DOI: 10.1016/j.isci.2026.115609

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DOI: 10.1016/j.isci.2026.115560

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DOI: 10.1016/j.isci.2026.115560

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DOI: 10.1016/j.isci.2026.115560

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DOI: 10.1016/j.isci.2026.115560

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DOI: 10.1016/j.isci.2026.115560

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DOI: 10.1016/j.isci.2026.115560

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DOI: 10.1016/j.hlife.2026.05.003

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DOI: 10.1016/j.hlife.2026.05.003

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DOI: 10.1016/j.hlife.2026.05.003

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DOI: 10.1016/j.hlife.2026.05.003

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DOI: 10.1016/j.hlife.2026.05.003

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What is this?

Note: This response was posted by the corresponding author to Review Commons. The content has not been altered except for formatting.

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Reply to the reviewers

Please see the uploaded "Response to Reviewers" PDF file which contains figures.

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Referee #2

Evidence, reproducibility and clarity

In the manuscript titled "Multiple Molecular Pathways to Longevity: Opposing Gene Expression Programs Define Distinct Aging Strategies", the authors investigated diverse genetic pathways that contribute to lifespan extension in Caenorhabditis elegans and aimed to identify shared and distinct molecular mechanisms among various longevity mutants. Through comprehensive RNA sequencing of different longevity mutants representing seven distinct pathways, the authors showed that these mutants cluster into three primary groups based on their gene expression profiles. This transcriptomic analysis revealed that while some longevity genes are commonly regulated across multiple pathways, others exhibit opposing expression patterns, suggesting that distinct molecular strategies can lead to increased lifespan. Specifically, they identified a set of 196 genes that are consistently upregulated in most longevity mutants, many of which are involved in innate immunity and stress defense. By performing RNAi-based screening, the authors further validated the functional roles of several candidates, including C08F11.7, ugt-62, and K05C4.9, supporting their contributions to longevity and stress resistance. The authors conclude that longevity is mediated through multiple molecular pathways and provide a public online tool to study these complex transcriptomic landscapes.

Major comments

1. While the authors identified a set of 196 upregulated genes, the rationale for narrowing these down to the three final candidates (C08F11.7, ugt-62, and K05C4.9) is not clearly described. The authors show that genetic inhibition of several genes, including DC2.5, C05B5.5, T07C4.5, and W03B1.7, decreases lifespan in both nuo-6 mutants and wild-type animals. However, the authors did not describe why these additional validated candidates, which also showed significant effects on longevity, were not pursued for further characterization. The authors should explicitly state the criteria used to prioritize these three genes over the other validated genes.
2. The authors conclude that longevity can be mediated by multiple molecular pathways. However, it remains unclear whether these distinct strategies can operate simultaneously or are mutually exclusive. The authors need to test whether lifespan extension in a Group 1 mutant is further enhanced or suppressed by the knockdown of a key Group 2-specific genes. These experiments would help determine these pathways act additively, antagonistically, or as partially redundant survival programs.
3. The authors provide interesting data on overexpression of the three candidate genes. However, whereas C08F11.7 clearly demonstrates both necessity and sufficiency for lifespan extension, overexpression of ugt-62 and K05C4.9 does not independently extend lifespan. To strengthen the manuscript, the authors should expand the discussion of these divergent results and clarify possible explanations.
4. Key citations are missing and the authors should add multiple citations including the following ones. Please cite the following paper and discuss the authors' finding with respect to the related work (Lee et al PMID: 40814218). Add citations in the sentence describing changes in the transcriptome of C. elegans associated with age (Lee et al., PMID: 38508494). Furthermore, please cite papers describing the overviews of survival assay using C. elegans (Kwon et al., PMID: 40436148, Hwang et al., PMID: 40436147).

Minor comments

1. To improve readability, please provide the full names for all abbreviations at their first appearance in the manuscript.
2. Please ensure that the labels in the figures match the text exactly. For instance, if different promoters are used for generating overexpression animals, it may be helpful to indicate the specific promoter in the figure panel or legend for clarity.
3. For all lifespan and stress resistance assays, please include the total number of animals (n) and the number of independent biological replicates (N) in the figure legends to confirm statistical reliability.
4. Please clearly specify the exact developmental stage of the animals used for the survival assays in the Materials and Methods section.

Referees cross-commenting

I also agree with reviewer #1's comments and recommend revision to further improve the manuscript.

Significance

This study provides a systematic, side-by-side transcriptomic comparison of nine genetically distinct long-lived C. elegans mutants, revealing that lifespan extension arises from both shared and opposing gene expression programs. By identifying three distinct longevity groups and demonstrating that key pathways can be modulated in opposite directions to achieve long life, the work challenges the notion of a single universal transcriptional signature of aging. Importantly, functional validation shows that select commonly regulated genes can directly modulate lifespan and stress resistance, highlighting actionable molecular targets for promoting healthy aging.

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Referee #1

Evidence, reproducibility and clarity

Summary

This manuscript by Rudich ZD et al. systematically profiled the transcriptomic changes in nine long-lived C. elegans mutants and presented a careful and informative comparative analysis of these aging-related changes. In addition to these valuable datasets and bioinformatics analyses, the authors performed a large-scale RNAi screen to assess the role of the differentially expressed genes (DEGs) in these mutants and identify several potential targets to promote healthy aging. Moreover, the authors have provided a user-friendly website to examine genes of interest in those longevity mutants from their datasets.

Major comments

The conclusions of this manuscript are generally well supported. The study is also technically sound. Yet, I still have a few concerns that should be carefully addressed.

1. Although I myself believe that the datasets in this study should be more consistent and comprehensive, the authors should perform a data mining analysis of previously reported transcriptomic changes of these mutants or similar mutants in the same longevity pathway and compare the reported changes with their findings to highlight the necessity and advances of this study.
2. This manuscript does not perform any regulon or transcription factor (TF) analyses. TFs are the drivers of the transcriptomic changes and multiple conserved TFs (e.g., daf-16) have already been identified in these pathways. Therefore, it is necessary to examine and compare the regulons/TFs in these new datasets by bioinformatics. Such analyses can: a) provide more information of the driving force of these transcriptomic changes; b) show the role of these known longevity TFs; c) propose new TFs driving longevity; d) support the findings of 'longevity strategies' and 'longevity groups' from the perspective of TFs.
3. osm-5 and daf-2 are categorized into two different groups in this study. Since the longevity of cilia (-) mutants is through daf-16, the same master TF driving daf-2 longevity, please perform further analyses or discussion to clarify this issue.
4. This manuscript focused on genes whose RNAi suppressed the mutants longevity. Please also use bioinformatics to analyze the functions of those whose RNAi extends the mutants longevity, because these genes could tell the health price these mutants pay and help improve ageing interventions by reducing side effects.
5. (OPTIONAL) I strongly suggest a comprehensive comparison of these transcriptomic changes in long-lived mutants with published age-related transcriptomic changes in wild type worms. This comparison will significantly All the suggested analyses are pure bioinformatics and should be realistic to finish in several months.

Minor comments

I also have a few minor comments on data presentation: 1. Please further clarify the analysis of DEGs correlated with lifespan extension in Fig. 2 by a depiction. In Fig. 2C and D, please label data dots from different strains with different colors. 2. In Fig. 3 and S20, please label the percentage of overlapping genes on top of each bars.

Referees cross-commenting

I agree with Reviewer #2's comments and would suggest giving the authors enough time to revise their manuscript.

Significance

Compared to previous transcriptomic analyses of these mutants in differen reports, this study minimized the technical variations and benefitted from the advances in RNA-Seq technology and bioinformatics tools. Therefore, it should provide a more consistent and comprehensive view of the molecular mechanisms underlying the longevity of these mutants. The datasets in this manuscript are valuable to other researchers in the biology of aging.

Meanwhile, since these mutants have been extensively studied, the advance of this study in unknown mechanisms remains limited. Therefore, I would recommend its publication as a 'Resource' article after addressing my concerns.

(I am an expert in the biology of ageing, using C. elegans and mouse as major models.)

Related to first millennium math prize conjecture…

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I have witnessed harassment on social media, my friend was being harassed by a kid at our school and everytime she would block them, they would make a new account. It got to the point where we had to tell the staff at our school.

Ini adalah contoh Greenwashing yang amat nyata,Walaupun menonjolkan kejayaan jualan EV, artikel ini tidak menyertakan maklumat tentang impak alam sekitar sebenar, seperti pengurangan karbon, keberkesanan tenaga, atau keberlanjutan jangka panjang.

Jika identiti baharu ini melanggar hak cipta atau tanda dagangan pihak lain, berpotensi melanggar Akta Tanda Dagangan 1976 , sekaligus menunjukkan legal risk sekaligus menujukkan "Legal Risk" kepada kerajaan dan korporat.

Greenwashing happens when an organisation claims to be environmentally friendly but does not provide enough proof or action to support the claim. In UUM cafés, the “no-plastic” campaign is a positive step because it encourages students to reduce single-use plastic. However, the campaign may become greenwashing if cafés still use plastic cups, food containers, or non-recyclable packaging while promoting themselves as environmentally friendly. Therefore, cafés should provide clearer evidence and specific actions to make the campaign more credible and transparent.

Esto ya no

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Know More: https://callyzer.co/blog/how-to-handle-call-me-later-in-telecalling/

Enforced configuration là cấu hình được hệ thống bắt buộc thực thi bất kể AI quyết định gì.

CLAUDE.md chỉ là text, được đưa vào context window như một tin nhắn.(có thể làm theo, quên, hoặc hiểu sai.)

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На диаграмме не хватает пунктирной стрелки от клиента к серверу Publishing stream

также Unpublish stream лучше заменить на Stop publishing

Метод WebSDK Session.submitBugReport() принимает на вход JSON объект. Не факт, что упаковка вообще поддерживается. Нужно проверить, как работает функционал, и скорректировать описание.

