Digital Approaches for Managing Brain Fog in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Interventions, Monitoring, and Future Directions

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review article addresses an important and timely topic by synthesizing digital approaches for assessing and managing cognitive dysfunction ("brain fog") in ME/CFS, focusing on tools such as computerized cognitive tests, neuroimaging, mobile apps, wearables, digital symptom trackers, and large-scale EHR/ML analyses. The manuscript is generally well written, logically structured, and grounded in a clearly described literature search, and it highlights both the promise of digital health tools and the current fragmentation and scarcity of ME/CFS‑specific evidence. However, the article sometimes reads more like an extended narrative of included studies than a critical, conceptually organized review, and several aspects require strengthening, including sharpening the conceptual framework around “brain fog”, clarifying methodological rigor and limitations, and improving consistency and precision in terminology, formatting, and referencing.

Major Concerns

1. The introduction provides a strong biomedical context (neuroinflammation, mitochondrial dysfunction, connectivity changes, interoception) for cognitive dysfunction in ME/CFS but does not clearly define how “brain fog” is operationalized in the digital literature reviewed (e.g., subjective cognitive fatigue vs. objective neuropsychological deficits vs. attentional/processing speed measures). In the Results, diverse cognitive outcomes (reaction time, working memory, attention, self‑reported cognitive failures, Reddit narratives) are grouped together without a framework that distinguishes cognitive domains or measurement levels (subjective, behavioral, neuroimaging), making it harder for readers to interpret how digital tools map onto specific aspects of brain fog.

2. Although PRISMA is cited and a flowchart is provided, the Methods section reads more like a descriptive narrative than a rigorously delimited review protocol, and several important details are missing (e.g., exact search dates per database, whether reference lists were hand‑searched, whether study quality or risk of bias was assessed). Inclusion/exclusion criteria are specified, but there is no explicit description of how inter‑reviewer agreement was quantified, nor is there any appraisal of methodological quality or risk of bias of the 16 included studies, which limits the strength of the conclusions.

3. The article convincingly shows that ME/CFS‑specific digital work on cognition is sparse, but it would benefit from explicitly positioning itself against prior reviews on ME/CFS cognitive impairment and digital biomarkers of fatigue. Currently, the narrative mainly contrasts the small ME/CFS literature with a large generic “cognition + digital health” body (>23,000 records) without detailing how this review adds novel insights beyond being a catalog of 16 studies.

4. The Results section provides a detailed study‑by‑study description (especially in Table 1) but offers limited cross‑study synthesis regarding strengths, limitations, and consistency of findings (e.g., which digital cognitive tools show the most robust discrimination, which settings are feasible for longitudinal monitoring, where findings are contradictory or underpowered). The Discussion references general limitations (small samples, heterogeneity, lack of validation) but does not adequately differentiate stronger from weaker evidence or highlight where claims need caution (e.g., single‑case multi‑omics study, pilot SGB cohort, protocol‑only telerehabilitation trial).

5. The stated aim focuses on digital tools relevant to "assessment and management" of brain fog, but the narrative devotes extensive space to pathophysiological background and to digital approaches not directly targeting cognition (e.g., some trials in chronic fatigue or persistent physical symptoms more broadly). Conversely, practical aspects of digital implementation for ME/CFS patients (burden, accessibility, pacing, risk of symptom exacerbation) and specific implications for clinical practice receive comparatively less emphasis.

6. Table 1 is rich and informative but dense; some column headings and content are long, and abbreviations are sometimes used before being clearly defined in the table or footnotes. Figure 2 is conceptually useful but currently text‑heavy; the legend is brief and does not fully explain categories or the criteria for assigning tools to each component of the diagram.

Minor Concerns

1. The introduction is comprehensive but somewhat lengthy, with a detailed discussion of neuroinflammation, mitochondrial dysfunction, connectivity, and interoception that occasionally drifts beyond what is necessary to motivate a digital‑health‑focused review. Some pharmacological and mind–body treatment details (e.g., AEO, specific supplements, detailed mind–body intervention mechanisms) feel tangential to the main focus on digital tools for brain fog.

2. The manuscript alternates between describing itself as a "descriptive review" and invoking systematic review elements (PRISMA, structured search), which may confuse readers about its status and expectations. Terms such as "digital" are used very broadly in the search strategy (e.g., including tele, apps, wearable, sensor, EHR) but in the Results, only a subset of these modalities is actually recovered, which could be better acknowledged.

3. Overall language quality is good, but there are occasional long, multi‑clause sentences that reduce readability, especially in the Introduction and Discussion. A few minor typographical or stylistic issues appear, such as inconsistent hyphenation ("eHealth" vs. "e‑Health", "on line" vs. "online" if present) and some instances of awkward phrasing (e.g., “while, a systematic review…”).

4. The abbreviations list is extensive and helpful, but some abbreviations appear first in the text before being defined, and a few standard terms may not need to be listed (e.g., ATP), whereas key digital tools (e.g., CPT3™, BrainCheck, DANA) are handled inconsistently as abbreviations vs. product names. There may also be opportunities to reduce redundancy between the abbreviations list and the main text.

