Non-invasive Brain Stimulation and Exercise Intervention for Patients With Motor Neuron Disease

Motor neuron disease (MND) is a progressive neurological disorder involving degeneration of motor neurons, leading to muscle weakness, speech and swallowing difficulties, and respiratory failure. This study aims to develop a novel treatment approach combining personalized repetitive transcranial magnetic stimulation (rTMS) with mixed reality (MR) exercise-based games (exergames) to slow disease progression and improve quality of life. In this randomised controlled trial study will compare three groups: (1) rTMS with MR exercise (personalized intervention), (2) rTMS with MR exercise (standard intervention), and (3) sham rTMS with MR exercise. Outcomes will be assessed at baseline, 3 months, and 6 months post intervention. The long-term goal is to implement this approach in clinical settings to enhance care for people with MND.

Study Overview

• Status: Recruiting
• Conditions: ALS (Amyotrophic Lateral Sclerosis)
• Intervention / Treatment: Device: Personalized rTMS; Device: Standard rTMS; Device: Sham rTMS

Detailed Description

After screening process, eligible participants will be invited to visit Chula Neuroscience Center for the baseline assessments which will take proximately 2 hours.

The baseline assessments will be as follow:

1. Demographic information such as age, sex, body height, body weight, body mass index, date of diagnosis, type of MND, and current medications.
2. Questionnaires including amyotrophic lateral sclerosis functional rating scale - revised version (ALSFRS-R), penn upper motor neuron score (PUMNS), patient health questionnaire (PHQ-9), and EuroQol 5-Dimension 5-level (EQ-5D-5L).
3. Clinical assessments including hand grip test, pinch grip test, and hand function.
4. Lung function tests such as forced vital capacity (FVC).
5. Neurophysiological assessment by using transcranial magnetic stimulation (TMS)
6. Electromyography (EMG) including compound muscle action potential (CMAP), motor unit number estimation (MScan fit-MUNE), and motor unit number index (MUNIX).
7. Magnetic resonance imaging (MRI)

• Study Type: Interventional
• Enrollment (Estimated): 100
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Jakkrit Amornvit, MD; Phone Number: Thailand: 88-951-9195; Email: jakkrit.a@chula.ac.th
• Study Contact Backup: Name: Phunsuk Kantha, PT.,PhD; Phone Number: Thailand: 93-295-1646; Email: phunsuk.kan@mahidol.ac.th

Study Locations

• Thailand
  • Pathumwan
    • Bangkok, Pathumwan, Thailand, 10330
      • Recruiting
      • King Chulalongkorn Memorial hospital, The Thai Red Cross Society
      • Principal Investigator: Jakkrit Amornvit, MD
      • Contact: Jakkrit Amornvit, MD; Phone Number: +66622169338; Email: jakkrit.a@chula.ac.th
      • Contact: Phuettha Sangrut, MSc; Phone Number: 80722 6622564000; Email: phuettha.s@chulahospital.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Participants aged between 18 and 80 years
• Diagnosed with any type of motor neuron disease (MND)
• Have mild to moderate severity, as assessed by the Sinaki-Mulder scale, with a severity level between 1 and 3

Exclusion Criteria:

• History of other neurological disorders, such as stroke
• Use of ventilatory support
• Severe dementia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Personalized intervention group; Participants will receive personalised repetitive transcranial magnetic stimulation mixed reality.	Device: Personalized rTMS; Personalized repetitive transcranial magnetic stimulation (TMS) together with mixed-reality (MR) exercise
Active Comparator: Standard intervention group; Participants will receive standard repetitive transcranial magnetic stimulation plus mixed reality.	Device: Standard rTMS; Standard repetitive transcranial magnetic stimulation (TMS) together with mixed-reality (MR) exercise
Sham Comparator: Sham group; Participants will receive sham repetitive transcranial magnetic stimulation mixed reality.	Device: Sham rTMS; Sham rTMS together with mixed-reality (MR) exercise