Здесь на диаграмме не хватает пунктирной стрелки от сервера к клиенту Playing stream

stopStream идет только доя PLAYING сессий, для PUBLISHING есть свой хук unPublishStream

На диаграмме выглядит так, что 200 OK в сторону REST клиента уходит (ну или статус задания меняется на DONE) только после срабатывания хука. Необходимо проверить, так это или нет, и, если не так, то скорректировать диграмму

Здесь на диаграмме можно уточнить, что на клиенте вызывается метод Session.startDebug

Этот хук предназначен только для аутентификации https://docs.flashphoner.com/static/WCS53/Streaming_video_functions/Playing_a_video_stream_from_the_server/In_a_player_via_RTSP/#rtsp_playback_authentication_via_rest_hook

URL, имя и другие параметры стрима при этом не меняются. В custom передаются параметры, которые должны проверяться (например, accessKey)

Этот хук предназначен только для аутентификации https://docs.flashphoner.com/static/WCS53/Streaming_video_functions/Playing_a_video_stream_from_the_server/In_a_browser_via_HLS/#hls_playback_authentication_using_rest_hook

URL, имя и другие параметры стрима при этом не меняются. В custom передаются параметры, которые должны проверяться (например, accessKey)

Этот функционал вообще работает? Не помню такого метода в WebSDK, автоматической документации на него тоже нет, нужно проверифицировать

Этот хук работает не только для Websocket (DefaultApp), но и для cdnApp, и для falshStreamingApp. Во всех случаях триггером служит сам факт установки TCP соединения. Поэтому правильнее будет не заостряться именно на Websocket

диаграмма:

1. Open Websoket and sebd connect меняем на TCP connect

Неверно. call - это звонок, инициированный клиентом, а не входящий звонок. См метод WebSDK Call.call()

диаграмма:

1. Стрелка от PBX к серверу SIP INVITE
2. Стрелка от сервера к клиенту Incoming call notification
3. И т.д.

этот функционал вообще работает?

в документации, генерируемой по коду WebSDK, нет метода для отправки такого запроса. нужно проверифицировать, как он должен работать

если это легаси, лучше будет его из документации убрать вообще

диаграмма:

1. Пунктирная стрелка от клиента к серверу Publishing stream
2. POST и 200 OK остаются
3. Notify stream status (PUBLISHING)

это не информационное сообщение, это управление потоком (остановка потока на стороне сервера) документация здесь: https://docs.flashphoner.com/static/WCS53/Streaming_video_functions/Captured_stream_management/Stopping_the_video_stream_on_the_server_side/

нужно скорректировать описание и диаграмму

лучше показать пример остановки стрима: 1. верхняя стрелка оставляем только publishing stream 2. бэкенд отвечает 403 Forbidden 3. от клиента к серверу перечеркнутая стрелка publishing stream 4. от сервера к клиенту стрелка Notify stream status (FAILED)

если приходит 200 OK, сервер ничего с потоком не делает, но если приходит что-то иное (в клиентской доке мы рекомендуем 403, т.к. это ближе всего по смыслу), сервер останавливает медиасессию, клиент получает нотификацию StreamStatusEvent с FAILED

диаграмма:

1. Пунктирная стрелка от клиента к серверу Publishing stream
2. Пунктирная стрелка от сервера ко второму клиенту Playing stream
3. Стрелка от паблишера к серверу Mute stream audio
4. Стрелка от сервера к паблишеру audioMuted
5. POST /apps/DefaultApp/StreamEvent к бэкенду и т.д.

Вообще, зеленый квадратик желательно расшифровывать во всех случаях

Стрелка audioMuted должна быть от сервера к зрителю, а не к паблишеру

Claude не разобрался, откуда этот хук берется. надо разобраться и поправить формулировку и диаграмму

исходным событием должен быть вызов Session.startDebug() на стороне клиента (WebSDK). возможно, этот функционал уже и не работает, нужно проверифицировать.

ConnectionStatusEvent содержит разный состав полей для различных кейсов: WebRTC, Flash, SIP

и кейса Status там точно нет

рекомендуется протестировать вручную и посмотреть, как это работает

WebRTC и Flash здесь нет, только SIP

состав параметров не соответствует хуку. RegistrationStatusEvent выглядит так (пример из логов сервера) OBJECT: { "nodeId" : "f02vkq9PbK9A8MrBnKatCK9clLbHbPyR@95.191.130.39", "appKey" : "defaultApp", "sessionId" : "/5.129.23.83:53866/95.191.130.39:8443-caab56ae-481a-484e-8ca6-ff8a47456080", "status" : "REGISTERED" }

на диаграмме не хватает connect от клиента к серверу

иначе непонятно, откуда взялось SIP REGISTER

не TCP connect, просто connect, т.к. SIP REGISTER мы отправляем не только по факту websocket connect, там еще идет сигналинговое сообщение connection с параметрами регистрации

диаграмма:

1. От клиента к серверу пунктирная стрелка Publishing stream
2. От клиента к серверу стрелка POST /recorder/startup
3. Далее POST /apps/DefaultApp/RecordingStatusEvent к бэкенду и т.д.

и надо проверифицировать, отправляется ли этот хук, не помню, чтобы видел его в логах сервера

диаграмма:

Send data меняем на POST /data/send

I would ordinarily ask to define "good enough" -- but to be fair "good enough" here is in the context of marketing.

This indicates a strategic pivot from purely commercial or academic AI development to direct government-level collaboration. This suggests Gemini Omni is being positioned as a foundational infrastructure for national-level AI initiatives, a non-obvious geopolitical application.

The specification of 'cinematic' video generation implies a deep, model-inherent understanding of professional filmmaking principles like shot composition, pacing, and narrative structure. This goes beyond simple video creation into the realm of professional content production.

The claim to 'design advanced algorithms' for mathematics and computing places this model in a meta-cognitive category. It's not just solving problems but creating new methodologies, positioning it as a potential co-architect for future AI and scientific discovery.

The phrase 'learns with you' is a subtle but powerful deviation from standard AI terminology. It implies a collaborative, co-evolutionary learning process rather than a one-way training dynamic, suggesting a more human-like interactive agent.

The explicit inclusion of 'use tools' alongside core cognitive functions like 'perceive' and 'reason' highlights a significant architectural focus on embodied AI. This suggests the model is being designed with a direct path to physical agency, a non-obvious but critical distinction.

This phrasing suggests a level of creative sovereignty not typically claimed by AI models. It implies a fundamental shift from content generation to content creation, suggesting a more autonomous and less tool-dependent creative process.

This demonstrates the model's capacity for complex, structured problem-solving. To apply this, frame your prompts around a specific problem, provide all necessary constraints and requirements, and ask the model to design a step-by-step solution or algorithm.

This suggests a focus on complex, multi-step reasoning and tool use. To apply this, structure your prompts as a sequence of tasks or a workflow, where the model must first perceive information, then reason, and finally decide on a tool or action to take.

This points to the model's specialized audio generation. To apply this, provide specific prompts that reference musical genres, instruments, tempo, and mood to guide the creation of high-fidelity audio outputs.

This underscores the importance of detailed language for visual generation. To apply this, use rich, evocative language in your prompts, specifying lighting, composition, style, and subject details to achieve the desired image quality.

This highlights the model's advanced creative capabilities. To apply this, be highly descriptive in your prompts, specifying mood, shot type, pacing, and audio cues to guide the model towards producing a specific cinematic result.

This indicates the model's strength in creating agents with specific roles and behaviors. To apply this, use persona prompting by defining a character, its expertise, its communication style, and its goals before asking it to perform a task.

This tagline suggests a core capability: use diverse inputs to generate diverse outputs. To apply this, pair unexpected modalities in your prompt, such as asking the model to generate a poem based on a data table or a musical score from a photograph.

This article talks about how Twitter forces users to write short messages, which encourages them to make inside jokes and look for a close connection with strangers. However, the platform also provides a retweet button that makes people who don't fully understand the real meaning behind the words to record or even broadcast the jokes to millions of other users. This causes outsiders to misunderstand the messages, often leading to public criticism, shaming, and attack towards that original account.

This source highlights that its repeated situations of feeling shame and guilt that can cause problems in children. When people send clips to Jimmy Kimmel, it is assumed that parents did this to their kids as a one off prank, which shouldn't be all that harmful. However, this can get out of hand if it influences a repetitive trend on the same kids. A lot of family influencers have been found guilty of doing this.

After reading this, I thought it was so interesting that shame activates the parasympathetic system instead of the sympathetic system. The parasympathetic system is the one responsible fort doing day to day things such as resting and digesting. This is because it helps manage your emotions by slowing down your heart rate. I thought the biology aspect was so interesting and I would love to learn more.

An instance of public shaming is considered bad when it leaves those shamed with "names" or "references" which people joke about for a long term. To be more specific, if a celebrity has an interview with a famous MC, whose mean words has a big impact on forming the viewers' perspectives, and they're made fun of publicly, they will tend to be remembered with how the MC describe them. For most of the time, those "references" are only meant for entertainment and attention-seeking; however, they definitely make the celebrity feels uncomfortable when their fans (or even non-fans) call them or simply remember them by those "names." Even if that's what make the celebrity famous, no one would want to be linked to others' jokes in a very disrespectful way like that.

Public shaming becomes harmful when the punishment doesn't match the action. This whole point of this chapter indicates that shaming can sometimes be used by people with less power to hold powerful people or groups accountable, especially when there isn't any formal way to punish harmful behavior. I think it becomes unethical when normal people are suddenly exposed to huge online crowds even when they get doxxed. At that point, it isn't about accountability but more for personal entertainment and anger stemming from the original person. These listed factors are important whether the person has a real chance to fix the harm done and return to the community in one piece. Either way, it can cause permanent damage to someone and rarely be a change for good towards a person.

This kind of reminds me of one of the Ethics Frameworks that I have reviewed over time; Egoism. Egoism focuses on your own pleasure. An individual with Egoism Lifestyle may do things selfishly and in order to please only themselves.

How productivity tools can make people less productive in terms of actually producing things of value.

What. The fuck.

aka Twitter. In a totally normal, not at all sketchy "acquisition"

They really got everyone, didn't they? Was Scrooge McDuck, Inc. not available?

This will be filled in with the actual share amounts later

This isn't surprising - a "non-accelerated" filer is the default for S-1s, since that is the first time a company is exposed to the requirements of being a public company.

https://www.sec.gov/resources-small-businesses/going-public/smaller-reporting-companies

On switching from a SSG to WordPress because WordPress is more conducive to focusing on writing than the underlying tech.

Why the most recent example from 2014?

They are not impacted alike. Borrowers and lenders are impacted differently. Borrowers gain from inflation.

compared to the previous month.

it is seasonal

Tibullus, the inspo for many writers.

That's not what Johnson thinks

Shackles / chain for the feet, like prisoner.

make this estimate a bit more prominent

Heads up that there's typo here!

sea

este

lleragras

quieran

diera

sea

paresca

puedan

prefieras

diga

9

1

4

6

7

2

8

5

3

Racism still exists though.