5. The reference list appears comprehensive and relevant, but there are minor inconsistencies in formatting, such as spacing, punctuation, and journal name presentation, and at least one URL appears to have a missing "h" in "https" in the European Commission document ("ttps://..."). It is not fully clear whether all citations are ordered strictly by order of appearance, and some recent or closely related digital‑health cognition references outside ME/CFS (used as comparators) might further contextualize the 23,000‑publication figure mentioned in the Discussion.

6. In Table 1, some entries include very long “Cognition digital assessment‑related results and conclusions” text that could be shortened or made more telegraphic for better readability, and not all studies explicitly indicate whether the digital approach directly assessed cognition vs. being more general (e.g., social support, symptom tracking). Figure labels and numbering (Figure 1 PRISMA, Figure 2 conceptual overview) appear correct, but adding brief panel labels or clarifying text in Figure 2 might help readers quickly understand its structure.

7. The manuscript broadly follows MDPI/Life formatting, but minor inconsistencies may remain in section headings (e.g., capitalization), spacing around section breaks, and presentation of funding/ethics statements. There are also a few truncated or hyphen‑broken words due to PDF line breaks (e.g., “in‑novation”, if imported from another source) that should be corrected in the final manuscript file.

Author Response

This review article addresses an important and timely topic by synthesizing digital approaches for assessing and managing cognitive dysfunction ("brain fog") in ME/CFS, focusing on tools such as computerized cognitive tests, neuroimaging, mobile apps, wearables, digital symptom trackers, and large-scale EHR/ML analyses. The manuscript is generally well written, logically structured, and grounded in a clearly described literature search, and it highlights both the promise of digital health tools and the current fragmentation and scarcity of ME/CFS specific evidence. However, the article sometimes reads more like an extended narrative of included studies than a critical, conceptually organized review, and several aspects require strengthening, including sharpening the conceptual framework around “brain fog”, clarifying methodological rigor and limitations, and improving consistency and precision in terminology, formatting, and referencing.

Response: Thank you for your valuable and constructive comments. We appreciate the reviewer’s positive evaluation of the relevance and overall structure of the manuscript. The suggestions have been carefully considered and have helped us to improve the clarity and coherence of the review. In response, we have strengthened the conceptual framework surrounding “brain fog,” clarified methodological aspects of the literature search and study selection, and improved the consistency and precision of terminology, formatting, and referencing throughout the manuscript. Please find the detailed responses to each comment below. All corresponding revisions have been incorporated into the revised manuscript and are highlighted in the resubmitted version.

Major Concerns

Comments 1: The introduction provides a strong biomedical context (neuroinflammation, mitochondrial dysfunction, connectivity changes, interoception) for cognitive dysfunction in ME/CFS but does not clearly define how “brain fog” is operationalized in the digital literature reviewed (e.g., subjective cognitive fatigue vs. objective neuropsychological deficits vs. attentional/processing speed measures). In the Results, diverse cognitive outcomes (reaction time, working memory, attention, self‑reported cognitive failures, Reddit narratives) are grouped together without a framework that distinguishes cognitive domains or measurement levels (subjective, behavioral, neuroimaging), making it harder for readers to interpret how digital tools map onto specific aspects of brain fog.

Response 1: We appreciate this important comment. While biomedical mechanisms such as neuroinflammation, mitochondrial dysfunction, and altered connectivity may contribute to cognitive impairment in ME/CFS, the lived experience of brain fog reflects a dynamic interaction between biological vulnerability, psychological factors (e.g., cognitive fatigue perception, stress), and contextual influences (e.g., activity pacing, environmental demands). Therefore, a biopsychosocial perspective is particularly relevant when evaluating digital tools, which often target symptom monitoring, behavioral adaptation, and functional support rather than underlying pathophysiology.

In the revised manuscript, we have clarified the operationalization of “brain fog” and now conceptualize it as a multidimensional construct encompassing (1) subjective cognitive symptoms reported by patients, (2) objectively measurable cognitive performance deficits objective neuropsychological performance, and (3) neurobiological or physiological correlates (Materials and Methods section, lines: 247-288).

We have also reorganized the Results section to classify studies according to cognitive domain (e.g., processing speed, attention, working memory), measurement level (subjective, behavioral, neurobiological), and digital function (assessment, monitoring, intervention). A revised summary table has been added to improve clarity and interpretability (lines: 387-527).

Comments 2: Although PRISMA is cited and a flowchart is provided, the Methods section reads more like a descriptive narrative than a rigorously delimited review protocol, and several important details are missing (e.g., exact search dates per database, whether reference lists were hand searched, whether study quality or risk of bias was assessed). Inclusion/exclusion criteria are specified, but there is no explicit description of how inter reviewer agreement was quantified, nor is there any appraisal of methodological quality or risk of bias of the 16 included studies, which limits the strength of the conclusions. 

