The Electromechanical Connectome: Integrating Voltage, Mechanical Nano-Forces, and Subcellular Fluid Phase Dynamics in Human Neural Computation
Fuqiang Wu
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis paper systematically integrates evidence of interactions among multiple physical processes, such as electrical signals, mechanical properties, and phase separation in neurons, proposing an electromechanical connectome framework and, based on this, constructing a multiphysical attractor model to explain the mechanisms of cognition and neurodegenerative diseases. In general, this work is interesting and well-written, however the following points should be corrected by the authors.
1.In recent years, memristors, serving as artificial synapses to connect neurons for building memristive synapse-coupled neural networks, have become a research hotspot. It is suggested that the authors incorporate a supply of related research work in this area.
- The spelling mistakes and grammatical mistakes such as:
1) In the first paragraph of Section 2.1, the sentence “...the movement of charges associated with the gating of the channel does not only come from the movement of positive charges, but also comes from the rearrangement...” should be “comes not only from... but also from...”.
2) In the paper, the terms "micro-domain" and "microdomain" appear multiple times. Are they the same? If so, please maintain a consistent spelling.
Authors should read the paper carefully and correct some minor mistakes.
3.The readability of Figure 1 is currently compromised, making it hard to discern the details. Could you please provide a revised, higher-resolution version?
Author Response
Dear Esteemed Academic Reviewer,
We are grateful for your careful reading of our manuscript and for your thoughtful and constructive comments. We deeply appreciate your recognition of the conceptual intent of the work and your suggestions for improving clarity, completeness, and presentation quality. Your observations have helped us strengthen both the scientific context and the precision of the manuscript.
Comment 1:
In recent years, memristors, serving as artificial synapses to connect neurons for building memristive synapse-coupled neural networks, have become a research hotspot. It is suggested that the authors incorporate a supply of related research work in this area.
Response 1:
We thank the reviewer for this insightful suggestion. We agree that the rapidly expanding field of memristive neuromorphic systems offers an important technological parallel to the multiphysical computational framework proposed in our manuscript. In response, we have incorporated a dedicated paragraph in Section 6 (immediately before Section 7), where we discuss memristive devices as engineered systems in which electrical inputs are coupled to ionic motion, structural rearrangement, and in some cases phase transitions.
Comment 2.1:
In the first paragraph of Section 2.1, the sentence “…does not only come from… but also comes from…” should be corrected to “comes not only from… but also from…”.
Response 2.1:
We appreciate the reviewer’s careful attention to grammatical precision. The sentence has been corrected as suggested to improve clarity and syntactic accuracy. Thank you for identifying this oversight.
Comment 2.2:
In the paper, the terms “micro-domain” and “microdomain” appear multiple times. Are they the same? If so, please maintain a consistent spelling.
Response 2.2:
We thank the reviewer for noting this inconsistency. The terms refer to the same structural concept. To ensure terminological consistency throughout the manuscript, we have standardized the spelling to “microdomain” (without hyphen) in all occurrences.
Comment 2.3:
Authors should read the paper carefully and correct some minor mistakes.
Response 2.3:
We are grateful for this recommendation. The manuscript has been carefully re-read in its entirety, and minor typographical, grammatical, and formatting issues have been corrected to improve overall clarity and readability.
Comment 3:
The readability of Figure 1 is currently compromised. Please provide a revised, higher-resolution version.
Response 3:
We thank the reviewer for pointing this out. Figure 1 has been revised in high-resolution format to ensure full legibility of all labels, interaction pathways, and graphical elements.
Once again, we thank you for your careful and constructive evaluation of our work. Your comments have meaningfully contributed to strengthening the clarity, precision, and interdisciplinary scope of the manuscript.
With respect and appreciation!
Reviewer 2 Report
Comments and Suggestions for AuthorsWhat are the core differences between the electromechanical connectome and traditional neural computing models?
What key roles does liquid-liquid phase separation (LLPS) play in neural computation?
How does the disruption of the electromechanical connectome lead to neurodegenerative diseases, and what are the potential therapeutic targets?
Author Response
Dear Esteemed Academic Reviewer,
We thank you for your thoughtful and conceptually incisive questions. We are particularly grateful for your request to further clarify the distinctions, mechanisms, and translational implications of the electromechanical connectome framework. Your comments have helped us refine the manuscript by making several core arguments more explicit and structurally visible to the reader.
Comment 1:
What are the core differences between the electromechanical connectome and traditional neural computing models?
Response 1:
We appreciate this important request for clarification. In response, we have expanded the Introduction (Section 1) to explicitly contrast the electromechanical connectome framework with traditional neural computing models.
Comment 2:
What key roles does liquid-liquid phase separation (LLPS) play in neural computation?