Este es un comentario prueba

I personally don't find these kinds of things to be very problematic at the level it is at right now. A huge reason cancel culture is more rampant now more than ever is because people want influencers, and anyone who posts online, to follow strict morals. I don't want to say that people have gotten "too sensitive" exactly, because this exact culture shift has brought many issues I find valid, to attention. But that is exactly the issue -> opinions on morals. What is right and what is wrong.

• The Mathematics of Existence: The probability of you being born exactly as you are is calculated to be roughly 1 in $$10^{2,685,000}$$—a number so large that it is effectively zero, making your existence mathematically improbable.
• Ancestral Convergence: Every individual is the result of an unbroken chain of millions of generations of ancestors who successfully reproduced, spanning back to the first single-celled organisms.
• Overcoming Historical Obstacles: Your specific lineage survived ice ages, plagues, wars, famines, and countless near-miss accidents over billions of years.
• The Uniqueness of Your Consciousness: Because the exact combination of genetic material, environmental factors, and historical events that created you will never happen again, your unique perspective and experience of the universe are irreplaceable.
• A Rational Source of Gratitude: Understanding these staggering odds provides a secular, logic-based foundation for immense gratitude, showing that life is a statistical miracle without needing a religious framework.

Hacker News Discussion

• Anthropic Principle Bias: Several commenters noted that calculating post-hoc probabilities is misleading; while the chance of a specific person existing is low, the probability that someone would exist to contemplate it is 100%.
• The "Deck of Cards" Analogy: Users compared existence to shuffling a deck of cards—any specific sequence of 52 cards is incredibly improbable (1 in $$52!$$), yet every time you shuffle, a unique and highly unlikely arrangement occurs.
• Critique of Large Numbers: Some users argued that multiplying probabilities back to the Big Bang inflates the sense of meaning artificially, noting that the same logic applies to a specific pebble on a beach or a piece of dust.
• Philosophical Value vs. Mathematical Rigor: Despite the mathematical critiques, many readers defended the essay, stating its true value lies in its poetic reminder to practice mindfulness, appreciate being alive, and not take existence for granted.

• Demokratyzacja medycyny długowieczności (Longevity): Choć temat longevity kojarzy się z milionerami pokroju Briana Johnsona i wielkimi nakładami finansowymi, jego fundamentalne filary są bezpłatne lub bardzo niskokosztowe. Istotą jest zmiana filozofii życiowej i traktowanie zdrowia jako kapitału, który buduje się latami, a nie jedynie jako braku zdiagnozowanej jednostki chorobowej [00:02:17], [00:02:25].
• Przejście od Medycyny 2.0 do Medycyny 3.0: Współczesna medycyna konwencjonalna (2.0) uczy lekarzy bycia „menedżerami chorób” – pacjent zgłasza się z objawami i otrzymuje leczenie mające je zaleczyć. Medycyna długowieczności (3.0), spopularyzowana m.in. przez Petera Atię, działa o krok przed chorobą. Skupia się na wczesnej detekcji indywidualnych ryzyk oraz optymalizacji parametrów, zanim dojdzie do patologii [00:03:59], [00:04:17], [00:06:27].
• Lifespan kontra Health Span: Medycyna konwencjonalna skutecznie wydłużyła całkowitą długość życia (lifespan), jednak nie przełożyła się na wydłużenie życia w zdrowiu (health span). Statystyczny Polak ostatnie 10-15 lat spędza zmagając się z chorobami przewlekłymi i przyjmując liczne leki. Celem longevity jest skrócenie tego okresu chorobowego i przesunięcie szczytowej formy życiowej nawet powyżej 60. roku życia [00:05:00], [00:05:48], [00:58:04].
• Nowe podejście do norm laboratoryjnych: Zamiast zero-jedynkowego patrzenia na wyniki (zdrowy vs. chory po przekroczeniu sztywnej granicy), medycyna 3.0 dąży do wyznaczania norm optymalnych i indywidualnych trendów. Przykładowo, wynik hemoglobiny glikowanej w tzw. szarej strefie (np. 5,7%) już jest sygnałem do działania w kierunku insulinooporności, a docelowy poziom cholesterolu LDL powinien być dobierany ściśle do osobistego ryzyka sercowo-naczyniowego pacjenta [00:11:10], [00:12:43], [00:13:46].
• Kompleksowa wizyta i wywiad w medycynie 3.0: Konsultacja u lekarza medycyny stylu życia trwa znacznie dłużej niż standardowe 15 minut (często około godziny). Obejmuje niezwykle szczegółowe pytania o historię rodzinną, jakość i czas snu, relacje, libido, ekspozycję na stres, nawyki żywieniowe oraz metody radzenia sobie z napięciem psychicznym, co pozwala stworzyć spójny obraz pacjenta [00:15:08], [00:15:15].
• Kluczowy panel badań diagnostycznych: * Metabolizm i stan zapalny: ocena glikemii, hemoglobiny glikowanej, kwasu moczowego (marker stresu oksydacyjnego) oraz morfologii i białka HSCRP [00:17:56], [00:18:27].
  • Zaawansowany lipidogram: standardowy profil rozszerza się o apolipoproteinę B (ApoB) oraz lipoproteinę a (Lp(a)), która wskazuje na genetyczne uwarunkowania ryzyka blaszki miażdżycowej [00:18:09], [00:18:17].
  • Podstawowe narządy: parametry wątrobowe oraz kreatynina do oceny pracy nerek [00:18:54].
• Polisa ubezpieczeniowa na życie – Mięśnie i VO2 Max: Skład ciała i wydolność to najsilniejsze predyktory zdrowego starzenia. Najważniejszymi wskaźnikami są wysoka masa mięśniowa oraz wysoki pułap tlenowy (VO2 max). Z kolei największym ukrytym wrogiem jest tkanka tłuszczowa trzewna (otaczająca narządy wewnętrzne), która wywołuje groźny, przewlekły stan zapalny i psuje metabolizm, będąc niewidoczną nawet u osób szczupłych i wysportowanych [00:19:22], [00:19:41], [00:21:13].
• Metody oceny składu ciała, snu i genetyki: W diagnostyce składu ciała bardzo ceniona jest densytometria (DXA), precyzyjnie pokazująca rozłożenie tkanek i gęstość kości, a pomocniczo bioimpedancja. Do zaawansowanej oceny snu i wykluczenia bezdechów sennych stosuje się poligrafię lub polisomnografię. Badania genetyczne (np. w kierunku Alzheimera czy nowotworów) są cenne, ale traktowane opcjonalnie – geny nie są ostatecznym wyrokiem, a styl życia zachowuje ogromną sprawczość [00:19:58], [00:20:30], [00:32:14], [00:35:11].
• Zarządzanie stresem, układ autonomiczny i wskaźnik HRV: * Przewlekły stres i stale podwyższony kortyzol niszczą gospodarkę hormonalną, prowadzą do insulinooporności oraz ułatwiają odkładanie tłuszczu trzewnego [00:29:48], [00:30:12].
  • Narzędziem monitorującym ten stan jest HRV (zmienność rytmu serca). Wysoka zmienność oznacza dominację regeneracyjnego układu przywspółczulnego i dobrą elastyczność organizmu [00:25:31], [00:26:35].
  • Układ współczulny („walka i ucieczka”) dominuje w ciągu dnia, ale w nocy i w momentach odpoczynku stery musi przejąć układ przywspółczulny. Można go aktywować poprzez mikrowyciszenia, spacery oraz ćwiczenia oddechowe, które mechanicznie i biochemicznie stymulują nerw błędny [00:23:00], [00:23:30], [00:24:44].
• Ruch, mikronawyki i unikanie „pandemii siedzenia”: Ogólne wytyczne mówią o 150 minutach umiarkowanego wysiłku tlenowego, dwóch treningach siłowych i ćwiczeniach na balans tygodniowo. Jednak dla osób prowadzących skrajnie siedzący tryb życia narzucenie reżimu nie działa. Kluczem jest spontaniczna aktywność pozatreningowa (NEAT) i wdrażanie mikronawyków: parkowanie dalej od biura, wybieranie schodów zamiast windy, rozmawianie przez telefon w trakcie marszu czy robienie regularnych przerw od komputera [00:50:10], [00:50:44], [00:51:30], [00:52:04].
• Harmonia fundamentów i pułapka ekstremizmu sportowego: Skupianie się wyłącznie na jednym elemencie (np. bycie radykałem dietetycznym przy braku ruchu lub forsowanie ciężkich treningów przy jednoczesnym braku snu) niszczy zdrowie. Przykładem są odnoszący sukcesy biznesmeni i triatloniści po czterdziestce, którzy forsując organizm ponad siły, wpadają w bezsenność, mają ekstremalnie wysoki kortyzol i rozwijają choroby serca przez całkowite zignorowanie regeneracji [00:54:25], [00:55:15], [00:55:42].
• Zegary biologiczne i epigenetyka: W medycynie longevity stosuje się algorytmy obliczające wiek metaboliczny czy wiek serca. Najbardziej zaawansowane i obiecujące naukowo są jednak zegary epigenetyczne (np. DunedinPACE), które badają tempo starzenia się komórek na poziomie DNA. Wynik poniżej 1 oznacza, że organizm starzeje się wolniej niż upływający czas kalendarzowy. Zegary te służą głównie jako potężne narzędzie motywacyjne do śledzenia trendów po wprowadzeniu zmian w stylu życia [00:38:47], [00:40:12], [00:41:45], [00:44:37].
• Weryfikacja metod biohackingu i geroterapeutyków: * Krioterapia i morsowanie: skutecznie wspomagają regenerację mięśni i metabolizm, ale brak jest dowodów na ich bezpośredni wpływ na długowieczność [00:57:07].
  • Sauna: posiada silne i twarde dane naukowe potwierdzające wsparcie układu sercowo-naczyniowego, imitując w pewnym stopniu wysiłek aerobowy [00:59:00].
  • Komory hiperbaryczne: wykazują mniejsze, choć zauważalne dowody w obszarze dotleniania tkanek i wsparcia mitochondriów [00:59:37].
  • Farmakoterapia (Rapamycyna i Metformina): Rapamycyna jest uznawana za „królową geroterapeutyków” (leków na starzenie) z rewelacyjnymi wynikami przedłużania życia u zwierząt, jednak u ludzi wciąż brakuje precyzyjnych danych dotyczących bezpiecznego dawkowania i bilansu zysków do strat. Duże nadzieje budzą również agoniści GLP-1 ze względu na swoje wielokierunkowe (plejotropowe) działanie ochronne na serce, mózg i metabolizm [00:59:58], [01:00:09], [01:01:26], [01:01:55].
• Darmowy, uniwersalny Game Changer: Najbardziej uniwersalną, bezkosztową rekomendacją przynoszącą natychmiastową poprawę jakości snu i odciążenie przebodźcowanego układu nerwowego jest całkowite odstawienie ekranów (telefonów, telewizorów) na godzinę przed snem oraz na minimum pół godziny po obudzeniu. Dodatkowym ułatwieniem w walce z dopaminowym uzależnieniem od smartfona jest przełączenie trybu wyświetlacza na czarno-biały [01:02:32], [01:02:51], [01:03:36].

it's basically a rules engine that evolves on its own

Missing "Who this is for" section above, like Salesforce Revive and Managed Services pages do.