Response 2: We appreciate this important observation. In the revised manuscript, we have

clarified that this is a structured descriptive review conducted according to PRISMA-informed principles rather than a full systematic review with meta-analysis.

Materials and Methods section has been revised and supplemented by the conceptualization issues (lines: 247-288).

Manuscripts published up to 31 December 2025, in English, were considered for inclusion, and no start date restriction was applied. References were identified using the search and selection tools available within the respective databases.

Titles and abstracts were independently screened by three reviewers to assess eligibility based on the predefined inclusion and exclusion criteria. Articles deemed potentially relevant proceeded to full-text review. Discrepancies between reviewers were resolved through discussion and consensus.

A formal assessment of methodological quality or risk of bias was not performed, following the nature of a descriptive review and ineligibility of grey literature and un-published manuscripts in the present review. Given the heterogeneity of designs, a quantitative risk-of-bias summary was not performed; instead, quality considerations were integrated narratively into the Results and Discussion.

Comment 3: The article convincingly shows that ME/CFS specific digital work on cognition is sparse, but it would benefit from explicitly positioning itself against prior reviews on ME/CFS cognitive impairment and digital biomarkers of fatigue. Currently, the narrative mainly contrasts the small ME/CFS literature with a large generic “cognition + digital health” body (>23,000 records) without detailing how this review adds novel insights beyond being a catalog of 16 studies.

Response 3: Thank you for this helpful suggestion. We have revised the Discussion to more explicitly position the present review in relation to prior reviews on cognitive impairment in ME/CFS and on digital biomarkers in fatigue-related conditions. In particular, we now clarify that the novelty of this review lies in its focus on digital approaches specifically targeting cognitive dysfunction (“brain fog”) in ME/CFS, and in the systematic mapping of digital tools across three functional domains: assessment, monitoring, and intervention. The Discussion now also highlights how digital methods may address limitations identified in earlier non-digital reviews, such as the need for objective cognitive metrics, longitudinal symptom tracking, and remote assessment capabilities (lines: 626-721).

Comment 4: The Results section provides a detailed study by study description (especially in Table 1) but offers limited cross study synthesis regarding strengths, limitations, and consistency of findings (e.g., which digital cognitive tools show the most robust discrimination, which settings are feasible for longitudinal monitoring, where findings are contradictory or underpowered). The Discussion references general limitations (small samples, heterogeneity, lack of validation) but does not adequately differentiate stronger from weaker evidence or highlight where claims need caution (e.g., single case multi omics study, pilot SGB cohort, protocol only telerehabilitation trial).

Response 4: We agree and have restructured the Results to emphasize cross-study synthesis rather than sequential description. The revised section now compares digital modalities in terms of discriminatory strength, feasibility for longitudinal monitoring, scalability, and methodological robustness. We explicitly identify which cognitive domains show the most consistent findings (e.g., processing speed and sustained attention) and highlight areas where evidence remains limited or underpowered (lines: 388-528).

Regarding the Discussion, we agree and have revised the Discussion to better differentiate levels of evidence across the included studies (lines: 660-721). The revised text now explicitly distinguishes exploratory or preliminary findings (e.g., single-case multi-omics analyses, pilot cohorts, or protocol-only studies) from approaches with more robust empirical support, such as computerized cognitive testing and neuroimaging-based digital analyses. Additional statements of caution have been introduced where appropriate to avoid overinterpretation of early-stage or small-sample studies.

Comment 5: The stated aim focuses on digital tools relevant to "assessment and management" of brain fog, but the narrative devotes extensive space to pathophysiological background and to digital approaches not directly targeting cognition (e.g., some trials in chronic fatigue or persistent physical symptoms more broadly). Conversely, practical aspects of digital implementation for ME/CFS patients (burden, accessibility, pacing, risk of symptom exacerbation) and specific implications for clinical practice receive comparatively less emphasis.

Response 5: Thank you for this important comment. We agree that the practical implications of digital approaches for individuals with ME/CFS, including issues related to patient burden, accessibility, pacing, and the potential risk of symptom exacerbation, are important considerations. In the revised manuscript, these aspects are more explicitly addressed and synthesized in the Discussion section, where the practical challenges of implementing digital tools in ME/CFS populations are discussed alongside their potential benefits. In addition, the Discussion highlights the distinction between digital approaches specifically targeting cognitive assessment and those addressing broader symptom domains, and considers their implications for clinical practice and future research. These revisions aim to provide a more balanced interpretation of the reviewed literature in relation to the stated aim of the review.

Comment 6: Table 1 is rich and informative but dense; some column headings and content are long, and abbreviations are sometimes used before being clearly defined in the table or footnotes. Figure 2 is conceptually useful but currently text heavy; the legend is brief and does not fully explain categories or the criteria for assigning tools to each component of the diagram.

Response 6: Thank you for this helpful comment. In order to improve clarity and readability, we have revised the presentation of the tables and figures. The original Table 1, which contained detailed descriptions of the included studies and digital tools, has been moved to the Appendix (Table A1) to retain the full information while reducing the density of the main text. In its place, a new Table 1, “Classification of digital approaches to cognitive dysfunction in ME/CFS according to cognitive domain, measurement level, and digital function,” has been introduced in the main manuscript to provide a clearer and more concise conceptual overview.