Response 2:
We are grateful for this opportunity to elaborate on the computational role of LLPS. In the revised manuscript, we have expanded the end of Section 5.2 to explicitly articulate LLPS as a computational primitive rather than solely a structural phenomenon.
Comment 3:
How does the disruption of the electromechanical connectome lead to neurodegenerative diseases, and what are the potential therapeutic targets?
Response 3:
We appreciate this translationally oriented question. In response, we have expanded the final part of Section 7.3 to provide a more explicit mechanistic mapping between multiphysical disruption and neurodegenerative trajectories.
We are grateful for your insightful questions. They have allowed us to clarify foundational distinctions, deepen the mechanistic discussion of LLPS, and more clearly articulate the translational implications of the framework. We believe the manuscript is substantially improved as a result of your careful evaluation.
With respect and appreciation!
Reviewer 3 Report
Comments and Suggestions for AuthorsIn the manuscript titled "The Electromechanical Connectome: Integrating Voltage, Mechanical Nano-Forces, and Subcellular Fluid-Phase Dynamics in Human Neural Computation," the Authors combine data from electrophysiology, mechanobiology, soft matter biophysics, and molecular biology. The authors effectively integrate results from multiple fields (electrophysiology, AFM, cryo-EM, LLPS, microrheology), making the article a valuable reference point for researchers outside of narrow specializations. The concept of the electromechanical connectome and the treatment of neurons as multiphysics systems is original and well-grounded in current research trends. The article is logically organized, and tables organize the complex material. This review can inspire new directions of research, especially in the context of neurodegeneration and biomarkers. To maintain the high quality of the manuscript, the authors are requested to make the following corrections to the manuscript:
• Since this is a review paper, it would be valuable for the reader to know what selection criteria the authors used, what year range the materials were collected for, what keywords were used to filter the search for publications, etc. The reference list shows that most of the cited works are from 2022-2025. It is worth justifying this choice.
• Figure 1 and Figure 2: in their current form, they are difficult to read. The Authors should improve the quality of the graphics, colors, and font size. There is a lot of content presented, and the use of too small a font in the graphics makes it difficult to read. Furthermore, the white font is difficult to read against a light background.
• The authors should pay attention to the proportion of detail in the text. Some sections are very detailed, while others remain rather general.
• The authors should more clearly separate hypotheses from established knowledge.
Author Response
Dear Esteemed Academic Reviewer,
We are grateful for your careful, high-level evaluation of our review and for the constructive specificity of your recommendations. We especially appreciate your emphasis on transparency, visual communication, proportional rigor, and conceptual hygiene dimensions that are essential for an integrative review intended to be useful across disciplinary boundaries. We have revised the manuscript with these priorities in mind, and we believe the clarity and scholarly utility of the article have improved substantially as a result of your guidance.
Comment 1:
Since this is a review paper, it would be valuable for the reader to know what selection criteria the authors used, what year range the materials were collected for, what keywords were used to filter the search for publications, etc. The reference list shows that most of the cited works are from 2022–2025. It is worth justifying this choice.
Response 1:
We thank the reviewer for underscoring the importance of methodological transparency in review articles. In response, we have added a compact but explicit “literature scope and selection strategy” paragraph at the end of Section 1. The added text clarifies that the manuscript was developed as a structured, mechanism-oriented scoping synthesis (rather than a formal systematic review), and it specifies the databases consulted, the iterative refinement of search strings, representative keyword families used to capture both domain-specific and integrative concepts, and the inclusion emphasis on primary experimental studies and quantitatively grounded models that directly measure, infer, or perturb defined physical state variables and link them to electrophysiological, signaling, trafficking, or synaptic outcomes.
Comment 2:
Figure 1 and Figure 2: in their current form, they are difficult to read. The Authors should improve the quality of the graphics, colors, and font size. There is a lot of content presented, and the use of too small a font in the graphics makes it difficult to read. Furthermore, the white font is difficult to read against a light background.
Response 2:
We appreciate this important point and agree that the figures must be legible at standard journal viewing scale, particularly given their role in summarizing dense multiphysics content. We have therefore revised.
Comment 3:
The authors should pay attention to the proportion of detail in the text. Some sections are very detailed, while others remain rather general.
Response 3:
We thank the reviewer for this structural observation.
Comment 4:
The authors should more clearly separate hypotheses from established knowledge.
Response 4:
We are grateful for this recommendation, as it strengthens interpretive clarity. We have revised the manuscript to more explicitly distinguish empirically established findings from integrative hypotheses and model-level extrapolations.
We once again thank you for your rigorous and constructive feedback. Your comments have helped us make the manuscript more transparent, visually accessible, proportionally balanced, and conceptually precise, strengthening its value as a reference for researchers across multiple domains.
With profound respect and appreciation!!!