Please add: Header: For organizations that want to grow into Salesforce — not grow out of it (? what do you think about this header? or maybe: For organizations ready to build Salesforce right — before it becomes a rescue case) * You're migrating from HubSpot, spreadsheets, or a legacy CRM that no longer fits * You're launching a new business unit that needs its own Salesforce environment * You're scaling past what your current setup can handle * You want to build it right the first time — not fix it later

If Salesforce is already live but broken or drifting, [Salesforce Revive →] is usually the better first step.

Change to : We bring ownership, structure, and operational clarity into environments that have become difficult to trust. And we stay — through stabilization, through adoption, through the long-term work of keeping a system aligned with a growing business.

Let's make it a litlle warmer and a little more "me":

Hi, my name is Alesia, and I am the proud founder of Hmara Solutions. My journey as an immigrant and a "woman in tech" hasn't always been easy, but every challenge has shaped who I am today. More importantly, it has shaped who we are as a team at Hmara, what we stand for, and the values we uphold.

​

From a young age, I was passionate about solving problems. Technology fascinated me, but growing up, I was often told that it was a field meant for men. Despite this, I found joy in coding and designing user interfaces for websites whenever (limited) opportunities presented themselves.

When I moved to the US, I was incredibly fortunate to have supportive managers who recognized my hard work. I still remember my first day in a corporate job in finance, where I was introduced to Salesforce. As the Salesforce Admin explained the system, I thought, "This is what I want to do. I want to work with Salesforce." I am not exaggerating when I say that it was truly “love at first sight”. ​I knew this platform was doing exactly the kind of work I cared about - making people's lives easier through technology.

I taught myself everything I could. I moved from end user to admin, from admin to architect, from architect to leading a large Salesforce team inside a real organization with real pressure - budgets, timelines, leadership expectations, team morale. I've sat in the same room as you, watching a report that no one trusted drive a decision that cost the business. I know what it feels like when the system is supposed to be helping and it's quietly making everything harder.

Over the next decade, I became a speaker and mentor in the Salesforce User Group community. And the same story kept surfacing: organizations buying the tools and not seeing the return. Smart, capable teams being let down by systems that were never properly built, or consultants who disappeared after go-live, or junior admins stretched far beyond what any one person can handle alone.

That's why I built Hmara Solutions. Not to implement features. To restore systems that leaders can finally rely on.

The name "Hmara" means "cloud" in my native language -Belarusian. This is a nod to my heritage and to the people who shaped me. I am proud to lead a team that reflects where I've come from: talented people who have built their expertise from the ground up, including young women from Belarus and beyond who are establishing themselves in the field. We bring the same care to our team that we bring to every client, because the way we work matters as much as what we build.

Let's replace with: We know what it costs when Salesforce stops working — because we've been on both sides of that table.

eLife Assessment

This Review Article provides a scholarly, clear and well-structured review of intracranial research into the neural correlates of consciousness (NCCs). To our knowledge this is the first such review and is therefore likely to become a must-read for anyone working in the field of consciousness research. The authors discuss the difficulties that researchers must face when studying NCCs and how insights may emerge via intracranial recordings in humans. This no doubt reflects an in-depth, timely, and insightful contribution to the literature.

Reviewer #1 (Public review):

Summary:

In this review paper, the authors describe the concept of neural correlates of consciousness (NCC) and explain how noninvasive neuroimaging methods fall short of being able to properly characterise an unconfounded NCC. They argue that intracranial research is a means to address this gap and provide a review of many intracranial neuroimaging studies that have sought to answer questions regarding the neural basis of perceptual consciousness.

Strengths:

The authors have provided an in-depth, timely, and scholarly contribution to the study of NCCs. First and foremost, the review surveys a vast array of literature. The authors synthesise findings such that a coherent narrative of what invasive electrophysiology studies have revealed about the neural basis of consciousness can be easily grasped by the reader. The authors also succeed in describing how single-cell recordings can interface with task-design to help mitigate the impact of confounded neural activity when searching for NCCs.

The review is also, to the best of my knowledge, the first review to specifically target intracranial approaches to consciousness and to describe their results in a single article. This is a credit to the authors - as it becomes ever harder to apply strict tests to theories of consciousness using methods such as fMRI and M/EEG, it is important to have informative resources describing the results of human intracranial research so that theorists will have to constrain their theories further in accordance with such data. Additionally, the authors provide a compelling case for single-celled research in consciousness science, despite the dominance of theories situated at the system and circuit level of analysis. As far as the authors were aiming to provide a complete and coherent overview of intracranial approaches to the study of NCCs, I believe they have achieved their aim.

Weaknesses:

Overall, I feel positive about this paper. The authors have addressed my comments from my previous review and I see no significant weaknesses in the current version.

Comment on revised version:

No comments - congratulations to the authors!

Reviewer #2 (Public review):

Summary:

In this work, the authors review the study of the neural correlates of consciousness (NCCs). They discuss several of the difficulties that researchers must face when studying NCCs, and argue that several of these difficulties can be alleviated by using intracranial recordings in humans.

They describe what constitutes an NCC, and the difficulties to distinguish between an NCC proper from the prerequisites and consequences of conscious processing.

They also describe the two main types of experimental designs used to study NCCs. These are the contrastive approach (with its report and non-report variants), and the supraliminal approach, each with their own merits and pitfalls.

They discuss the limitations of non-invasive methods, such as fMRI, EEG and MEG, as well as the limitations of the use of invasive recordings in non-human animals.

After setting the stage in this way, the authors provide an extensive review on the knowledge acquired by using invasive recordings in humans. This included population level measurements in vision and in other sensory modalities, as well as single neuron level studies. The authors also discuss studies of subcortical NCCs.

The second half of this work discusses the theoretical insights gained through the use of intracranial recordings, as well as their limitations, and a perspective for future work.

Strengths:

This work offers an impressive review, which will serve as a useful reference document, both for newcomers to the study of NCC as for experienced researchers. The inclusion of non-visual and subcortical NCCs is of particular merit, as these have been understudied.

Besides serving as a review, this work includes a perspective, exploring several directions to pursue for the progress of the field.

Weaknesses:

No major weaknesses.

Appraisal of whether the authors achieved their aims:

In this work, the authors have gathered an impressive review, and have discussed several important problems in the field of study of NCCs, as well as provided a perspective on how the field could move forward.

Discussion of the likely impact of the work on the field:

This work has the potential of becoming a must read for anyone working in the field of consciousness research.

Comment on revised version:

The authors have addressed all my concerns. Once again, my compliments for a nice piece of work.

Reviewer #3 (Public review):

Summary:

This narrative review provides a clear, well-structured, and comprehensive synthesis of intracerebral recording work on the neural correlates of consciousness. It is written in an accessible manner that will be useful to a broad community of researchers, from those new to iEEG to specialists in the field.

Strengths:

The manuscript successfully integrates methodological and theoretical perspectives and offers a balanced overview of current sometimes contradicting evidence. As such, the manuscript is important as call for a concernted better exploration of NCCs using iEEG in the future.

Weaknesses:

The manuscript discusses extensively the use of "report" as a criterion for identifying conscious perception and its limitations for separating between correlates of consciousness and post consciousness processes, yet the term is not defined at the outset. The authors should specify what they mean by "report" (e.g., verbal report, nonverbal self-report, or any meta-cognitive indication of experience). Importantly, this definition should be explicitly linked to the theoretical landscape: whether the authors adopt an access-consciousness perspective in which (self) reportability is central, or whether the review also aims to address phenomenal consciousness. Making this conceptual grounding explicit at the beginning will help readers interpret the empirical work surveyed throughout the review.

In addition, the review would benefit from an earlier introduction of the distinction between states and contents of consciousness. This distinction becomes important in the later section on anesthesia, sleep, and epileptic seizures, where the focus shifts from content-specific NCCs to alterations in global states. Presenting these definitions upfront, and briefly explaining how states and contents interact, would strengthen the coherence of the manuscript.

Overall, this is an excellent and timely review. With clearer initial theoretical definitions of consciousness, the manuscript will offer an even stronger conceptual framework for interpreting intracerebral studies of consciousness.

Comments on revised version:

The current version of the manuscript is clear and complete. Kudos to the authors for their thorough revisions.

My only remaining point concerns the definition of "report": "We define a report as any explicit behavioral response (whether verbal, manual, or otherwise) that communicates a participant's subjective state."

It would be helpful to clarify whether this definition is intended to exclude purely internal, explicit self-reports that are not externally expressed. As currently formulated, the definition appears to require overt behavioral communication. However, this raises a conceptual issue in relation to the no-report paradigm literature, where the distinction between report, metacognitive access, and overt motor/verbal expression is precisely at stake.

Could the authors specify whether "report" is meant to (i) be restricted to externally observable, behaviorally expressed reports, or (ii) extend to internally generated, explicit metacognitive judgments even when they are not communicated? Clarifying this point would help situate the manuscript more precisely within ongoing debates on the role of report in identifying neural correlates of consciousness.

Author response:

The following is the authors’ response to the original reviews

Public Reviews:

Reviewer #1 (Public review):

Summary

In this review paper, the authors describe the concept of neural correlates of consciousness (NCC) and explain how noninvasive neuroimaging methods fall short of being able to properly characterise an unconfounded NCC. They argue that intracranial research is a means to address this gap and provide a review of many intracranial neuroimaging studies that have sought to answer questions regarding the neural basis of perceptual consciousness.

Strengths

The authors have provided an in-depth, timely, and scholarly contribution to the study of NCCs. First and foremost, the review surveys a vast array of literature. The authors synthesise findings such that a coherent narrative of what invasive electrophysiology studies have revealed about the neural basis of consciousness can be easily grasped by the reader. The review is also, to the best of my knowledge, the first review to specifically target intracranial approaches to consciousness and to describe their results in a single article. This is a credit to the authors, as it becomes ever harder to apply strict tests to theories of consciousness using methods such as fMRI and M/EEG it is important to have informative resources describing the results of human intracranial research so that theorists will have to constrain their theories further in accordance with such data. As far as the authors were aiming to provide a complete and coherent overview of intracranial approaches to the study of NCCs, I believe they have achieved their aim.