In addition, the previous Figure 1 has been replaced with a new figure (Figure 3, “Biopsychosocial conceptualization of brain fog in ME/CFS and digital approaches used for its assessment and management”), presented in the Discussion section. This revised figure provides a clearer conceptual framework and visually summarizes the multidimensional nature of brain fog in ME/CFS together with the roles of different digital approaches in its assessment and monitoring. 

Minor Concerns

Comment 1: The introduction is comprehensive but somewhat lengthy, with a detailed discussion of neuroinflammation, mitochondrial dysfunction, connectivity, and interoception that occasionally drifts beyond what is necessary to motivate a digital health focused review. Some pharmacological and mind–body treatment details (e.g., AEO, specific supplements, detailed mind–body intervention mechanisms) feel tangential to the main focus on digital tools for brain fog.

Response 1: Thank you for this thoughtful comment. We agree that the Introduction contains an extensive overview of the biological and clinical background of ME/CFS. However, we intentionally retained the discussion of key pathophysiological mechanisms, including neuroinflammation, mitochondrial dysfunction, altered brain connectivity, and interoceptive processes, as these elements provide the conceptual context for understanding the multidimensional nature of cognitive dysfunction (“brain fog”) in ME/CFS. Since the present review examines digital approaches to the assessment and management of cognitive symptoms, a brief overview of these mechanisms was considered important for framing why multidimensional and potentially integrative digital assessment strategies may be relevant in this condition.

At the same time, in response to the reviewer’s suggestion, we carefully revised the Introduction to reduce content that was less directly related to the central topic. In particular, nutritional and supplementation approaches have been removed.

Comment 2: The manuscript alternates between describing itself as a "descriptive review" and invoking systematic review elements (PRISMA, structured search), which may confuse readers about its status and expectations. Terms such as "digital" are used very broadly in the search strategy (e.g., including tele, apps, wearable, sensor, EHR) but in the Results, only a subset of these modalities is actually recovered, which could be better acknowledged.

Response 2: We agree that clearer positioning was needed. The revised manuscript now explicitly defines the review as a structured descriptive review with systematic search and transparent selection procedures. We clarify that broad digital health terminology was intentionally used to capture the interdisciplinary scope of the field; however, only a subset of modalities directly addressing cognitive dysfunction met inclusion criteria. This is now explicitly acknowledged as reflecting the early and heterogeneous state of the literature.

This review was conducted as a structured descriptive review following PRISMA-informed principles to ensure transparency in search strategy, screening, and study selection. Given the heterogeneity of study designs, digital modalities, and outcome measures, and the absence of comparable quantitative endpoints, a formal systematic review with meta-analysis was not feasible. The primary objective was to provide an integrative and critical synthesis of digital approaches to the assessment and management of brain fog in ME/CFS and related conditions rather than quantitative effect estimation.

The search strategy intentionally employed broad digital health terminology (e.g., telehealth, wearable devices, mobile applications, sensors, electronic health records, machine learning) to capture the evolving and interdisciplinary nature of digital cognitive assessment and management. However, only a subset of these modalities met inclusion criteria when specifically linked to cognitive dysfunction or brain fog in ME/CFS and related conditions. This reflects both the emerging nature of the field and the limited number of studies directly addressing cognition using digital platforms.

Comment 3: Overall language quality is good, but there are occasional long, multi‑clause sentences that reduce readability, especially in the Introduction and Discussion. A few minor typographical or stylistic issues appear, such as inconsistent hyphenation ("eHealth" vs. "e‑Health", "on line" vs. "online" if present) and some instances of awkward phrasing (e.g., “while, a systematic review…”).

Response 3: Thank you for your suggestions. The corrections have been made. The MDPI Authors Service performed the English editing.

Comment 4: The abbreviations list is extensive and helpful, but some abbreviations appear first in the text before being defined, and a few standard terms may not need to be listed (e.g., ATP), whereas key digital tools (e.g., CPT3™, BrainCheck, DANA) are handled inconsistently as abbreviations vs. product names. There may also be opportunities to reduce redundancy between the abbreviations list and the main text.

Response 4: Thank you for your suggestions. The corrections have been made.

Comment 5: The reference list appears comprehensive and relevant, but there are minor inconsistencies in formatting, such as spacing, punctuation, and journal name presentation, and at least one URL appears to have a missing "h" in "https" in the European Commission document ("ttps://..."). It is not fully clear whether all citations are ordered strictly by order of appearance, and some recent or closely related digital health cognition references outside ME/CFS (used as comparators) might further contextualize the 23,000 publication figure mentioned in the Discussion.

Response 5: Thank you for your suggestions. The corrections have been made. We have expanded the contextual discussion to include examples from the broader literature on digital cognitive assessment and digital biomarkers in neurological and fatigue-related conditions, which helps clarify how digital approaches have been applied more extensively outside ME/CFS. These additions provide a clearer comparison and reinforce the observation that digital cognitive research in ME/CFS remains relatively underdeveloped.

