Effects of Transcranial Direct Current Stimulation Combined with Physiotherapy on Gait Pattern, Balance, and Functionality in Stroke Patients. A Systematic Review

Round 1

Reviewer 1 Report

In this review paper, the authors synthesize data from 10 research articles reporting the effects of combined physiotherapy and transcranial direct current stimulation (tDCS) in stroke rehabilitation. Gate, balance, and long-term functional effectiveness are examined as outcome measures across studies. Although methodologically sound, the paper suffers from a low N, and little synthesis is made across studies. I have included specific points below that may help for future submissions.  

1. The introduction should include at least a cursory review of the proposed mechanism of the therapeutic effects of tDCS in stroke patients. For example, what polarity should be used (ipsilateral/contralateral to the affected area)? Why is depth important? Each of these issues are mentioned in passing, but none are introduced in detail.
2. At the end of the penultimate paragraph of the introduction, the authors seem to conflate two independent issues. The polarity of current and strength of the electric field are completely independent; however, the authors introduce these topics as if they are the same.
3. In section 2.2, the authors describe the characteristics of studies reviewed for inclusion. However, it would be much more informative to summarize the characteristics of the studies included in the final synthesis. This should be added as another paragraph following the current description.
4. It is interesting that there was an even split between single-session and multi-session tDCS studies. The authors should compare the two types of studies to afford inference about the relative utility of single-session vs multi-session tDCS.
5. The authors should clarify which hemisphere is stimulated (ipsilateral/contralateral to stroke) in each of the studies reviewed.
6. The figure caption for Figure 2 is incorrect.
7. The discussion seems to stop short of synthesis in many instances. For example, what can we infer from the fact that tDCS currents below 2 mA were not successful? What recommendations can be made for future research, given the outcome of this review?

Minor comments:

1. The abbreviation “PT” is not defined.
2. What is meant by “an instrumental process” in the first paragraph of the Methods?
3. The final sentence of paragraph #3 in the discussion seems out of place, or perhaps a sentence is missing?

Author Response

Dear reviewers of Diagnostics,

Thank you for your suggestions and comments. We have made the pertinent modifications in the attached manuscript. We reply to your suggestions in the following text.

Reviewer 1.

1- The introduction should include at least a cursory review of the proposed mechanism of the therapeutic effects of tDCS in stroke patients. For example, what polarity should be used (ipsilateral/contralateral to the affected area)? Why is depth important? Each of these issues are mentioned in passing, but none are introduced in detail.

We have included in the introduction section. We have explored further into some detail, such as the depth of the lower limbs motor representations.

2- At the end of the penultimate paragraph of the introduction, the authors seem to conflate two independent issues. The polarity of current and strength of the electric field are completely independent; however, the authors introduce these topics as if they are the same.

We have corrected the sentence, separating the statement regarding the type of simulation, and the statement regarding the intensity of the current.

3- In section 2.2, the authors describe the characteristics of studies reviewed for inclusion. However, it would be much more informative to summarize the characteristics of the studies included in the final synthesis. This should be added as another paragraph following the current description.

We have made the modification, including section 3.2 as a summary of results at the end of section 3.3

4- It is interesting that there was an even split between single-session and multi-session tDCS studies. The authors should compare the two types of studies to afford inference about the relative utility of single-session vs multi-session tDCS.

In the results section, we have included two different analyzes: the studies that applied a single session and those that applied several treatment sessions, to be consistent with the discussion.

5- The authors should clarify which hemisphere is stimulated (ipsilateral/contralateral to stroke) in each of the studies reviewed.

We have included the information in table 2.

6- The figure caption for Figure 2 is incorrect.

Modified

7-The discussion seems to stop short of synthesis in many instances. For example, what can we infer from the fact that tDCS currents below 2 mA were not successful? What recommendations can be made for future research, given the outcome of this review?

We have included several paragraphs in the discussion as a conclusion for future research.

Minor comments:

1- The abbreviation “PT” is not defined.

The abbreviation “PT” is indicated in the text after “physical therapy”.

2- What is meant by “an instrumental process” in the first paragraph of the Methods?

Thanks, we have modified it, we wanted to say conventional physical therapy.

3- The final sentence of paragraph #3 in the discussion seems out of place, or perhaps a sentence is missing?

Thank you, it is out of place, it has been modified.

Reviewer 2 Report

This is a good manuscript with a clear and well construct methodology. Because of my expertise in SR and MA methodology, I mainly reviewed this part.

I have some comments/remarks:

1/ I am not convinced with the quality of the search strategy. Some terms such as brain cerebral accident, brain vascular accident have not been considered. Building a search strategy is a work that need some expertise and often requires the help of an experimented librarian. For example, if authors had written “((cerebrovascular or cerebral or brain) adj 2 accident)” this would have covered all possible keywords related to stroke. Moreover, it is not clear which terms are subjects’ headings and which ones are not.

2/ Authors are invited to justify their choice for including only English and Spanish literature.

3/ Did the authors published their protocol somewhere (e.g. PROSPERO)? It is highly recommended to make the protocol available.

4/ Did the authors used a software for study selection, removal of duplicates, etc?

5/ Authors are invited to provide a list of the 25 studies rejected at the step of full-text screening with individual reasons of exclusion (this list can be available in Appendices).

6/ Additional search is only composed with the screening of bibliography of included articles. AMSTAR2 quality criteria requires additional techniques to be sure to have a systematic search; For example: investigation of the grey literature, contact with experts, search for protocols published on registries, etc.

Author Response

Dear reviewers of Diagnostics,

Thank you for your suggestions and comments. We have made the pertinent modifications in the attached manuscript. We reply to your suggestions in the following text.

Reviewer 2.

1- I am not convinced with the quality of the search strategy. Some terms such as brain cerebral accident, brain vascular accident have not been considered. Building a search strategy is a work that need some expertise and often requires the help of an experimented librarian. For example, if authors had written “((cerebrovascular or cerebral or brain) adj 2 accident)” this would have covered all possible keywords related to stroke. Moreover, it is not clear which terms are subjects’ headings and which ones are not.

Thank you for the contribution, it will be considered for future searches. The text has been modified, indicating the subjects' headings.

2- Authors are invited to justify their choice for including only English and Spanish literature.

The research group was made up of Spanish-speaking researchers, with knowledge of English, but not other languages, so given that the volume of articles is written mostly in English, they decided to limit the search to these languages.

3 - Did the authors published their protocol somewhere (e.g. PROSPERO)? It is highly recommended to make the protocol available.

We agree with this comment. However, the deadline for registering with PROPERO is higher than the deadline for submitting the manuscript review. Furthermore, Diagnostics is an open access journal, therefore the protocol will be available.

4- Did the authors used a software for study selection, removal of duplicates, etc?

The removal of duplicates works, and the selection of studies was done by hand from the MENDELEY bibliographic manager. To avoid errors, two authors performed the screening independently and a third author was consulted in case of discrepancies.

5- Authors are invited to provide a list of the 25 studies rejected at the step of full-text screening with individual reasons of exclusion (this list can be available in Appendices).

We attach it below. We have included this information in Appendices.

6- Additional search is only composed with the screening of bibliography of included articles. AMSTAR2 quality criteria requires additional techniques to be sure to have a systematic search; For example: investigation of the grey literature, contact with experts, search for protocols published on registries, etc.

Thank you, you are right. For the present review, experts were consulted in addition to searching for protocols published in registries. The gray literature was consulted in search of doctoral theses that answered the research question. We have added it to the text.

Appendices:

Articles excluded in the systematic review:

• Danzl MM, Chelette KC, Lee K, Lykins D, Sawaki L. Brain stimulation paired with novel locomotor training with robotic gait orthosis in chronic stroke: a feasibility study. NeuroRehabilitation, 2013;33(1):67-76. Article excluded because it uses robotic therapy
• Geroin C, Picelli A, Munari D, Waldner A, Tomelleri C, Smania N. Combined transcranial direct current stimulation and robot-assisted gait training in patients with chronic stroke: a preliminary comparison. Clin Rehabi, 25(6):537–48. Article excluded because it uses robotic therapy
• Leon D, Cortes M, Elder J, Kumru H, Laxe S, Edwards DJ, et al. tDCS does not enhance the effects of robot-assisted gait training in patients with subacute stroke. Restor Neurol Neurosci, 2017;35(4):377–84. Article excluded because it uses robotic therapy
• Seo HG, Lee WH, Lee SH, Yi Y, Kim KD, Oh B-M. Robotic-assisted gait training combined with transcranial direct current stimulation in chronic stroke patients: A pilot double-blind, randomized controlled trial. Restor Neurol Neurosci, 2017;35(5):527–36. Article excluded because it uses robotic therapy
• Picelli A, Chemello E, Castellazzi P, Roncari L, Waldner A, Saltuari L, et al. Combined effects of transcranial direct current stimulation (tDCS) and transcutaneous spinal direct current stimulation (tsDCS) on robot-assisted gait training in patients with chronic stroke: A pilot, double blind, randomized controlled trial. Restor Neurol Neurosci, 2015;33(3):357–68. Article excluded because it uses other stimulations (spinal direct current stimulation)
• Picelli A, Brugnera A, Filippetti M, Mattiuz N, Chemello E, Modenese A, et al. Effects of two different protocols of cerebellar transcranial direct current stimulation combined with transcutaneous spinal direct current stimulation on robot-assisted gait training in patients with chronic supratentorial stroke: A single blind, randomized controlled trial. Restor Neurol Neurosci. 2019;37(2):97–107. Article excluded because it uses other stimulations (cerebellar transcranial direct current stimulation)
• Picelli A, Chemello E, Castellazzi P, Filippetti M, Brugnera A, Gandolfi M, et al. Combined effects of cerebellar transcranial direct current stimulation and transcutaneous spinal direct current stimulation on robot-assisted gait training in patients with chronic brain stroke: A pilot, single blind, randomized controlled trial. Restor Neurol Neurosci, 2018;36(2):161–71. Article excluded because it uses other stimulations (cerebellar transcranial direct current stimulation)
• Ang KK, Guan C, Phua KS, Wang C, Zhao L, Teo WP, et al. Facilitating effects of transcranial direct current stimulation on motor imagery brain-computer interface with robotic feedback for stroke rehabilitation. Arch Phys Med Rehabil, 2015;96(3):S79–87. Article excluded because it uses robotic therapy
• Cho HS, Cha HG. Effect of mirror therapy with tDCS on functional recovery of the upper extremity of stroke patients. Journal of physical therapy science, 2015;27(4), 1045-47. Article excluded because it assesses the upper limb
• Zheng X, Schlaug G. Structural white matter changes in descending motor tracts correlate with improvements in motor impairment after undergoing a treatment course of tDCS and physical therapy. Frontiers in human neuroscience, 2015;9, 229. Article excluded because it assesses the upper limb
• Allman C, Amadi U, Winkler AM, Wilkins L, Filippini N, et al. Ipsilesional anodal tDCS enhances the functional benefits of rehabilitation in patients after stroke. Science translational medicine, 2016;8(330),330re1-330re1. Article excluded because it assesses the upper limb
• Rocha S, Silva E, Foerster Á, Wiesiolek C, Chagas AP, et al. The impact of transcranial direct current stimulation (tDCS) combined with modified constraint-induced movement therapy (mCIMT) on upper limb function in chronic stroke: a double-blind randomized controlled trial. Disability and rehabilitation, 2016;38(7), 653-60. Article excluded because it assesses the modified constraint-induced movement therapy
• Cha HK, Ji SG, Kim MK, Chang JS. Effect of transcranial direct current stimulation of function in patients with stroke. Journal of physical therapy science, 2014;26(3), 363-65. Article excluded because it assesses the upper limb
• Tedesco Triccas L, Burridge JH, Hughes AM, Meadmore KL, Donovan-Hall M, Rothwell JC, et al. A qualitative study exploring views and experiences of people with stroke undergoing transcranial direct current stimulation and upper limb robot therapy. Top Stroke Rehabil, 2018;20,1–9. Article excluded because it uses a qualitative design
• Sattler V, Acket B, Raposo N, Albucher JF, Thalamas C, et al. Anodal tDCS combined with radial nerve stimulation promotes hand motor recovery in the acute phase after ischemic stroke. Neurorehabilitation and neural repair, 2015;29(8), 743-54. Article excluded because it uses other stimulations (radial nerve stimulation)
• Ilić NV, Dubljanin-Raspopović E, Nedeljković U, Tomanović-Vujadinović S, Milanović SD, et al. Effects of anodal tDCS and occupational therapy on fine motor skill deficits in patients with chronic stroke. Restorative neurology and neuroscience, 2016;34(6), 935-945. Article excluded because it assesses the upper limb
• Bolognini N, Vallar G, Casati C, Latif LA, El-Nazer R, Williams, et al. Neurophysiological and behavioral effects of tDCS combined with constraint-induced movement therapy in poststroke patients. Neurorehabilitation and neural repair, 2011;25(9), 819-29. Article excluded because it assesses the modified constraint-induced movement therapy
• Flöel A. tDCS-enhanced motor and cognitive function in neurological diseases. Neuroimage, 2014;85, 934-47. Article excluded because it is a systematic review
• Schlaug G, Renga V, Nair D. Transcranial direct current stimulation in stroke recovery. Archives of neurology, 2008;65(12), 1571-1576. Article excluded because it is a systematic review
• Lefaucheur JP, Antal A, Ayache SS, Benninger DH, Brunelin J, Cogiamanian, et al. Evidence-based guidelines on the therapeutic use of transcranial direct current stimulation (tDCS). Clinical Neurophysiology, 2017;128(1),56-92. Article excluded because it is a systematic review
• Ambrosini E, Ferrante S, Ferrigno G, Molteni F, Pedrocchi A. Cycling induced by electrical stimulation improves muscle activation and symmetry during pedaling in hemiparetic patients. IEEE Trans neural Syst Rehabil Eng a Publ IEEE Eng Med Biol Soc. 2012 ;20(3):320–30. Article excluded because it uses other stimulations
• Yotnuengnit P, Bhidayasiri R, Donkhan R, Chaluaysrimuang J, Piravej K. Effects of transcranial direct current stimulation plus physical therapy on gait in patients with Parkinson disease: a randomized controlled trial. American journal of physical medicine & rehabilitation, 2018;97(1), 7-15. Article excluded because it included participants with Parkinson disease
• Grecco LA, Duarte NA, Zanon N, Galli M, Fregni F, Oliveira CS. Effect of a single session of transcranial direct-current stimulation on balance and spatiotemporal gait variables in children with cerebral palsy: a randomized sham-controlled study. Brazilian journal of physical therapy, 2014;18(5), 419-27. Article excluded because it included participants with cerebral palsy
• Kumru H, Murillo N, Benito-Penalva J, Tormos JM, Vidal J. Transcranial direct current stimulation is not effective in the motor strength and gait recovery following motor incomplete spinal cord injury during Lokomat® gait training. Neuroscience letters, 2016;620,143-47. Article excluded because it included participants with Spinal Cord Injury
• Kaski D, Dominguez RO, Allum JH, Islam AF, Bronstein AM. Combining physical training with transcranial direct current stimulation to improve gait in Parkinson’s disease: a pilot randomized controlled study. Clinical rehabilitation, 2014;28(11),1115-24. Article excluded because it included participants with Parkinson disease

Round 2

Reviewer 1 Report

The authors have been responsive to all comments.