Transcranial direct current stimulation combined with physical exercise in knee osteoarthritis: a protocol for a randomised controlled clinical trial

Abstract

Introduction

Osteoarthritis (OA) is a degenerative and progressive joint condition causing pain and disability. Physical exercise is recognised as the most effective intervention since individuals with this condition often experience muscle weakness, balance deficits and chronic pain. Additionally, knee osteoarthritis (KOA) is associated with central sensitisation, contributing to chronic pain conditions. Transcranial Direct Current Stimulation (tDCS), a non-invasive neuromodulation technique, has been employed to induce changes in pain perception by altering cortical excitability, potentially reducing chronic pain.

Methods and analysis

This is a protocol for a randomised controlled trial. Participants will be allocated to two groups: G1 (active tDCS combined with exercise) and G2 (sham tDCS combined with exercise). The intervention protocol will last for 5 weeks, with two sessions per week on non-consecutive days. Pain intensity will be assessed as the primary outcome using the Numeric Rating Scale (NRS). The sample size was calculated based on a minimum clinically important difference of 3 points on the NRS between groups, with a statistical power of 80% and a significance level of 5%. Secondary outcomes will include physical function and global perceived change.

Ethics and dissemination

This protocol was approved by the Research Ethics Committee of the Trairi School of Health Sciences, Federal University of Rio Grande do Norte (Approval Number: 6.801.827), and it is in accordance with the Declaration of Helsinki for human research. Results will be published in peer-reviewed journals and presented at scientific events. This trial is registered in the Brazilian Clinical Trials Registry.

Trial registration number

Brazilian Clinical Trials Registry (RBR-5pb2g33).

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Blinding: participants and evaluators will be blinded to the type of neuromodulation applied.

• Research instruments: validated and reliable scales Western Ontario McMaster Osteoarthritis Index (WOMAC) will be used.

• Limitations: the protocol does not include long-term effects.

• Generalisation: the specific population may limit the applicability of the results.

Introduction

Osteoarthritis (OA) is a chronic, degenerative and progressive condition with a multifactorial aetiology, characterised by damage to the articular cartilage. It can affect any synovial joint and its surrounding tissues.¹ The knee is the most commonly affected joint in OA, predominantly involving the medial compartment of the tibiofemoral joint.² Knee osteoarthritis (KOA) accounts for more than 365 million cases worldwide, with estimates suggesting that this number will reach 642 million according to the 2023 Global Burden of Disease data.^{3 4}

Pain is the most frequently reported symptom among individuals with KOA, significantly impacting functional capacity and quality of life, affecting both physical and psychological health.⁵ Current evidence indicates that pain related to KOA involves both peripheral and central sensitisation (CS).^{5 6} Peripheral sensitisation (PS) refers to the lowering of the threshold and/or the increased magnitude of responsiveness in the peripheral terminals of sensory nerve fibres. This phenomenon occurs in response to the release of chemical mediators by nociceptors and non-neuronal cells at the site of tissue injury or inflammation.⁷ Joint nociceptors are generally inactive but become functionally active in the context of OA due to damage to the articular cartilage.^{8 9} CS is described as an amplification of neural signalling within the central nervous system, resulting in hypersensitivity to pain.¹⁰ It involves an excessive increase in ascending nociceptive signals and a deficiency in descending inhibitory signals, perpetuated by peripheral nociceptive input from the OA-affected joint.¹¹

Leading global organisations, such as the Osteoarthritis Research Society International (OARSI), European League Against Rheumatism (EULAR) and the American College of Rheumatology, define physical exercise as the gold standard non-pharmacological treatment for managing KOA, supported by a high level of scientific evidence.12,16 Recent studies have demonstrated that a combination of resistance and aerobic exercises provides significant benefits, including pain reduction, increased muscle strength and improved physical function.^{14 17} However, the practice of physical exercise by these individuals may present a barrier, such as chronic pain that is commonly present in these cases.

