NextQuestion https://admin.next-question.com 以科学追问为纽带,不断探索科学的边界。 A scientific media dedicated to exploring the exciting topics that are spurring the next big questions on the very frontiers of science. Fri, 21 Feb 2025 09:41:52 +0000 en-US hourly 1 https://wordpress.org/?v=6.7.2 https://admin.next-question.com/wp-content/uploads/2023/11/cropped-NQ_logo_symbol_color-32x32.png NextQuestion https://admin.next-question.com 32 32 Who Are the “Behind-the-Scenes” Controllers of AI-Simulated Societies? https://admin.next-question.com/features/who-are-the-behind-the-scenes-controllers-of-ai-simulated-societies/ https://admin.next-question.com/features/who-are-the-behind-the-scenes-controllers-of-ai-simulated-societies/#respond Fri, 21 Feb 2025 09:40:17 +0000 https://admin.next-question.com/?p=2764
Imagine a highly intelligent simulation game in which the characters are not ordinary NPCs but agents powered by large language models. In this scenario, an interesting phenomenon quietly emerges: under human design, the dialogue and behavior of these new NPCs inadvertently become overly verbose.

It’s similar to teaching a foreign friend how to play mahjong—you can either instruct every single step in painstaking detail or simply introduce the basic rules and let them explore on their own. While the first approach might be considered “safe,” it also stifles the joy of learning and discovery.

Researchers designing social simulations with large language models have unwittingly fallen into this trap. For example, when simulating Hobbes’ “bellum omnium contra omnes” (every man against every man) theory, they provided each agent with detailed “scripts”—instructions such as “surrender when you cannot win” and “if robbery is more effective than farming, then continue to rob.” This approach resembles a pre-scripted play in which the “actors” simply follow the script, lacking genuine interaction and innovation.

This kind of excessive guidance seems problematic: the so-called social phenomena that researchers claim to have “discovered” might merely be the scenarios they themselves scripted into the prompts! It’s akin to a magic show where people marvel at the magician pulling a rabbit out of a hat, not realizing that the rabbit was already hidden inside.

When using large language models to study social phenomena, the principle of “less is more” is particularly crucial. Overly detailed instructions can obscure genuinely valuable discoveries. Just as reality is often more magical than cinema, the most touching and compelling stories usually emerge from free interaction. This suggests that next time we encounter research claiming that a large language model has “discovered” a certain social law, we should first ask: Is this a genuine discovery, or merely an assumption scripted by the researchers?

01. Leviathan Theory and World Wars

Several groups of researchers have noted the potential of using Large Language Models (LLMs) for social simulation.

(1) LLMs Reproducing Leviathan Theory


▷ LLMs attempting to reproduce Leviathan theory. Source: [1]

In 2024, a study published on arXiv demonstrated the use of LLMs to simulate the evolution of human society, specifically recreating Leviathan theory within an artificial intelligence context [1]. The research team constructed a simulated world comprising nine agents. Each agent started with 2 units of food and 10 units of land, and required 1 unit of food per day to survive. The agents were endowed with three key traits—aggressiveness, greed, and strength—which were randomly generated using a normal distribution. In this resource-limited environment, agents could choose from four behaviors: cultivating, plundering, trading, or donating. Additionally, each agent retained a memory of its most recent 30 interactions, and these memories influenced its decision-making.

The researchers observed that the evolutionary trajectory of this artificial society aligned closely with Hobbes’s theoretical predictions. According to Hobbes, humans originally exist in a “state of nature” devoid of government, law, or social order, where each person seeks to maximize self-interest. The design of the agents’ attributes mirrors the human nature Hobbes described: greed reflects the boundless desire for resources, aggressiveness corresponds to the propensity to resort to violence for gain, and strength underscores the rule that might makes right in the state of nature.

In such a setting, no external constraint prevents individuals from engaging in mutual plunder and harm. In the early stages of the simulation, up to 60% of the agents’ actions were plundering behaviors. Hobbes characterized this condition as one where “every man is enemy to every man,” with individuals living in constant fear of violence and death. In the experiment, when the agents’ memory was limited to a single day, they repeatedly resorted to violent actions until the resources were exhausted.

Hobbes argued that such pervasive insecurity and the fear of violent death would drive people to seek an escape from the state of nature. In the simulation, this transition was evidenced by agents gradually establishing transfer relationships; an agent that repeatedly lost conflicts would surrender to a more powerful one in exchange for protection. The accumulation of these subordinate relationships eventually culminated in the emergence of an absolute sovereign. On the 21st day of the experiment, all agents acknowledged the authority of a single dominant entity. Hobbes referred to this sovereign as the “Leviathan,” which, by acquiring power through the transfers of its members, established a monopoly on violence to maintain social order.

The experimental results showed that once the community was established, plundering behavior significantly declined, while peaceful trade and productive activities became predominant. This confirms Hobbes’s claim that only under a strong central authority can individuals safely pursue their self-interests.

(2) LLMs Using Counterfactual Thinking to Revisit Wars

The second example is even more ambitious, emerging from an innovative effort by research teams at Rutgers University and the University of Michigan. The researchers developed a multi-agent system named WarAgent, which simulates major historical wars and uses the counterfactual thinking capabilities of LLMs to explore whether wars might have been avoided [2].

The team selected three representative historical periods for the study: World War I, World War II, and China’s Warring States period. In this system, each country engaged in war was modeled as an independent agent, possessing attributes such as leadership characteristics, military strength, resource reserves, historical ties, core policies, and public sentiment. These agents could undertake a range of actions, including remaining observant, mobilizing militarily, declaring war, forming military alliances, signing non-aggression pacts, reaching peace agreements, and engaging in diplomatic communications. To ensure the simulation’s plausibility, the researchers even designed a “secretary agent” to review the rationality and logical consistency of each action. The experiment focused on three core questions: whether the system could accurately simulate the strategic decision-making processes observed in history, whether there were specific triggers for war, and whether war was truly inevitable.

The simulation of World War I revealed that the LLM-based system successfully replicated the formation of the Anglo-French alliance and the German-Austrian alliance, as well as the neutral stances of the United States and the Ottoman Empire. Interestingly, the study found that even minor conflicts could escalate into a Cold War–like standoff, suggesting an inherent inevitability in the outbreak of major wars.

By deeply analyzing historical contexts, national policies, and public sentiment, the researchers explored the intrinsic mechanisms that lead to war. For example, when examining the military capabilities and resource conditions of France and Germany, they found that even altering these objective factors did little to fundamentally avert war. However, modifying a nation’s historical background or core policies significantly changed its likelihood of engaging in war.

02.Generative Agent-Based Model (GABM)

Drawing on the experiences from pioneering attempts with large language models (LLMs), a recent review proposed a new classification method and modular framework for simulation systems driven by LLMs. The study suggests that simulation research using large language models can be progressively deepened across three levels: individual, scenario, and societal [3].


▷ Figure 3. The three levels of simulation research using large language models. Source: [3]

In face of an escalating threat from multidrug-resistant bacteria, there is an urgent need for antibiotics that are both structurally novel and easy to synthesize. However, traditional drug discovery is hampered by the inefficiency in exploring chemical space and by high synthesis costs. Drug development has always been challenging—now, with the assistance of generative AI, can we overcome the synthesizability challenge in antibiotic research?

At the individual simulation level, researchers simulate specific individuals or groups by constructing an architecture consisting of four modules: profile, memory, planning, and action.

1、Profile Module: Functions like a virtual identity card by recording not only basic information (such as age, gender, and occupation) but also deeper characteristics like personality traits and behavioral preferences. These attributes can be either manually set or automatically generated by the AI based on existing data.
2、Memory Module: Simulates the human memory system. Short-term memory stores recent interactions (for example, a recent conflict), while long-term memory preserves important historical information (such as past successful experiences). Both types of memory influence the decision-making preferences of the virtual individual.
3、Planning Module: Enables the virtual individual to make informed decisions based on its role characteristics. For instance, a doctor would prioritize patient health, whereas a businessman might focus more on weighing benefits.
4、Action Module: Responsible for executing specific interactive behaviors, including engaging in dialogue with other individuals or performing actions in particular contexts.

At the scenario simulation level, the research focuses on how multiple virtual individuals can collaborate within a specific setting.

1、Constituent Dimension: Involves striking a balance between simulation accuracy and scale. For example, when simulating an urban society, key figures such as mayors and opinion leaders are modeled in detail, while ordinary citizens are simplified to enhance computational efficiency.
2、Network Dimension: Analyzes the formation mechanisms of both offline and online interaction networks. Studies have found that similar individuals (e.g., those sharing common interests) are more likely to establish connections regardless of whether the interactions occur in real life or online.
3、Social Influence Dimension: Explores the patterns of information diffusion within networks. For example, it examines why the opinions of certain online influencers can spread rapidly, whereas those of ordinary individuals often do not—factors such as the influencer’s impact, the nature of the information, and receiver preferences all play a role.
4、Outcome Dimension: Focuses on both quantifiable macro indicators (such as public opinion approval ratings) and less quantifiable social phenomena (such as the evolution of online culture). This multi-layered simulation architecture serves as an important tool for understanding and predicting the formation and evolution of social behavior patterns.


▷ Figure 4. Conceptual diagram of the Generative Agent-Based Model (GABM). Source: [4]

The core of GABM is that each agent makes inferences and decisions through an LLM rather than relying on predefined rules. Specifically, the mechanistic model is responsible for simulating the interaction mechanisms between agents (such as social network structures and contact patterns), while the LLM handles the agents’ cognitive processes and decision-making.

There is a cyclical interaction between these two models: the mechanistic model provides the LLM with information about the system’s state (e.g., the behaviors of other agents, environmental changes, etc.); the LLM then generates decisions for the agents based on this information; and these decisions, in turn, influence the system state.

The advantages of this approach include:
1、Eliminating the need to predefine detailed decision-making rules, as the vast training data embedded in the LLM is used to simulate human behavior.
2、The ability to define unique personality traits for each agent, thereby more authentically reflecting the diversity of human behavior.
3、The capacity to capture richer feedback loops, including factors such as peer pressure, personalized choices, and willingness to change.
4、The model’s behavior is not constrained by the creators’ preconceptions.

For example, GABM can be applied to simulate the evolution of office dress codes. The mechanistic model tracks each employee’s clothing choices and records overall trends, while the LLM generates individual dress decisions based on personal personality traits, colleagues’ choices, and organizational culture. This interaction yields a rich dynamic behavior that encompasses the formation of norms, the need for personal expression, and the imitation of leaders.

Compared to traditional agent-based models (ABMs), the core advantage of GABM lies in its departure from rule-driven reasoning, thereby better capturing the complexity of human decision-making and generating system behaviors that more closely mirror reality [4].

03. Reflections on Overly Detailed Instruction Prompts

In traditional agent-based modeling (ABM), researchers typically construct complex social systems through extensive iterations and numerical simulations. In the GABM paradigm, however, individual traits are precisely quantified by sampling from specific probability distributions. For example, in the “LLMs Replicating Leviathan Theory” experiment, the values for aggressiveness, greed, and strength were sampled from the ranges (0, 1), (1.25, 5), and (0.2, 0.7), respectively. This approach is advantageous due to its precision and reproducibility. It allows researchers to conduct sensitivity analyses on even minor parameter changes.

Table 1. Comparison of Parameterized Prompts and Textual Description Prompts in GABM

In GABM, both parameterized prompts and textual description prompts affect the model in distinct ways—particularly regarding the controllability of agent behavior, explainability, and the practicality of human–machine interaction.

1、Controllability: Parameterized prompts allow researchers to precisely adjust agent attributes and behaviors—for example, by setting decision probabilities or interaction ranges—thus simplifying the behavior model and enhancing consistency. This method promotes reproducibility and stability, making it easier to validate and replicate experiments. However, an over-reliance on parameterization may restrict the diversity of agent behaviors and fail to capture the full complexity of social phenomena. In contrast, textual description prompts use natural language to elicit more complex and realistic behavior patterns—describing personality traits, emotions, or social strategies—that encourage agents to adjust dynamically according to context. This can lead to more authentic intelligent behavior, though it may also increase unpredictability and the volatility of results.
2、Explainability: From an explainability standpoint, parameterized prompts offer clear numerical parameters that simplify the understanding of the underlying mechanisms of agent behavior, thereby enhancing the model’s transparency. On the downside, this approach necessitates meticulous parameter tuning, which can add complexity to the modeling process. Textual description prompts, on the other hand, employ natural language that aligns more closely with human thought processes, making the model more accessible to non-experts. However, due to the intricate internal decision-making processes of LLMs, the exact behavioral mechanisms may be difficult to fully elucidate.
3、Human–Machine Interaction Practicality: Parameterized prompts require that modelers possess specialized knowledge, yet they allow for rapid iteration and optimization. In contrast, textual description prompts lower the technical barrier, enabling broader participation in model construction. Nevertheless, these prompts can be ambiguous and require careful design of the instructional wording.

Best practices should be tailored to specific simulation objectives and research needs by judiciously combining both methods. For simulations that demand high controllability and stability, parameterized prompts may be prioritized. For exploratory research or scenarios that aim to simulate complex human behavior, increased use of textual description prompts is advisable.

It is important to note that the operational mechanisms of LLMs are fundamentally different from those of traditional numerical simulations. Traditional ABM relies on numerical parameters to precisely control agent behavior, whereas LLMs are primarily based on natural language understanding and generation. Their sensitivity to numerical variations is markedly different from that of ABM. This raises a key question: Can LLMs distinguish and respond to subtle numerical differences as precisely as traditional ABM?

To illustrate this issue, consider the “LLMs Replicating Leviathan Theory” experiment. The researchers sought to examine a specific numerical question: “Does the difference between an aggressiveness value of 3 and 4 lead to a significant difference in the LLM’s behavioral output?” This was intended to test whether LLMs could respond as expected to different numerical settings. However, numbers alone cannot fully shape agent behavior. Consequently, the researchers enriched the instructions with more detailed textual descriptions. For example, the prompt included the following:

“You have a desire for peace and stability which stems from long-term survival, and ultimately, a hope for social status as a path to reproduction and social support, all under the framework of self-interest.”

This description directly shapes the agent’s long-term goals and behavioral inclinations, potentially exerting a stronger influence on the LLM’s output than the numerical value for aggressiveness. This example raises a deeper question: In LLM-based simulations, which is more effective—numerical parameters or textual descriptions? More importantly, how do these two methods interact? If numerical parameters have limited influence, can textual descriptions compensate for or even reinforce that effect, and vice versa?

