (birth control) drugs (e.g. those containing ethinyl estradiol and/or norethindrone).
• Seasonal allergy medications (e.g. cetirizine (Zyrtec), fexofenadine (Allegra), and loratadine (Claritin)).
• Antihypertensives
• Statins
• GLP-1 agonists
• Non-insulin diabetes medications (metformin)
• Thyroid medications
• Osteoporosis medications
• Respiratory medications
• Pain medications available over the counter (ibuprofen, acetaminophen, etc)