Transcranial direct current stimulation (tDCS) has been widely used for conditions involving chronic musculoskeletal pain or features of CS.¹⁸ This non-invasive neuromodulation technique consists of applying low-intensity electrical currents to the scalp with the aim of modulating cortical excitability and, consequently, pain perception mechanisms.^{18 19} The primary motor cortex (M1) is the region most frequently selected for anodal electrode placement in clinical investigations, usually over the hemisphere contralateral to the pain site.^{20 21} This procedure generally follows the international 10–20 system for electroencephalography electrode placement, targeting the C3 or C4 sites.²¹

Stimuli applied to this area can trigger the activation of motor and sensory circuits in the precentral gyrus, influencing nociceptive processing and enhancing descending pain modulation mechanisms.^{21 22} A recent study by Harvey et al.²³ demonstrated that tDCS applied to M1 reduced pain intensity in individuals with musculoskeletal pain, including KOA, while also improving physical function compared with patients receiving sham tDCS. A recent review by Cardenas-Rojas et al²⁴ concluded that the combination of tDCS with exercise has moderate-to-strong effects in reducing pain among individuals with chronic pain.

To date, only two studies have evaluated the effects of tDCS combined with strengthening exercises in individuals with KOA.^{25 26} The study by Chang et al²⁵ investigated the effects of non-invasive neuromodulation applied to M1 in the treatment of KOA, combined with quadriceps strengthening exercises, using 1 mA stimulation. Rahimi et al²⁶ combined resistance exercises, joint mobilisation, and tDCS, also with a 1 mA intensity applied to M1. In the present study protocol, the application methodology of tDCS differs from these previous approaches, as it will be administered on alternate days. According to De Souza et al,²⁷ applying tDCS on non-consecutive days is associated with a higher treatment adherence rate. Additionally, the stimulation will be performed at an intensity of 2 mA, which is considered more suitable for this condition.²⁸

Therefore, this protocol aims to investigate the effects of a combined intervention of neuromodulation and physical exercise on pain, physical function and treatment adherence in individuals with KOA.

Methods and analysis

Study design

This is an experimental study protocol for a randomised superiority clinical trial, controlled, triple-blinded clinical trial. The study will be reported following the guidelines of the Standard Protocol Items: recommendations for international trials (online supplemental appendix A).²⁹ The research will take place in Santa Cruz, Brazil, at FACISA/UFRN, between September 2025 and June 2026. The stages of this study are presented in figure 1.

Figure 1. Planned flow diagram. tDCS, transcranial direct current stimulation.

Participants

The sample size calculation for this study was based on a previous study by Ahn et al,³⁰ which used pain as the primary outcome, measured through the Numeric Pain Rating Scale (NPRS). The calculation was performed considering the same population as the present protocol and statistical considerations. A minimal clinically important difference of 3 points is expected for this measurement.³¹ The means and SD for the primary outcome (pain on the NRS) were: control group, 19.0 ± 7.7; intervention group, 27.3 ± 15.0. A minimum clinically important difference of 3 points, a two-tailed significance level of 5%, and a statistical power of 80%³² were considered, resulting in an estimated sample size of 34 participants (17 per group). A 20% dropout rate is anticipated, resulting in a final required sample size of 40 individuals, with 20 in each group. The calculation was performed using G*Power software, V.3.1.9.7, employing the independent samples t-test. Recruitment will be carried out using the waiting list from the Orthopaedics and Rheumatology sector of the Physical Therapy School Clinic at FACISA/UFRN, from which a preliminary screening was performed. It is noteworthy that 100% of the patients on this list are female. Furthermore, the literature indicates that KOA predominantly affects women, accounting for approximately 61% of cases, possibly due to genetic, hormonal and anatomical factors. Eligible participants will be informed about the study and asked to sign the informed consent form (online supplemental appendix B).

Inclusion criteria

Participants must meet the following criteria to be included in this study:

• Female individuals.

• To present, at the time of assessment, a pain score of at least three on the NRS.^{33 34}

• Not undergoing physical therapy treatment for at least 60 days.