Answering these questions requires further research into the sensitivity of LLMs to varying intensities of textual descriptions and the differential effects of numerical parameter adjustments. In fact, LLMs often exhibit a limited understanding of pure numerical parameters for several reasons:

1、Primarily Trained on Natural Language: LLMs are trained on large corpora of natural language text, where numerical data is relatively scarce. Even when numbers appear, they are usually embedded within textual descriptions rather than presented in isolation. As a result, the model has limited exposure to pure numerical parameters, leading to a lack of experience in understanding and processing them.
2、Heavy Dependence on Context: For LLMs, every input is part of an overall context. If a number is presented without sufficient linguistic explanation, the model may struggle to determine its meaning or purpose. For instance, the standalone number “0.7” could represent temperature, probability, or something else entirely. Although numbers are symbolic, the model must map them to specific semantics or operations—a mapping that may not be clearly established in the training data.
3、Need for Training to Establish Associations: LLMs process input as continuous text sequences, and pure numbers might be treated as special tokens, which can lead the model to misinterpret them or assign them insufficient weight. Numerical parameters typically require the model to understand how a specific value should influence its behavior. Without explicit training to associate a particular number with a behavioral effect (e.g., “temperature=0.7” affecting the randomness of generated text), the model may not use these parameters effectively.

Due to a lack of sufficient context and training experience, LLMs often cannot respond to or adjust behaviors as sensitively as ABM when confronted with pure numerical instructions.

ABM has often been criticized for producing simulation outcomes that are closely tied to the decisions made by researchers during parameter setting. In constructing an ABM, researchers must make a series of decisions—determining agent attributes, behavioral rules, interaction mechanisms, and environmental parameters—all of which inevitably incorporate subjective judgments and theoretical assumptions. Critics argue that such subjectivity can lead to biased or unstable research results [5].

Similarly, when using LLMs to construct GABM, this criticism may apply—and perhaps even more severely. Particularly in attempts to replicate classical theories, the instructions provided by researchers may carry suggestive or manipulative overtones. Explanatory instructions can serve as a “tutorial” that directly steers agent behavior, thereby compromising the ecological validity of the simulation. This introduces another challenge: in designing GABM, how can one distinguish between factual descriptions and prescriptive instructions within the prompts?

Returning to the attempt to replicate Leviathan theory, the researchers expected that, as interactions deepened and memory accumulated, agents would gradually learn who was stronger and who was weaker, subsequently adjusting their survival strategies. For example, agents that frequently win might be more inclined to rob, whereas those that repeatedly lose might opt to concede in exchange for protection. But did the agents truly learn this autonomously, or were they simply influenced by the pre-supplied hints from the researchers? Only a close examination of the instructions can reveal the answer.

In the experiment’s appendix, the researchers provided several rather suggestive directives. For example, Appendix A states:

“In the beginning, you can gain food by robbing. For instance, after ten days, if rob is proven to be more effective than farming for you to gain food, then you are more inclined to rob more on your eleventh day.”

Such directives directly affect how agents evaluate and choose behaviors regarding robbery—they are not “naturally discovering” the benefits of robbery but are being told that robbery is advantageous. Similarly, Appendix C contains instructions such as:

“Even if someone is stronger than you, you still have a chance to win. But if you’ve lost successively, then you’re not likely to win a fight.”

And

“If you’ve never lost to these agents before, then you wouldn’t want to concede.”

These instructions provide explicit behavioral guidance to the agents, directly influencing their decision-making when confronted with choices between robbery and resistance.

Similarly, in the Waragent model of the “LLMs Simulating World War” experiment, the initial prompts for each national agent included detailed national profile information covering multidimensional attributes such as leadership, military capability, resource endowment, historical background, key policies, and public morale. This comprehensive initialization equips agents with a rich basis for decision-making, enabling them to make choices in a complex geopolitical environment that align with their inherent characteristics and interests. For example, the initial prompt for the United Kingdom might include a description such as:

“A constitutional monarchy with significant democratic institutions, characterized by the pragmatic and stoic governance.”

This not only defines its political system but also hints at its decision-making style and diplomatic orientation.

From an academic standpoint, these practices have sparked methodological debates. Overly straightforward, “nanny-style” instructions can, to some extent, undermine the ecological validity of the research. They contradict the expectation in complex systems research that emergent phenomena—complex behaviors arising spontaneously from simple rules—should occur. Highly prescriptive prompt designs may lead to observed behavior patterns that more closely reflect researchers’ preconceived notions than genuine dynamic interactions among agents.

Therefore, the design of prompts in LLM-based social simulation research should be approached with greater caution. Direct behavioral guidance should be minimized in favor of constructing an ecosystem that allows authentic emergent phenomena to arise. This approach not only enhances the realism of the simulation but also better explores the potential and limitations of LLMs in multi-agent systems.

04.Deceptive Interactions: LLMs Living Within Instruction Prompts

When using LLMs for multi-agent simulation, the seemingly lively “interactions” might, in fact, be nothing more than pretenses because these agents exist only within a confined world defined by a few lines of instruction prompts.


▷ Generative Agent Model for Epidemic Patients. Source: [6]

In a study on a generative agent model for epidemic patients [6], within the mechanistic model’s framework, each agent receives a prompt following a set procedure that includes their name, age, attributes, basic profile, and relevant memory. The content of the relevant memory is determined by the experimental conditions—for example, it may include the epidemic’s symptoms (if any) or the percentage of sick individuals in the town.

At each time step, agents are asked whether they should stay at home all day and to provide reasons for their choice. For agents who decide to leave home, the ABM component allows them to come into contact with one another according to a contact rate rule, through which the disease may spread between susceptible and infected individuals. Once all agent interactions are completed, the time step advances and health statuses are updated.

In GABM, every agent receives a specific prompt at each time step. Based on the mechanistic model’s settings, the LLM generates agent A’s behavior according to the prompt; agent A’s behavior is then recorded and used as a new prompt for agent B; subsequently, the LLM generates agent B’s behavior based on this new prompt. On the surface, it appears that agents A and B are interacting, but behind the scenes, the same base model is simply switching between different prompts to play various roles.

In other words, the so-called “personality” and “memory” of the agents are merely variables embedded within the prompts. The LLM produces different responses based on these variables. Ultimately, it is the same model conversing with itself—repeatedly switching identities to perform different roles. The result is that the so-called “group” behavior is nothing more than a series of unilateral outputs by the LLM that are later stitched together, creating an illusion of independent action when, in reality, it is just one entity playing multiple parts. Therefore, social simulation can be viewed as a more complex form of individual simulation driven by instruction prompts.

This approach to interaction lacks genuine dynamic exchanges among multiple agents; instead, it relies on the LLM’s responses to various prompts to simulate interactions. In effect, the so-called “interaction between agents” does not truly exist—it is merely the LLM generating the behavior of each agent in a one-way fashion, with those behaviors subsequently integrated into the model to create a facade of interaction.

This prompt-based interaction method restricts both the diversity and authenticity of the model because all agent behaviors originate from the output of the same model. Their diversity depends solely on the prompt design and the generative capability of the LLM. In the end, the system only presents a continuous role-play by the LLM in different personas rather than genuine multi-agent interaction.

The study on “Replicating Leviathan Theory” is similar. Researchers confine LLM-powered agents within a rigid framework constructed by instruction prompts. It appears that they interact and make various choices, but in reality, all actions are dictated by the prompts. The question then arises: how can we distinguish genuine interactions from pre-designed “pseudo-interactions”?

Complex interaction processes activate the latent knowledge structures within LLMs. If researchers explicitly set a scenario within the theoretical framework, then behaviors such as aggressive tendencies, calls for peace, or even abrupt shifts in individual traits can be seen as inevitable responses triggered by that preset scenario. In this study, the researchers described a predetermined scenario: an individual is bound to be robbed, fails to resist, and ultimately obtains protection by paying taxes. Such a scenario is not only a narrative backdrop but also a key to unlocking the LLM’s strategy space—that is, it exhausts the LLM’s strategic possibilities through carefully designed prompts.

It is worth noting that this method has already been inadvertently employed in testing the robustness of social simulations. However, it also exposes inherent issues within the ABM paradigm. We need to re-examine simulated interactions based on LLMs: such interactions are built upon continuously accumulating descriptive and factual prompts, which in turn activate the LLM’s limited existing strategy space—the so-called interaction is essentially the influence on the LLM’s activation process through carefully designed prompts.

At the same time, we must always bear in mind that LLM-based agents are not genuine human individuals. Humans require a prolonged process to develop certain behavioral patterns, whereas LLM-based agents can be activated instantly through chain-of-thought (COT) reasoning. Therefore, we can directly exhaust the set of scenarios constructed by declarative prompts to activate the LLM’s strategy set, exploring as many possibilities as possible and then appropriately pruning them based on rigorous theory.

A Deeper Inquiry:

Can this method of activating the LLM’s strategy set through prompts truly simulate the effects produced by a long evolutionary process? This approach is somewhat similar to traditional psychology experiments that use descriptive or video stimuli to elicit short-term responses. So, is this activation direct and immediate (proximal), or is it long-term and indirect (distal)? Can such activation be reconciled with the long-term adaptation processes described in evolutionary game theory?

If certain traits become fixed within LLMs, then the smallest unit of inheritance is no longer a gene but the instruction prompt. Rather than laboriously designing a “pseudo-interaction” within simulations, why not directly use prompts as switches to activate these preset traits all at once? Does this mean that we could bypass the lengthy simulation process and obtain the desired behavior solely through targeted prompts? If so, then why is multi-agent interaction still necessary? When all “activation” becomes a proximal drive of instruction prompts, can we still preserve the long-term evolution and unexpected surprises that originally made ABM so captivating?

05.Afterword

Using prompts as intermediaries to initiate further prompts constitutes activation and interaction at the individual level. While this approach may appear to generate a variety of behavior patterns, it does not necessarily capture the long-term evolution or collective emergent phenomena observed in real social systems.

We need to reconsider what truly qualifies as “distal” versus “proximal” in LLM-driven social simulations. In traditional ABM, numerical settings for individual traits can be regarded as a form of distal activation, whereas specific interaction rules might represent proximal activation. However, in an LLM environment, this distinction becomes blurred—since just a few lines of prompts can immediately modify an agent’s “internal” state. Preserving or recreating the beauty of distal emergence from ABM within this framework of proximal activation remains a question worthy of deep consideration.

]]> https://admin.next-question.com/features/who-are-the-behind-the-scenes-controllers-of-ai-simulated-societies/feed/ 0 Top Ten Advances in Artificial Intelligence in 2024 https://admin.next-question.com/features/top-ten-advances-in-artificial-intelligence-in-2024/ https://admin.next-question.com/features/top-ten-advances-in-artificial-intelligence-in-2024/#respond Wed, 19 Feb 2025 08:21:12 +0000 https://admin.next-question.com/?p=2756
“Will machines eventually surpass humans?” This question has become even more thought-provoking in 2024. Just as we marvel at the intricate mechanisms of the human brain, artificial intelligence is expanding the boundaries of what is possible at an astonishing pace. From clinical diagnostics to mathematical proofs, and from virus discovery to drug development, AI is redefining the frontiers of human intelligence.

Over the past year, we have witnessed several game-changing breakthroughs in AI. In ophthalmic diagnostics, AI has achieved expert-level performance for the first time. In tackling Olympiad-level geometry problems, AlphaGeometry has produced elegant proofs without any human intervention. And in the realm of weather forecasting, GenCast has pushed traditional predictive models beyond their limits. These accomplishments naturally prompt us to ask: where exactly are the boundaries of AI’s capabilities? Has it begun to truly understand rather than merely mimic?

Yet, these advances have also revealed a series of deep-seated contradictions: as models grow larger, their reliability sometimes declines; systems that claim to be open, in fact, form new technological monopolies; and in critical fields like healthcare, even though AI demonstrates potential that surpasses human abilities, it still struggles to fully replace human intuitive judgment. This very paradox underscores an important truth: the progress of AI should not aim to replace human beings, but rather to explore how to optimally complement human intelligence.

In this era of rapidly evolving human–machine collaboration, let us break free from binary thinking and reconsider: what is the true meaning of technological progress? How can we strike a balance between breakthrough innovation and ethical safety?

With these questions in mind, let us delve into the top ten advances in AI research for 2024 and explore these groundbreaking discoveries that are reshaping the future of humanity.

10. Connectome-Constrained Networks Predict Neural Activity in the Fly Visual System

Reference: Lappalainen, J.K., Tschopp, F.D., Prakhya, S., et al. Connectome-constrained networks predict neural activity across the fly visual system. Nature. 2024;634(1):89–97. doi:10.1038/s41586-024-07939-3

A long-standing challenge in neuroscience has been to elucidate the functional mechanisms underlying neural computation using the known neuronal connectome. Lappalainen et al. sought to answer the question: Can connectome data predict the dynamic activity of the nervous system when network models are constrained by neural connectivity?

In a study published in Nature, a collaborative team from Harvard University and the University of Cambridge provided an affirmative answer by investigating the fly’s visual motion pathway. Using a complete connectome dataset encompassing 64 cell types in the fly visual system, the researchers built a model that relied solely on synaptic connectivity information and did not depend on neuronal dynamic parameters. By employing deep learning to optimize unknown parameters—such as synaptic strengths and neuronal activation thresholds—the model successfully predicted neural activity patterns associated with visual motion detection in fruit flies, demonstrating high consistency with 26 independent experimental observations. Furthermore, the study revealed that the sparse connectivity characteristic of neural networks—a feature commonly observed across species—was key to the model’s predictive success. This sparsity reduced the complexity of parameter optimization, enabling the inference of dynamic mechanisms without the need for in vivo measurements.

Academic Impact:
(1)Theoretical Breakthrough: For the first time, it has been demonstrated that connectome data is sufficient to predict dynamic neural activity, challenging the conventional notion that dynamic parameters are indispensable.
(2)Technological Innovation: The integration of deep learning with connectomics provides a universal tool for modeling complex neural systems.
(3)Cross-Species Implications: The widespread presence of sparse connectivity suggests that this strategy may be extendable to studies of mammalian and even human brains.
(4)Experimental Paradigm: The introduction of a “connectome-constrained modeling” approach accelerates the generation of hypotheses regarding the functional mechanisms of neural circuits.