We appreciate the reviewer's positive feedback on our work.

Weaknesses

Overall, I feel positive about this paper. However, there are a couple of aspects to the manuscript that I think could be improved.

(1) Distinguishing NCCs from their prerequisites or consequences

This section in the introduction was particularly confusing to me. Namely, in this section, the authors' aim is to explain how intracranial recordings can help distinguish 'pure' NCCs from their antecedents and consequences. However, the authors almost exclusively describe different tasks (e.g., no-report tasks) that have been used to help solve this problem, rather than elaborating on how intracranial recordings may resolve this issue. The authors claim that no-report designs rely on null findings, and invasive recordings can be more sensitive to smaller effects, which can help in such cases. However, this motivation pertains to the previous sub-section (limits of noninvasive methods), since it is primarily concerned with the lack of temporal and spatial resolution of fMRI and M/EEG. It is not, in and of itself, a means to distinguish NCCs from their confounds.

As such, in its current formulation, I do not find the argument that intracranial recordings are better suited to identifying pure NCCs (i.e. separating them from pre- or post-processing) convincing. To me, this is a problem solved through novel paradigms and better-developed theories. As it stands, the paper justifies my position by highlighting task developments that help to distinguish NCCs from prerequisites and consequences, rather than giving a novel argument as to why intracranial recordings outperform noninvasive methods beyond the reasons they explained in the previous section. Again, this position is justified when, from lines 505-506, the authors describe how none of the reported single-cell studies were able to dissociate NCCs from post-perceptual processing. As such, it seems as if, even with intracranial recording, NCCs and their confounds cannot be disentangled without appropriate tasks.

The section 'Towards Better Behavioural Paradigms' is a clear attempt to address these issues and, as such, I am sure the authors share the same concerns as I am raising. Still, I remain unconvinced that the distinguishing of NCCs from pre-/post- processing is a fair motivation for using intracranial over noninvasive measures.

We agree that distinguishing proper NCCs from their prerequisites or consequences is primarily a matter of experimental design and theoretical framework, not merely of recording modality. We did not mean to imply that intracranial recordings inherently solve this dissociation.This is now explicitly stated that at the beginning of this section. Instead, we argued that the high signal-to-noise ratio and spatiotemporal accuracy of sEEG offer a stronger "testing ground" for the null findings often relied on by no-report paradigms. This is now also further clarified in the revised section “Limits of noninvasive measures”.

We also explicitly acknowledge, as the reviewer noted, that even the most precise recordings require careful task dissociations to distinguish NCCs from their prerequisites and consequences.

(2) Drawing misleading conclusions from certain studies

There are passages of the manuscript where the authors draw conclusions from studies that are not necessarily warranted by the studies they cite. For instance:

Lines 265 - 271: "The results of these two studies revealed a complex pattern: on the one hand, HGA in the lateral occipitotemporal cortex and the ventral visual cortex correlated with stimulus strength. On the other hand, it also correlated with another factor that does not appear to play a role in visibility (repetition suppression), and did not correlate with a non-sensory factor that affects visibility reports (prior exposure). These results suggest that activity in occipitotemporal cortex regions reflecting higher-order visual processing may be a precursor to the NCC but not an NCC proper."

It's possible to imagine a theory that would predict HGA could correlate with stimulus strength and repetition suppression, or that it would not correlate with prior exposure (e.g. prior exposure could impact response bias without affecting subjective visibility itself). The authors describe this exact ambiguity in interpretation later in the article (line 664), but in its current form, at least in line 270 (when the study is most extensively discussed), the manuscript heavily implies that HGA is not an NCC proper. This generates a false impression that intracranial recordings have conclusively determined that occipitotemporal HGA is not a pure NCC, which is certainly a premature conclusion.

We agree that our interpretation of these studies (lines 265–271 of the previous version of the manuscript) was presented too definitively. We have modified the text (now lines 314-317) to soften this conclusion and align it with the more nuanced discussion later in the manuscript. Specifically, we now frame this as a "suggested dissociation" rather than a conclusive finding (line 730), and we explicitly acknowledge that alternative interpretations remain viable.

Line 243: "Altogether, these early human intracranial studies indicate that early-latency visual processing steps, reflected in broadband and low gamma activity, occur irrespective of whether a stimulus is consciously perceived or not. They also identified a candidate NCC: later (>200 ms) activity in the occipitotemporal region responsible for higher-order visual processing."

The authors claim in this section that later (>200ms) activity in occipitotemporal regions may be a candidate for an NCC. However, the Fisch et al. (2009) study they describe in support of this conclusion found that early (~150ms) activity could dissociate conscious and unconscious processing. This would suggest that it is early processing that lays claim to perceptual consciousness. The authors explicitly describe the Fisch et al results as showing evidence for early markers of consciousness (line 240: '...exhibited an early...response following recognized vs unrecognised stimuli.) Yet only a few lines later they use this to support the conclusion that a candidate NCC is 'later (>200ms) activity in the occipitotemporal region' (line 245). As such, I am not sure what conclusion the authors want me to make from these studies.

This problem is repeated in lines 386-387: "Altogether, studies that investigated the cortical correlates of visual consciousness point to a role of neural responses starting ~250 ms after stimulus onset in the non-primary visual cortex and prefrontal cortex."

This seems to be directly in conflict with the Fisch et al results, which show that correlates of consciousness can begin ~100ms earlier than the authors state in this passage.

We thank the reviewer for pointing out this inconsistency. We agree that stating ">200 ms" conflicts with the findings of Fisch et al. (2009), who observed dissociations as early as ~150 ms. Our goal was to contrast the very early, stimulus-driven responses with the later responses that reflect consciousness. However, as the reviewer correctly notes, the exact "onset" of these signals varies across studies and paradigms. To address this, we have removed the specific ">200 ms" mentioned in line 245 of the previous version of the manuscript and updated the timing in line 284 to "starting 150 ms" to better reflect the results of Fisch et al. We also clarify that while the exact latency depends on the paradigm, a consistent finding is that activity representing conscious contents in higher-order visual cortex follows an initial wave of unconscious processes (lines 809-810).

(3) Justifying single-neuron cortical correlates of consciousness

The purpose of the present manuscript is to highlight why and how intracortical measures of neural activity can help reveal the neural correlates of perceptual consciousness. As such, in the section 'Single-neuron cortical correlates of perceptual consciousness', I think the paper is lacking an argument as to why single-neuron research is useful when searching for the NCC. Most theories of consciousness are based around circuit or system-level analyses (e.g., global ignition, recurrent feedback, prefrontal indexing, etc.) and usually do not make predictions about single cells. Without any elaboration or argument as to why single-cell research is necessary for a science of consciousness, the research described in this section, although excellent and valuable in its own right, seems out of place in the broader discussion of NCCs. A particularly strong interpretation here could be that intracranial recordings mislead researchers into studying single cells simply because it is the finest level of analysis, rather than because it offers helpful insight into the NCCs.

It is true that many prominent theories of consciousness were developed based on macroscopic observations, largely due to the prevalence of non-invasive recordings in humans. However, we argue that recording single-unit activity is important for several reasons, and we made this clearer in the revised version. First, signals like fMRI, EEG (or even LFP) often conflate multiple distinct neural populations. SUA allows us to dissociate neurons representing the percept from neighboring neurons involved in task-related confounds (e.g., motor preparation or arousal) that would otherwise be blurred together. Therefore, some percepts might be represented by sparse coding involving a small, specific population of "concept" or "percept" cells. Electrophysiological studies in animal models reveal that various cognitive processes are encoded within neuronal subspaces that only emerge when single-unit activity is analyzed as lower-dimensional projections of the broader neural activity manifold (Mante et al., 2013; Ebitz & Hayden, 2021; Jayazeri & Afraz, 2017). Importantly, many neural computations are only discernible through the lens of population dynamics (i.e. with single neuron activity) (Vyas et al., 2021). We believe that providing high granularity through SUA recordings prevents over-aggregation of data, ensuring that even system-level theories can build on biologically accurate foundations.

Moreover, some theories are defined at the cellular level. For instance, the Dendritic Integration Theory (Bachmann et al., 2020) posits that the integration of feedforward and feedback signals occurs at the level of individual pyramidal neurons. Without SUA, these cellular mechanisms remain untestable. Beyond spatial granularity, SUA also provides excellent temporal granularity, which is crucial for testing theories that rely on the precise timing of spikes (e.g., neural synchrony). As LFPs reflect average activity across populations, only SUA can confirm whether individual neurons lock their spikes to a specific phase, a mechanism hypothesized to bind features into a conscious whole.

We added these points to a new section in the revised manuscript. References:

Bachmann, T., Suzuki, M., & Aru, J. (2020). Dendritic integration theory: A thalamo-cortical theory of state and content of consciousness. Philosophy and the Mind Sciences, 1(II).

Ebitz, R. B., & Hayden, B. Y. (2021). The population doctrine in cognitive neuroscience. Neuron, 109(19), 3055-3068.

Jazayeri, M., & Afraz, A. (2017). Navigating the neural space in search of the neural code. Neuron, 93(5), 1003-1014.

Mante, V., Sussillo, D., Shenoy, K. V., & Newsome, W. T. (2013). Context-dependent computation by recurrent dynamics in prefrontal cortex. nature, 503(7474), 78-84.

Vyas, S., Golub, M. D., Sussillo, D., & Shenoy, K. V. (2020). Computation Through Neural Population Dynamics. Annual Review of Neuroscience, 43(1), 249-275.

(4) No mention of combined fMRI-EEG research

A minor point, but I was surprised that the authors did not mention any combined fMRI-EEG research when they were discussing the limits of noninvasive recordings. Intracortical recordings are one way to surpass the spatial and temporal resolution limits of M/EEG and fMRI respectively, but studies that combine fMRI and EEG are also an alternative means to solve this problem: by combining the spatial resolution of fMRI with the temporal resolution of EEG, researchers can - in theory - compare when and where certain activity patterns (be they univariate ERPs or multivariate patterns) arise. The authors do cite one paper (Dellert et al., 2021 JNeuro) that used this kind of setup, but they discuss it only with respect to the task and ignore the recording method. The argument for using intracranial recordings is weaker for not mentioning a viable, noninvasive alternative that resolves the same issues.