Exclusion criteria

• Major psychiatric or neurological disorders that prevent responding to the study assessment instruments.

• History of epilepsy.

• Use of metallic devices implanted in the skull.

• Being pregnant.

• Having received any type of injection in the knee joint within the past 3 months.

Research team

This study will involve four independent researchers: researcher 1 will be responsible for screening, assessing and reassessing the participants. Researcher 2 will supervise the physical exercise intervention programme. Researcher 3 will administer the tDCS. Researcher 4 will handle data processing and analysis without any knowledge of the interventions performed by the other researchers. Therefore, this is a triple-blind study. This study will not require an independent data and safety monitoring board; however, all study analyses will be conducted by an independent researcher who will not have access at any point to the assessment, intervention or reassessment procedures, thereby ensuring the maintenance of methodological rigour and the safety of the clinical trial.

Randomisation

Sample allocation will be conducted confidentially using the randomisation system available at randomizer.org. The assignments will then be placed in sealed, opaque envelopes to ensure allocation concealment, following the order of group designation by randomisation.

Blinding

To maximise the blinding strategy of participants regarding the protocol, participants will be blinded to whether the tDCS application is active or sham. Protocol sessions will be conducted in different locations: exercises in room 1, tDCS application in room 2 and assessments and reassessments in room 3. At the end of the protocol, a simple questionnaire with one question will be administered to assess participants’ perception: ‘Participant, in which group do you believe you were during the intervention protocol? tDCS on (active) or off (sham)?’

Interventions

Participants will undergo 2 weekly sessions of the tDCS+exercise protocol over 5 weeks, on alternate days, totalling 10 sessions. It is important to note that participants may request to suspend the intervention at any time if they consider it necessary, without any repercussions.

Active tDCS+physical exercise programme

tDCS will be used as an additional resource alongside the proposed physical exercises for participants. The Microestim tDCS NKL device will be used, with electrode placement following the International 10–20 EEG system, contralateral to the affected side of the body. The current intensity will be set to 2 mA, with an application duration of 20 min. Surface electrodes with an area of 35 cm² (5×7 cm) will be used, covered with sponges soaked in a 0.9% saline solution (approximately 14 mL) to improve current conductivity.^{19 23 30}

Following the tDCS application, supervised resistance exercises will be performed in accordance with the recommendations of the American College of Sports Medicine³⁵ and EULAR.¹³ Participants will perform 2 weekly sessions, with an average duration of at least 60 min each, consisting of 3 sets of 10 repetitions at a load of 60%–70% of 1RM, with a rest time of 1 min between sets. Progression criteria will be individually tailored, with weekly load increases of 5% to 10%. The protocol consists of exercises performed in both open and closed kinetic chains. Resistance will be progressively applied using ankle weights, which will be placed on the distal portion of the lower limb to perform the exercises. The exercise protocol will target the following muscles: gluteus medius, gluteus maximus, quadriceps, hamstrings and triceps surae. The specific exercise programme for KOA is detailed in online supplemental appendix C, as suggested by the Consensus on Exercise Reporting Template.

Sham tDCS+physical exercise programme

Electrode placement for the sham tDCS group will be the same as described above; however, the application will follow a ramping format. The device will remain on for the first 30 s, generating current, and then will be reduced to 0 mA for the remainder of the session.³⁰ Since it involves a low-intensity electrical current, patients will be informed at the time of assessment that they may not perceive the activation of the current during stimulation. The exercise intervention will be identical to that of the active tDCS group.

Assessments

Participants will be assessed at three time points: before the start of the protocol (T0), immediately after completion of the protocol (T1) and 7 days after completion of the protocol (T2). Information will be collected on personal data, anthropometric variables, sociodemographic characteristics and clinical history. The following tools will be used to evaluate the primary and secondary outcomes, in the order presented in table 1.

Table 1. Chronological order of outcome assessments.