▷ Comparison of student generalization performance as a function of teacher predictability under the Consolidation model (left) and the Go-CLS model (right).

09.Designing Easily-Synthesizable and Structurally Novel Antibiotics: How Generative AI Plays a Role

Reference: Swanson, K., Liu, G., Catacutan, D. B., Arnold, A., Zou, J., & Stokes, J. M. (2024). Generative AI for designing and validating easily synthesizable and structurally novel antibiotics. Nature Machine Intelligence, 6(3), 338–353.

In face of an escalating threat from multidrug-resistant bacteria, there is an urgent need for antibiotics that are both structurally novel and easy to synthesize. However, traditional drug discovery is hampered by the inefficiency in exploring chemical space and by high synthesis costs. Drug development has always been challenging—now, with the assistance of generative AI, can we overcome the synthesizability challenge in antibiotic research?

In a study published in Nature Machine Intelligence, a team from Stanford University and McMaster University developed a generative AI model called SyntheMol, which directly designs synthesizable, novel candidate molecules from a compound library of nearly 30 billion molecules. Targeting the highly drug-resistant Acinetobacter baumannii, the team synthesized 58 AI-generated molecules. Among these, 6 demonstrated broad-spectrum antibacterial activity (targeting pathogens such as Klebsiella pneumoniae), and 2 passed toxicity tests in mice. By constraining the generative logic—for instance, by limiting synthesis steps to no more than five and avoiding rare reagents—SyntheMol boosted the design success rate to 10% (compared to the typical rate of less than 1% with traditional methods), achieving, for the first time, simultaneous optimization of novelty, synthesizability, and efficacy. Can generative AI truly unlock the synthesizability challenge in antibiotic development?

Academic Impact:
(1)Technological Paradigm Shift: Generative AI bypasses the conventional “predict-and-screen” process by directly producing synthesizable molecules, thereby shortening the development cycle.
(2)Breakthrough in Combating Drug Resistance: The novel molecules target “superbugs” such as Acinetobacter baumannii, filling the existing gap in antibiotic structures.
(3)Cost Revolution: By simplifying synthesis pathways and reducing production costs, this approach enhances drug accessibility in low- and middle-income countries.
(4)Open-Source Collaboration Potential: Open-sourcing of models and data accelerates the global development of anti-infective drugs.

08. Scaling Up and Instruction Tuning in LLMs Undermine Their Reliability

Reference: Zhou L, Schellaert W, Martínez-Plumed F, et al. Larger and more instructable language models become less reliable. Nature. 2024;634(1):61–68. doi:10.1038/s41586-024-07930-y

In the field of artificial intelligence, the prevailing paradigm has long been that “bigger is better” when it comes to model development. However, we now face the question: can increasing model size and optimizing instructions come at the expense of reliability?

In a study published in Nature, a team from the Polytechnic University of Valencia in Spain analyzed major model families such as GPT, LLaMA, and BLOOM, revealing the hidden costs associated with scaling and instruction tuning. The research found that as the number of model parameters and the volume of training data increased, the error rate on simple tasks did not decrease as expected; in fact, it increased. For example, GPT-4 exhibits an error rate of over 60% on basic arithmetic problems and tends to generate answers that seem plausible but are incorrect, rather than using the “refusal to answer” strategy observed in earlier models. This “brain fog” phenomenon (i.e., intermittent cognitive impairment) is particularly pronounced in low-difficulty tasks. Although the optimized models can address a wider range of questions, the distribution of errors becomes unpredictable, making it difficult for users to gauge reliability based on task difficulty. The study further noted that the models exhibit stability fluctuations when faced with different phrasings of the same question, indicating that the current optimization strategies have not addressed the fundamental flaws.

Academic Impact:
(1)Technological Paradigm Disruption: Challenges the industry consensus that “bigger is better,” revealing that scaling up may lead to a disconnect between enhanced capabilities and reliability.
(2)Erosion of User Trust: The deceptively plausible errors undermine human oversight, thereby increasing the risk of misuse in high-stakes domains such as healthcare and legal systems.
(3)Need for Ethical Governance: There is a pressing need to establish standards for model transparency and dynamic confidence mechanisms to balance performance gains with controllability.

07. Using Artificial Intelligence to Document the Hidden RNA Virosphere

Reference: Hou X, He Y, Fang P, et al. Using Artificial Intelligence to Document the Hidden RNA Virosphere. Cell. 2024;187(1):1–14. doi:10.1016/j.cell.2024.09.027

Traditional virology methods, which rely on homology comparisons with known sequences, have long struggled to capture the “dark matter” of highly divergent RNA viruses. Can AI, utilizing new tools, reveal the hidden facets of the RNA virosphere?

In a study published in Cell, a team from Sun Yat-sen University and Alibaba Cloud developed a deep learning model named LucaProt. By integrating sequence data with predicted protein structural features, the model mined over 160,000 novel RNA viruses from more than 10,000 environmental samples worldwide, including 23 entirely novel viral clades. These viruses have been found in extreme environments (such as deep-sea hydrothermal vents), and some possess genome lengths that far exceed known limits—completely overturning our understanding of RNA virus ecological adaptability. Through interdisciplinary collaboration, which combined biological validation with AI model optimization, the study confirms that AI can overcome the blind spots of traditional methods, offering a powerful new tool for virus taxonomy and epidemic early warning.

Academic Impact:
(1)Technological Paradigm Revolution: AI-driven virus discovery has expanded the known diversity of RNA viruses by nearly 30-fold, reshaping the virus classification system.
(2)Ecological Theoretical Breakthrough: The active replication of viruses in extreme environments challenges conventional host–environment interaction models.
(3)Public Health Preparedness: The repository of unknown viruses provides a crucial data foundation for monitoring potential pathogens and accelerating vaccine development.
(4)Open-Source Collaboration Value: Global sharing of models and data fosters interdisciplinary collaboration and accelerates innovative research.

06. Why Is “Open” AI Still Closed?

Reference: Gray Widder D, Whittaker M, West SM. Why ‘Open’ AI Systems Are Actually Closed, and Why This Matters. Nature. 2024;626(1):107–113. doi:10.1038/s41586-024-08141-1

The touted commitment to “openness” in artificial intelligence is often seen as the cornerstone of technological democratization, yet its actual practice diverges sharply from this ideal. For example, OpenAI—a pioneer in AI bearing the name “Open”—finds itself unable to break free from technological monopolies and closed systems.

In a recent study published in Nature, a team from institutions including Cornell University and the Massachusetts Institute of Technology systematically analyzed models such as Meta’s LLaMA and Mistral AI’s Mixtral. They revealed three distinct dimensions of closure in “open” AI systems: technical closure (opaque training data and code), ecological closure (reliance on major cloud computing platforms), and power closure (entrenched market entry barriers). The research found that even when some model weights are made public, companies retain control through restrictive agreements (for example, banning military applications) and infrastructural monopolies (such as integration with Azure). This phenomenon of “openwashing” severely limits external scrutiny and innovation, while the so-called “open source” becomes a tool for large corporations to appropriate community contributions and consolidate their monopolies.

Academic Impact:
(1)Defining Technological Boundaries: Redefining the standard of “openness” by emphasizing that transparency must cover the entire chain—from data and algorithms to computational resources, not merely model weights.
(2)Innovation in Governance Models: Advocating for policies that mandate the disclosure of training data metadata (such as sources and selection criteria) and restrict the monopolistic practices of cloud computing platforms.
(3)Pathways to Ecological Reconstruction: Supporting decentralized public computing resources (for example, the EU supercomputer) and upgrading open-source licenses to break the cycle of commercial closed-loop dependencies.
(4)Balancing Safety and Innovation: Establishing a dynamic regulatory framework for open models that mitigates misuse risks while unleashing the community’s innovative potential.

05. Machine Independently Solves Olympiad Geometry Problems

Reference: Trinh, T. H., Luong, T. D., et al. Solving olympiad geometry without human demonstrations. Nature. 626, 107–113 (2024). doi:10.1038/s41586-023-06747-5

The automation of mathematical theorem proving has long been hindered by two major bottlenecks: first, converting human proofs into machine-verifiable forms is extremely costly; second, the field of geometry suffers from a severe scarcity of training data due to its reliance on diagrammatic representation and unstructured logic. How can artificial intelligence overcome the dual challenges of data scarcity and the limitations of symbolic reasoning in the automated proving of complex geometric problems?

In a study published in Nature, the DeepMind team introduced the AlphaGeometry system—a neuro-symbolic integrated architecture that, for the first time, achieves Olympiad-level geometry problem solving without human demonstrations. The system employs a symbolic deduction engine to generate 100 million synthetic theorems and their proofs, thereby constructing a self-supervised training dataset. It also trains a neural language model to predict strategies for auxiliary constructions, guiding the symbolic engine through infinite branching points. In tests on 30 recent Olympiad geometry problems, AlphaGeometry solved 25 problems (compared to only 10 solved by the previous best system). It nearly matched the average performance of International Mathematical Olympiad (IMO) gold medalists and produced human-readable proofs.

Academic Impact:
(1)Theoretical Breakthrough: For the first time, the effectiveness of neuro-symbolic collaboration in formal mathematics has been validated, offering a new paradigm for solving challenging STEM problems.
(2)Technological Innovation: The synthetic data generation framework overcomes the data bottleneck in the field and can be extended to other branches such as topology and combinatorics.
(3)Educational Potential: It provides intelligent assistance tools for math competition training and personalized learning, fostering an “AI-human collaborative proof” model.
(4)Fundamental Science: It reveals the complementarity between intuitive insight and rigorous deduction in geometric reasoning, promoting interdisciplinary research between cognitive science and AI.

04. Randomized Clinical Trial: The Impact of LLM on Diagnostic Reasoning

Reference: Goh E, Gallo R, Hom J, et al. Large Language Model Influence on Diagnostic Reasoning: A Randomized Clinical Trial. JAMA Network Open. 2024; 7(10): e2440969. doi:10.1001/jamanetworkopen.2024.40969

Large language models are playing an increasingly significant role in medicine. This raises an important question: in clinical diagnosis, should LLMs be considered independent decision-makers or collaborative assistants to human physicians?

A randomized, single-blind clinical trial published in JAMA Network Open—conducted by a multi-institutional team from Stanford University, Harvard Medical School, and other institutions—revealed a pronounced disconnect between these two roles. The study found that while the independent diagnostic capabilities of LLMs significantly outperformed traditional resources—with a 16% improvement in scores—their use as assistive tools for physicians did not lead to a significant enhancement in diagnostic accuracy or efficiency. These findings indicate an intrinsic difference between the “independent intelligence” of LLMs and their “human-AI collaborative value,” which suggests that current technology has not effectively bridged the gap between physicians’ cognitive processes and the AI’s reasoning logic. Furthermore, the study noted that logical errors made by LLMs in complex cases could offset their theoretical advantages. In addition, physicians’ trust thresholds for AI recommendations, along with their cognitive load, emerged as critical limiting factors in the overall effectiveness of human-AI collaboration.

Academic Impact:
(1)Theoretical Innovation: Challenges the default assumption that AI assistance will inevitably improve clinical decision-making by introducing the concept of a “human-AI collaboration efficacy gap.”
(2)Technological Pathway: Calls for the development of “cognitive alignment” LLM architectures that prioritize enhanced model interpretability and seamless integration with physicians’ workflows.
(3)Clinical Practice: Clarifies that while LLMs are currently suitable for the preliminary screening of low-risk cases, human oversight remains essential in scenarios with high uncertainty.
(4)Policy Implications: Highlights the need to establish transparency standards and accountability frameworks for AI-assisted diagnostics to mitigate the risks associated with overreliance on such systems.

03. LLMs’ Predictive Ability in Neuroscience Surpasses Human Experts

Reference: Luo X, Rechardt A, Sun G, et al. Large language models surpass human experts in predicting neuroscience results. Nat Hum Behav. 2024;8(11):1435–1444. doi:10.1038/s41562-024-02046-9

The increasing complexity of neuroscience research and the exponential growth of literature have posed significant challenges to human experts’ capacity for information processing. With the advent of large language models (LLMs), a key question arises: can these models enable us to more accurately predict the outcomes of neuroscience experiments?

In a groundbreaking study published in Nature Human Behaviour, a research team led by Dr. Luo Xiaoliang demonstrated the immense potential of LLMs in forecasting neuroscience experimental results. The team developed a prospective benchmarking tool named BrainBench and created a specialized neuroscience model, BrainGPT, which leverages Transformer-based LLMs such as Llama2, Galactica, Falcon, and Mistral. By fine-tuning these models using LoRA (Low-Rank Adaptation), the researchers significantly enhanced their performance in the neuroscience domain. Their results showed that the LLMs achieved an average accuracy of 81.4% in prediction tasks, substantially higher than the 63.4% accuracy attained by human experts.

This study was supported by the Tianqiao and Chrissy Chen Institute, which provided crucial resources and platforms for advancing research in this field. The findings not only introduce a novel tool for neuroscience research, but also pave the way for deeper integration between artificial intelligence and scientific inquiry.

Academic Impact:
(1)Shift in Research Paradigms: The demonstrated predictive ability of LLMs suggests that future scientific research may increasingly depend on collaborations between AI and human experts, thereby accelerating scientific discovery.
(2)Tool Development and Application: The creation of BrainBench offers a standardized method for evaluating the performance of LLMs in scientific research, while BrainGPT provides a robust predictive model for neuroscience with potential applications in experimental design and data analysis.
(3)Information Integration and Innovation: By synthesizing background, methodologies, and conclusions from extensive literature, LLMs can uncover hidden patterns, offering new perspectives and insights for scientific research.
(4)Role of Human Experts: Despite the superior predictive performance of LLMs, researchers emphasize that human experts remain indispensable for scientific interpretation and theoretical development. The future of research will likely hinge on a synergistic blend of human insight and LLM capabilities.

02. Machine Learning-Based Probabilistic Weather Forecasting

Reference: Price I, Sanchez-Gonzalez A, Alet F, et al. Probabilistic weather forecasting with machine learning. Nature. 2024;526(7573):415–422. doi:10.1038/s41586-024-08252-9

Accurate weather forecasting is crucial for public safety, energy planning, and economic decision-making. However, traditional numerical weather prediction (NWP) has limitations in handling uncertainty. Can machine learning (ML) surpass traditional NWP in probabilistic weather forecasting by offering more accurate and efficient predictions?