We thank the reviewer for this point. We have added a discussion of fMRI-EEG to the "Limits of noninvasive measures" section (lines 167-171). While we acknowledge that fMRI-EEG is a powerful non-invasive tool for bridging spatial and temporal scales, we note that it relies on merging an indirect metabolic signal with a weak electrophysiological one filtered by the skull, which is computationally complex and often noisy. In contrast, intracranial recordings provide direct measures of both local field potentials and spiking activity within the same neural population, offering interpretability and signal-to-noise ratio that non-invasive combinations cannot match. In our view, this is not just an alternative to these methods, but a unique means of accessing the underlying neuronal ground truth.

Reviewer #2 (Public review):

Summary:

In this work, the authors review the study of the neural correlates of consciousness (NCCs). They discuss several of the difficulties that researchers must face when studying NCCs, and argue that several of these difficulties can be alleviated by using intracranial recordings in humans.

They describe what constitutes an NCC, and the difficulties to distinguish between an NCC proper from the prerequisites and consequences of conscious processing.

They also describe the two main types of experimental designs used to study NCCs. These are the contrastive approach (with its report and non-report variants), and the supraliminal approach, each with its own merits and pitfalls.

They discuss the limitations of non-invasive methods, such as fMRI, EEG and MEG, as well as the limitations of the use of invasive recordings in non-human animals.

After setting the stage in this way, the authors provide an extensive review of the knowledge acquired by using invasive recordings in humans. This included population-level measurements in vision and in other sensory modalities, as well as single-neuron level studies. The authors also discuss studies of subcortical NCCs.

The second half of this work discusses the theoretical insights gained through the use of intracranial recordings, as well as their limitations, and a perspective for future work.

Strengths:

This work offers an impressive review, which will serve as a useful reference document, both for newcomers to the study of NCC and for experienced researchers. The inclusion of non-visual and subcortical NCCs is of particular merit, as these have been understudied.

Besides serving as a review, this work includes a perspective, exploring several directions to pursue for the progress of the field.

We thank the reviewer for acknowledging the strength of our work.

Weaknesses:

The intention of the authors is to argue how some of the problems faced when studying NCCs are alleviated by the use of intracranial recordings in humans. But in some cases, the link between the problems related to the study of NCCs and the advantages of intracranial recordings over non-invasive methods is not clear.

For example, the authors explain the difficulties in distinguishing between true NCCs from their prerequisites and consequences. This constitutes a difficult conceptual problems that plague all recording techniques. The authors don't provide a convincing explanation of how intracranial recordings offer advantages over EEG or MEG when dealing with these problems.

We agree that the distinction between proper NCCs and their prerequisites or consequences is a fundamental challenge that affects all recording modalities. We did not intend to imply that intracranial recordings are a "silver bullet" for solving this conceptual problem in isolation, and we now explicitly state that at the beginning of this section (line 101).

We have revised the section on "Distinguishing NCCs from their prerequisites or consequences" to clarify that intracranial recordings are a powerful tool when used in conjunction with appropriate experimental designs, rather than a standalone solution to these conceptual difficulties.

For example, the authors explain how the use of non-report designs to rule out post-perceptual processing relies on null results, which, according to them, are harder to interpret given the low resolution of non-invasive methods. But the interpretation of null results is actually more complicated in the case of intracranial recordings. As the coverage achieved by the electrodes is sparse, if a null result is attested, it remains possible that a true effect was present in a nearby patch of cortex out of coverage.

It is true that a null result in an intracranial study may simply reflect that the relevant neural population was not sampled by the specific electrode implantation scheme. However, we argue that interpreting null results is equally, if not more, complicated in non-invasive methods, albeit for different reasons. While M/EEG offers broader coverage, it is blind to many cortical sources because of their orientation (radial sources in MEG) or their location in deep sulci and subcortical structures. The signal-to-noise ratio of M/EEG is also much lower than that of intracranial EEG, making it more likely that null results obscure the existence of subtle effects (Parvizi & Kastner, 2018).

To address this, we revised the manuscript to clarify that intracranial recordings provide high local certainty within the sampled regions (lines 224-227), whereas non-invasive methods provide broader coverage (lines 247-249). We now explicitly emphasize that drawing conclusions from null results based on intracranial recordings requires caution regarding electrode placement. We also point out that these approaches are complementary: M/EEG can identify large regions of interest, while sEEG can then provide high-resolution "ground truth" to confirm whether those regions are part of the NCC.

Reference: Parvizi, J., & Kastner, S. (2018). Promises and limitations of human intracranial electroencephalography. Nature Neuroscience, 21(4), 474-483. https://doi.org/10.1038/s41593-018-0108-2

The authors argue that the spatial resolution of intracranial recordings is better than that of EEG and MEG. While this is technically true (especially compared to EEG), the true spatial scale of the NCCs is unknown. If NCCs' span is in the mm range, then the additional spatial resolution of intracranial recordings might not be an advantage.

We agree with the reviewer that the exact spatial scale of the NCC remains a topic of ongoing debate. However, we believe that the advantage of intracranial recordings holds true whether the NCC spans millimeters or centimeters. The main spatial limitation of non-invasive electrophysiology (M/EEG) is not just its spatial resolution but also the inverse problem. Since scalp sensors detect a mixture of signals from across the brain, different cortical configurations can produce identical scalp patterns. This makes it challenging to precisely locate the NCC or distinguish it from nearby activity (e.g., motor or attentional signals). When recording intracortically, a widespread NCC could be captured across multiple adjacent channels with high accuracy. Conversely, if the NCC is focal, it can be isolated with high spatial resolution. In either case, intracranial recordings eliminate the spatial ambiguity inherent in scalp recordings. We have revised the Introduction (lines 158-164) to clarify that the "spatial advantage" of intracranial recordings also pertains to the inverse problem, not merely to the ability to record from smaller cortical areas.

Another factor that should be taken into consideration when assessing the spatial resolution of intracranial recordings is that while the listening zone of individual intracranial contacts is small, coverage is sparse and defined by clinical criteria (something that the authors discuss). In practice, the activity recorded by contacts is usually attributed to anatomically defined ROIs with a scale in the cm range. Given the sparse and uneven (across regions and patients) coverage afforded by intracranial recordings, the advantage of intracranial recordings in terms of spatial resolution is overstated.

We thank the reviewer for raising this point regarding how intracranial data is often aggregated into regions of interest. We agree that if researchers generalize findings to large anatomical regions without accounting for single-channel recordings, some of the spatial benefits of intracranial recordings are indeed mitigated. We toned down some of the original claims accordingly, and acknowledged more clearly that clinical constraints of sEEG lead to sparse coverage (245-249).

However, we maintain that even when using an ROI-based approach, intracranial recordings offer a clear advantage over non-invasive methods, in that they represent a direct measure from a specific patch of tissue, rather than a statistical estimate that may be contaminated by "leakage" from distant sources. To address the reviewer’s concern, we have updated the manuscript (lines 244-245) to emphasize the importance of relying on MNI coordinates and individual anatomy rather than solely on broad ROI labels.

Appraisal of whether the authors achieved their aims:

In this work, the authors have gathered an impressive review and have discussed several important problems in the field of study of NCCs, as well as provided a perspective on how the field could move forward.

What is less clear is how the use of intracranial recordings per se holds potential to overcome problems such as the distinction between true NCCs and the prerequisites and consequences of conscious processing.

Discussion of the likely impact of the work on the field:

This work has the potential of becoming a must-read for anyone working in the field of consciousness research.

Reviewer #3 (Public review):

Summary:

This narrative review provides a clear, well-structured, and comprehensive synthesis of intracerebral recording work on the neural correlates of consciousness. It is written in an accessible manner that will be useful to a broad community of researchers, from those new to iEEG to specialists in the field.

Strengths:

The manuscript successfully integrates methodological and theoretical perspectives and offers a balanced overview of current, sometimes contradicting evidence. As such, the manuscript is important as it calls for a concerted and better exploration of NCCs using iEEG in the future.

We thank the reviewer for stating the importance of our work and its potential contribution to the field.

Weaknesses:

The manuscript extensively discusses the use of "report" as a criterion for identifying conscious perception and its limitations for separating between correlates of consciousness and post-consciousness processes, yet the term is not defined at the outset. The authors should specify what they mean by "report" (e.g., verbal report, nonverbal self-report, or any meta-cognitive indication of experience). Importantly, this definition should be explicitly linked to the theoretical landscape: whether the authors adopt an access-consciousness perspective in which (self) reportability is central, or whether the review also aims to address phenomenal consciousness. Making this conceptual grounding explicit at the beginning will help readers interpret the empirical work surveyed throughout the review.

We agree that a clear definition of report is essential for the reader to interpret the empirical findings presented. We have added a definition to the Introduction (lines 108-111), specifying that we use "report" to refer to any explicit behavioral response (whether verbal, manual, or otherwise) that communicates a subject’s subjective state.

Regarding the conceptual distinction between Phenomenal and Access consciousness, we refer to recent work from some of the co-authors (Mudrik et al., 2025), which suggests that P and A should not be seen as two types of consciousness, but rather as two necessary conditions for conscious experience. While a full discussion of this distinction is beyond the scope of this review, we now clearly state that our focus is on identifying neural activity that reflects the subjective experience itself, regardless of the downstream requirements of report.

Reference: Mudrik, L., Faivre, N., Pitts, M., & Schurger, A. (2025). On a confusion about there being two types of consciousness. Trends in Cognitive Sciences. https://doi.org/10.1016/j.tics.2025.11.012

In addition, the review would benefit from an earlier introduction of the distinction between states and contents of consciousness. This distinction becomes important in the later section on anaesthesia, sleep, and epileptic seizures, where the focus shifts from content-specific NCCs to alterations in global states. Presenting these definitions upfront and briefly explaining how states and contents interact would strengthen the coherence of the manuscript.

We agree that clarifying the distinction between contents and levels of consciousness early on provides a stronger framework for the paper.

We have added a brief clarification in the Introduction (lines 63-76): "It is also helpful to distinguish between levels of consciousness, defined as a global level of arousal or wakefulness (e.g., being awake vs. under anesthesia), and the contents of consciousness, defined as the specific subjective experiences one has while conscious (e.g., perceiving a visual stimulus; Bayne et al., 2016; Laureys, 2005). While the majority of this review focuses on 'content-specific' NCCs, the two dimensions are intrinsically linked, as global states typically set the conditions for the occurrence of specific conscious contents."

Overall, this is an excellent and timely review. With clearer initial theoretical definitions of consciousness, the manuscript will offer an even stronger conceptual framework for interpreting intracerebral studies of consciousness.