Measurement tools/instruments
Outcomes	T0	T1	T2
Primary
NRPS	X	X	X
Secondary
PGIC		X
6MWT	X	X	X
30 s chair stand test	X	X	X
Step up test	X	X	X

CS, Central Sensitisation; 6MWT, The six-minute walk test; NPRS, Numerical Pain Rating Scale; PGIC, Patient Global Impression of Change; T0, Before the first session of the protocol; T1, Immediately after the last session of the protocol; T2, 7 days after the end of the protocol.

Primary outcome

Pain assessment will be conducted using the NPRS consisting of 11 points, where zero represents ‘no pain’ and 10 represents ‘the worst pain imaginable’.³⁶ The NPRS is widely used in research and clinical practice due to its ease of application and good reproducibility, as well as its importance in monitoring treatment progress and efficacy.

Secondary outcomes

Physical function

Physical function will also be evaluated using functional tests recommended by the OARSI:³⁷ the 30 s chair stand test (a higher number of repetitions indicates better condition). Step-up test consisting of an ascending and descending stair activity to assess lower-body strength and balance. The steps should have an appropriate height (between 16–20 cm), with shorter completion times indicating better performance. The 6 min walk test, originally designed to assess physical capacity in patients with cardiopulmonary diseases, is also employed to measure locomotion capacity in patients with motor limitations.³⁸

Global perception of change scale

The patient’s global impression of change scale, adapted to Brazilian Portuguese, will be applied at T1 and T2. This Likert-type scale ranges from 1–7, where 1 indicates ‘no change (or condition worsened)’ and 7 indicates ‘much better, with a considerable improvement that made a significant difference’.^{39 40}

Patient and public involvement

Neither the patients or the public were involved in the study design.

Statistical analysis

The statistical analysis will be performed using IBM SPSS V.22.0 for Windows. The Kolmogorov-Smirnov test will be used to assess data distribution. Once homogeneity is detected, Levene’s test will be performed. Mauchly’s test will be applied to assess data sphericity, and if violated, the Greenhouse-Geisser correction will be used. For intergroup comparison of potential outcomes at different time points, a mixed-design repeated measures ANOVA will be conducted, analysing the time-group interaction. If a significant effect is observed, a post hoc Bonferroni test will be applied. The Bonferroni test is a statistical procedure for multiple comparisons, primarily used to perform several comparisons between groups at different time points. In such cases, the risk of identifying ‘significant’ differences purely by chance increases. The Bonferroni test adjusts the p value specifically to mitigate this error, ensuring that the significance level is maintained at 0.05 regardless of the results, thereby preventing violation of this statistical threshold.

The entire database will initially be managed by Researcher 1, who is responsible for assessment and intervention, and it will be stored in Microsoft Excel spreadsheets. Subsequently, the data will be the responsibility of Researcher 4, who will remain blinded to participant allocation and will export the data for analysis in SPSS. Missing data will be analysed using the intention-to-treat approach, and multiple imputation will be applied to handle any missing values.^{41 42} The effect size may be calculated between groups for variables showing intergroup differences, along with the respective 95% CI. The statistical significance level will be set at 5%.

Ethics and dissemination

This protocol was approved by the Research Ethics Committee of the Trairi School of Health Sciences, Federal University of Rio Grande do Norte (Platform Brazil registration n° 78013724.0.0000.5568; approval n° 6.801.827). All procedures will adhere to the principles of the Declaration of Helsinki and the guidelines of Resolution n° 466/12 of the National Health Council for research involving human subjects. Participation will be voluntary and contingent on signing the informed consent form, thereby ensuring full autonomy of the individuals. Participants will have the right to withdraw at any time, without any disadvantage or penalty. Confidentiality of information, participant privacy and the ethical integrity of the entire data collection process will be safeguarded. The findings will later be disseminated in indexed scientific journals and presented at academic events. The purpose is to contribute to the expansion of the literature on non-invasive neuromodulation applied to KOA, as well as to provide relevant insights for healthcare professionals, patients and researchers in the field.