Association of Long-Term Speech Therapy and Neuromodulation in Primary Progressive Aphasia: Lessons from a Case Report

Round 1

Reviewer 1 Report

 

Summary and overall impression

The manuscript reports data from an individual with Primary Progressive Aphasia (PPA), who underwent several rounds of language treatment combined with transcranial direct current stimulation (tDCS) over the left inferior frontal gyrus (IFG). Treatment was provided in a hospital setting for the first 5 months, and then continued at the participant’s home for 3 additional months. Changes in language performance over time were measured using several measures, including picture naming and connected speech (picture description). Changes in mood were also monitored throughout the study, using a dedicated questionnaire. Results showed that language performance remained stable throughout the study (i.e., there was no evidence of decline, which is expected in PPA), and that mood improved following tDCS sessions.

 

For the most part, the manuscript is well-written. The introduction provides an adequate background and the clinical presentation of the case, as well as the description of the neuropsychological and language profile are excellent. Results are clearly presented and the manuscript is easy to follow. The topic is also of great interest and extremely relevant to clinical practice, given the scarce availability of language treatment studies in PPA. Unfortunately, the experimental design suffers from some major shortcomings that prevent to draw any conclusions about the efficacy of tDCS on language or neuropsychological performance, as well as on changes in mood.

 

Major comments

• The major issue with the study design lies in the lack of a sham condition, which prevents to unequivocally ascribe any of the changes in (or lack thereof) language performance and/or mood to tDCS. Because of the placebo effect, it is plausible that the changes in mood reported in the manuscript result from the participant’s perception of receiving brain stimulation, and not from the stimulation itself.
• The other major issue is the choice of the time points for the main analysis, which – if I understand correctly – compares language performance two months prior to starting treatment with tDCS and one month after treatment ended. Within this time frame, the participant underwent periods of time in which language treatment was provided in conjunction with tDCS and periods of time in which language treatment was provided in absence of tDCS (with different frequency than during the tDCS phase). In addition, during this time frame, treatment was provided in a hospital setting for 5 months and at home for 3 months. It is therefore impossible to disentangle the effects of tDCS from those of language treatment, which we have to assume it would be effective.
• Page 2, lines 80-84: The study aims and predictions could be more clearly stated and better justified. What is the rationale behind expecting that changes in mood and behavior would be longer lasting than changes in language performance? Also, what were the predictions for brain morphometry?
• Page 4, lines 152-165: How much time was spent on each of the language tasks provided during stimulation? The authors should also explain why the language tasks provided AFTER the stimulation different than the ones provided DURING the stimulation.
• Page 5, lines 166-171: how long were the rest sessions?
• Page 5, lines 200-204: it is unclear how changes in motivation/adherence to treatment were quantified.
• Page 6, line 205: at what point in time was the mood questionnaire administered?
• Page 7, lines 244-245: it is unclear at what points of treatment these measures were administered.

 

Minor comments

• Page 2, line 62: Although this is true for many studies, some (see Thompson et al., 2021) have provided speech therapy for longer periods of time.
• Page 2, line 68: significative -> significant
• Page 2, line 70: I am not sure this statement is justified. The meta-analysis of tDCS and TMS studies in aphasia by Norise & Hamilton (2017) has shown that the effect sizes of language treatment combined with tDCS and TMS were very similar.
• Page 3, line 111: discrete -> moderate
• Page 3, line 116: MLU is not too informative about syntactic complexity. For example, MLU could be high because of coordination in the utterance (she went to the store and got fruits and vegetables and milk and cereals).
• Page 4, Figure 1: it would be helpful to indicate in the Figure (and also clarify in the text) which language measures were administered at the different time points, and to clarify which time points are used for the main analysis
• Page 4, line 149: the statement is inconsistent with the previous sentence (line 136): “LA received a twenty-minute tDCS stimulation while doing multiple types of language exercises”.
• Page 5, line 174: it would be helpful to clarify at which time points the reported dates correspond.
• Page 6, line 233: word retrieving -> word retrieval

Author Response

Please see the attachement 

Author Response File: Author Response.pdf

Reviewer 2 Report

The authors present a case study of a patient with primary progressive aphasia (non-fluent variant) that underwent treatment with tDCS and language therapy for 8 months. The patient was evaluated with a language protocol and MRI (T1) before and after the treatment. Adherence was evaluated. The main limitation of the study is the lack of a control group. However, the study is interesting, because there are no cases published in the literature with PPA treated for long periods of time, and this type of case reports may be useful to generate hypothesis for future clinical trials.

