Neuroregeneration Enhanced by Transcranial Direct Current Stimulation (TDCS) in Stroke (NETS)

Neuroregeneration Enhanced by TDCS in Stroke

Testing the hypothesis that non-invasive brain stimulation by transcranial direct current stimulation (tDCS) combined with functional training in the subacute phase of first-ever stroke will enhance functional regeneration compared with a Placebo intervention.

Study Overview

• Status: Active, not recruiting
• Conditions: Stroke
• Intervention / Treatment: Device: DC-Stimulator to apply tDCS; Device: DC-Stimulator to apply Sham tDCS

Detailed Description

Stroke is the leading cause of long-term disability, which significantly impairs the economic and social life of patients and society. Every year 200 000 to 250 000 patients suffer a stroke in Germany. Only a small number of the stroke survivors recover to a degree that allows them to return into their professional and private life. Despite significant efforts to develop novel and efficient treatment strategies the level of functional regeneration is still not satisfying. Thus, the development of innovative and effective treatment strategies will have a major impact for the patients' life, the society and the public health system.

Within the proposed project an innovative, non-invasive and cost effective interventional strategy, based on the combination of a specific rehabilitative training and brain stimulation by transcranial direct current stimulation (tDCS), will be used to enhance functional regeneration in stroke patients. The intervention will be applied in an early stage in which plasticity, cortical reorganization and functional improvement is most pronounced. We hypothesize that the combination of anodal tDCS delivered to the motor cortex of the affected hemisphere combined with training over a period of two weeks in the subacute stage after stroke will significantly enhance cortical plasticity, functional regeneration and long-term outcome determined by clinical and functional outcome measures compared with Placebo stimulation.

• Study Type: Interventional
• Enrollment (Actual): 119
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Austria
  • Wien, Austria, 1090
    • Neurologische Universitätsklinik Wien
• Germany
  • Bad Aibling, Germany, 83043
    • Neurologische Klinik Bad Aibling
  • Bad Segeberg, Germany, 23795
    • Neurologisches Zentrum Segeberger Kliniken
  • Bennewitz, Germany, 04828
    • NRZ Leipzig
  • Berlin, Germany, 14089
    • MEDIAN Klinik Berlin-Kladow
  • Hamburg, Germany, 20246
    • University Medical Center Hamburg Eppendorf (UKE)
  • Heidelberg, Germany, 69120
    • University Medical Center Heidelberg
  • Bayern
    • Kipfenberg, Bayern, Germany, 85110
      • Klinik Kipfenberg
  • Berlin
    • Bernau bei Berlin, Berlin, Germany, 16321
      • Brandenburgklinik Berlin-Brandenburg
  • Thüringen
    • Bad Klosterlausnitz, Thüringen, Germany, 07639
      • Neurologie Moritzklinik
• Italy
  • Rome, Italy, 00179
    • Fondazione Santa Lucia

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Subacute stroke patients (5-45 days after stroke) with thromboembolic non-hemorrhagic subcortical or cortical, first clinically overt stroke will be included. Moderate to moderately severe upper-extremity hemiparesis, defined as an Upper Extremity Fugl-Meyer score (UEFMA) between 20 and 58 (inclusive).

Exclusion Criteria:

• pre-existing large lesions (> 1.5 cm maximum diameter) in a brain area that belongs to the anatomically established sensorimotor/premotor system
• progressive stroke
• completely lesioned hand knob area of M1 affected if no motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS) are present
• bilateral motor impairment
• florid alcohol and/or drug abuse
• florid severe psychiatric illness (e.g. schizophrenia)
• severe language disturbances that prevents the patient to give informed consent or inhibit adequate scoring because of insufficient understanding of scoring introductions
• tumor diseases with a life expectancy less than one year
• increased intracranial pressure
• polyneuropathy and/or ischemic peripheral disease if the sensorimotor functions of the upper extremities are affected clinically relevant
• severe cognitive deficits (MMSE ≤ 23)
• pregnancy
• contraindication for MRI or TMS