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Amyotrophic Lateral Sclerosis Functional rating scale - revised version (ALSFRS-R)	The Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS-R) is a 12-item questionnaire used to assess functional ability in people with ALS across four domains: bulbar, fine motor, gross motor, and respiratory function. Each item is scored from 0 (unable) to 4 (normal), with a total score ranging from 0 to 48. It can be self-reported or clinician-administered in person, by phone, or online. Lower scores indicate greater disability. The ALSFRS-R is used to monitor disease progression and guide clinical care.	ALSFRS-R will be measured at three time points (baseline, 3-month, and 6-month post intervention).
Muscle evoke potential (MEP)	Participants will be stimulated at the primary motor cortex by transcranial magnetic stimulation to measure cortical excitability, which sends the motor outputs to Tibialis Anterior (TA) and Abductor Pollicis Brevis (APB) muscles. The MEP will be used to assess muscle activity in these muscles during the stimulation. The MEP will be measured in mV.	MEP will be mesured at three time points (baseline, 3-month, and 6-month post intervention).
Motor unit number estimation (MScan fit-MUNE)	For MScan fit-MUNE, CMAP is recorded at multiple stimulation intensities. The MScan fit-MUNE software then generates a curve representing the relationship between stimulation intensity and CMAP amplitude. A mathematical model is fitted to this curve to estimate the number of motor units contributing to the generation of the CMAP.	MScan fit-MUNE will be mesured at three time points (baseline, 3-month, and 6-month post intervention).
Motor unit number index (MUNIX)	For MUNIX (Motor Unit Number Index), the procedure begins with recording the CMAP. Then, the participant is asked to gently contract the muscle. During this contraction, the interference pattern of muscle electrical activity is recorded. The MUNIX value is calculated by analyzing the ratio between the CMAP amplitude and the amplitude of the interference pattern. This provides an estimate of motor unit function.	MUNIX will be measured at three time points (baseline, 3-month, and 6-month post intervention).
Cortical silent period (CSP)	Participants will be stimulated at the primary motor cortex by transcranial magnetic stimulation to measure cortical excitability, which sends the motor outputs to Tibialis Anterior (TA) and Abductor Pollicis Brevis (APB) muscles. The CSP will be used to assess muscle activity in these muscles during the stimulation. The CSP will be measured in ms.	Muscle evoke potential will be measured at three time points (baseline, 3-month, and 6-month post intervention).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle mass	We will used the bioelectrical impedance analysis (BIA), which is a method used for measuring body composition.Participants will be asked to step on to the BIA device, placing their feet on the foot electrodes. The muscle mass will be recored in kilograms.	Muscle mass will be measured at three time points (baseline, 3-month, and 6-month post intervention).
Body mass index (BMI)	We will used the bioelectrical impedance analysis (BIA), which is a method used for measuring body composition.Participants will be asked to step on to the BIA device, placing their feet on the foot electrodes. The BMI will be recored in kg/m^2.	BMI will be measured at three time point (baseline, 3-month, 6-month post intervention).
Hand grip test	The Hand Grip Test is an objective measure of isometric grip strength, commonly used to assess overall muscle strength and functional status. The test is performed using a handheld dynamometer, which the participant squeezes with maximum effort, typically while seated with the elbow at a 90-degree angle. The test is usually repeated three times per hand, and the highest or average value measured in kilograms is recorded. Lower grip strength is associated with reduced physical function and is often used as an indicator of frailty, sarcopenia, or neuromuscular decline.	Hand grip test will be measured at three time points (baseline, 3-month, and 6-month post intervention).
Pinch grip test	The Pinch Grip Test is used to assess the strength of the thumb muscles in individuals with motor neuron disease (MND). Participants are asked to hold a pinch grip dynamometer with their arm positioned at a 90-degree angle and squeeze as hard as possible for 3 to 5 seconds. Each set consists of 10 repetitions, and the test includes 5 sets in total, with a 1-minute rest between sets. The goal is to measure the maximum force generated during the test. Afterward, participants are instructed to maintain a pinch force at 50% ± 5% of their maximum strength for as long as possible. Results are recorded in kilograms (kg) and duration (seconds).	Pinch grip test will be measured at three time points (baseline, 3-month, and 6-month post intervention).
