Transcraneal Magnetic Stimulation for Treatment of Non-nociceptive Pain in Chronic Diseases

2\. FUNDAMENTALS OF TMS/rTMS Transcranial magnetic stimulation (TMS) is a non-invasive neuromodulation technique that uses a time-varying magnetic field to induce electrical currents in the brain. Repetitive TMS (rTMS) delivers trains of pulses capable of producing lasting neurophysiological effects beyond the stimulation period. The magnitude and direction of these effects depend on the cortical target, stimulation frequency and intensity, number of pulses and sessions, and the neurophysiological state of the participant. Low-frequency protocols (e.g., 1 Hz) are generally associated with reduced cortical excitability, whereas higher frequencies may increase excitability. However, responses vary substantially among individuals and should not be considered universal. The effects of rTMS have been linked to synaptic plasticity mechanisms resembling long-term potentiation (LTP) and long-term depression (LTD), as well as changes in functional connectivity. These mechanisms provide the biological rationale for its use as an adjunct to rehabilitation. 2.1 Post-Stroke Applications In stroke rehabilitation, rTMS is primarily used to modulate the balance of cortical excitability between hemispheres. Inhibitory stimulation may be applied to the contralesional hemisphere, whereas excitatory stimulation may target the affected hemisphere. Potential benefits have been reported for motor recovery, spasticity, and language rehabilitation when combined with conventional therapy. 2.2 Chronic Pain and Fibromyalgia Motor cortex stimulation has been investigated as a treatment for chronic pain conditions. Proposed mechanisms involve modulation of thalamocortical and sensorimotor networks involved in pain processing. Meta-analyses suggest that rTMS may reduce pain in selected conditions, although clinical responses remain variable. 2.3 ME/CFS and Long COVID Evidence supporting rTMS in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID remains limited. Interest in neuromodulation stems from reported abnormalities in cortical excitability, network connectivity, cognition, and fatigue. Its use should therefore be regarded as investigational and complementary. 3\. STUDY RATIONALE Stroke, fibromyalgia, chronic pain disorders, ME/CFS, and Long COVID significantly affect functional capacity, independence, and quality of life. Many individuals continue to experience disabling symptoms despite standard treatments. Neuromodulation may represent a useful complementary therapeutic strategy. The central hypothesis is that an individualized and standardized rTMS protocol will demonstrate a favorable safety profile and produce clinically meaningful improvements, although treatment responses may differ across diagnostic groups due to distinct pathophysiological mechanisms. 4\. HYPOTHESES rTMS administered using a standardized and individualized protocol will be safe and well tolerated. Treatment will be associated with favorable changes in pain, fatigue, functionality, and quality of life. Standardized procedures for target localization and intensity determination will reduce inter-session variability. The magnitude and pattern of clinical response will differ among diagnostic groups. 5\. OBJECTIVES 5.1 General Objective To evaluate the safety, tolerability, and clinical effects of rTMS as a complementary therapeutic intervention in patients with fibromyalgia, ME/CFS, post-stroke sequelae, and Long COVID. 5.2 Specific Objectives Assess safety and tolerability through systematic recording of adverse events. Evaluate clinical outcomes using validated scales before and after treatment and during follow-up. Analyze changes in pain, fatigue, functionality, and quality of life. Apply standardized procedures for target localization and coil positioning. Determine individual motor thresholds and use them to guide stimulation intensity when appropriate. Explore relationships between TMS-EMG measures and clinical outcomes. Compare response patterns across clinical subgroups. 6. MATERIALS AND METHODS 6.1 Study Design This clinical study includes baseline assessment, rTMS intervention, post-treatment evaluation, and follow-up. The protocol consists of ten treatment sessions administered over two consecutive weeks. Outcomes are assessed immediately after treatment and approximately one month later. 6.2 Participants Adults aged 18-75 years who meet diagnostic criteria for the study conditions will be eligible. Approximately 46 participants per condition are expected to provide preliminary information regarding feasibility, adherence, attrition, and potential efficacy signals. 6.3 Baseline Assessment Baseline evaluations include demographic and clinical data, medical history, medication review, physical examination, and condition-specific outcome measures. Instruments may assess motor function, cognition, spasticity, pain, fatigue, sleep quality, and quality of life. 6.4 Target Localization When individual MRI data are available, neuronavigation will be used to improve target accuracy and reproducibility. In the absence of MRI, stimulation targets will be identified using the International 10-20 EEG system. Target selection will be based on clinical indication and available evidence. 6.5 TMS-EMG and Motor Threshold Assessment Combining TMS with electromyography (EMG) allows recording of motor evoked potentials (MEPs) and assessment of corticospinal excitability. Resting motor threshold (RMT) will be used to individualize stimulation intensity. Neurophysiological findings will be interpreted together with clinical outcomes. 6.6 Stimulation Protocols For fibromyalgia, ME/CFS, Long COVID, and nociplastic pain conditions, the protocol uses excitatory 10-Hz stimulation over the left primary motor cortex. For post-stroke participants, inhibitory 1-Hz stimulation may be applied to cortical regions selected according to the predominant clinical deficit. These parameters are protocol-specific and not intended as universal recommendations. 7\. SAFETY MONITORING rTMS generally demonstrates a favorable safety profile when administered according to established guidelines. Common adverse effects include headache, scalp discomfort, neck pain, dizziness, and transient fatigue. Seizure is a rare but serious adverse event requiring careful risk assessment. Screening procedures include evaluation of metallic implants, electronic devices, and other contraindications. Adverse events will be systematically recorded and classified according to severity and relationship to treatment. 8\. OUTCOME EVALUATION The primary safety outcome is the frequency and severity of adverse events. Clinical outcomes include pain, fatigue, sleep quality, quality of life, motor function, cognition, and disability measures. Particular attention will be paid to the clinical relevance of observed changes and to the relationship between neurophysiological and functional outcomes. 9\. ETHICAL CONSIDERATIONS AND DATA MANAGEMENT Written informed consent will be obtained before any study procedures. Participants will be identified using coded records, and all personal information will remain confidential. The study will comply with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable data protection regulations, including GDPR requirements. Participants may withdraw from the study at any time without penalty.