Acupressure in MS Patients

Background Multiple Sclerosis (MS) is a chronic autoimmune and neurodegenerative disease affecting the central nervous system (CNS). It is characterized by inflammation, demyelination, gliosis (scar formation), and axonal damage. These pathological changes lead to impairments in motor and cognitive functions, sensory perception, vision, and balance. The unpredictable progression of MS contributes to physical disability and psychological distress, significantly reducing patients' quality of life.

Current treatments primarily focus on disease-modifying therapies (DMTs) to slow disease progression and symptomatic management strategies to address pain, fatigue, depression, and cognitive impairments. However, conventional approaches often fail to fully alleviate symptoms, leading patients to seek complementary and alternative therapies. Acupressure has emerged as a promising complementary method due to its non-invasive, low-cost, and easy-to-apply nature.

Acupressure is based on Traditional Chinese Medicine principles and involves applying pressure to specific points on the body. It aims to balance energy flow and promote physiological and psychological well-being. Studies have demonstrated its effectiveness in reducing pain, fatigue, and stress and improving sleep quality and cognitive function. However, evidence on its impact on neuropeptides such as beta-endorphin and hypocretin in MS patients remains limited.

Beta-endorphin is an endogenous opioid peptide known for its analgesic properties, stress modulation, and role in emotional regulation. Hypocretin (also called orexin) regulates arousal, wakefulness, and energy balance. Dysregulation of these neuropeptides has been implicated in MS-related symptoms, including fatigue, pain, and cognitive decline. This study aims to explore whether acupressure can modulate these biomarkers and improve clinical outcomes in MS patients.

The APEX-MS study (Trial of Acupressure and Patient Experience in Multiple Sclerosis) aims to investigate the effects of acupressure on beta-endorphin levels, hypocretin levels, cognition, and patient-reported outcome measures (PROMs) in individuals with MS.

Methods This study will be conducted using a single-blind, randomized, controlled, and experimental design. The research will take place at the Neurology Clinic of Bolu Abant İzzet Baysal University İzzet Baysal Training and Research Hospital. The study population will consist of individuals who have been diagnosed with MS and followed up for at least six months. The sample size was determined using the GPower 3.1.9.7 software, and a total of 82 participants (41 in each group) were calculated to be sufficient for the study.

Participants will be randomly assigned to either the intervention group (receiving acupressure therapy) or the control group (receiving placebo intervention) using stratified randomization. Stratified randomization will ensure balanced distribution of key variables such as age, gender, disease severity, and disease duration. The randomization sequence will be generated by an independent researcher who is not involved in data collection or analysis.

As required by the single-blind design, researchers assessing outcomes, including beta-endorphin and hypocretin levels, cognitive functions, and PROMs, will remain unaware of group assignments. This approach will minimize evaluation bias and ensure reliable results.

Inclusion Criteria:

* Diagnosis of MS confirmed by a neurologist based on the McDonald criteria. * Having the Relapsing-Remitting MS (RRMS) subtype. * Diagnosed with MS for at least one year. * Individuals aged between 18 and 65 years. * Expanded Disability Status Scale (EDSS) score between 0 and 5 (indicating mild to moderate disability). * No use of steroid treatment or discontinuation of steroid therapy at least 3 months prior to study participation. * No MS relapse in the past 3 months. * No prior use of acupressure or similar complementary therapies. * Sufficient language proficiency to understand and complete study assessments and questionnaires.

Exclusion Criteria:

* Presence of any open wounds or deformities at the acupressure application site. * Diagnosis of neurodegenerative or neuropsychiatric diseases such as - - * Parkinson's or Alzheimer's, which may potentially confound study results. * Pregnant or breastfeeding women, due to potential hormonal changes that may affect results. * Presence of severe cardiovascular, pulmonary, hepatic, renal, or psychiatric conditions.

Hypotheses of the study:

H1-1: Acupressure increases beta-endorphin levels in MS patients, contributing to the alleviation of symptoms such as pain, fatigue, and stress.

H1-2: Acupressure regulates hypocretin levels in MS patients, leading to improvements in fatigue and cognitive functions.

H1-3: Acupressure enhances cognitive functions in MS patients, and this improvement is associated with changes in beta-endorphin and hypocretin levels.

H1-4: Acupressure improves PROMs, resulting in reduced pain and fatigue, decreased depression scores, and enhanced overall quality of life.

Data collect and measures As part of the study, individuals registered at the neurology outpatient clinic will first be screened using the hospital's database. During this screening process, eligibility will be assessed based on inclusion and exclusion criteria, including age (18-65 years), duration of diagnosis (at least one year), and the presence of additional diagnosed and monitored conditions (e.g., neurodegenerative and neuropsychiatric diseases). Information on eligible patients will be recorded in a list. Patients included in the list will be contacted by phone, and further assessments will be conducted based on the inclusion and exclusion criteria. The Expanded Disability Status Scale (EDSS) score (0-5 points) will be evaluated, along with the presence of steroid therapy, the time since the last MS relapse, pregnancy or breastfeeding status, and prior use of acupressure or similar complementary therapies. Patients will receive preliminary information about the study's purpose, goals, expected outcomes, and duration, and their willingness to participate voluntarily will be assessed. Patients who do not meet the criteria will be excluded from the list, while eligible patients will be invited to the hospital's outpatient clinic for the study initiation. Prior to the clinic visit, a randomization sequence will be generated, and participants will be assigned to either the intervention or control group. The study flow diagram is provided in Figure 1 for detailed reference. Upon arrival at the clinic, participants will be thoroughly informed about the study (its purpose, goals, responsibilities, and duration), and written informed consent will be obtained.