Comment 6: In Table 1, some entries include very long “Cognition digital assessment related results and conclusions” text that could be shortened or made more telegraphic for better readability, and not all studies explicitly indicate whether the digital approach directly assessed cognition vs. being more general (e.g., social support, symptom tracking). Figure labels and numbering (Figure 1 PRISMA, Figure 2 conceptual overview) appear correct, but adding brief panel labels or clarifying text in Figure 2 might help readers quickly understand its structure.

Response 6: Thank you for your suggestions. The corrections have been made.

Comment 7: The manuscript broadly follows MDPI/Life formatting, but minor inconsistencies may remain in section headings (e.g., capitalization), spacing around section breaks, and presentation of funding/ethics statements. There are also a few truncated or hyphen‑broken words due to PDF line breaks (e.g., “in‑novation”, if imported from another source) that should be corrected in the final manuscript file.

Response 7: Thank you for your suggestions. The corrections have been made. A hyphenated word occurs when a sentence is transferred from one MDPI template section to another.

 

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript presents a descriptive review of digital approaches applied to the assessment and management of cognitive impairment (“brain fog”) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The topic is timely and relevant, particularly given the growing interest in digital health technologies and the persistent difficulty of objectively assessing cognitive symptoms in ME/CFS. The manuscript is generally well referenced and follows a structured approach. However, in its current form, it presents several major limitations that substantially reduce its scientific added value. I therefore recommend major revisions.

Major comments

• Lack of critical analysis and overly descriptive approach

Throughout the manuscript, the literature is presented in a largely descriptive and sequential manner, with limited critical synthesis. This is particularly evident in the Results section (Section 2, approximately lines 223-336) and its subsections (Sections 2.1-2.6), where studies are summarized one after another, often following a one-reference–one-paragraph or one-reference–one-sentence structure. While this approach provides an overview of the field, it does not sufficiently compare studies, assess methodological quality, discuss potential biases, or highlight contradictions and limitations across the literature. As a result, the review reads more as a catalogue of existing studies than as an integrative or analytical review. A stronger critical perspective is needed, including explicit discussion of study quality, validation status of digital tools, and relative strengths and weaknesses of the different approaches.

• Limited originality and insufficient differentiation from existing reviews

Although the focus on digital approaches to brain fog in ME/CFS is relevant, the originality of the manuscript remains limited in the context of existing literature. Cognitive impairment and brain fog in ME/CFS have already been extensively reviewed from clinical, neuropsychological, and mechanistic perspectives. Cortes Rivera et al. (DOI: 10.3390/diagnostics9030091) provided a comprehensive overview of ME/CFS, including cognitive dysfunction and its neuroimmune and neuroendocrine underpinnings. Aoun Sebaiti et al. (DOI: 10.1038/s41598-021-04764-w) conducted a systematic review and meta-analysis defining the cognitive profile of ME/CFS based on objective assessments and highlighting the heterogeneity and methodological limitations of the field. More recently, Bansal et al. (DOI: 10.3390/ijms26051896) focused specifically on cognitive dysfunction in ME/CFS, discussing aetiology, neuroimaging findings, and potential therapeutic avenues. In addition, Denno et al. (DOI: 10.1016/j.tins.2025.01.003) critically examined the concept of “brain fog” across medical conditions, including ME/CFS, and highlighted important conceptual ambiguities between subjective symptoms and objective cognitive measures.

In comparison, the present manuscript largely revisits established observations and applies them to a digital context without clearly demonstrating how this perspective advances current knowledge. The authors should more explicitly differentiate their review from existing work by clarifying the specific added value of digital approaches, for example through a critical comparison with non-digital methods, a hierarchy of digital tools according to their level of validation and clinical relevance, or a discussion of how digital technologies may address limitations identified in previous reviews. Without clearer differentiation, the added value of a new review on this topic remains insufficiently justified.

• Conceptual breadth and lack of a unifying framework

The review covers a very broad range of digital approaches, including computerized cognitive testing, neuroimaging with advanced analytics, mobile applications, social media analyses, electronic health record–based studies, and digitally delivered interventions (Sections 2.1-2.6). While this breadth may appear comprehensive, the absence of a unifying conceptual framework makes it difficult to extract clear conclusions. The manuscript would benefit from a clearer distinction between digital tools used for assessment, monitoring, and intervention, as well as a discussion of which approaches are specific to ME/CFS and which are borrowed from other conditions. As currently written, the term “digital approaches” remains overly broad and insufficiently defined.

• Presentation and readability of Table 1

Table 1 (lines ~242-244 and following pages) is extremely dense and difficult to read in its current portrait format. Several cells contain extensive textual descriptions, which limits readability and reduces the practical usefulness of the table. Presenting this table in landscape format, dividing it into multiple tables, or moving a detailed version to supplementary materials while retaining a simplified summary table in the main manuscript would substantially improve clarity.