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: Anodal tDCS; Direct Current (DC)-Stimulator to apply tDCS + Training	Device: DC-Stimulator to apply tDCS; Anodal tDCS (20 minutes) stimulation will be applied once a day in combination with standardized upper extremity rehabilitative training
Sham Comparator: Sham tDCS; Direct Current (DC)-Stimulator to apply Sham tDCS (Placebo) + Training	Device: DC-Stimulator to apply Sham tDCS; Sham stimulation will be applied once a day in combination with standardized upper extremity rehabilitative training

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper Extremity Fugl-Meyer-Assessment (UEFMA)	standardized test of upper extremity function	1-7 days after the end of the intervention

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Upper Extremity Fugl-Meyer-Assessment (UEFMA)	standardized test of upper extremity function	30±10 days after the intervention
Upper Extremity Fugl-Meyer-Assessment (UEFMA)	standardized test of upper extremity function	90±20 days after the intervention
Upper Extremity Fugl-Meyer-Assessment (UEFMA) | Long-term outcome	standardized test of upper extremity function	12±1 months after the intervention
Action Research Arm Test (ARAT)	standardized tests of upper extremity function	1-7 days after the end of the intervention
Action Research Arm Test (ARAT)	standardized tests of upper extremity function	30±10 days after the intervention
Action Research Arm Test (ARAT)	standardized tests of upper extremity function	90±20 days after the intervention
Action Research Arm Test (ARAT) | Long-term outcome	standardized tests of upper extremity function	12±1 months after the intervention
Nine Hole Peg Test (NHPT)	standardized test to assess fine motor skills	1-7 days after the end of the intervention
Nine Hole Peg Test (NHPT)	standardized test to assess fine motor skills	30±10 days after the intervention
Nine Hole Peg Test (NHPT)	standardized test to assess fine motor skills	90±20 days after the intervention
Nine Hole Peg Test (NHPT) | Long-term outcome	standardized test to assess fine motor skills	12±1 months after the intervention
Stroke Impact Scale (SIS)	questionnaire is to evaluate how stroke has impacted health and life of patients	1-7 days after the end of the intervention
Stroke Impact Scale (SIS)	questionnaire is to evaluate how stroke has impacted health and life of patients	30±10 days after the intervention
Stroke Impact Scale (SIS)	questionnaire is to evaluate how stroke has impacted health and life of patients	90±20 days after the intervention
Stroke Impact Scale (SIS) | Long-term outcome	questionnaire is to evaluate how stroke has impacted health and life of patients	12±1 months after the intervention
Box-and-Block Test	standardized test to assess fine motor skills	1-7 days after the end of the intervention
Box-and-Block Test	standardized test to assess fine motor skills	30±10 days after the intervention
Box-and-Block Test	standardized test to assess fine motor skills	90±20 days after the intervention
Box-and-Block Test	standardized test to assess fine motor skills	12±1 months after the intervention
Grip Force	dynamometer-based test to assess grip strength	1-7 days after the end of the intervention
Grip Force	dynamometer-based test to assess grip strength	30±10 days after the intervention
Grip Force	dynamometer-based test to assess grip strength	90±20 days after the intervention
Grip Force	dynamometer-based test to assess grip strength	12±1 months after the intervention

Collaborators and Investigators

• Sponsor: Universitätsklinikum Hamburg-Eppendorf
• Investigators: Principal Investigator: Christian Gerloff, Prof. Dr., Department of Neurology, University Medical Center Hamburg-Eppendorf

