HD-tDCS in Amyotrophic Lateral Sclerosis: A Multicenter Randomized Controlled Trial (tDCS-ALS)

High-Definition Transcranial Direct Current Stimulation (HD-tDCS) in Amyotrophic Lateral Sclerosis: A Multicenter Randomized Controlled Trial

Amyotrophic Lateral Sclerosis (ALS) is a nervous system disease that causes muscle weakness and rapidly progresses to the loss of mobility and functionality. Studies suggest that High-Definition Transcranial Direct Current Stimulation (HD-tDCS) is a technique for modulating motor cortical hyperexcitability. However, evidence on the use of HD-tDCS as a neuromodulator of the diaphragmatic motor cortex in people with ALS is inconclusive.

Study Overview

• Status: Not yet recruiting
• Conditions: Amyotrophic Lateral Sclerosis (ALS)
• Intervention / Treatment: Device: Active HD-tDCS; Device: Simulated HD-tDCS

Detailed Description

A multicenter, randomized controlled clinical trial will be conducted. Participants will be randomized into two groups: the HD-tDCS group (gTDCS) and the sham tDCS group (gSham). The intervention protocol will assess the effects of HD-tDCS on respiratory parameters and ALS progression. The study will include individuals of both sexes, aged 18 to 80 years, with a clinical diagnosis of ALS, evaluated before, during, and after the home-based HD-tDCS protocol. The electrodes will be positioned in a circular arrangement over the primary diaphragmatic motor cortex, applying a continuous anodal current intensity. For placebo comparison, only an initial 30-second ramp stimulus will be applied, followed by a minimal current, resulting in no significant intervention. The intervention will be conducted at the participant's home, once daily, five days per week, for two weeks. Patients will undergo evaluations of lung function, cough peak flow, respiratory muscle strength, nasal respiratory pressures, functional capacity, muscle fatigue, cognitive function, as well as surface electromyography of respiratory muscles during active and assisted breathing curves using transcranial magnetic stimulation (TMS), cortical excitability, central tissue oxygenation, respiratory muscle tissue oxygenation, functionality and disease progression, motor control and muscle performance, fatigue and dyspnea, sleep analysis, quality of life, and adverse effects.

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Guilherme A. F Fregonezi, PhD; Phone Number: +55(84)99426-7896; Email: guilherme.fregonezi@ufrn.br
• Study Contact Backup: Name: Edna K. F Laurentino, MSc; Phone Number: +55(84)99471-5172; Email: ednakarlaferreira@gmail.com

Study Locations

• Brazil
  • DF
    • Brasília, DF, Brazil, 72220-275
      • Universidade de Brasília - Campus Ceilândia
      • Contact: Vinicius Z Maldaner da Silva, PhD; Phone Number: +55 61 99652-2517; Email: pneumocardiovascularlab@gmail.com
      • Principal Investigator: Vinicius Z Maldaner da Silva, PhD
      • Sub-Investigator: Sergio R. M Mateus, PhD
      • Sub-Investigator: Hamilton C Fernandes Franco, PhD
  • RN
    • Natal, RN, Brazil, 59010-090
      • PneumoCardioVascular Lab - HUOL/UFRN
      • Contact: Guilherme A. F Fregonezi, PhD; Phone Number: 3624 +55 84 3092-3624; Email: pneumocardiovascularlab@gmail.com
      • Contact: Edna K Ferreira Laurentino, MSc; Phone Number: +55 084 99471-5172; Email: ednakarlaferreira@gmail.com
      • Principal Investigator: Guilherme A. F Fregonezi, PhD
      • Principal Investigator: Ana Rodrigues Lindquist, PhD
      • Sub-Investigator: Edna K Ferreira Laurentino, MSc
      • Sub-Investigator: Wesley R Costa Meneses, BSc
      • Sub-Investigator: Mario E Teixeira Dourado Junior, PhD
      • Sub-Investigator: Lariza M da Costa, BSc
      • Sub-Investigator: Vanessa R. F Resqueti, PhD
      • Sub-Investigator: Danilo A. A Pinto Nagem, PhD
      • Sub-Investigator: Mario E. T Dourado Junior, PhD
      • Sub-Investigator: Suellen M. M dos Santos Andrade, PhD
      • Sub-Investigator: Ricardo A de Medeiros Valentim, PhD
      • Sub-Investigator: Rodrigo P de Abreu Freitas, PhD
      • Sub-Investigator: Bruna R Carneiro de Sousa, MSc
• Chile
  • Región Metropolitana
    • Santiago, Región Metropolitana, Chile, 7500912
      • Universidad Autónoma de Chile
      • Contact: Matias Otto Yañez, PhD; Phone Number: +56 9 8885-6626; Email: matiasotto.kine@gmail.com
      • Contact: Matias Otto Yañez, PhD; Phone Number: +56 9 8885-6626
      • Principal Investigator: Matias V Oto Yañez, PhD
    • Santiago, Región Metropolitana, Chile, 8380453
      • Universidad do Chile
      • Contact: Roberto Vera Uribe, MsC; Email: robertovera@uchile.cl
      • Contact: Rodrigo Torres Castro, MsC; Email: klgorodrigotorres@gmail.com
      • Principal Investigator: Roberto Vera Uribe, MsC
      • Principal Investigator: Rodrigo Torres Castro, MsC