• Disproportionate Materials and Methods section for a descriptive review

The inclusion of a Materials and Methods section is acceptable for a structured descriptive review following PRISMA principles (Section 4, lines ~433-504). However, the level of methodological detail appears disproportionate given the relatively small number of included studies (n = 16) and the absence of quantitative synthesis. Moreover, the methodological rigor described in this section is not fully reflected in the analytical depth of the Results and Discussion. The authors should consider streamlining this section and ensuring closer alignment between the methodological description and the level of critical analysis presented.

• Writing style and presentation issues

The manuscript is generally clear, but the writing style is highly uniform and formulaic across sections with different purposes, including the Introduction, Results, and Discussion. This uniformity, combined with repeated generic phrasing, reduces readability and gives the impression of limited authorial interpretation. In addition, the use of bold text in conceptual figures and summaries (Figure 2, lines ~421-432) is unusual for this journal and should be reconsidered. Several parts of the Discussion (Section 3, lines ~337-432) reiterate results rather than providing higher-level synthesis or critical interpretation.

Minor comments

• Some digital approaches included in the review, such as social media analyses and virtual environments (e.g., Section 2.4, lines ~301-315), would benefit from clearer justification of their relevance to cognitive assessment or management rather than general patient experience.
• The Discussion would benefit from a more explicit separation between summary of findings and interpretation, as several paragraphs currently restate results without advancing conceptual insight (Section 3, lines ~337-399).
• Minor inconsistencies in terminology and phrasing could be addressed to improve overall clarity and coherence, although these do not substantially affect the scientific content.

Conclusion

In summary, while the manuscript addresses an important and timely topic, it currently lacks the critical depth, analytical structure, and originality expected of a review article in this journal. Substantial revisions are required to strengthen the critical appraisal of the literature, clarify the added value relative to existing reviews, and improve clarity and readability. I therefore recommend major revisions.

Author Response

This manuscript presents a descriptive review of digital approaches applied to the assessment and management of cognitive impairment (“brain fog”) in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The topic is timely and relevant, particularly given the growing interest in digital health technologies and the persistent difficulty of objectively assessing cognitive symptoms in ME/CFS. The manuscript is generally well referenced and follows a structured approach. However, in its current form, it presents several major limitations that substantially reduce its scientific added value. I therefore recommend major revisions.

Response: Thank you for your valuable and thoughtful comments. We appreciate the reviewer’s recognition of the relevance and timeliness of the topic addressed in this manuscript. We have carefully considered the concerns raised regarding the scientific added value of the review. In response, we have revised the manuscript to further clarify the conceptual framework, strengthen the synthesis of the reviewed literature, and improve the presentation and consistency of the methodological and analytical aspects. Please find our detailed point-by-point responses below. All corresponding revisions have been incorporated into the revised manuscript and are highlighted in the resubmitted version.

Major comments

Comments 1: Lack of critical analysis and overly descriptive approach

Throughout the manuscript, the literature is presented in a largely descriptive and sequential manner, with limited critical synthesis. This is particularly evident in the Results section (Section 2, approximately lines 223-336) and its subsections (Sections 2.1-2.6), where studies are summarized one after another, often following a one-reference–one-paragraph or one-reference–one-sentence structure. While this approach provides an overview of the field, it does not sufficiently compare studies, assess methodological quality, discuss potential biases, or highlight contradictions and limitations across the literature. As a result, the review reads more as a catalogue of existing studies than as an integrative or analytical review. A stronger critical perspective is needed, including explicit discussion of study quality, validation status of digital tools, and relative strengths and weaknesses of the different approaches.

Response 1: We thank the reviewer for this constructive critique. We agree that stronger critical analysis improves the manuscript.

We have strengthened the critical perspective throughout the Results and Discussion. The revised manuscript now explicitly addresses study design limitations (e.g., small samples, cross-sectional designs), validation status of digital tools, potential biases (e.g., reliance on self-report), and inconsistencies between subjective and objective findings. This revision shifts the manuscript from a descriptive overview toward an integrative and analytical review.

Accordingly, we revised the Discussion section (lines: 388-528) and, in Discussion, we have: 

• Added explicit discussion of study design limitations (e.g., small sample sizes, cross-sectional predominance, limited validation).
• Assessed the methodological robustness of digital cognitive tools (e.g., established neuropsychological batteries vs. exploratory ML phenotyping).
• Discussed potential biases.
• Highlighted contradictions or inconsistencies, including variability between subjective and objective cognitive findings.
• Clarified where evidence is preliminary versus more robust.

These revisions ensure the review functions as an integrative and critical analysis rather than a descriptive inventory.