All participants in this study, regardless of group assignment, will first undergo data collection procedures to obtain baseline (Time-0/T0) measurements. A "Demographic and Clinical Information Form" will be administered at the start of the study to gather data on participants' age, gender, education level, employment status, disease duration, EDSS score, and the number of MS relapses experienced in the past year. The study will examine the measurement variables detailed below, and the corresponding data collection tools will be applied at the specified time points listed. All data will be collected through face-to-face interviews with participants. However, data on pain and fatigue measured at the T1 time point will be collected via telephone interviews.

Measurement variable-1: Laboratory Data (Beta-Endorphin and Hypocretin Levels) Data collection form: Laboratory Data Monitoring Form Description: Measurement of beta-endorphin and hypocretin levels will not require any additional blood sampling from participants as part of the study. The levels of these biomarkers will be obtained from blood samples collected during routine clinical follow-ups requested by the neurologist. Blood samples will be drawn via venous access into 2 ml biochemistry tubes as part of standard clinical procedures in the neurology department. No additional invasive procedures will be performed for this study. Beta-endorphin and hypocretin levels will be analyzed using specialized ELISA kits. Samples will be sent to an external laboratory following routine blood collection in the outpatient clinic. Reported results will be recorded in the monitoring form and used for the study's statistical analyses.

Measurement time points: T0 and T2.

Measurement Variable-2: Cognition Data Collection Tool: Brief International Cognitive Assessment for MS (BICAMS)

Description:

BICAMS is a test battery with strong psychometric properties, developed in 2012 to rapidly and effectively assess cognitive dysfunction in patients with MS. The Turkish version of this form was validated in 2017. BICAMS consists of three short tests that evaluate three key cognitive domains:

Symbol Digit Modalities Test (SDMT): This test includes a key table with symbols and corresponding numbers, along with a sequence of symbols. The key table shows which number corresponds to each symbol (e.g., a triangle corresponds to the number "3"). The participant is presented with the key table and a series of symbols underneath it. The participant is asked to write the correct number below each symbol by referring to the key table. Two methods are available for administration: written (pen-and-paper) and oral (verbal response). In this study, the oral method will be individually administered. The participant's score is based on the number of correct matches completed within 90 seconds. The SDMT measures information processing speed and attention, and the highest possible score is 110. The test takes approximately 5 minutes to complete.

California Verbal Learning Test, Second Edition (CVLT-II): CVLT-II is a standard measure of auditory/verbal learning and memory widely used in clinical neuropsychology. In this study, the first five trials assessing verbal memory will be used. The test consists of 16 words grouped into 4 categories (4 vehicles, 4 vegetables, 4 animals, and 4 pieces of furniture). CVLT-II evaluates not only the number of words recalled but also learning and recall strategies, including errors, repetitions (perseverations), and intrusions. The total correct recall across the five trials represents the learning score. The maximum possible score is 80.

Brief Visuospatial Memory Test Revised (BVMT-R): BVMT-R assesses visuospatial memory through three recall trials. The test consists of a stimulus card displaying six geometric figures arranged in a 2x3 grid. In each trial, participants are shown the card for 10 seconds and then asked to draw as many figures as possible in their correct positions on a blank sheet of paper. Each correctly drawn figure earns a maximum of two points, and the total score for all six figures across three trials is 36 points. The difference between the first and third trials is used to assess learning progress.

Measurement Time Points: T0 (Baseline) and T2 (Post-intervention).

Measurement variable-3: PROMs (pain, fatigue, depression, quality of life) Pain Severity Assessment: Pain severity will be evaluated using the Visual Analog Scale (VAS). The VAS consists of a 10 cm scale (0 = no pain, 10 = worst possible pain), where participants will mark the point that best represents their pain intensity (measured at time points: T0, T1, and T2).

Fatigue Assessment: Fatigue will be assessed using the Fatigue Severity Scale (FSS). This is a 9-item test that evaluates how fatigued participants have felt during the past week, including the day of assessment. Participants rate each item on a scale from 1 (strongly disagree) to 7 (strongly agree) based on their experience. The total score is divided by the number of items to calculate the average score. A score of 4 or higher typically indicates pathological fatigue. The Turkish validity and reliabil

• Pain measurement [Time frame: from baseline to two months]
• Fatigue [Time frame: from baseline to two months]
• Depression [Time frame: from baseline to two months]
• Quality of life measurement [Time frame: from baseline to two months]