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Both sexes; diagnosis of ALS according to the revised El Escorial criteria;
• Age between 18 and 80 years;
• Forced Vital Capacity greater than 50% of predicted;
• Sniff nasal inspiratory pressure greater than 40 cmH2O;
• A telephone number to contact the care team and who signed the study consent form.

Exclusion Criteria:

• Subjects who are unable to understand or perform any of the study procedures;
• Subjects who do not agree to participate or voluntarily request withdrawal from the study at any time;
• Subjects with cardiac, respiratory, or musculoskeletal comorbidities;
• Subjects using invasive mechanical ventilation;
• Subjects with a tracheostomy;
• Subjects with a pacemaker;
• Subjects with metallic brain implants or other electronic implants;
• Subjects with a cochlear implant;
• Subjects with epileptic activity or a history of epilepsy, or a family history of epilepsy;
• Subjects with a history of stroke or tumor;
• Subjects prone to severe hemodynamic fluctuations, acute infectious processes, and/or inflammatory conditions;
• Pregnant women at the time of recruitment;
• Subjects who are unable to complete the intervention protocol.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active HD-tDCS Group; Patients randomly included in this group will receive 10 sessions of anodal HD-tDCS stimulation. The intervention will take place at the participant's home, with electrodes positioned in a circular arrangement-one central electrode and four peripheral electrodes-over the cortical representation zone of the left primary diaphragmatic motor cortex, with a continuous current applied	Device: Active HD-tDCS; 10 sessions of anodal HD-tDCS stimulation (neurostimulator coupled with a 4x1 HD-tDCS multichannel adapter) with a defined electrical current intensity over the cortical representation zone of the left diaphragmatic motor cortex
Placebo Comparator: HD-tDCS sham group; Patients randomly included in this group will receive 10 sessions of sham HD-tDCS stimulation. The intervention will take place at the participant's home, with electrodes positioned in a circular arrangement-one central electrode and four peripheral electrodes-over the cortical representation zone of the left primary diaphragmatic motor cortex. Only an initial 30-second ramp stimulus will be applied, followed by a non-effective current	Device: Simulated HD-tDCS; 10 sessions of sham anodal HD-tDCS stimulation (neurostimulator coupled with a 4x1 HD-tDCS multichannel adapter) over the cortical representation zone of the left diaphragmatic motor cortex. The device will provide a 30-second ramp and then maintain a minimal, non-effective continuous current