Comments 2: Limited originality and insufficient differentiation from existing reviews

Although the focus on digital approaches to brain fog in ME/CFS is relevant, the originality of the manuscript remains limited in the context of existing literature. Cognitive impairment and brain fog in ME/CFS have already been extensively reviewed from clinical, neuropsychological, and mechanistic perspectives. Cortes Rivera et al. (DOI: 10.3390/diagnostics9030091) provided a comprehensive overview of ME/CFS, including cognitive dysfunction and its neuroimmune and neuroendocrine underpinnings. Aoun Sebaiti et al. (DOI: 10.1038/s41598-021-04764-w) conducted a systematic review and meta-analysis defining the cognitive profile of ME/CFS based on objective assessments and highlighting the heterogeneity and methodological limitations of the field. More recently, Bansal et al. (DOI: 10.3390/ijms26051896) focused specifically on cognitive dysfunction in ME/CFS, discussing aetiology, neuroimaging findings, and potential therapeutic avenues. In addition, Denno et al. (DOI: 10.1016/j.tins.2025.01.003) critically examined the concept of “brain fog” across medical conditions, including ME/CFS, and highlighted important conceptual ambiguities between subjective symptoms and objective cognitive measures.

In comparison, the present manuscript largely revisits established observations and applies them to a digital context without clearly demonstrating how this perspective advances current knowledge. The authors should more explicitly differentiate their review from existing work by clarifying the specific added value of digital approaches, for example through a critical comparison with non-digital methods, a hierarchy of digital tools according to their level of validation and clinical relevance, or a discussion of how digital technologies may address limitations identified in previous reviews. Without clearer differentiation, the added value of a new review on this topic remains insufficiently justified.

Response 2: Thank you very much for your suggestions. The first three mentioned references were already investigated in the review:

[6] Aoun Sebaiti, M.; Hainselin, M.; Gounden, Y.; Sirbu, C. A.; Sekulic, S.; Lorusso, L.; Nacul, L.; Authier, F. J. (2022). Systematic review and meta-analysis of cognitive impairment in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Scientific reports 2022, 12(1), 2157. https://doi.org/10.1038/s41598-021-04764-w

[10] Cortes Rivera, M.; Mastronardi, C.; Silva-Aldana, C.T.; Arcos-Burgos, M.; Lidbury, B.A. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Comprehensive Review. Diagnostics 2019, 9, 91. https://doi.org/10.3390/diagnostics9030091

[15] Bansal, A.S.; Seton, K.A.; Brooks, J.C.W.; Carding, S.R. Cognitive Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome-Aetiology and Potential Treatments. International journal of molecular sciences 2025, 26(5), 1896. https://doi.org/10.3390/ijms26051896

and we appreciated including the fourth reference for conceptualization process in the Materials and Methods section [21].

Additionally, we have revised the Discussion to clarify the added value of a digital perspective. Specifically, the revised manuscript now highlights how digital technologies may address limitations of traditional approaches by enabling remote assessment, ecologically valid monitoring of fluctuating symptoms, integration of patient-reported outcomes with objective data streams, and potential digital biomarker development. We also developed the Table 2 Conceptual synthesis of digital approaches for assessment and management of ME/CFS to introduce a conceptual view of digital tools according to their level of validation and clinical applicability, which helps clarify their relative strengths and potential roles in future research and care.

Comment 3: Conceptual breadth and lack of a unifying framework

The review covers a very broad range of digital approaches, including computerized cognitive testing, neuroimaging with advanced analytics, mobile applications, social media analyses, electronic health record–based studies, and digitally delivered interventions (Sections 2.1-2.6). While this breadth may appear comprehensive, the absence of a unifying conceptual framework makes it difficult to extract clear conclusions. The manuscript would benefit from a clearer distinction between digital tools used for assessment, monitoring, and intervention, as well as a discussion of which approaches are specific to ME/CFS and which are borrowed from other conditions. As currently written, the term “digital approaches” remains overly broad and insufficiently defined.

Response 3: Thank you for this important comment. We agree that the breadth of digital approaches covered in the review may make it challenging to identify a clear conceptual structure. In response, we have strengthened the conceptual synthesis of the reviewed literature in the Discussion section, where digital approaches are now more explicitly organized into three functional domains: (1) digital tools for cognitive assessment, (2) digital platforms for longitudinal monitoring and data integration, and (3) digitally mediated interventions or rehabilitation approaches. This structure aims to provide a clearer framework for interpreting the diverse methodologies.

In addition, the Discussion now more clearly distinguishes between digital approaches that have been specifically investigated in ME/CFS populations and those that are adapted from broader digital health research in related conditions, where methodological parallels may still offer useful insights. To further support this conceptual clarification, a new Table 1 (“Classification of digital approaches to cognitive dysfunction in ME/CFS according to cognitive domain, measurement level, and digital function”) and a revised conceptual Figure 3 (“Biopsychosocial conceptualization of brain fog in ME/CFS and digital approaches used for its assessment and management”) have been included to visually summarize these relationships. These revisions aim to provide a clearer interpretative framework while preserving the descriptive scope of the review.

Comment 4: Presentation and readability of Table 1

Table 1 (lines ~242-244 and following pages) is extremely dense and difficult to read in its current portrait format. Several cells contain extensive textual descriptions, which limits readability and reduces the practical usefulness of the table. Presenting this table in landscape format, dividing it into multiple tables, or moving a detailed version to supplementary materials while retaining a simplified summary table in the main manuscript would substantially improve clarity.