I have some suggestions for improvement:

1) I suggest adding some additional papers in the Introduction about the effect of non-invasive brain stimulation in PPA: 10.3233/JAD-210566; 10.1016/j.nicl.2018.05.023 .

2) Language assessment at baseline should be further specified. For instance, what task was used to elicit spontaneous speech?

3) What is the rationale for the tDCS protocol? (three rounds of alternating tDCS and rest phases). Please address the different maintenaince protocols (not limited to aphasia) (for instance, daily or weekly stimulations for the follow-up) and the potential application to PPA (pros and cons) in the Discussion section.

4) Please specify further details about the training protocol. Were the tasks used in the assessment related with tasks used in training?

Author Response

Please see the attachement under "Reviewer 2"  answers section. 

Author Response File: Author Response.pdf

Reviewer 3 Report

Paper revision

 

 Association of long-term speech therapy and neuromodulation 2 in primary progressive aphasia: lessons from a case report

Introduction

Line 52-53 – “The rationale behind their application in aphasia rehabilitation is that both methods modulate synaptic plasticity which in turn facilitates language recovery or maintenance.”  Please be more accurate: tDCS indeed facilitates synaptic plasticity while TMS directly causes action potential.

In general, brief explanation of traditional language therapy that is used for PPA and specifically for nfvPPA is needed.

In addition, please add a short paragraph about the brain area you stimulated with tDCS (left IFG) and its connection to the language deterioration in PPA.

 

Material and Methods

Was the study approved by ethic committee? If yes it should be written. It should be mentioned that LA signed a consent forum approving his willing to participate in the study.

Medical history and clinical examination – It is unclear what was LA mother tongue? English? French? Was he Bi-lingual?

Figure 1: Please delete the dates- it is confusing and does not contribute to the paper.

Line 147- Why did you located the cathode on the right inferior frontoparietal gyrus? It may have possible influence there. A figure of the current distribution could add a lot.

Line 148- Why did you choose 1 mA, most of the studies use at least 1.5 mA

Line 159- How were the items chosen? Were they balanced for frequency of use or for words length?

In general? Did you used sham tDCS as a control condition? If not it should at least be mentioned and explained.

Statistical analysis

Should not contain predication and  hypothesis.

Line 226- "In" should be "influence"?

 

Discussion

 

Line 335-337- Which brain area was stimulated in the described studies?

 

It should be noted that further research studying patients with the opposite order (first only speech therapy and then speech therapy combined with tDCS) is needed to reassure your findings.

 

Author Response

Please see the attachement under the "Reviewer 3" answer section.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The authors have amended the manuscript to incorporate some of my comments, which is very much appreciated. However, the main issue of the manuscript lies in the experimental design, which does not allow to disentangle the effect of real tDCS from a placebo effect, or the effect of real tDCS from that of traditional speech therapy. The study shows that the language profile of the participant did not change over the course of the study, which is a positive outcome for individuals with PPA, but - in the absence of a control participant who did not receive the same course of treatment - this is not very informative, unfortunately. Changes in mood, which were mostly evaluated qualitatively, may also have been due to a placebo effect, as acknowledged by the authors in the limitation section. 

In view of the extant literature on the effects of tDCS on language performance in PPA (see the work by Tsapkini and co-workers), which provides evidence for the efficacy of tDCS using controlled experimental designs, I am unsure about the scientific contribution of the present manuscript. Therefore, unfortunately, I cannot recommend this manuscript for publication. 

Author Response

Please see the attachement

Author Response File: Author Response.pdf