Hand function	Hand function will be assessed using the Wolf Motor Function Test (WMFT) to evaluate gross motor movements, such as placing the hand on a table, placing the arm on a box, and extending the arm. The Jebsen-Taylor Test of Hand Function will be used to assess fine motor movements, such as picking up objects, grasping a can, and handling a paperclip. The outcomes will be recorded as the time taken to complete each task.	Hand function will be measured at three time points (baseline, 3-month, and 6-month post intervention).
Penn upper motor neuron score (PUMNS)	The PUMNS is a questionnaire used to assess neurological responses (reflexes) and spasticity in individuals with motor neuron disease (MND). It helps evaluate the severity of the disease and monitor changes in the patient's nervous system. The researcher will assess various reflexes and signs of spasticity, such as Hoffman's sign and Babinski's sign.	PUMNS will be measured at three time points (baseline, 3-month, and 6-month post intervention).
Patient health questionnaire (PHQ-9)	The Patient Health Questionnaire-9 (PHQ-9) is a widely used self-report screening tool for assessing the presence and severity of depression. It consists of 9 items, each corresponding to one of the diagnostic criteria for major depressive disorder as defined by the DSM-IV. The total score ranges from 0 to 27, with higher scores indicating more severe depressive symptoms.	PHQ-9 will be measured at three time points (baseline, 3-month, and 6-month).
EuroQol 5-Dimension 5-level (EQ-5D-5L)	The EuroQol 5-Dimension 5-Level (EQ-5D-5L) is a standardized questionnaire used to measure health-related quality of life (HRQoL). It is widely used in clinical, public health, and economic evaluations to assess the overall health status of individuals. The EQ-5D-5L includes two parts: 1) Descriptive System whhich assesses health across five dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and 2) EQ Visual Analogue Scale (EQ VAS - A vertical scale ranging from 0 (worst imaginable health) to 100 (best imaginable health) on which the respondent rates their overall health.	EQ-5D-5L will be measure at three time ponts (baseline, 3-month, and 6-months post intervention).
Forced vital capacity (FVC)	Forced Vital Capacity (FVC) is a key measure of lung function that assesses the amount of air a person can forcefully exhale after taking the deepest possible breath. It is measured in litres (L) using a device called a spirometer. During the test, the person inhales fully and then exhales as hard and fast as possible until no more air can be expelled. The total volume of air exhaled is recorded as the FVC. This test helps evaluate lung capacity and is commonly used to monitor respiratory conditions such as asthma, chronic obstructive pulmonary disease (COPD), and motor neuron disease (MND).	FVC will be measured at three time points (baseline, 3-month, and 6-month post intervention).
Magnetic resonance imaging (MRI)	Brain imaging using MRI is a technique used to measure cortical thickness by capturing high-resolution images of brain structures. Participants lie in an MRI scanner for approximately 10 to 20 minutes during data acquisition. After the scan, the images are processed using FreeSurfer software. Cortical thickness is calculated by measuring the distance between the white matter surface and the outer surface of the cerebral cortex.	Brain imaging using MRI will be measured at three time points (baseline, 3-month and 6-month post intervention).
Compound muscle action potential (CMAP)	To record Compound Muscle Action Potential (CMAP), electrical stimulation is applied to the nerve, gradually increasing the intensity step by step. The muscle responses are recorded to determine the maximum CMAP response, which is achieved at supramaximal stimulation. CMAP is a key parameter in studies related to nerve conduction and provides important information about motor neuron function. A higher CMAP value indicates greater muscle fiber activation, which reflects the number of functional motor units still intact.	CMAP will be meausred at three time points (baseline, 3-month, and 6-month post intervention).

Collaborators and Investigators

• Sponsor: Chulalongkorn University
• Collaborators: King Chulalongkorn Memorial Hospital
• Investigators: Principal Investigator: Jakkrit Amornvit, MD, Chulalongkorn University; Principal Investigator: Phunsuk Kantha, PT.,PhD, Mahidol University; Principal Investigator: Kulvara Lapanan, PT, Chulalongkorn University and Neuroscience Resesarch Australia

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2025
• Primary Completion (Estimated): August 30, 2027
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: July 5, 2025
• First Submitted That Met QC Criteria: July 5, 2025
• First Posted (Actual): July 16, 2025

Study Record Updates

• Last Update Posted (Estimated): September 25, 2025
• Last Update Submitted That Met QC Criteria: September 21, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Amyotrophic Lateral Sclerosis; Transcranial Magnetic Stimulation; Intervention; Augmented Reality
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Motor Neuron Disease; Nutritional and Metabolic Diseases; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: COA No. 1142/2024

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No