We thank the reviewer again for this highly positive assessment of the manuscript.

Recommendations for the authors:

Reviewer #1 (Recommendations for the authors):

I would like to reiterate that I believe this is a very scholarly piece of writing, and I congratulate the authors on producing such a useful and timely manuscript. Below, I suggest just a few ways the authors may resolve some of the issues I raised in the public review. However, I would like to emphasise that these are merely suggestions - the authors may think of different and better ways to address these comments that are more in line with either their thinking or writing style, and I would certainly encourage the authors to follow their own preferences if they feel they are at odds with my suggestions.

For the longer comment questioning whether intracranial recordings are really a way to isolate NCCs from their pre- and post-processing, there are two ways the authors could resolve this. One is that they collapse the section distinguishing NCCs from their prerequisites and consequences into the previous section regarding limits of noninvasive measures. For instance, they could make the point that null results are easier to interpret with intracranial recordings in this previous section. Then they could discuss how specific intracranial studies have been able to resolve questions of pre-/post- processing confounds when they introduce studies later in the manuscript. At the moment, the Distinguishing NCCs from their prerequisites and consequences section, at least to me, undermines the argument of why intracranial recordings are important because it spends too much time describing how tasks are the core component of isolating pure NCCs, and not the recording method.

Alternatively, the authors could keep the structure as it is. In this case, I would urge the authors to emphasise the role of intracortical recordings here and to make the argument that this is a problem that intracortical recordings (rather than novel tasks) can solve more convincingly. Citing specific studies that combined intracortical recordings with no-report paradigms and emphasising how the invasive recording allowed the researchers to reach a conclusion that would not have been possible with noninvasive measures would also be helpful.

We thank the reviewer for these useful suggestions and agree that we would not want readers to take from this paper that design issues can be fixed by using invasive recordings. Because confounding issues are crucial in research on the NCC, we believe it is important to include a section on this topic in the Introduction. However, as we explained in our response to the public review, we revised the section introducing Human intracranial electrophysiology to reflect that intracranial recordings are a complementary tool that improves the interpretability of no-report paradigms, rather than a “silver bullet” solution for confound issues. We also explicitly say now that this problem is relevant to all techniques in the study of consciousness, including intracranial recordings (line 101). Additionally, based on the reviewer’s suggestion, we have added a more detailed explanation of how studies that pair intracranial recordings with no-report paradigms provide a unique insight in the Temporal Insights section (lines 822-823).

For my comment: Drawing misleading conclusions from certain studies, I think the public review speaks for itself. I would recommend that the authors make sure they are drawing correct conclusions from the studies they cite, and make clear from the outset where there is ambiguity in interpretation.

We thank the reviewer for bringing these ambiguities to our attention. As explained in the response to the public review, we have modified the text accordingly.

Finally, with regard to the single-cell analyses, I would imagine that most readers will share at least some scepticism around single neurons being the appropriate level of analysis for revealing the basis of perceptual experience. As such, I think it would strengthen the manuscript greatly if the authors could provide a brief argument as to how such work can either inform theories of consciousness or contribute more generally to the study of NCCs, given that the field and its theories are mostly biased towards studying system-level neural processes. I think single-cell analyses are extremely valuable to NCC research, and the authors have a good opportunity to frame these studies accordingly.

We agree. As detailed in the response to the public review, we now specify (1) how a higher level of granularity in electrophysiological measurements can distinguish between awareness-related signals and confounds, (2) that these measurements provide an opportunity to study neuronal population dynamics where various cognitive processes have been shown to emerge in animals and (3) that single-neuron measurements are necessary to test predictions of theories that are defined at the cellular level

Reviewer #2 (Recommendations for the authors):

Recommendations for improving the writing and presentation:

My compliments for having written an impressive review. Overall, I think that this is a beautiful piece of work that will be of great use to the community. My only concern is that the advantages of intracranial recordings over non-invasive methods in solving the difficulties faced in the study of NCCs are overstated.

Here I provide more precise comments for your consideration.

(1) On page 5, lines 100 to 102, you argue that "Scalp EEG and MEG have limitedanatomical resolution due to the overlap of deep and superficial brain signals at the scalp level and, in the case of EEG, the scattering of the adjacent electrical signals through the scalp". It would be good to provide precise estimates of the spatial resolutions of EEG, MEG and intracranial recordings, with accompanying references. Consider also that MEG is relatively insensitive to deep sources. I recommend this paper: Piastra et al. 2020 https://onlinelibrary.wiley.com/doi/10.1002/hbm.25272

We thank the reviewer once again for their positive evaluation of our work. As detailed in the response to the public reviews, we now clarify that intracranial recordings provide high local certainty within the sampled regions (lines 224-227), whereas non-invasive methods provide broader coverage (lines 247-249). We thank the reviewer for their additional suggestions and have clarified our concern about the anatomical conclusions that can be drawn from scalp EEG and MEG data (lines 158-164).

(2) On page 11, you describe work showing that activity in the occipitotemporal cortex mightreflect a precursor to consciousness, but not an NCC proper, except for the case of faces, in which the fusiform seems to behave like a true NCC. Could you discuss how these seemingly contradictory results could be reconciled?

One possibility is that activity in some parts of the occipitotemporal cortex instantiates content-specific NCCs, i.e., correlates that are only specific to certain stimulus types (in this case: faces), while activity in other parts instantiates precursors of the NCCs. Because faces have been extensively studied, we might have uncovered the content-specific NCCs for these stimuli but not for others. This is now discussed in the text on lines 342-344. Based on reviewer 1’s suggestion, we have also toned down our claim about occipitotemporal activity being a precursor to the NCC.

(3) From line 322, you start to discuss connectivity analyses. Adding a subheading mightimprove readability.

We appreciate the suggestion; however, adding a subheading to a single paragraph would require restructuring the entire section, which could disrupt the flow. We believe the current format maintains clarity and cohesion.

(4) In line 329, you write "It remains unclear to what extent these connectivity patterns reflectpost-perceptual processing and how the signals associated with perceptual consciousness in the occipitotemporal cortex interact with frontoparietal regions." But it's not clear why this is the case.

We meant to make two separate points: (1) these studies did not control for report-related activity using no-report paradigms and (2) there has been no investigation so far of the interaction between occipitotemporal and frontoparietal signals associated with perceptual consciousness. These two points have been clarified in the text (lines 378-381).

(5) In line 692, it would be good to clarify that Pereira 2021 is a single-neuron study.

This has been clarified in the text.

(6) The phrase "more research/work is needed" is repeated several times.

Thank you for pointing this out. To avoid redundancy, we have deleted the second mention of this phrase.

eLife Assessment

The authors provide a scholarly review of intracranial research into the neural correlates of consciousness (NCCs). To our knowledge, this is the first such review, and it therefore may become a must-read for anyone working in the field of consciousness research. It is not so persuasive that intracranial recordings are better suited to identifying pure NCCs than other methods, which appears a problem instead solved through novel paradigms and better-developed theories - but this no doubt reflects an in-depth, timely, and insightful contribution to the literature.

Reviewer #1 (Public review):

Summary

In this review paper, the authors describe the concept of neural correlates of consciousness (NCC) and explain how noninvasive neuroimaging methods fall short of being able to properly characterise an unconfounded NCC. They argue that intracranial research is a means to address this gap and provide a review of many intracranial neuroimaging studies that have sought to answer questions regarding the neural basis of perceptual consciousness.

Strengths

The authors have provided an in-depth, timely, and scholarly contribution to the study of NCCs. First and foremost, the review surveys a vast array of literature. The authors synthesise findings such that a coherent narrative of what invasive electrophysiology studies have revealed about the neural basis of consciousness can be easily grasped by the reader. The review is also, to the best of my knowledge, the first review to specifically target intracranial approaches to consciousness and to describe their results in a single article. This is a credit to the authors, as it becomes ever harder to apply strict tests to theories of consciousness using methods such as fMRI and M/EEG it is important to have informative resources describing the results of human intracranial research so that theorists will have to constrain their theories further in accordance with such data. As far as the authors were aiming to provide a complete and coherent overview of intracranial approaches to the study of NCCs, I believe they have achieved their aim.

Weaknesses

Overall, I feel positive about this paper. However, there are a couple of aspects to the manuscript that I think could be improved.

(1) Distinguishing NCCs from their prerequisites or consequences

This section in the introduction was particularly confusing to me. Namely, in this section, the authors' aim is to explain how intracranial recordings can help distinguish 'pure' NCCs from their antecedents and consequences. However, the authors almost exclusively describe different tasks (e.g., no-report tasks) that have been used to help solve this problem, rather than elaborating on how intracranial recordings may resolve this issue. The authors claim that no-report designs rely on null findings, and invasive recordings can be more sensitive to smaller effects, which can help in such cases. However, this motivation pertains to the previous sub-section (limits of noninvasive methods), since it is primarily concerned with the lack of temporal and spatial resolution of fMRI and M/EEG. It is not, in and of itself, a means to distinguish NCCs from their confounds.

As such, in its current formulation, I do not find the argument that intracranial recordings are better suited to identifying pure NCCs (i.e. separating them from pre- or post-processing) convincing. To me, this is a problem solved through novel paradigms and better-developed theories. As it stands, the paper justifies my position by highlighting task developments that help to distinguish NCCs from prerequisites and consequences, rather than giving a novel argument as to why intracranial recordings outperform noninvasive methods beyond the reasons they explained in the previous section. Again, this position is justified when, from lines 505-506, the authors describe how none of the reported single-cell studies were able to dissociate NCCs from post-perceptual processing. As such, it seems as if, even with intracranial recording, NCCs and their confounds cannot be disentangled without appropriate tasks.

The section 'Towards Better Behavioural Paradigms' is a clear attempt to address these issues and, as such, I am sure the authors share the same concerns as I am raising. Still, I remain unconvinced that the distinguishing of NCCs from pre-/post- processing is a fair motivation for using intracranial over noninvasive measures.

(2) Drawing misleading conclusions from certain studies

There are passages of the manuscript where the authors draw conclusions from studies that are not necessarily warranted by the studies they cite. For instance:

Lines 265 - 271: "The results of these two studies revealed a complex pattern: on the one hand, HGA in the lateral occipitotemporal cortex and the ventral visual cortex correlated with stimulus strength. On the other hand, it also correlated with another factor that does not appear to play a role in visibility (repetition suppression), and did not correlate with a non-sensory factor that affects visibility reports (prior exposure). These results suggest that activity in occipitotemporal cortex regions reflecting higher-order visual processing may be a precursor to the NCC but not an NCC proper."

