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

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.

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.

Anodal tDCS (20 minutes) stimulation will be applied once a day in combination with standardized upper extremity rehabilitative training

Sham stimulation will be applied once a day in combination with standardized upper extremity rehabilitative training

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

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.

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.

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.

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.