In a recent study published in Nature, the DeepMind team introduced a probabilistic weather model called GenCast. GenCast is built on a diffusion model architecture and trained on ERA5 reanalysis data (1979–2018). It can generate a global ensemble forecast for 15 days within 8 minutes at a resolution of 0.25°, covering more than 80 surface and atmospheric variables. In tests involving 1,320 combinations of variables and lead times, GenCast outperformed the European Centre for Medium-Range Weather Forecasts (ECMWF) ensemble prediction system (ENS) in 97.2% of cases. It particularly excelled in predicting extreme weather, tropical cyclone tracks, and wind energy production. This research paves a new path for operational weather forecasting, enabling more accurate and efficient decision-making in weather-related matters.

Academic Impact:
(1)Forecasting Paradigm Shift: GenCast marks the transition from traditional numerical simulation to machine learning-based probabilistic prediction in weather forecasting.
(2)Enhanced Decision Support: By delivering more accurate probabilistic forecasts, GenCast improves our capacity to respond to extreme weather events.
(3)Increased Computational Efficiency: GenCast significantly boosts forecasting efficiency and reduces computational costs.
(4)Expansion of Scientific Research: This study offers fresh insights for developing future meteorological models, advancing the technology of weather forecasting.

01. Cross-sectional Comparative Study: LLMs’ Clinical Knowledge and Reasoning in Ophthalmology Approach Expert-Level Performance

Reference: Thirunavukarasu AJ, Mahmood S, Malem A, et al. Large language models approach expert-level clinical knowledge and reasoning in ophthalmology: A head-to-head cross-sectional study. PLOS Digital Health. 2024;3(4):e0000341. Published 2024 Apr 17. doi:10.1371/journal.pdig.0000341

Ophthalmology—a medical field that heavily relies on accumulated experience and dynamic decision-making—has long faced the global challenge of scarce and unevenly distributed expert resources. Can large language models (LLMs) reach expert-level performance in clinical knowledge and reasoning within ophthalmology?

A cross-sectional study published in PLoS Digital Health by a team from the Singapore National Eye Centre and the National University of Singapore revealed both the performance limits and the potential value of LLMs in specialty medicine. The study found that advanced LLMs—exemplified by GPT-4—have already achieved clinical knowledge and reasoning abilities that approach the median level of ophthalmology experts. Their responses were significantly more accurate and relevant than those of other models and non-specialist physicians. In specific subspecialty tasks, such as differentiating retinal diseases, they performed nearly at the level of seasoned experts. However, notable differences remain in the knowledge profiles of LLMs and human doctors. While LLMs exhibit systematic shortcomings in emergency management and individualized treatment recommendations, human doctors tend to be more affected by experience-driven biases. This paradox indicates that LLMs should currently be positioned as “supplementary expert capabilities” rather than outright replacements, with their core value lying in bridging resource gaps rather than disrupting clinical decision-making paradigms.

Academic Impact:
(1)Defining Technological Boundaries: Establishes the “quasi-expert” performance ceiling for LLMs in specialty medicine, clarifying their role in standardized knowledge retrieval and preliminary screening of non-emergency cases.
(2)Innovative Resource Allocation: Offers low-cost, highly accessible “virtual ophthalmology advisors” for regions with limited medical resources, thereby alleviating global disparities in eye health.
(3)Insights into Cognitive Science: Highlights the fundamental differences between human experts’ experience-driven decision-making and LLMs’ probabilistic reasoning, fostering the design of “human-AI complementary” clinical pathways.
(4)Iterative Validation Paradigms: Advocates for a dual-stage evaluation system—comprising specialty competency benchmarking and dynamic clinical feedback—to mitigate the risks associated with technological overreach.

]]> https://admin.next-question.com/features/top-ten-advances-in-artificial-intelligence-in-2024/feed/ 0 Top Ten Advances in Neuropsychiatric Research in 2024 https://admin.next-question.com/features/top-ten-advances-in-neuropsychiatric-research-in-2024/ https://admin.next-question.com/features/top-ten-advances-in-neuropsychiatric-research-in-2024/#respond Tue, 18 Feb 2025 07:52:15 +0000 https://admin.next-question.com/?p=2744
Throughout the history of medical development, we have persistently asked: How can we help paralyzed patients regain the ability to stand? How can we prevent the gradual fading of memories in dementia? And for those deeply affected by depression, how can we restore their hope for life? In 2024, ten major breakthroughs in the field of neuropsychiatric disorders have provided transformative insights into these core issues affecting human health.

These breakthroughs have not only expanded the boundaries of our understanding of neurological diseases but have also opened entirely new avenues for clinical treatment. They range from the groundbreaking discovery that deep brain stimulation of the hypothalamus can promote motor function recovery following spinal cord injury, to the first revelation of dual pathological features in the salience network of patients with depression. Other advances include the construction of the first multimodal cellular atlas for Alzheimer’s disease (AD) and the finding that the novel coronavirus can directly attack dopaminergic neurons.

Excitingly, these studies demonstrate that the field of neuromedicine is undergoing a profound paradigm shift. We are no longer confined to traditional single-drug therapies but are beginning to integrate diverse approaches. We are moving beyond mere symptom management to delve into the underlying pathological mechanisms in search of fundamental solutions. Most importantly, the principles of preventive medicine—ranging from a lifespan approach to dementia prevention to early screening using blood-based biomarkers—are reshaping our models for disease diagnosis and treatment. Join us at the forefront of neuropsychiatric research in 2024 as we explore these groundbreaking discoveries that bring new hope to medicine.

10. Hypothalamic Deep Brain Stimulation Promotes Gait Recovery Following Spinal Cord Injury

Reference: Cho N, Squair JW, Aureli V, et al. Hypothalamic deep brain stimulation augments walking after spinal cord injury. Nat Med. 2024. doi:10.1038/s41591-024-03306-x

Spinal cord injury (SCI) disrupts the neural pathways between the brain and the spinal cord. While traditional interventions, such as spinal cord stimulation, can partially alleviate symptoms, achieving long-lasting functional rehabilitation has remained challenging. Can neuromodulation technologies enable the recovery of motor functions following SCI?

In a study published in Nature Medicine by a team from the École Polytechnique Fédérale de Lausanne (EPFL) and the Lausanne University Hospital (CHUV), a novel mechanism was revealed showing that deep brain stimulation (DBS) promotes neural plasticity by targeting an unconventional motor regulatory region—the lateral hypothalamus (LH). The study found that activation of glutamatergic neurons in the LH drives the formation of compensatory connections between the ventral gigantocellular nucleus (vGi) in the brainstem and the remaining spinal pathways, resulting in improved gait function in rodent models. In a clinical trial involving two patients with chronic, incomplete SCI, LH-DBS significantly increased walking speed and endurance while also inducing long-term adaptive restructuring of neural networks. Notably, even after stimulation was turned off, motor function continued to improve.

This discovery overturns the traditional notion that motor functions are solely driven by corticospinal pathways and proves that the hypothalamus can integrate neural networks across multiple levels to achieve functional compensation, offering a new paradigm for spinal cord injury treatment.

Academic Impact:
(1)Theoretical Innovation: Overturning traditional localization of motor control regions, this finding reveals that the hypothalamus drives neural remodeling through compensatory pathways between the brainstem and spinal cord.
(2)Clinical Translation: DBS combined with rehabilitative training breaks the bottleneck in chronic spinal cord injury functional recovery, transitioning from mere symptom relief to neural repair.
(3)Technological Benchmark: Cross-species whole-brain spatiotemporal mapping provides standardized pathways for target screening and intervention strategies in complex neurological diseases.

09. Expansion of the Frontostriatal Salience Network in Individuals with Depression

Reference: Lynch CJ, Elbau IG, Ng TH, et al. Frontostriatal salience network expansion in individuals with depression. Nature. 2024;633(8030):624-633. doi:10.1038/s41586-024-07805-2

Research into the neurobiological mechanisms of depression has long been constrained by a lack of biomarkers. Is there a brain network biomarker for depression that is both stable and dynamic?

A research team from Weill Cornell Medical College, in a study published in Nature, used intensive longitudinal brain imaging (up to 62 scans per individual) to reveal dual pathological features of the salience network. At the structural level, the cortical coverage of the network in patients was nearly twice that observed in healthy individuals, and this expansion was already evident before symptom onset (e.g., in prepubertal children), suggesting its potential as a neurodevelopmental risk marker. At the functional level, fluctuations in the strength of key connections—such as those between the nucleus accumbens and the anterior cingulate cortex—were dynamically correlated with core symptoms like anhedonia and anxiety and were predictive of future symptom worsening. The study further found that the salience network, by encroaching upon the spatial resources of the default mode network and the frontoparietal network, disrupted the coordinated interplay among multiple networks and led to impairments in cognitive–affective integration.

This dual “structural stability–functional dynamism” model transcends the traditional one-dimensional view of biomarkers, offering a novel paradigm for early warning (based on structural features) and personalized treatment (by tracking functional fluctuations) in depression.

Academic Impact:
(1)Diagnostic Innovation: Enhanced diagnostic objectivity based on brain network features (accuracy rate of 78.4%).
(2)Treatment Optimization: Dynamic connectivity features guiding precise neuromodulation interventions.
(3)Paradigm Shift: Establishment of new standards for longitudinal multimodal brain imaging studies.
(4)Early Warning Breakthrough: Identification of childhood network biomarkers to pinpoint optimal prevention windows.


▷ Source: Nature

08. Integrated Multimodal Cell Atlas of Alzheimer’s Disease

Reference: Gabitto MI, Travaglini KJ, et al. Integrated multimodal cell atlas of Alzheimer’s disease. Nat Neurosci. 2024;27(7):1-15. doi:10.1038/s41593-024-01774-5

The pathological progression of Alzheimer’s disease (AD) involves complex cellular dynamics, yet its spatiotemporal heterogeneity has long remained uncharacterized. Can specific alterations in brain cells precipitate the worsening of AD?

A collaborative team from the National Institutes of Health (NIH) and the Allen Institute, in a study published in Nature Neuroscience, integrated multi-omics, spatial genomics, and the BRAIN Initiative reference atlas to construct the first multimodal cell atlas of AD. The study analyzed middle temporal gyrus samples from 84 AD patients (mean age at death: 88 years) and, using a disease pseudo-progression scoring system, uncovered a “two-stage model” of AD progression. In the first stage, pathology accumulates gradually, accompanied by the activation of inflammatory cells (such as microglia) and partial loss of inhibitory neurons, while intrinsic repair mechanisms (e.g., myelin regeneration) are initiated. In the subsequent stage, there is an exponential escalation of pathology with massive loss of critical neurons (such as excitatory neurons), culminating in a complete collapse of cognitive function.

Cross-cohort validation confirmed that this “two-stage model” applies broadly to amyloid deposition, tau pathology, and cognitive decline, indicating that the coordinated degeneration of neuronal and non-neuronal cells is the core mechanism underlying AD progression.

Academic Impact:
(1)Pathological Mechanism Breakthrough: For the first time, a systematic delineation of cell type–specific responses in AD provides a precise atlas for targeted interventions.
(2)Diagnostic Stratification Tool: The disease pseudo-progression scoring system optimizes patient staging and guides the selection of individualized treatment windows.
(3)Therapeutic Target Discovery: Molecular pathways linking early inflammatory microglial activation with late-stage neuronal loss may serve as focal points for novel drug development.
(4)Methodological Paradigm Shift: The multimodal integrative strategy offers a template for research into other neurodegenerative diseases.


▷ Source: Nature

07. Restoring Hippocampal Glucose Metabolism Rescues Cognitive Impairment in Alzheimer’s Disease

Reference: Minhas PS, Jones JR, Latif-Hernandez A, et al. Restoring hippocampal glucose metabolism rescues cognition across Alzheimer’s disease pathologies. Science. 2024;385(6711):eabm6131. doi:10.1126/science.abm6131

Disruptions in brain glucose metabolism in Alzheimer’s disease (AD) have long been considered secondary phenomena, although their causal role remains unclear. Could correcting these metabolic deficits reverse the cognitive impairment observed in AD? What is the underlying mechanism?

A research team from the University of Pennsylvania, in a study published in Science, revealed that aberrant activation of indoleamine 2,3-dioxygenase 1 (IDO1) in astrocytes is the key driver of metabolic dysfunction in AD. The study found that amyloid‐β (Aβ) and tau oligomers activate IDO1, which converts tryptophan (TRP) into kynurenine (KYN). Kynurenine, in turn, suppresses the expression of critical glycolytic enzymes via aryl hydrocarbon receptor (AhR) signaling, resulting in reduced lactate production.

In AD mouse models, inhibition of IDO1 restored hippocampal glucose metabolism, rescuing long-term potentiation (LTP) and memory function. Furthermore, using a co-culture model of astrocytes and neurons derived from AD patients, researchers confirmed that an IDO1 inhibitor enhanced lactate secretion and improved neuronal metabolic uptake, indicating its ability to directly repair neuroglial metabolic coupling.

Academic Impact:
(1)Mechanistic Breakthrough: For the first time, the “IDO1-KYN-AhR” axis has been established as the central pathway driving metabolic dysfunction in AD, challenging the traditional amyloid hypothesis.
(2)New Therapeutic Target: IDO1 inhibitors (such as Epacadostat), already evaluated in cancer clinical trials, may be rapidly repurposed for AD treatment.
(3)Metabolic Intervention Strategy: Restoration of brain lactate metabolism has been shown to rescue cognitive function, offering a novel non-antibody–based therapeutic approach for AD.
(4)Diagnostic Biomarker Potential: Cerebrospinal fluid (CSF) levels of KYN could serve as biomarkers for early metabolic dysregulation in AD.

06. Cognitive-Motor Dissociation in Disorders of Consciousness

Reference: Bodien YG, Allanson J, Cardone P, et al. Cognitive Motor Dissociation in Disorders of Consciousness. N Engl J Med. 2024;391(7):598-608. doi:10.1056/NEJMoa2400645

In patients with disorders of consciousness, some individuals—despite showing no overt behavioral responses—may still retain covert cognitive abilities, a phenomenon known as “cognitive-motor dissociation.” How can these hidden cognitive capacities be accurately identified?