Publications and helpful links

General Publications

• Elsner B, Kugler J, Pohl M, Mehrholz J. Transcranial direct current stimulation (tDCS) for improving activities of daily living, and physical and cognitive functioning, in people after stroke. Cochrane Database Syst Rev. 2020 Nov 11;11(11):CD009645. doi: 10.1002/14651858.CD009645.pub4.
• Bikson M, Grossman P, Thomas C, Zannou AL, Jiang J, Adnan T, Mourdoukoutas AP, Kronberg G, Truong D, Boggio P, Brunoni AR, Charvet L, Fregni F, Fritsch B, Gillick B, Hamilton RH, Hampstead BM, Jankord R, Kirton A, Knotkova H, Liebetanz D, Liu A, Loo C, Nitsche MA, Reis J, Richardson JD, Rotenberg A, Turkeltaub PE, Woods AJ. Safety of Transcranial Direct Current Stimulation: Evidence Based Update 2016. Brain Stimul. 2016 Sep-Oct;9(5):641-661. doi: 10.1016/j.brs.2016.06.004. Epub 2016 Jun 15.
• Bonstrup M, Schulz R, Schon G, Cheng B, Feldheim J, Thomalla G, Gerloff C. Parietofrontal network upregulation after motor stroke. Neuroimage Clin. 2018 Mar 7;18:720-729. doi: 10.1016/j.nicl.2018.03.006. eCollection 2018.
• Buch ER, Santarnecchi E, Antal A, Born J, Celnik PA, Classen J, Gerloff C, Hallett M, Hummel FC, Nitsche MA, Pascual-Leone A, Paulus WJ, Reis J, Robertson EM, Rothwell JC, Sandrini M, Schambra HM, Wassermann EM, Ziemann U, Cohen LG. Effects of tDCS on motor learning and memory formation: A consensus and critical position paper. Clin Neurophysiol. 2017 Apr;128(4):589-603. doi: 10.1016/j.clinph.2017.01.004. Epub 2017 Jan 29.
• Wessel MJ, Zimerman M, Timmermann JE, Heise KF, Gerloff C, Hummel FC. Enhancing Consolidation of a New Temporal Motor Skill by Cerebellar Noninvasive Stimulation. Cereb Cortex. 2016 Apr;26(4):1660-7. doi: 10.1093/cercor/bhu335. Epub 2015 Jan 20.
• Pisegna JM, Kaneoka A, Pearson WG Jr, Kumar S, Langmore SE. Effects of non-invasive brain stimulation on post-stroke dysphagia: A systematic review and meta-analysis of randomized controlled trials. Clin Neurophysiol. 2016 Jan;127(1):956-968. doi: 10.1016/j.clinph.2015.04.069. Epub 2015 May 9.
• Bonstrup M, Krawinkel L, Schulz R, Cheng B, Feldheim J, Thomalla G, Cohen LG, Gerloff C. Low-Frequency Brain Oscillations Track Motor Recovery in Human Stroke. Ann Neurol. 2019 Dec;86(6):853-865. doi: 10.1002/ana.25615. Epub 2019 Oct 30.
• NETS Trial Collaboration Group. A multicenter, randomized, double-blind, placebo-controlled trial to test efficacy and safety of transcranial direct current stimulation to the motor cortex after stroke (NETS): study protocol. Neurol Res Pract. 2022 Apr 18;4(1):14. doi: 10.1186/s42466-022-00171-2.

Study record dates

Study Major Dates

• Study Start (Actual): July 1, 2009
• Primary Completion (Anticipated): June 30, 2021
• Study Completion (Anticipated): September 30, 2021

Study Registration Dates

• First Submitted: May 12, 2009
• First Submitted That Met QC Criteria: May 27, 2009
• First Posted (Estimate): May 28, 2009

Study Record Updates

• Last Update Posted (Actual): May 4, 2021
• Last Update Submitted That Met QC Criteria: May 3, 2021
• Last Verified: May 1, 2021

More Information

Terms related to this study

• Keywords: stroke; TDCS; motor recovery; cortical plasticity; non-invasive cortical stimulation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Stroke
• Other Study ID Numbers: NETS Trial

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data sharing is planned after main publication of results.
• IPD Sharing Time Frame: Within 24 months after main publication.
• IPD Sharing Access Criteria: Personal login into UKE data repository.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP