Perspectives on the Combined Use of Electric Brain Stimulation and Perceptual Learning in Vision

Round 1

Reviewer 1 Report

This is an interesting and timely review of the literature on the effect of transcranial electrical stimulation combined with perceptual learning (training) on performance in visual tasks. The different variants of tES are described (tDCS, tACS and tRNS) and the findings for these different stimulation techniques are discussed in conjunction with their ability to enhance VPL. The major take home points is that tES can be coupled with VPL to facilitate VPL and the transfer of VPL effects to other stimuli or locations in the visual field. I have a few suggestions for minor revision (see below).

1) The section on "Mechanisms of tES" appears to me to be too speculative. What sort of evidence is there for these intracellular changes during/after prolonged tDCS? The Messer paper cited seems to be a more general review of neuronal functioning and not specific for the effects of tDCS or tACS. There seems to be a lack of animal models of the effects of tES combined with VPL. This section would benefit by a more candid statement regarding the lack of experimental findings concerning the exact mechanisms of tES.

2) The author should note either in the Introduction or in the Discussion sections that his review is based on published studies. So there is a bias in the database, since mostly studies with positive results in support of the combined effects of VPL and tES are reported in these studies. Many other unpublished studies may have been conducted, but their results do not find any differences between tES and sham. Some mention of this publication bias would be needed to better frame the findings reported.

3) The description of the Herpich et al. (2019) study needs more work. First the study shows that tDCS coupled with VPL (coherent motion detection task) has basically no effect. The study also shows a specific benefit of tRNS in n = 3 stroke patients with hemifield or quadrant deficits that is not apparent for tDCS or sham control conditions. It would also be important to note that the Herpich et al 2019 study had a 6-month follow-up that pointed to long-lasting changes in RDK thresholds for stimuli presented in the blind field. Please add a more detailed description of the results of this important study.

4) The Melnick et al. (2020) study should also be described in more detail or omitted. The paper has not been peer-reviewed and is only available in BioArXiv. The study is basically presenting the results of simulations of the effects of noise. Please elaborate here.

5) There seems to be a lack of follow-up studies on the long-term effects of VPL for visual rehabilitation. As mentioned above, the Herpich et al 2019 study had a 6-month follow-up that pointed to long-lasting changes. Which other studies have looked at performance 6 months after the end of training or later? Can tES have a benefit to prolong the effects of VPL?

6) A table of all of the studies reviewed would be helpful. In the table the method of stimulation, type of VPL, subject sample and size, results supportive of tES effect, etx. could be listed. This would provide the reader at a glance insights into the overall basis for a role of tES in promoting VPL.

Author Response

Responses to the reviewer's comments are provided below in bold.

This is an interesting and timely review of the literature on the effect of transcranial electrical stimulation combined with perceptual learning (training) on performance in visual tasks. The different variants of tES are described (tDCS, tACS and tRNS) and the findings for these different stimulation techniques are discussed in conjunction with their ability to enhance VPL. The major take home points is that tES can be coupled with VPL to facilitate VPL and the transfer of VPL effects to other stimuli or locations in the visual field. I have a few suggestions for minor revision (see below).

We thank the reviewer for the positive overview of the manuscript. We provided a point-by-point response below.

1) The section on "Mechanisms of tES" appears to me to be too speculative. What sort of evidence is there for these intracellular changes during/after prolonged tDCS? The Messer paper cited seems to be a more general review of neuronal functioning and not specific for the effects of tDCS or tACS. There seems to be a lack of animal models of the effects of tES combined with VPL. This section would benefit by a more candid statement regarding the lack of experimental findings concerning the exact mechanisms of tES.

We appreciate the reviewer’s comments. In this new version of the manuscript we toned down the section accordingly, removing some of the speculations on the mechanisms and explicitly acknowledging current limitations.

2) The author should note either in the Introduction or in the Discussion sections that his review is based on published studies. So there is a bias in the database, since mostly studies with positive results in support of the combined effects of VPL and tES are reported in these studies. Many other unpublished studies may have been conducted, but their results do not find any differences between tES and sham. Some mention of this publication bias would be needed to better frame the findings reported.

We agree with the reviewer. We added a sentence at the end of the ‘Open questions’ section to address this point.

3) The description of the Herpich et al. (2019) study needs more work. First the study shows that tDCS coupled with VPL (coherent motion detection task) has basically no effect. The study also shows a specific benefit of tRNS in n = 3 stroke patients with hemifield or quadrant deficits that is not apparent for tDCS or sham control conditions. It would also be important to note that the Herpich et al 2019 study had a 6-month follow-up that pointed to long-lasting changes in RDK thresholds for stimuli presented in the blind field. Please add a more detailed description of the results of this important study.

We thank the reviewer for the comment. We updated the description of the paper accordingly.

4) The Melnick et al. (2020) study should also be described in more detail or omitted. The paper has not been peer-reviewed and is only available in BioArXiv. The study is basically presenting the results of simulations of the effects of noise. Please elaborate here.

We thank the reviewer for pointing this out. We decided to remove the reference, as the paper has not been peer-reviewed as yet.

5) There seems to be a lack of follow-up studies on the long-term effects of VPL for visual rehabilitation. As mentioned above, the Herpich et al 2019 study had a 6-month follow-up that pointed to long-lasting changes. Which other studies have looked at performance 6 months after the end of training or later? Can tES have a benefit to prolong the effects of VPL?

The reviewer makes here an excellent point. We decided to add it as point of discussion in the ‘Open questions’ section of the paper.

6) A table of all of the studies reviewed would be helpful. In the table the method of stimulation, type of VPL, subject sample and size, results supportive of tES effect, etx. could be listed. This would provide the reader at a glance insights into the overall basis for a role of tES in promoting VPL.

We thank the reviewer for the suggestion. The new version of the manuscript provides a table summarizing the studies that used brain stimulation in combination with perceptual learning training.

Reviewer 2 Report

In this perspective study, the author covered carefully the history and mechanisms behind the visual perceptual learning and non-invasive electrical stimulations and their combined effects. The author further expanded the study to cover relevant aspects concerning the use of these techniques. The objective of the study is relevant and I have only a few comments/suggestions as follow:

1. Recent studies have shown dosage-dependent non-linear effects of tES with intensity, duration, repetition rate, and age/gender as contributing factors. I would suggest including/referring to those in the relevant sections ‘Optimize stimulus and stimulation intensity’ and ‘individual difference’. See e.g. Johnson et al., Science Advances. 2020. Mosayebi Samani et el,. Cortex. 2019. Agboada et al., Brain Stimulation. 2020. Hassanzahraee et al., Brain Stimulation. 2020. Also, the effects of electrode configuration might also contribute. For example, Antal and colleagues found enhanced amplitudes with anodal, and reduced amplitudes with cathodal tDCS with the return electrode positioned anterior of the target electrode (Antal et al., IOVS. 2004), while Accornero et al. describe conversed effects with the return electrode placed posterior from the target, and thus antagonistic directionality of the EFs in the anterior-posterior plane (Accornero et al., Exp. Brain Res. 2007).
2. I would suggest expanding the ‘individual differences’ section. Potential contributors might be physical (anatomy), physiological (genetic, sex- and age-dependency), and functional (psychological and behavioral processes) factors. For example, see: Kasten et al., Nature Communication. 2019. Mosayebi-Samani et al., Brain Stimulation. 2021. Huang et al., Clinical Neurophysiology. 2017.
3. One might be important in future studies is to go toward integrative approach by combining neuroimaging, brain stimulation, and behavioral paradigms. See e.g. Beli aeva et al., Nature Communication. 2021. This might be discussed in the Future Direction section.

Author Response

Responses to the reviewer's comments are provided below in bold.

1. Recent studies have shown dosage-dependent non-linear effects of tES with intensity, duration, repetition rate, and age/gender as contributing factors. I would suggest including/referring to those in the relevant sections ‘Optimize stimulus and stimulation intensity’ and ‘individual difference’. See e.g. Johnson et al., Science Advances. 2020. Mosayebi Samani et el,. Cortex. 2019. Agboada et al., Brain Stimulation. 2020. Hassanzahraee et al., Brain Stimulation. 2020. Also, the effects of electrode configuration might also contribute. For example, Antal and colleagues found enhanced amplitudes with anodal, and reduced amplitudes with cathodal tDCS with the return electrode positioned anterior of the target electrode (Antal et al., IOVS. 2004), while Accornero et al. describe conversed effects with the return electrode placed posterior from the target, and thus antagonistic directionality of the EFs in the anterior-posterior plane (Accornero et al., Exp. Brain Res. 2007).

We greatly appreciate the reviewer’s suggestions of these papers that we appear to have missed in our review of the literature.

1. I would suggest expanding the ‘individual differences’ section. Potential contributors might be physical (anatomy), physiological (genetic, sex- and age-dependency), and functional (psychological and behavioral processes) factors. For example, see: Kasten et al., Nature Communication. 2019. Mosayebi-Samani et al., Brain Stimulation. 2021. Huang et al., Clinical Neurophysiology. 2017.

We followed the reviewer’s suggestion and slightly expanded this section.

1. One might be important in future studies is to go toward integrative approach by combining neuroimaging, brain stimulation, and behavioral paradigms. See e.g. Beli aeva et al., Nature Communication. 2021. This might be discussed in the Future Direction section.

We thank the reviewer for this suggestion. We mentioned the paper in the Conclusions section.