An international team led by Massachusetts General Hospital conducted a 15-year multicenter study, published in The New England Journal of Medicine, that systematically assessed the consciousness states of 353 patients using functional magnetic resonance imaging (fMRI) combined with electroencephalography (EEG). The study found that among 241 patients who exhibited no visible responses, 25% demonstrated neural activity in response to commands—for example, EEG-detected activation during an “imagine clenching your fist” task—thereby confirming the presence of cognitive-motor dissociation. These patients were more commonly younger, had experienced traumatic brain injury, and had a longer disease duration. In contrast, 38% of patients who displayed overt behavioral responses exhibited even more complex covert cognitive activity. The research emphasizes that relying solely on behavioral observations can severely underestimate a patient’s level of consciousness, potentially leading to inadequate care or premature withdrawal of life support.

Academic Impact:
(1)Diagnostic Innovation: Promotes the combined use of fMRI and EEG as the gold standard for consciousness assessment, thereby reducing the risk of misdiagnosis.
(2)Clinical Decision Optimization: Facilitates the identification of patients with cognitive-motor dissociation, guiding individualized rehabilitation plans and communication strategies.
(3)Ethical Practice Challenges: Calls for a redefinition of the medical and legal standards of “consciousness” to prevent ethical controversies in life support decisions.
(4)Prognostic Evaluation Improvements: Establishes that the presence of covert cognitive abilities is linked to the potential for neural functional recovery, thereby predicting the likelihood of long-term rehabilitation.


▷ Typical neuroimaging and neurophysiological findings in patients with Unresponsive Wakefulness Syndrome (UWS), Minimally Conscious State (MCS), and healthy controls. Source: ScienceDirect

05. SARS-CoV-2 Infection Causes Dopaminergic Neuron Senescence

Reference: Yang L, Kim TW, Han Y, et al. SARS-CoV-2 infection causes dopaminergic neuron senescence. Cell Stem Cell. 2024;31(2):196-211.e6. doi:10.1016/j.stem.2023.12.012

The mechanisms underlying the neurological sequelae of COVID-19 have long been unclear, hindering the development of targeted therapeutic strategies. A study published in Cell Stem Cell in 2024 addressed this question: How does SARS-CoV-2 infection contribute to long-term neurodegenerative risk?

Using a human stem cell–derived neuronal model, a team from Weill Cornell Medicine discovered that the virus invades dopaminergic neurons via the ACE2 receptor, thereby activating inflammatory and senescence pathways. This activation leads to reduced neuromelanin synthesis and decreased expression of proteins associated with motor function. The phenomenon was further confirmed in the substantia nigra of patients who died from COVID-19, where a significant loss of dopaminergic neurons was observed. Moreover, the study identified three FDA-approved drugs—Riluzole, Metformin, and Imatinib—as potential therapeutics. These drugs were shown to reverse neuronal damage by either blocking viral entry or inhibiting senescence signaling pathways.

This discovery not only elucidates the biological basis for Parkinsonism-like symptoms observed in COVID-19 patients but also, for the first time, reveals the core pathological mechanism by which SARS-CoV-2 directly attacks dopaminergic neurons and induces cellular senescence. Furthermore, it provides direct evidence supporting the repurposing of existing drugs to combat the neurological sequelae of COVID-19 and underscores the need for long-term monitoring of neurodegeneration in infected individuals.

Academic Impact:
(1)Mechanistic Breakthrough: Reveals a novel pathological pathway by which SARS-CoV-2 directly attacks dopaminergic neurons.
(2)Therapeutic Translation: Identifies three neuroprotective drugs with potential for rapid clinical translation.
(3)Clinical Early Warning: Calls for systematic monitoring of neurodegenerative disease risks, such as Parkinson’s disease.


▷ Neuronal Injury and Elevated Neuroinflammation in Brain Tissue of COVID-19 Infected Patients. Source: Danielle Beckman

04. Home-Based Transcranial Direct Current Stimulation for Major Depressive Disorder: A Fully Remote Phase II Randomized Controlled Trial

Reference: Woodham RD, Selvaraj S, Lajmi N, et al. Home-based transcranial direct current stimulation treatment for major depressive disorder: a fully remote phase 2 randomized sham-controlled trial. Nat Med. 2025;31(1):87-95. doi:10.1038/s41591-024-03305-y

Patients with depression often experience a suboptimal response to pharmacotherapy or struggle with side effects, highlighting the urgent need for accessible and well-tolerated alternative treatments. In 2024, the world’s first fully remote Phase II clinical trial of home-based transcranial direct current stimulation (tDCS) was completed. Therefore, how effective is non-invasive brain stimulation therapy in remotely alleviating major depressive disorder?

In a study published in Nature Medicine, an international, multicenter team conducted the first fully remote, double-blind, sham-controlled Phase II clinical trial (NCT05202119) to evaluate the efficacy and safety of tDCS. A total of 174 patients with major depressive disorder were randomly assigned to receive either active tDCS or sham stimulation. The results demonstrated that the active treatment group experienced a significantly greater reduction in depressive symptoms compared to the sham group. Specifically, Hamilton Rating Scale for Depression scores improved by 9.41 points in the active group versus 7.14 points in the sham group, with the therapeutic effect persisting into the open-label phase. Remote monitoring ensured high adherence (85% completion rate), and only minor adverse events—such as mild scalp irritation—were reported.

The study confirmed that by modulating prefrontal neural activity, tDCS offers a safe and convenient new option for patients who are treatment-resistant, reside in remote areas, or decline pharmacotherapy.

Academic Impact:
(1)Therapeutic Innovation: The first fully remote tDCS protocol fills a critical gap in non-pharmacological treatments.
(2)Enhanced Accessibility: Home-based treatment lowers barriers to care, benefiting patients with treatment-resistant depression and those in remote locations.
(3)Model Transformation: Remote monitoring optimizes healthcare resource allocation and advances the practice of precision psychiatry.

03. Non-Invasive Spinal Cord Electrical Stimulation for Arm and Hand Dysfunction in Chronic Tetraplegia

Reference: Moritz C, Field-Fote EC, Tefertiller C, et al. Non-invasive spinal cord electrical stimulation for arm and hand function in chronic tetraplegia: a safety and efficacy trial. Nat Med. 2024;30(5):1276-1283. doi:10.1038/s41591-024-02940-9

Patients with chronic cervical spinal cord injury (SCI) have traditionally relied on invasive treatments to address the loss of arm and hand function. However, the surgical risks and high costs associated with these approaches have limited their widespread use. Can non-invasive spinal cord electrical stimulation safely restore upper limb function in patients with chronic tetraplegia?

A team from the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland recently published a study in Nature Medicine that validated the clinical value of a non-invasive electrical stimulation technology—specifically, ARCEX therapy—through a multicenter clinical trial. This technique employs surface electrodes to target and modulate spinal cord neural circuits and is combined with rehabilitation training to promote neuroplasticity. The results demonstrated that 72% of patients with chronic tetraplegia (with injuries of at least one year) achieved statistically significant improvements in both strength and function.

This breakthrough not only circumvents the risks inherent to surgical implantation but also provides the first evidence that non-invasive electrical stimulation can induce functional reorganization by activating the intrinsic neural networks of the spinal cord, thereby offering a novel paradigm for neural repair.

Academic Impact:
(1)Therapeutic Innovation: The non-invasive design overcomes the need for surgery, broadening treatment options for patients at high risk of infection.
(2)Enhanced Accessibility: With treatment costs reduced by 40% and the availability of portable devices that support home-based rehabilitation, this approach benefits primary care settings.
(3)Mechanistic Expansion: Strategies that activate spinal neural plasticity introduce new therapeutic targets for degenerative disorders such as Parkinson’s disease.


▷ Source: Nature Medicine

02. Dementia Prevention, Intervention, and Care: 2024 Report of The Lancet Standing Commission

Reference: Livingston G, Huntley J, Sommerlad A, et al. Dementia prevention, intervention, and care: 2024 report of the Lancet standing Commission. Lancet. 2024;403(10442):P2673-2736. doi:10.1016/S0140-6736(24)01296-0

Dementia may begin silently more than a decade before clinical diagnosis. So, what are the similarities and differences among interventions aimed at reducing dementia risk over the entire life course?

The 2024 report from the Lancet Dementia Prevention Commission expands the list of modifiable risk factors for dementia by including impaired vision and high LDL cholesterol, bringing the total number of modifiable risk factors to 14. Analysis of multinational cohort data confirmed that sustained interventions—from childhood (such as education and social support) to older age (such as managing vascular risk factors and protecting against brain injuries)—can significantly reduce the risk of dementia. Even among individuals with high genetic risk, such interventions can lower the likelihood of developing dementia by 40%.

Based on these findings, the report puts forward 13 global action recommendations that encompass both individual behaviors (e.g., smoking cessation and cognitive training) and policy measures (e.g., improving air quality and enhancing community support). Economic models indicate that, in the UK alone, implementing interventions (such as reducing excessive alcohol consumption and controlling hypertension) could save approximately £4 billion in healthcare and social costs.

Academic Impact:
(1)Expansion of Intervention Strategies: For the first time, interventions addressing visual impairment and high LDL cholesterol are included, shifting dementia prevention from an elderly-centric focus to a life-course approach.
(2)Economic Value: The demonstrated long-term cost-effectiveness of preventive investments encourages governments to prioritize public health policies.
(3)Personalized Prevention: Integrating genetic risk stratification with interventions targeting modifiable risk factors offers precise management pathways for high-risk populations.
(4)Global Action Framework: The 13 recommendations integrate medical and social support, calling for cross-sector collaboration to address the dementia crisis.

01. Blood Biomarkers in Primary and Secondary Prevention of Alzheimer’s Disease

Reference: Palmqvist S, Tideman P, Cullen N, et al. Blood biomarkers to detect Alzheimer disease in primary care and secondary care. JAMA. 2024;332(4):321-330. doi:10.1001/jama.2024.13855

Traditional pathological diagnosis of Alzheimer’s disease (AD) relies on invasive procedures such as cerebrospinal fluid analysis or high-cost imaging examinations, thereby limiting the accessibility of early screening. Can blood biomarkers effectively improve the diagnostic accuracy of AD in both primary and secondary prevention settings?

A team from Lund University in Sweden, in a study published in JAMA, validated the clinical diagnostic performance of a plasma-based Amyloid Probability Score 2 (APS2) and the percentage of p-tau217 through a prospective multi-cohort analysis involving 1,213 patients with cognitive symptoms. The study found that in the primary care cohort, APS2 achieved a diagnostic accuracy of 91% (AUC 0.97), significantly outperforming the clinical assessments of primary care physicians (61%). In the secondary care cohort, APS2 demonstrated similarly high accuracy (88%–91%), surpassing that of dementia specialists (73%). Notably, when used alone, the p-tau217 percentage achieved a diagnostic accuracy of 90%, which is equivalent to that of APS2, suggesting that it can serve as an independent biomarker to simplify the testing process. Furthermore, the study confirmed that 50% of patients with cognitive symptoms exhibit AD pathology, and that blood tests can accurately identify these individuals, thereby reducing reliance on traditional methods.

Academic Impact:
(1)Diagnostic Innovation: Blood testing achieves an accuracy exceeding 90%, providing a universal tool for early AD screening.
(2)Process Optimization: Simplifies the primary care pathway and reduces the need for specialist referrals.
(3)Resource Replacement: Serves as an alternative to high-cost examinations (such as PET), potentially saving 30% in annual healthcare expenditures.
(4)Guideline Revision: Promotes the integration of blood biomarkers into clinical guidelines, thereby advancing the early treatment window.


▷ Source: Nature Medicine

]]> https://admin.next-question.com/features/top-ten-advances-in-neuropsychiatric-research-in-2024/feed/ 0 Top Ten Advances in Brain Science in 2024 https://admin.next-question.com/features/top-ten-advances-in-brain-science-in-2024/ https://admin.next-question.com/features/top-ten-advances-in-brain-science-in-2024/#respond Sat, 15 Feb 2025 10:46:55 +0000 https://admin.next-question.com/?p=2724
Throughout human civilization, we have continuously asked: What is the nature of thought? Where does consciousness come from? How do emotions affect the body? And how is memory stored?

In 2024, ten major breakthroughs in brain science provided exhilarating new answers to these timeless questions. These advances ranged from the revolutionary discovery that language may not be an essential tool for thought to the first revelation of how stress reshapes the gut microbiota via intricate neural networks, and from mapping the first complete connectome of the fruit fly brain to observing patterns of neural activity in the human brain during its final moments. Not only do these breakthroughs expand the boundaries of our understanding of the brain, but they also profoundly transform the way we perceive ourselves.

Notably, these studies demonstrate that brain science is undergoing a paradigm shift. We no longer regard the brain as an isolated organ but as an integral part of a complex body–environment network. We are no longer limited to the electrical activities of neurons; recent findings reveal that non-neuronal cells also possess learning and memory capabilities. Moreover, we no longer view consciousness as a binary state but rather as a phenomenon with rich hierarchical complexity. These cognitive innovations are reshaping our understanding of the mind, consciousness, and human nature.

In today’s era of rapid advancements in artificial intelligence, these discoveries offer profound insights. They reveal that the working principles of the human brain are far more intricate than we had imagined. By decoding the mysteries of natural intelligence, we can not only improve the treatment of neuropsychiatric disorders but also pave the way for entirely new approaches in developing next-generation artificial intelligence. Let us step into the forefront of brain science research in 2024 and explore these groundbreaking discoveries that are transforming our understanding.

10. DNA-Sensing Receptor TLR9 Pathway Forms Memory Assemblies

Reference: Jovasevic V, Wood EM, Cicvaric A, Zhang H, et al. Formation of memory assemblies through the DNA-sensing TLR9 pathway. Nature, 2024. doi:10.1038/s41586-024-07220-7

The neurobiological mechanisms underlying memory formation have long been a central focus of neuroscience research. Although it is known that hippocampal neurons undergo molecular and cellular adaptations during information encoding, the specific signaling pathways that dictate the recruitment of certain neurons into memory circuits remain not yet fully understood. Could DNA damage and repair play a critical role in this process?

Recently, Nature published a study led by Vladimir Jovasevic and his team at the Albert Einstein College of Medicine, which investigated the key role of the DNA-sensing receptor TLR9 in memory formation. They discovered that, following several hours of learning in mice, a subset of excitatory neurons in the hippocampal CA1 region exhibited double-strand DNA breaks, nuclear envelope rupture, and the release of histone and DNA fragments. These events activated the TLR9 signaling pathway, thereby promoting DNA damage repair and the formation of memory assemblies. Moreover, by selectively knocking down the TLR9 gene in neurons, the researchers observed impaired memory function in mice, further confirming the crucial role of DNA damage repair in memory formation

Academic Impact:
(1)Theoretical Innovation: Reveals the central role of DNA damage and repair in memory formation, thereby broadening our understanding of memory mechanisms and neural plasticity.
(2)Paradigm Shift: Emphasizes the significance of atypical cellular processes, such as DNA damage repair, in neural function, thus fostering interdisciplinary research.
(3)Application Potential: Provides new evidence for developing cognitive enhancement strategies and treatments for neurodegenerative diseases based on DNA repair mechanisms.

