Letter to the Editor Response to: Is Transcranial Direct Current Stimulation Really Beneficial for Frontotemporal Dementia? (Published 12-18-2024)

Comment 1

Mini-Mental State Examination (MMSE) roughly captures cognitive deficits and cannot be used to differentiate different cognitive abilities.

Response

We agree that the MMSE has limitations as cited in Devenney and Hodges. ¹ Nevertheless, the MMSE is a widely used index of global cognitive function and has been used to track change over time in many studies of frontotemporal dementia. ² According to studies comparing the MMSE and Montreal Cognitive Assessment (MoCA), both instruments offer similar breadth in the cross-sectional and longitudinal assessment cognitive impairments. ³ However, MoCA scores are consistently lower than MMSE scores, ⁴ suggesting a higher level of difficulty. In addition, MoCA and MMSE scores may differ in individuals with focal distributions of cognitive dysfunction. ⁵ Furthermore, we report several specific cognitive tests in which the patient’s scores improved, including in immediate recall (in RAVLT and WAIS paired associates), syntactic comprehension (SOAP task), and total accurate words in sentence repetition (NACC task). Finally, the tests listed by Dr Finsterer as more comprehensive measures are merely alternatives to the MMSE or MoCA, with the exception of the FAQ which is a bedside measure of functional status. The cognitive/language scales that we used in our case report ⁶ are common in clinical trials with PPA participants (and that can be used in future studies) to assess the effects of tDCS on frontotemporal dementia include: Rey Auditory Verbal Learning Test, digit span forward and backward, Trail Making, WAIS Digit Symbol, Ravens Colored Progressive Matrices, WMS Verbal Paired Associates, semantic and phonemic fluency tasks, Subject Relative, Object Relative, Active and Passive (SOAP) Comprehension Task, spelling to dictation, Pyramids and Palm Trees, Kissing and Dancing, and NACC Sentence Repetition. Other relevant cognitive/language tasks are available from the FTLD Neuropsychological Battery (https://naccdata.org/data-collection/forms-documentation/ftld-3). In addition, functional communication rating scales and discourse measures are indicated to assess generalization of treatment to everyday life. Functional communication scales, completed by individuals with FTLD and their care partners, can provide insights into the successes and challenges experienced in a variety of communication contexts. Many of these scales are designed for stroke aphasia, such as the Communication Effectiveness Index (CETI), ⁷ the Communication Outcome after Stroke (COAST) Scale ⁸ and, the Aphasia Communication Outcome Measure (ACOM). ⁹ The development of a new tool, the Functional Communication Checklist, is underway. ¹⁰ This is intended to capture and track clinically relevant aspects of functional communication of individuals with primary progressive aphasia and may have application to the FTLD population. Spoken and written discourse can be elicited from picture descriptions, story narratives, interviews, and responses to topic prompts which are thought to are thought to reflect communication as it occurs in everyday life. These connected language samples can be analyzed for parts of speech, length of utterance, and content and function words to assess carryover of naming treatments.

Comment 2

The patient received two therapies (behavioral and neuromodulatory) at the same time, therefore it is difficult to assess where the effects come from.

Response

We fully agree with this concern and acknowledged in the discussion of the limitations that our case study had an open-label, single-subject design, and that the results may reflect a combination of the behavioral and neuromodulatory treatments. The neural mechanism of tDCS (i.e., functional coupling between the behavioral task and the area of stimulation) ‘obliges’ a pairing between a behavioral treatment (in our case, cognitive-language therapy) and stimulation of its neural substrate.^11,12 In all our previous work, we have used a sham tDCS condition with a behavioral task to isolate the effects of tDCS.^13-20 In our view, our case study may serve as a springboard for a randomized, double-blind clinical trial, as we pointed out in the Conclusions section.

Comment 3

The single-case study is unsuitable for assessing the effectiveness of a particular therapy.

Response

We fully agree that our study does not provide a definitive demonstration of the efficacy of tDCS for cognitive and behavioral dysfunction in FTD. This was acknowledged in the Conclusions section: “…this study provides a premise for the possible effectiveness of long-term, home-based tDCS in FTD. Rigorous evaluation of tDCS coupled with behavioral intervention in a randomized double-blind design is required to establish the efficacy and clinical utility of tDCS in treating cognitive and behavioral symptoms in FTD, and further investigation is necessary regarding the implementation of home-based tDCS.” Case reports, such as ours, offer detailed descriptions of patients and interventions, which can be foundational for developing randomized clinical trials. In a systematic review, Coemans et al. ²¹ reported that between-subjects and within-subjects study designs are commonly employed to investigate the potential of tDCS to improve language outcomes, or slow down cognitive/language decline, in PPA. In between-subjects designs, participants are enrolled in either active tDCS or sham conditions, whereas in within-subjects designs, participants are enrolled in active and sham conditions in randomized order. An advantage of a within-subjects design is that the effects of tDCS can be compared in the same individual, minimizing individual variability in response to neuromodulation. In previous ¹⁵ and current clinical trials (clinicaltrials.gov NCT03887481, NCT04122001, NCT05386394), we have employed a double-blind, sham-controlled, within-subjects, cross-over design to: 1) investigate whether the benefits of neuromodulation to language-specific areas generalize to other language functions within the language network, while neuromodulation of a domain-general/multiple-demands area generalizes to both domain-general, executive and language functions in high-definition tDCS vs sham conditions, 2) evaluate cognitive and neural effects of word-list learning as modulated by tDCS compared to sham stimulation, and 3) determine whether tDCS (versus sham) paired with naming treatment will improve oral and written naming outcomes. Sample size calculations are based on: (1) the effect size (usually the difference between two groups); (2) the population standard deviation available from pilot data or published studies, (3) the desired power of the experiment to detect the postulated effect; and (4) the significance level. ²² Typical sample sizes in within-subjects crossover studies in PPA is 40-60 participants. We aim to expand the current study with such a design in the future.

Concern 4

Frontotemporal dementia (FTD) is usually associated with familial amyotrophic lateral sclerosis (fALS) and we should know whether any first-degree relatives had any symptoms of motor neuron disease (MND).

Response

The patient and her first-degree relatives did not have symptoms or signs of motor neuron disease. We would also like to note that it has been shown that both familial and non-familial FTD present with the same clinical symptoms, although the distribution of age at onset has been shown to be wider in sporadic cases than in familial cases. ²³

Comment 5

We do not know if the patient had a history of seizures as EEG results are not reported.

Response

Seizures are not part of the time course of FTD, although it may be complicated in the later stages of illness in some cases. We verified that the patient did not have a history of seizures. Three months after study completion, her family reported intermittent episodes of inattention, staring and non-communicativeness. During subsequent 6-day admission to our Epilepsy Monitoring Unit, continuous EEG assessment did not show any epileptiform activity during the behaviors.