It's possible to imagine a theory that would predict HGA could correlate with stimulus strength and repetition suppression, or that it would not correlate with prior exposure (e.g. prior exposure could impact response bias without affecting subjective visibility itself). The authors describe this exact ambiguity in interpretation later in the article (line 664), but in its current form, at least in line 270 (when the study is most extensively discussed), the manuscript heavily implies that HGA is not an NCC proper. This generates a false impression that intracranial recordings have conclusively determined that occipitotemporal HGA is not a pure NCC, which is certainly a premature conclusion.

Line 243: "Altogether, these early human intracranial studies indicate that early-latency visual processing steps, reflected in broadband and low gamma activity, occur irrespective of whether a stimulus is consciously perceived or not. They also identified a candidate NCC: later (>200 ms) activity in the occipitotemporal region responsible for higher-order visual processing."

The authors claim in this section that later (>200ms) activity in occipitotemporal regions may be a candidate for an NCC. However, the Fisch et al. (2009) study they describe in support of this conclusion found that early (~150ms) activity could dissociate conscious and unconscious processing. This would suggest that it is early processing that lays claim to perceptual consciousness. The authors explicitly describe the Fisch et al results as showing evidence for early markers of consciousness (line 240: '...exhibited an early...response following recognized vs unrecognised stimuli.) Yet only a few lines later they use this to support the conclusion that a candidate NCC is 'later (>200ms) activity in the occipitotemporal region' (line 245). As such, I am not sure what conclusion the authors want me to make from these studies.

This problem is repeated in lines 386-387: "Altogether, studies that investigated the cortical correlates of visual consciousness point to a role of neural responses starting ~250 ms after stimulus onset in the non-primary visual cortex and prefrontal cortex."

This seems to be directly in conflict with the Fisch et al results, which show that correlates of consciousness can begin ~100ms earlier than the authors state in this passage.

(3) Justifying single-neuron cortical correlates of consciousness

The purpose of the present manuscript is to highlight why and how intracortical measures of neural activity can help reveal the neural correlates of perceptual consciousness. As such, in the section 'Single-neuron cortical correlates of perceptual consciousness', I think the paper is lacking an argument as to why single-neuron research is useful when searching for the NCC. Most theories of consciousness are based around circuit or system-level analyses (e.g., global ignition, recurrent feedback, prefrontal indexing, etc.) and usually do not make predictions about single cells. Without any elaboration or argument as to why single-cell research is necessary for a science of consciousness, the research described in this section, although excellent and valuable in its own right, seems out of place in the broader discussion of NCCs. A particularly strong interpretation here could be that intracranial recordings mislead researchers into studying single cells simply because it is the finest level of analysis, rather than because it offers helpful insight into the NCCs.

(4) No mention of combined fMRI-EEG research

A minor point, but I was surprised that the authors did not mention any combined fMRI-EEG research when they were discussing the limits of noninvasive recordings. Intracortical recordings are one way to surpass the spatial and temporal resolution limits of M/EEG and fMRI respectively, but studies that combine fMRI and EEG are also an alternative means to solve this problem: by combining the spatial resolution of fMRI with the temporal resolution of EEG, researchers can - in theory - compare when and where certain activity patterns (be they univariate ERPs or multivariate patterns) arise. The authors do cite one paper (Dellert et al., 2021 JNeuro) that used this kind of setup, but they discuss it only with respect to the task and ignore the recording method. The argument for using intracranial recordings is weaker for not mentioning a viable, noninvasive alternative that resolves the same issues.

Reviewer #2 (Public review):

Summary:

In this work, the authors review the study of the neural correlates of consciousness (NCCs). They discuss several of the difficulties that researchers must face when studying NCCs, and argue that several of these difficulties can be alleviated by using intracranial recordings in humans.

They describe what constitutes an NCC, and the difficulties to distinguish between an NCC proper from the prerequisites and consequences of conscious processing.

They also describe the two main types of experimental designs used to study NCCs. These are the contrastive approach (with its report and non-report variants), and the supraliminal approach, each with its own merits and pitfalls.

They discuss the limitations of non-invasive methods, such as fMRI, EEG and MEG, as well as the limitations of the use of invasive recordings in non-human animals.

After setting the stage in this way, the authors provide an extensive review of the knowledge acquired by using invasive recordings in humans. This included population-level measurements in vision and in other sensory modalities, as well as single-neuron level studies. The authors also discuss studies of subcortical NCCs.

The second half of this work discusses the theoretical insights gained through the use of intracranial recordings, as well as their limitations, and a perspective for future work.

Strengths:

This work offers an impressive review, which will serve as a useful reference document, both for newcomers to the study of NCC and for experienced researchers. The inclusion of non-visual and subcortical NCCs is of particular merit, as these have been understudied.

Besides serving as a review, this work includes a perspective, exploring several directions to pursue for the progress of the field.

Weaknesses:

The intention of the authors is to argue how some of the problems faced when studying NCCs are alleviated by the use of intracranial recordings in humans. But in some cases, the link between the problems related to the study of NCCs and the advantages of intracranial recordings over non-invasive methods is not clear.

For example, the authors explain the difficulties in distinguishing between true NCCs from their prerequisites and consequences. This constitutes a difficult conceptual problems that plague all recording techniques. The authors don't provide a convincing explanation of how intracranial recordings offer advantages over EEG or MEG when dealing with these problems.

For example, the authors explain how the use of non-report designs to rule out post-perceptual processing relies on null results, which, according to them, are harder to interpret given the low resolution of non-invasive methods. But the interpretation of null results is actually more complicated in the case of intracranial recordings. As the coverage achieved by the electrodes is sparse, if a null result is attested, it remains possible that a true effect was present in a nearby patch of cortex out of coverage.

The authors argue that the spatial resolution of intracranial recordings is better than that of EEG and MEG. While this is technically true (especially compared to EEG), the true spatial scale of the NCCs is unknown. If NCCs' span is in the mm range, then the additional spatial resolution of intracranial recordings might not be an advantage.

Another factor that should be taken into consideration when assessing the spatial resolution of intracranial recordings is that while the listening zone of individual intracranial contacts is small, coverage is sparse and defined by clinical criteria (something that the authors discuss). In practice, the activity recorded by contacts is usually attributed to anatomically defined ROIs with a scale in the cm range. Given the sparse and uneven (across regions and patients) coverage afforded by intracranial recordings, the advantage of intracranial recordings in terms of spatial resolution is overstated.

Appraisal of whether the authors achieved their aims:

In this work, the authors have gathered an impressive review and have discussed several important problems in the field of study of NCCs, as well as provided a perspective on how the field could move forward.

What is less clear is how the use of intracranial recordings per se holds potential to overcome problems such as the distinction between true NCCs and the prerequisites and consequences of conscious processing.

Discussion of the likely impact of the work on the field:

This work has the potential of becoming a must-read for anyone working in the field of consciousness research.

Reviewer #3 (Public review):

Summary:

This narrative review provides a clear, well-structured, and comprehensive synthesis of intracerebral recording work on the neural correlates of consciousness. It is written in an accessible manner that will be useful to a broad community of researchers, from those new to iEEG to specialists in the field.

Strengths:

The manuscript successfully integrates methodological and theoretical perspectives and offers a balanced overview of current, sometimes contradicting evidence. As such, the manuscript is important as it calls for a concerted and better exploration of NCCs using iEEG in the future.

Weaknesses:

The manuscript extensively discusses the use of "report" as a criterion for identifying conscious perception and its limitations for separating between correlates of consciousness and post-consciousness processes, yet the term is not defined at the outset. The authors should specify what they mean by "report" (e.g., verbal report, nonverbal self-report, or any meta-cognitive indication of experience). Importantly, this definition should be explicitly linked to the theoretical landscape: whether the authors adopt an access-consciousness perspective in which (self) reportability is central, or whether the review also aims to address phenomenal consciousness. Making this conceptual grounding explicit at the beginning will help readers interpret the empirical work surveyed throughout the review.

In addition, the review would benefit from an earlier introduction of the distinction between states and contents of consciousness. This distinction becomes important in the later section on anaesthesia, sleep, and epileptic seizures, where the focus shifts from content-specific NCCs to alterations in global states. Presenting these definitions upfront and briefly explaining how states and contents interact would strengthen the coherence of the manuscript.

Overall, this is an excellent and timely review. With clearer initial theoretical definitions of consciousness, the manuscript will offer an even stronger conceptual framework for interpreting intracerebral studies of consciousness.

Add this text: And when we fix it, the change isn't just technical. It's the moment a leadership team stops questioning whether the numbers are real.

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AI recommends to add a Subheader before this to lead into this "solution":

Most organizations don't lose trust in Salesforce all at once. It drifts. Quietly. One workaround at a time.

OK, here I want to add a little: 1) Main text/body Once the system is stable and the foundation is sound, the question becomes: how do you keep it that way — and keep building on it?

I want to see if the other services can we placed/stretched out for the whole section, not only under the paragraph, and when you navigate - each of these would open with the following descriptions. If not possible, we can discuss alternatives:

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RevOps, Integrations, and Data Initiatives Targeted work connecting Salesforce to the rest of your tech stack, improving pipeline visibility, or establishing the data governance that makes reporting trustworthy.

AI also offered to add this section at the bottom:

"Already stable?" qualifier — new, appears at the bottom of this section:

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replace with "Meet Alesia" ( a little more personal)

Replace with:

Hmara Solutions was founded by Alesia Dvorkina. She didn't come to this work through a consulting firm or a services catalog. She built her understanding of Salesforce from the inside — as an admin, a business analyst, an architect, and eventually the leader of a large Salesforce team inside a real organization.

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Replace with "Founder Story"

Not sure if visually it is possible to make it more aligned with the text when on large screen and it shows on the right, or centered for this section. Looks OK when a small screen.

What do you think about inserting this text in the section above after the 6 "pain points"

Headline: We've seen this before. We know the way out.

The organizations we work with aren't struggling because their teams aren't smart or their leaders aren't capable. They're struggling because a CRM that was never properly structured (or was once good and has since drifted) creates pressure that compounds. Escalations. Workarounds. Reports that contradict each other. A backlog nobody owns.

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replace with "Decisions about pipeline, headcount, and growth are being made on data no one fully trusts"

I would just say line this up with the top of the photo like the other sections.

Could I see what 1.875rem looks like on these h2s?

Could I see what 1.875rem looks like on these h2s?

This just looks a little squished. Could we add a little space between these lines?

Invokes the whole of psalm 22

he could have cried one of the last words here. But I think he's just yelling

definitely unironic in matthew