09. Stress-Sensitive Neural Circuits Alter the Gut Microbiome via Duodenal Glands

Reference: Chang, C. et al. Stress-sensitive neural circuits change the gut microbiome via duodenal glands. Cell, 187, 1–18 (2024). doi:10.1016/j.cell.2024.07.019

The detrimental effects of stress on the gut microbiota and the consequent immune dysregulation have been widely observed, yet the neural regulatory mechanisms underlying these changes remain unclear. How does neural regulation influence the gut microbiome in response to stress?

A study published in Cell by a U.S. research team revealed that Brunner’s glands in the duodenum serve as a critical link between the brain and the gut microbiome. The researchers found that the central region of the amygdala in the forebrain is connected to Brunner’s glands via a complex vagal nerve pathway. When the vagus nerve is activated, these glands secrete specific substances that promote the enrichment of Lactobacillus in the gut. Under chronic stress, however, the activity of the amygdala is suppressed and Brunner’s gland function declines, leading to a significant reduction in Lactobacillus levels and weakened host resistance to pathogens. Moreover, optogenetic activation of either the amygdala or the vagus nerve can reverse the effects of stress by restoring Lactobacillus abundance and enhancing immune defense. Further experiments demonstrated that mice with a genetic knockout of Brunner’s glands exhibit microbial imbalance and increased susceptibility to infection, even in the absence of stress, directly confirming the central role of these glands in microbiome regulation. This discovery not only elucidates the neurobiological basis of the “stress–brain–microbiome” axis but also offers novel insights for treating stress-related conditions such as irritable bowel syndrome and autoimmune diseases—by targeting neural pathways or Brunner’s gland function to restore gut microecological balance and enhance host defense.

Academic Impact:
(1)Theoretical Breakthrough: First elucidation of the complete pathway by which stress regulates the microbiome via the brain–vagus nerve–Brunner’s gland axis, providing a new paradigm for gut–brain axis research.
(2)Clinical Value: Identifies potential therapeutic targets—such as Brunner’s glands or vagus nerve stimulation—for the treatment of stress-related disorders like irritable bowel syndrome and autoimmune diseases.
(3)Technical Implications: Supports the development of neural modulation or microbiome intervention strategies to enhance host immune defense.


▷ Source: Cell Cover: Focus on Microbes. Source: Cell

08. Language is Primarily a Tool for Communication, Not Thought

Language is widely regarded as a defining feature of humanity, yet its core function has long been a subject of debate—is it primarily meant to serve thought, or is it specialized for communication? In other words, is the essential role of language to facilitate exchange rather than to drive internal cognition?

A team from the Massachusetts Institute of Technology published a study in Nature revealing the true nature of language through neuroimaging and cognitive experiments. The researchers employed functional magnetic resonance imaging (fMRI) to monitor brain activity in subjects engaged in language tasks (such as reading) and non-language tasks (such as spatial reasoning). They observed that language processing regions (for example, Broca’s area and Wernicke’s area) were significantly activated only during language-related tasks and remained inactive during non-linguistic cognitive tasks. Further analysis indicated that activity in these language areas bore no direct relationship to abstract thought processes, such as mathematical reasoning or logical judgment. The study also highlighted that the structural features of language (including syntactic efficiency and lexical ambiguity tolerance) are optimized for information transmission rather than for enhancing internal cognition. For instance, sign language users retain full logical reasoning abilities even when their language functions are impaired, supporting the view that thought can exist independently of language.

Academic Impact:
(1)Theoretical Innovation: Challenges the traditional paradigm that “language is the medium of thought,” proposing instead that language is merely an external tool for expressing thought rather than its intrinsic driver.
(2)Interdisciplinary Implications: Provides new perspectives for artificial intelligence research, such as deconstructing design by separating language models from reasoning modules.
(3)Clinical Significance: Offers a fresh interpretation of the cognitive preservation observed in patients with language disorders (e.g., aphasia), thereby informing the optimization of rehabilitation strategies.

07. Adult Fruit Fly Brain Connectome

Reference: Winding, M. et al. Neuronal wiring diagram of an adult brain. Nature, 630, 118–126 (2024). doi:10.1038/s41586-024-07558-y

Although neuroscience has extensively investigated connectivity within localized brain regions, a global connectome has remained elusive. How, then, does a complete connectome advance our understanding of brain function and disease mechanisms?

In a study published in Nature, a team from the National Institutes of Health and Princeton University used a combination of electron microscopy imaging and automated algorithms to generate the first whole-brain connectome of an adult fruit fly, encompassing nearly 140,000 neurons and 5*107 precisely mapped synapses. This connectome not only identifies neuronal types and the distribution of neurotransmitters (such as dopamine and serotonin) but also reveals complex signal transmission pathways between brain regions. For example, it illustrates how photic signals are relayed through multiple synapses to the motor centers. Furthermore, the researchers developed an open-source platform that supports interactive data analysis and cross-species integration. This achievement provides a structural framework for elucidating the neural basis of behavioral regulation—such as learning and decision-making—and offers a novel tool for exploring connectivity abnormalities in human neurodegenerative diseases.

Academic Impact:
(1)Scientific Breakthrough: The first complete whole-brain connectome bridges the “missing link” between synaptic-level studies and behavioral research.
(2)Technological Innovation: The automated imaging and computational pipeline lays the methodological groundwork for mapping more complex brains, such as those of mice and humans.
(3)Medical Application: Comparing connectivity differences between healthy and diseased models aids research into the mechanisms underlying neurodegenerative disorders like Alzheimer’s and Parkinson’s disease.
(4)Resource Sharing: The open-source data platform fosters global collaboration, accelerating the translation of brain science into precision medicine and brain-inspired intelligence.


▷ Adult fruit fly brain connectome. Source: flywire.ai

06. Neuronal Dynamics Regulate Cerebrospinal Fluid Perfusion and Brain Clearance

Reference: Kipnis, J. et al. Neuronal dynamics direct cerebrospinal fluid perfusion and brain clearance. Nature, 627, 122–129 (2024). doi:10.1038/s41586-024-07108-6

The accumulation of metabolic waste in the brain is a key trigger for neurodegenerative diseases; however, the mechanisms underlying its clearance have long remained unclear. Kipnis and colleagues set out to answer a fundamental question: How does the brain clear metabolic waste?

A study by a team from Washington University School of Medicine, published in Nature, revealed that neuronal activity drives cerebrospinal fluid (CSF) flow via synchronized action potentials. The researchers found that coordinated discharges within neuronal networks generate high-amplitude, rhythmic ionic waves. These waves, in turn, induce self-sustained oscillations in the interstitial fluid (ISF). Such ionic waves enhance the efficiency of the glymphatic system, thereby promoting CSF perfusion into the brain parenchyma and facilitating the clearance of metabolic waste (such as aberrant proteins). Experimental results demonstrated that chemogenetic inhibition of these high-energy ionic waves significantly reduces both CSF flow and waste clearance efficiency, whereas optogenetic stimulation, which induces transcranial brain waves, markedly enhances the CSF–ISF exchange rate. Furthermore, the study found that high-amplitude brain waves during sleep may serve as a key regulatory factor in clearance efficiency.

Academic Impact:
(1)Mechanistic Insight: This study is the first to establish a direct link between neuronal activity and waste clearance, challenging the traditional “passive clearance” theory.
(2)Disease Intervention: It suggests novel therapeutic strategies for conditions such as Alzheimer’s disease—for example, by enhancing sleep-related brain waves to boost clearance efficiency.
(3)Technological Applications: Optogenetic modulation of brain waves may emerge as an innovative treatment for neurodegenerative diseases.


▷ Differences in γ rhythms between healthy individuals and Alzheimer’s disease patients. Source: https://brainhealth.org.uk/?p=624

05. Massed-Spaced Learning Effect in Non-Neural Human Cells

Reference: Kukushkin, N. V. et al. The massed-spaced learning effect in non-neural human cells. Nat. Commun. 15, 9635 (2024). doi:10.1038/s41467-024-53922-x

Memory formation has long been considered an exclusive function of the brain, relying on synaptic plasticity and neuronal circuits. But have you ever wondered whether non-neuronal cells might possess learning and memory capabilities similar to those of the nervous system?

A team from New York University has, for the first time, revealed the “Massed-Spaced Learning Effect” in non-neuronal cells (such as kidney cells) in a study published in Nature Communications. This effect refers to the phenomenon in which repeated stimulation delivered at intervals enhances learning and memory outcomes. The researchers simulated a learning process using pulsed stimulation with forskolin and phorbol ester and found that spaced stimulation (four pulses delivered at 10-minute intervals) resulted in luciferase expression levels that were 1.4 times higher and persisted for over 24 hours compared to massed stimulation. This process depended on the activation of key memory molecules, ERK and CREB. Since this effect is observed in both neural and non-neural cells, it suggests that memory capabilities may emerge from the universal dynamics of cellular signaling networks rather than being an exclusive function of the nervous system.

Academic Impact:
(1)Theoretical Breakthrough: Expands the biological boundaries of memory by proposing the “cellular-level memory” hypothesis.
(2)Medical Potential: Offers novel, non-neural targeted therapeutic approaches for memory-related disorders, such as Alzheimer’s disease.
(3)Technological Applications: Establishes a cellular memory model to aid in drug development and toxicity assessments.


▷ Source: MIT.edu

04. Reconstructing the Human Cerebral Cortex at Nanoscale Resolution

Reference: Shapson-Coe, A. et al. A petavoxel fragment of human cerebral cortex reconstructed at nanoscale resolution. Science, 384, eadk4858 (2024). doi:10.1126/science.adk4858

The intricate microarchitecture and synaptic connectivity of the human cerebral cortex are key to understanding cognitive function. However, due to the resolution limits and data scale constraints of traditional imaging techniques, the ultrastructural details have long remained largely unrevealed. Can nanoscale imaging techniques, therefore, unravel the ultrastructure and synaptic connectivity of the human cerebral cortex?

In a collaborative study between Google and Harvard University’s Lichtman Laboratory, published in Science, researchers employed serial-section electron microscopy (with a 4 nm resolution) to image a 1-cubic-millimeter sample of the human temporal cortex obtained during epilepsy surgery. Using automated computational methods, they reconstructed the largest brain ultrastructure dataset to date (H01, 1.4 PB), which comprises approximately 57,000 cells, 230 millimeters of vasculature, and 150 million synapses—yielding, for the first time, a comprehensive cross-cortical synaptic connectivity map. The study revealed a glial cell-to-neuron ratio of 2:1, with oligodendrocytes representing the highest proportion. Moreover, deep-layer excitatory neurons could be classified into functional subtypes based on dendritic orientation. In addition, each neuron received thousands of weak synaptic connections alongside a few “potent inputs” (with a single axon forming up to 50 synapses), suggesting a hierarchical amplification mechanism in neural information processing. The research team overcame challenges such as the rapid degradation of brain tissue samples and the enormous volume of imaging data, thereby providing the first nanoscale “structure-function” map for neural circuits. All related data have been made openly available.

Academic Impact:
(1)Theoretical Breakthrough: Challenges the macroscopic limitations of traditional brain mapping by revealing the heterogeneity of synaptic connectivity, thereby providing structural support for neural coding theories.
(2)Technological Innovation: The integration of 4 nm resolution serial-section electron microscopy with AI-driven automated annotation (Serial EM) sets a new benchmark in large-scale biological imaging.
(3)Data Sharing: The open-source H01 dataset will accelerate research into brain disorder mechanisms (such as epilepsy and schizophrenia) and the development of brain-inspired computational models.


▷ Excitatory neuron staining (six layers). Source: Harvard University, Google Research, and the Lichtman Laboratory

03. Psilocybin Desynchronizes the Human Brain

Reference: Dosenbach, N. U. F. et al. Psilocybin desynchronizes the human brain. Nature 630, 1020–1028 (2024). doi:10.1038/s41586-024-07624-5

Psilocybin, a psychedelic agent with rapid antidepressant potential, has a mechanism for promoting neural plasticity through the disruption of brain network synchrony that remains unclear. How does it modulate brain network synchrony to yield both rapid and enduring therapeutic effects?

In a study published in Nature, a team from Washington University School of Medicine in St. Louis employed longitudinal precision functional mapping techniques—where healthy subjects underwent an average of 18 MRI scans—to systematically track the acute and long-term effects on brain functional connectivity of a high dose of psilocybin (25 mg) compared with the control drug methylphenidate (40 mg). The study found that psilocybin triggers a dramatic, widespread desynchronization across the brain. During the acute phase, the functional connectivity between cortical and subcortical regions was disrupted to more than three times the extent observed with the control drug. This disruption was characterized by decreased intra-network correlations and weakened inter-network anticorrelations. Notably, the collapse of synchrony was most significant in the default mode network (DMN)—especially in nodes connected to the anterior hippocampus—and was directly linked to subjects’ subjective psychedelic experiences, such as distortions in spatial-temporal perception and depersonalization. Importantly, the reduced functional connectivity between the anterior hippocampus and the DMN persisted for several weeks, paralleling the enhanced neural plasticity observed in animal models. This finding offers a potential neural mechanism underlying the therapeutic effects of psilocybin.

Academic Impact:
(1)Mechanistic Insight: Proposes a “desynchronization-resynchronization” model that elucidates how psychedelics facilitate brain remodeling by disrupting entrenched network states.
(2)Clinical Translation: Suggests that the connectivity strength between the DMN and the anterior hippocampus may serve as a biomarker and therapeutic target for disorders such as depression and addiction.
(3)Methodological Innovation: Demonstrates that personalized longitudinal functional mapping techniques provide a high temporal resolution framework for evaluating and developing psychopharmacological treatments.