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cortical excitability assessed via TMS	Cortical excitability assessed by means of Transcranial Magnetic Stimulation measuring motor evoked potentials, cortical inhibition and duration of the cortical silent period	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Cortical tissue oxygenation	Assessment of cortical tissue oxygenation using brain coupled near-infrared spectroscopy technique coupled to the brain to monitor cerebral oxygenation and regional cerebral oxygen saturation.	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Electromyographic activity of specific respiratory muscles	This outcome will be assessed through Electromyography of the sternocleidomastoid, scalene, parasternal, hemidiaphragm and rectus abdominis muscles	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Respiratory function assessed by spirometry	This outcome will be assessed using spirometry	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Maximum Inspiratory and Expiratory Pressure	This outcome will be assessed by assessing maximum inspiratory and expiratory pressure, Sniff Nasal Inspiratory Pressure and Sniff Nasal Expiratory Pressure curves	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Cough Peak Flow	This outcome will be assessed through Cough Peak Flow values	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Respiratory muscle oxygenation via near-infrared spectroscopy	This outcome will be assessed using the near-infrared spectroscopy technique coupled to the scalene and parasternal muscles	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Peripheral upper limb muscle activity assessed via electromyography	This outcome will be assessed through a protocol for assessing muscle activity positioned in the Lower Trapezius, Anterior Deltoid, Biceps Brachii (medial head), Triceps Brachii (lateral head), Brachioradialis, Extensor Carpi Radialis Longus, Abductor Pollicis Brevis and Upper Trapezius muscles, bilaterally	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Functionality and disease progression	This outcome will be assessed using the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised which has 12 items with a score from zero to 4, and its total score can range from zero to 48, where 48 means normal functionality and zero, severe disability	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Fatigue Severity	This outcome will be assessed using the Fatigue Severity Scale comprises nine statements ranging from 1 to 7, with 7 being the maximum level of agreement with the statement, with a minimum score of 9 and a maximum of 63, with values equal to or greater than 28 indicating fatigue	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Dyspnea assessed via Modified Borg Scales	The Modified Borg scale is numbered from 0 to 10, with each number referring to a textual description of the degree of respiratory fatigue, with 0 as the minimum and 10 as the maximum respiratory discomfort	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Quality of sleep assessment	This outcome will be assessed using the Mini-Sleep Questionnaire	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Quality of life assessed using the Brief ALS-specific Quality of Life Questionnaire	This outcome will be assessed using the Brief Specific Quality of Life Questionnaire for ALS Patients	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)
Subjective assessment of stimulation-related effects	This outcome will be assessed through a questionnaire about effects such as itching, tingling, redness of the skin, drowsiness, concentration problems, headache, fatigue, dizziness and others, indicating the intensity of these sensations on a scale of 1 to 4 (1 being none, 2 being mild, 3 being moderate and 4 being strong) and whether these effects are related to the stimulation, using a Likert scale from 1 (no relation) to 5 (strongly related)	From the date of randomization (1 week before the start of the intervention) up to 6 months (follow-up)

Collaborators and Investigators

• Sponsor: Universidade Federal do Rio Grande do Norte
• Collaborators: Financiadora de Estudos e Projetos

Study record dates

Study Major Dates

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

Study Registration Dates

• First Submitted: November 30, 2024
• First Submitted That Met QC Criteria: December 5, 2024
• First Posted (Actual): December 6, 2024

Study Record Updates

• Last Update Posted (Actual): July 2, 2025
• Last Update Submitted That Met QC Criteria: July 1, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Keywords: Transcranial Direct Current Stimulation; Electric Stimulation Therapy; Central Nervous System Diseases; Amyotrophic Lateral Sclerosis (ALS)
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; Pathologic Processes; Neuromuscular Diseases; Metabolic Diseases; Neurodegenerative Diseases; Spinal Cord Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Sclerosis; Motor Neuron Disease; Amyotrophic Lateral Sclerosis
• Other Study ID Numbers: HD-tDCSALS; U1111-1306-808 (Other Identifier: Universal Test Number (UTN))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

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