Response 4: Thank you for this helpful comment. In order to improve clarity and readability, we have revised the presentation of the tables. The original Table 1, which contained detailed descriptions of the included studies and digital tools, has been moved to the Appendix (Table A1) to retain the full information while reducing the density of the main text. In its place, a new Table 1, “Classification of digital approaches to cognitive dysfunction in ME/CFS according to cognitive domain, measurement level, and digital function,” has been introduced in the main manuscript to provide a clearer and more concise conceptual overview. 

Comment 5: Disproportionate Materials and Methods section for a descriptive review

The inclusion of a Materials and Methods section is acceptable for a structured descriptive review following PRISMA principles (Section 4, lines ~433-504). However, the level of methodological detail appears disproportionate given the relatively small number of included studies (n = 16) and the absence of quantitative synthesis. Moreover, the methodological rigor described in this section is not fully reflected in the analytical depth of the Results and Discussion. The authors should consider streamlining this section and ensuring closer alignment between the methodological description and the level of critical analysis presented.

Response 5: Thank you for this thoughtful comment. We acknowledge that the level of methodological detail in the Materials and Methods section may appear extensive in relation to the relatively small number of included studies and the descriptive nature of the review. However, we intentionally retained a structured methodological description to ensure transparency and reproducibility of the literature search and study selection process, particularly given the interdisciplinary scope of the topic and the heterogeneity of digital approaches addressed in the review.

In response to the reviewer’s suggestion, we have revised the manuscript to improve the alignment between the methodological description and the analytical synthesis presented in the Results and Discussion sections. Specifically, the Discussion now provides a clearer conceptual organization of the findings by grouping the identified digital approaches into three functional domains: digital tools for cognitive assessment, digital platforms for longitudinal monitoring and data integration, and digitally mediated interventions or rehabilitation approaches. These revisions aim to strengthen the interpretative synthesis of the reviewed literature while maintaining methodological transparency consistent with PRISMA-informed descriptive reviews.

Comment 6: Writing style and presentation issues

The manuscript is generally clear, but the writing style is highly uniform and formulaic across sections with different purposes, including the Introduction, Results, and Discussion. This uniformity, combined with repeated generic phrasing, reduces readability and gives the impression of limited authorial interpretation. In addition, the use of bold text in conceptual figures and summaries (Figure 2, lines ~421-432) is unusual for this journal and should be reconsidered. (15) Several parts of the Discussion (Section 3, lines ~337-432) reiterate results rather than providing higher-level synthesis or critical interpretation.

Response 6: Thank you for this observation. We have substantially revised the Results and Discussion to reduce repetition of study-level findings and to emphasize cross-study synthesis, methodological considerations, and conceptual implications. The revised text now focuses more strongly on interpreting patterns across studies, identifying evidence gaps, and outlining priorities for future research.

In addition, the previous Figure 1 has been replaced with a new figure (Figure 3, “Biopsychosocial conceptualization of brain fog in ME/CFS and digital approaches used for its assessment and management”), presented in the Discussion section. This revised figure provides a clearer conceptual framework and visually summarizes the multidimensional nature of brain fog in ME/CFS together with the roles of different digital approaches in its assessment and monitoring.

Minor comments

Comment 1: Some digital approaches included in the review, such as social media analyses and virtual environments (e.g., Section 2.4, lines ~301-315), would benefit from clearer justification of their relevance to cognitive assessment or management rather than general patient experience.

Response 1: Thank you for the comments. We have clarified the rationale for including these approaches. Social media analyses are now positioned as contributing to understanding the phenomenology and heterogeneity of “brain fog,” while virtual platforms are discussed in terms of functional adaptation and cognitive load management. We explicitly distinguish these approaches from formal neuropsychological assessment and clarify their relevance within a broader biopsychosocial and management-oriented framework.

Comment 2: The Discussion would benefit from a more explicit separation between summary of findings and interpretation, as several paragraphs currently restate results without advancing conceptual insight (Section 3, lines ~337-399).

Response 2: We agree and have restructured the Discussion accordingly. The revised section now includes clearer subsections separating (i) summary of key findings, (ii) interpretation and comparison with existing literature, and (iii) implications for future research and clinical practice. This restructuring improves readability and ensures that the interpretive discussion is more clearly distinguished from the descriptive summary of results.

Comment 3: Minor inconsistencies in terminology and phrasing could be addressed to improve overall clarity and coherence, although these do not substantially affect the scientific content.

Response 3: Thank you for your suggestions. The corrections have been made for those that have been identified. The MDPI Authors Service performed the English editing.

Conclusion: In summary, while the manuscript addresses an important and timely topic, it currently lacks the critical depth, analytical structure, and originality expected of a review article in this journal. Substantial revisions are required to strengthen the critical appraisal of the literature, clarify the added value relative to existing reviews, and improve clarity and readability. I therefore recommend major revisions.

Thank you for your valuable and thoughtful comments!

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I have no more concerns.