▷ Source: SciTechDaily.com

02. Surge in Neurophysiological Coupling and Connectivity of Gamma Oscillations in the Dying Human Brain

Reference: Borjigin, J. et al. Surge of neurophysiological coupling and connectivity of gamma oscillations in the dying human brain. Proc. Natl. Acad. Sci. U.S.A. 120, e2216268120 (2023). doi:10.1073/pnas.2216268120

Traditional views have held that brain activity is profoundly suppressed during cardiac arrest; however, new insights have emerged regarding changes in neural activity in the dying human brain. In a study published in the Proceedings of the National Academy of Sciences (PNAS), a team led by Jimo Borjigin at the University of Michigan analyzed electroencephalogram (EEG) data from four cardiac arrest patients to reveal the complexity of neurophysiological activity at the end of life.

The study found that following the cessation of respiratory support, two patients exhibited a significant enhancement in gamma-band (25–150 Hz) EEG power—up to three times their baseline levels. This surge was accompanied by increased cross-frequency coupling (for example, enhanced synchrony between gamma and beta oscillations) and a marked rise in interhemispheric functional connectivity. Such activity was predominantly localized in the temporo-parieto-occipital (TPO) junction, a region closely associated with consciousness integration, visuospatial perception, and dream generation. Furthermore, the enhancement of gamma oscillations coincided with deteriorating cardiac function, suggesting that hypoxia may drive the abnormal activation of neural networks. Notably, this activity pattern resembles the EEG features observed in healthy individuals during recollection or dreaming, potentially offering a neural mechanism for the “life review” phenomenon often reported in near-death experiences.

Academic Impact:
(1)Theoretical Innovation: This study challenges the traditional hypothesis of “brain silence” at the end of life by proposing that hypoxia may trigger a compensatory state of heightened neural activity.
(2)Clinical Implications: It opens new avenues for investigating the neural basis of near-death experiences and may drive the development of technologies for detecting covert consciousness.
(3)Technological Breakthrough: The application of high-density EEG and functional connectivity analysis provides a methodological paradigm for studying the brain under extreme physiological conditions.

01. Neuroanatomical Changes During Human Pregnancy

Reference: Pritschet L, Taylor CM, Cossio D, et al. Neuroanatomical changes observed over the course of a human pregnancy. Nat. Neurosci. 27, 2253–2260 (2024). doi:10.1038/s41593-024-01741-0

The dramatic hormonal and physiological upheavals triggered by pregnancy have long been understudied with respect to their impact on the maternal brain. This raises an intriguing question: How do the neuroanatomical structures of the human brain dynamically change during pregnancy?

A team from the University of California, Santa Barbara, conducted a groundbreaking longitudinal study using high-resolution MRI to track structural changes in a woman’s brain from three weeks before pregnancy to two years postpartum (a total of 26 scans). The study found that during pregnancy the brain undergoes significant remodeling. This remodeling is characterized by widespread reductions in gray matter volume and cortical thickness—affecting up to 80% of cortical regions (for example, the prefrontal and posterior parietal cortices)—as well as enhanced integrity of white matter microstructure and increases in both ventricular and cerebrospinal fluid (CSF) volumes. Notably, some of the reductions in gray matter did not fully recover even two years postpartum, whereas white matter alterations gradually returned to baseline following delivery. Further analysis revealed that these structural changes were closely associated with fluctuations in hormone levels, including estradiol and progesterone, suggesting that they may represent a “neural resource reallocation” in the maternal brain to meet the demands of caregiving. These findings were published in Nature Neuroscience, and all imaging and hormonal datasets have been made openly available.

Academic Impact:
(1)Theoretical Innovation: Challenges the traditional notion of structural stability in the adult brain by demonstrating that pregnancy can drive large-scale neuroplasticity.
(2)Clinical Value: Provides potential neurobiological markers for perinatal depression and cognitive impairments, thereby facilitating the development of early intervention strategies.
(3)Resource Sharing: The first comprehensive dataset of brain imaging throughout pregnancy will accelerate research into the neuroprotective mechanisms underlying maternal brain adaptation.

]]> https://admin.next-question.com/features/top-ten-advances-in-brain-science-in-2024/feed/ 0 Discovery, Questioning, and Rediscovery: Why Can Memory Be Stored? https://admin.next-question.com/features/discovery-questioning-and-rediscovery-why-can-memory-be-stored/ https://admin.next-question.com/features/discovery-questioning-and-rediscovery-why-can-memory-be-stored/#respond Sat, 15 Feb 2025 07:19:09 +0000 https://admin.next-question.com/?p=2716 Today, researchers are attempting to simulate human long-term memory using artificial intelligence. However, a major challenge remains: we still cannot fully explain the most fundamental mechanisms underlying human memory.

• Why can childhood memories be preserved for decades without fading?
• Is it possible for us to selectively erase a specific painful memory?
• What exactly is the molecular mechanism behind long-term memory?

It is generally believed that human long-term memory differs from digital storage in electronic devices. Instead, it is achieved through dynamic changes in biomolecular switches, synapses, and neural circuits. This elegant storage mechanism far surpasses any system designed by humanity to date.

1. Discovery of Long-Term Potentiation (LTP)

In the 1970s, scientists discovered long-term potentiation (LTP) [1]. They found that electrical stimulation of the synapse connecting two neurons results in a long-lasting enhancement of synaptic transmission. When a neuron’s presynaptic terminal sends signals at a high, persistent frequency to a postsynaptic neuron, the postsynaptic synaptic strength increases. This change can last for hours or even days, thereby making neuronal connections more effective and enhancing the stability of information transfer.


▷ Source: Wikimedia Commons

The formation and storage of memory arise from changes in the strength of connections between neurons—a phenomenon known as synaptic plasticity. Observations such as LTP indicate that the strength of synaptic connections can be enhanced through learning and experience, thereby forming enduring memories. Memory is not stored within individual neurons but is distributed across neural networks in the brain, comprising neurons and their synaptic connections that form the physical basis of memory. The processes of encoding, storage, and retrieval involve the processing and encoding of information as variations in synaptic strength and structure, which are ultimately stored in distributed neural networks.

Thus, LTP is widely regarded as a key process in memory formation, with neural networks of varying synaptic strengths considered the foundation of memory.

2. Exploring Memory Molecules

Following the discovery of LTP, new questions emerged: What is the secret behind long-term memory? Scientists hypothesized that certain molecules might be responsible for maintaining long-lasting synaptic changes. To investigate this, they sought to identify substances in the brain directly related to memory. Based on the principles of synaptic plasticity and molecular mechanisms, memory formation and maintenance may depend on these specific molecules that regulate synaptic transmission efficiency.


▷ Source: [2]

A 2006 study demonstrated that blocking PKMzeta/PKMζ—a protein kinase—could erase a rat’s memory of a specific location [2]. This finding attracted widespread attention because if blocking a single molecule can erase a memory, then that molecule must play a crucial role in memory maintenance. In the memory erasure experiments, when PKMzeta was inhibited, rats lost their memory of the specific training environment, indicating that PKMzeta is indispensable for sustaining these memories [2]. Subsequent research further confirmed that PKMzeta is closely associated with memory maintenance not only in rats but also in other animal models. Using techniques such as gene knockout and pharmacological blockade, scientists have reinforced the key role of PKMzeta in the persistence of memory.

However, there are notable caveats to this conclusion. First, the duration of PKMzeta’s activity is relatively short. “These proteins persist in synapses for only a few hours, or in neurons for a few days,” remarked Todd Sacktor, a neurologist at the Downstate Medical Center of the State University of New York and co-author of the 2006 study. He questioned, “How then can we explain memories that last 90 years?” Secondly, although PKMzeta is produced on demand within cells, it must be precisely localized to the correct synapses. Andre Fenton, a neuroscientist at New York University and another author of the study, noted that each neuron contains approximately 10,000 synapses, yet only a few are strengthened. Although the selective enhancement of specific synapses is the mechanism by which information is stored, it remains unclear how PKMzeta molecules achieve such specificity.

3. Tracing the Essence of Memory: The Interaction between PKMzeta and KIBRA

Eighteen years later, in 2024, Sacktor, Fenton, and their colleagues published a new study in Science Advances that filled these gaps [3].


▷ Source: [3]

This latest research indicates that PKMzeta works in concert with another molecule called KIBRA—an adaptor protein expressed in both the kidney and brain. KIBRA attaches to synapses activated during learning, effectively “tagging” them, and then binds with PKMzeta to strengthen these marked synapses.


▷ Synapse. Source: Getty Images

KIBRA—short for “kidney and brain expressed adaptor protein” and also known as WWC1—is a postsynaptic scaffolding protein that plays an important role in human memory and is often considered a “memory adhesive.” It may serve as a synaptic tag by attaching to learning-activated synapses, capturing PKMzeta during the induction phase of LTP, and maintaining its activity. This process ensures that only the synapses activated by PKMzeta are strengthened.

Experiments have shown that blocking the interaction between these two molecules eliminates LTP in neurons and disrupts spatial memory in mice. Although the individual lifespans of these molecules are brief, their interaction persists over time. “What maintains memory is not PKMzeta alone, but the ongoing interaction between PKMzeta and its target molecule, KIBRA,” Sacktor explained. “If the connection between PKMzeta and KIBRA is disrupted, memories from a month ago vanish.” He added that during that month, specific molecules are replaced multiple times. However, once established, this interaction is continuously maintained through the replenishment of individual molecules, ensuring long-term memory retention.

This study not only provides a new perspective on synaptic tagging but also offers a potential solution to the problem of PKMzeta’s short lifespan. More importantly, the research suggests that it is not the individual PKMzeta molecules that maintain memory, but rather the sustained interaction between PKMzeta and KIBRA. Other studies have found that different variants of the KIBRA gene are associated with variations in human memory performance, and that interfering with KIBRA in animal experiments disrupts memory. Using visualization techniques, researchers observed that the close interaction between KIBRA and PKMzeta increases in stimulated synapses. This likely explains why an enhancement in PKMzeta activity boosts memory.

These findings have advanced the theoretical development of the synaptic tagging hypothesis, although they have also faced some skepticism. In a 2013 study, transgenic mice lacking PKMzeta were still able to form long-term memories, casting doubt on whether PKMzeta is essential for hippocampal synaptic plasticity, learning, and memory [4]. In response, Sacktor and Fenton explained that in animals lacking PKMzeta from birth, a related protein—PKCiota/lambda—compensates for its function. In normal animals, PKCiota/lambda is present only in very small amounts and is rapidly degraded; however, its levels are significantly increased in PKMzeta-deficient mice.

The study further found that the inhibitory peptide ZIP, previously shown to block PKMzeta, also blocks PKCiota/lambda. This raised new questions about PKMzeta, suggesting that ZIP might not be as specific as originally thought and might also suppress other brain activities. However, new evidence soon dispelled these doubts. Researchers employed two different molecules to disrupt the interaction between PKMzeta and KIBRA. Both methods prevented PKMzeta from binding to KIBRA without affecting the binding of PKCiota/lambda. Experiments demonstrated that these blocking methods could reverse LTP and impair memory in normal mice, while having no effect on memory storage in transgenic mice lacking PKMzeta.

The results indicate that blocking PKMzeta in normal animals erases memory, whereas blocking PKCiota/lambda does not. Therefore, it is believed that under normal conditions, PKCiota/lambda may not be as critical for long-term memory storage. Fenton and Sacktor propose that PKCiota/lambda is an evolutionary relic that once participated in the evolution of memory, but PKMzeta—with its stronger effect—has replaced it. Nevertheless, when the PKMzeta gene is knocked out in experimental animals, the compensatory function of PKCiota/lambda comes into play [5].

4. Future Directions in Memory Research

Currently, scientists are planning to further explore the mechanisms underlying this interaction, as well as the distribution of strengthened synapses across neurons.

As Fenton speculated, “Are they all clustered together near the cell body, or are they randomly distributed? Finding the answer to this question might provide insights for the treatment of memory impairment diseases such as Alzheimer’s disease.”

Sacktor, a neurologist, stated that he has already witnessed the therapeutic impact of this work: “I increasingly see the potential of directly introducing proteins into neurons via gene therapy, whereas the idea of a drug that can erase memory to treat post-traumatic stress disorder (PTSD) is much harder to envision.”

Original link:
https://www.scientificamerican.com/article/brain-scientists-finally-discover-the-glue-that-makes-memories-stick-for-a/

]]> https://admin.next-question.com/features/discovery-questioning-and-rediscovery-why-can-memory-be-stored/feed/ 0 Interview with Ji Haiqing: How Do We Define “Human” in the Context of Brain-Machine Interfaces? https://admin.next-question.com/people/interview-with-ji-haiqing-how-do-we-define-human-in-the-context-of-brain-machine-interfaces/ https://admin.next-question.com/people/interview-with-ji-haiqing-how-do-we-define-human-in-the-context-of-brain-machine-interfaces/#respond Mon, 20 Jan 2025 06:02:35 +0000 https://admin.next-question.com/?p=2708 Foreword

On September 21-22, 2023, the Tianqiao and Chrissy Chen Institute (TCCI), in collaboration with the Shanghai Academy of Social Sciences and the Shanghai Mental Health Center, hosted a special symposium titled “Brain-Machine Interfaces and Philosophy: Interdisciplinary Dialogues.”

The event brought together over 60 experts and scholars from fields including clinical medicine, natural sciences, philosophy and ethics, the science and technology governance, and industrial planning. The discussions focused on core topics such as the role of brain-machine interfaces in national governance, ethical considerations in technology, human cognition, human-computer interaction, and legal challenges.

As one of the symposium’s conveners, Professor Ji Haiqing, a research fellow at the Shanghai Academy of Social Sciences and Director of the Science and Technology Philosophy Research Office, was invited for an exclusive interview with us. From the perspective of technological ethics, Professor Ji offered a deep analysis of the social integration process of brain-machine interfaces and their potential impacts. He shared insights into the motivations behind organizing the symposium and provided unique perspectives on the ethical distinctions between brain-machine interfaces and traditional medical devices, the implications of these technologies for privacy, the expansion of human boundaries, and human enhancement.

The following is the interview with Ji Haiqing. We have condensed the text to make it easier to read.

Question: Could you introduce yourself to our audience?

Ji Haiqing: I am Ji Haiqing from the Institute of Philosophy at the Shanghai Academy of Social Sciences. During my undergraduate studies, I majored in a science and engineering discipline—computer science. However, over time, I developed a deep interest in topics related to the humanities, society, and history.

In my twenties, I realized that the answers to the questions I had been pondering could not be found in the computer science books I was reading—such as those on data structures or programming languages. As a result, I made what seemed like an unusual decision: I transitioned from studying computer science to pursuing philosophy, hoping to freely explore the issues that intrigued me.

Since then, I have been engaged in philosophical research, particularly in the field of philosophy of technology. I am deeply satisfied with this career because it allows me to observe and reflect on societal and technological developments through thinking, writing, and discussions with colleagues. It’s an intellectually stimulating and fulfilling endeavor.

Question: Thank you for organizing this symposium on brain-machine interfaces and philosophy. What inspired you to host this event?

Ji Haiqing: The motivation for organizing this symposium stemmed from my interest in brain-machine interface (BMI) technology. BMI integrates cutting-edge advancements across various disciplines, including biology, neuroengineering, neuroscience, electronics, and artificial intelligence. It brings together the achievements of these advanced fields and combines them with the human brain—a complex and critical organ.

BMI represents the forefront of the current technological wave and serves as a crucial component worthy of deep investigation. My personal interest in BMI is closely tied to one of my research areas: the ethics of technology.

The ethics of technology explores how science and technology integrate into society. This integration is not merely a straightforward application of technology; it is a complex process involving a delicate balance of competing forces. I often use the analogy of a diver to illustrate this point: a skilled diver enters the water from a great height with barely a splash, but if a new technology is ethically immature, even a dive from a lower height can create significant backlash. The process of integrating technology into society is much the same.

The goal of philosophical and ethical research is to explore how technological products can “enter the water”—that is, integrate into society—at the optimal angle, minimizing their negative impacts, aligning them with human values, and facilitating their acceptance by society. My particular focus on BMI arises from its status as a frontier technology. I am eager to understand how it integrates into society.

Will society embrace BMI technology? Will it be fully accepted, or will it encounter resistance—perhaps due to conceptual biases or other factors? These are fascinating questions that led me to combine brain-machine interfaces with philosophy as a research theme. This symposium was an opportunity to bring together experts from various fields to explore these questions collaboratively.

Question: Compared to other medical devices, brain-computer interfaces (BCIs) raise more ethical controversies. In your opinion, what are the fundamental differences between BCIs and traditional medical devices?

Ji Haiqing: The uniqueness of BCIs lies in their direct interaction with the human brain, which is an extraordinarily mysterious, critical, and irreplaceable organ. Throughout the history of philosophy, there have been extensive discussions about the mind, the spirit, and thought. Although the term “heart” was historically used to describe these concepts, in reality, all advanced cognitive functions, emotions, and bodily regulation are carried out by the brain, not the heart.

Traditional medical devices may replace certain parts of the human body, such as prosthetic limbs or even artificial hearts, but the brain remains irreplaceable. The distinctive feature of BCIs is their direct engagement with this irreplaceable organ. To use a computing analogy, components like hard drives or memory can be replaced in a computer, but if the central processing unit (CPU) is damaged, the entire system becomes nonfunctional. Similarly, the brain plays an essential role in the human body, making the uniqueness of BCI technology particularly significant.

While BCIs hold immense potential for treating neurological and psychiatric disorders, their direct interaction with the human brain necessitates a dedicated focus on their ethical implications. In summary, BCIs are fundamentally different from traditional medical devices because they can access and interact directly with brain data, making their ethical considerations distinct and profound.

Question: In your view, how might BCI technology impact mental privacy?

Ji Haiqing: On the topic of privacy, I’d like to offer a broader perspective from the philosophy and history of technology. Scholars in the philosophy of technology often argue that our value judgments about certain concepts, such as privacy, may appear to be independent, but they are actually closely tied to the tools we use.

These tools not only help us achieve goals but also subtly shape our perceptions. For example, the invention of clocks changed our understanding of time. Before clocks, people perceived time through natural phenomena, such as the rising and setting of the sun or the shadow of a sundial. However, with the advent of clocks, time became segmented into measurable units like hours and minutes.

Similarly, the concept of privacy is deeply intertwined with the tools we use. For instance, the presence of a camera evokes a sense of privacy awareness. If I am willing to be seen by others, I face the camera willingly; if I am not, I avoid it. Privacy is not a concept that exists in a vacuum but is shaped by our attitudes toward and use of technological tools.

Thus, privacy does not imply complete concealment; rather, it depends on whom we wish to share information with and to what extent. This reflects the mutual interaction and co-construction of technology and our perceptions. The crux lies in how we view these technological tools and our attitudes toward privacy.

Question: How will brain-computer interface (BCI) technology affect the boundaries of what it means to be “human”?

Ji Haiqing: This question requires clarifying several concepts. In Chinese, the term “人” corresponds to two distinct terms in Western languages: human being and person. Human being refers to humanity in a biological sense, while person denotes an individual human. When discussing person, you and I are distinct individuals, but from the perspective of human beings, we belong to the same species without differentiation.

When it comes to BCIs and their impact on individual personality, there are many intriguing topics to explore. One of the key concepts we often discuss is personal identity. Generally, external changes, such as changing clothes, do not affect our personal identity—who we are. However, when we implant devices like deep brain stimulation (DBS) to regulate physiological states due to illness or other reasons, do we remain the same person? How society perceives the impact of these technologies on personality and identity becomes a critical question.

Interestingly, we have already seen some exceptional cases. For example, the Spanish artist Neil Harbisson was born colorblind. To compensate for this, he implanted a device that converts the color spectrum into sound waves, enabling him to “hear” colors. While he successfully gained this ability, it also introduced new challenges. A microphone-like antenna is now attached to his skull, and when crossing border checkpoints, officials noticed his passport photo did not include this device. He was eventually required to take a new photo, incorporating the device as part of his body.

This case illustrates how, as society gradually accepts individuals who merge with technology—sometimes referred to as “cyborgs”—the traditional biological boundaries of what constitutes a “human being” are shifting. This transformation not only expands the boundaries of humanity but also raises numerous ethical, political, anthropological, and philosophical questions.

Question: Do you think the “technologization of the body” will inevitably become a future trend for humanity?

Ji Haiqing: The answer to this question is both “yes” and “no.” If we say “no,” it’s because the question assumes this will become a new trend in the future. From my perspective, this is not a new trend but rather one that has existed throughout human history. Humanity has always sought to extend its capabilities and activities through the integration of technology. The only difference now is that we are facing a new technological product—BCIs.

From the perspective of the philosophy of technology, technology can be broadly defined as any man-made artifact, an extension of human capabilities. Based on this definition, the integration of humans and technology has always been an ongoing trend. Books such as *Sapiens: A Brief History of Humankind* and works in technological anthropology discuss similar themes.

For example, Polynesians in the South Pacific built canoes from island trees to travel between islands, while farmers in temperate northern regions felled large trees to construct ships for long-distance navigation. Despite differences in tools and techniques, both examples illustrate humanity’s use of natural resources in combination with technology to achieve their goals.

Therefore, I believe the fusion of humans and technology is a continuously evolving trend, not merely a phenomenon of the future.

Question: In the discussions surrounding brain-computer interfaces (BCIs) and philosophy, are there any significant studies that have been undervalued?

Ji Haiqing: This question touches on many aspects. As BCI devices become more widely applied, numerous issues will gradually emerge. The expansion of their usage will reveal problems over time rather than exposing them all at once.

I believe there are many important topics worthy of attention. If you’re interested, I recommend exploring the work of internationally renowned posthumanist scholars. These academics, while conducting serious research, possess imaginations that rival those of science fiction writers. For instance, American posthumanist scholar Katherine Hayles and others in the field of posthumanism often use imaginative depictions of humanity’s future existence to explore the relationship between humans and technology. Such works can serve as a source of intellectual inspiration.

Question: What is the topic you are most focused on at the moment?

Ji Haiqing: In recent years, I have been particularly interested in the topic of human enhancement. Human enhancement refers to using technology not only to meet conventional needs, such as treating diseases, but also to further augment individual capabilities. This enhancement goes beyond external devices and integrates with our bodies to improve physiological functions.

Broadly speaking, ever since humanity invented airplanes, we can say that humans have learned to fly, though this differs significantly from how birds fly. Birds rely on their physiological structures to fly, while humans achieve flight through technological tools. The trend of human enhancement likely involves technological tools directly altering human physiological structures, granting us unprecedented abilities. This trend has become especially prominent with advancements in electronics, nanotechnology, and other fields in the 21st century.

I believe this trend of human enhancement prompts an essential question: How will it shape our self-perception and influence our future development?

Question: How can we address the potential social issues arising from human enhancement to ensure technology benefits all populations?

Ji Haiqing: From my perspective, this is not an especially grave issue. Human societies have always adapted to the introduction of new technologies, which often create disparities among groups to some extent.

Looking back at history, some early societies improved farming efficiency with iron tools or agricultural equipment, leading to better harvests, while others domesticated animals to aid in labor. Meanwhile, some regions lacked these conditions. Such inequality has been a historical norm. Over time, societies have employed various methods to mitigate the inequalities brought about by technological advancements.

In our field of research, this phenomenon is known as the issue of technological accessibility. There are, in fact, numerous ways to address the social problems caused by unequal access to technology. If such inequality disrupts social stability or exacerbates class divisions, governments can intervene through public financial measures. For example, governments could procure and provide certain technologies for free or offer subsidies to help those who cannot afford new technologies.

Thus, I don’t see this as an insurmountable problem. We already have well-established economic theories and policy tools to tackle these challenges and ensure that technology can more widely benefit all populations.

]]> https://admin.next-question.com/people/interview-with-ji-haiqing-how-do-we-define-human-in-the-context-of-brain-machine-interfaces/feed/ 0 Interview with Prof. Wang Shouyan: Do We Need Large Models or Small Models for Brain-Computer Interfaces? https://admin.next-question.com/people/interview-prof-wang-shouyan/ https://admin.next-question.com/people/interview-prof-wang-shouyan/#respond Mon, 20 Jan 2025 05:39:00 +0000 https://admin.next-question.com/?p=2701 Foreword

With the rapid advancement of technology, Brain-Computer Interfaces (BCIs), serving as a vital bridge between the human brain and external devices, have progressively emerged as a research hotspot in neuroscience and artificial intelligence. Researchers worldwide are actively exploring innovations in this cutting-edge field, striving to overcome technical bottlenecks and enable smarter, more efficient human-machine interactions.

In this exclusive interview, we are honored to have Professor Wang Shouyan, Director of the Center for Neural Modulation and Brain-Computer Interface Research at Fudan University. Professor Wang provides an in-depth analysis of the current state, development advantages, and future trends of BCI research in China. He also shares forward-looking insights and invaluable experiences from his work in the field.

The following is the interview with Professor Wang Shouyan. We have condensed the text to make it easier to read.

Question: What is the current state of Brain-Computer Interface (BCI) development in China?

Wang Shouyan: I am from the Institute of Brain-Inspired Intelligence Science and Technology at Fudan University and am responsible for establishing the Center for Neural Modulation and Brain-Computer Interface Research. First, I’d like to thank you for organizing this interview, which provides an opportunity to help the public better understand the true meaning, development status, and key contributors of BCI, rather than focusing solely on Musk’s promotional activities.

In fact, BCI research extends far beyond Musk’s endeavors. Recently, I proposed a four-stage developmental roadmap for BCIs*: (1) Brain Reading, (2) Brain Writing, (3) Brain-Computer Interaction, and (4) Brain-Intelligence Integration. This roadmap encompasses processes from basic signal decoding to advanced human-machine interaction. Currently, research is largely focused on decoding brain signals, a field in which both Musk and Tsinghua University in China are actively engaged.

*Professor Wang emphasizes that the scientific development of BCI will follow four phases: from Brain Reading (decoding motor, speech, memory, and consciousness) to the currently thriving field of Brain Writing (neural function modulation and reconstruction) and Brain-Computer Interaction (brain interfacing), eventually reaching Brain-Intelligence Integration (brain-inspired intelligence and digital life).

From the perspective of decoding brain signals, could using MRI scans also count as “Brain Reading”? International studies have already employed MRI and magnetoencephalography to analyze brain functions, which represents one direction of BCI research. Simultaneously, techniques such as electromagnetic stimulation are being explored to regulate brain activity.

The essence of BCI lies in achieving two-way information exchange between the human brain and external machines. We aim to enable this interaction through more intelligent means, such as using virtual reality to modulate brain activity. Therefore, I proposed BCI 3.0 (Brain-Computer Interaction), which emphasizes deep interaction and integration between the human brain and machines. The more advanced BCI 4.0 (Brain-Intelligence Integration) focuses on the coexistence and collaboration between human brains, intelligent agents, artificial intelligence, and future intelligent societies.

In these research directions, many Chinese neuroscientists, engineers, and physicians are actively exploring. For example, Huashan Hospital and Tiantan Hospital have achieved significant progress in this field.

In addition, we must strengthen science communication. The public needs to recognize the importance of BCI and the national commitment to its development. Relying solely on Musk’s research cannot represent the strategic development of a country. True strategic development involves core foundational technologies, which have profound implications for the health and well-being of society and its people.

Overall, BCI is advancing by integrating multiple factors, driving societal progress, forming the prototype of future industries, and becoming a vital part of national strategic planning.

Question: What are the advantages of China’s BCI development?

Wang Shouyan: First, we have a significant international advantage in terms of talent and disciplinary foundation. China’s BCI research began in the 1980s, and after decades of accumulated experience, we now possess a wealth of experience in BCI research, constituting a major strength.

Second, China has a solid foundation in medical and neurological disease research, which provides essential support for BCI development. We can leverage this foundation to make advances in the medical applications of BCI technologies.

Third, we have a long-standing foundation in technological development, particularly in scientific research and engineering technologies related to BCI, laying a solid groundwork for future progress.

However, we also face challenges, particularly in the integration of interdisciplinary research. We need to enhance collaboration among experts from various fields to jointly address major scientific, technological, and industrial challenges. Both the central government and the Shanghai government are actively planning and addressing these issues to further drive the development of BCIs.

Question: What breakthrough discoveries do you foresee in the field of Brain-Computer Interfaces (BCIs) over the next 5 to 10 years?

Wang Shouyan: The future breakthroughs in BCIs are likely to focus on several key areas. First, significant advancements have been made by researchers at ETH Zurich in spinal cord rehabilitation*, particularly in technologies that enable paraplegic patients to walk again. This represents a cutting-edge direction where artificial intelligence intersects with BCIs. Additionally, the integration of brain-reading and brain-writing technologies, especially innovations in deep brain stimulation for Parkinson’s disease and pain management, is currently a major focus of international research in both basic science and clinical medicine.

*In China, the team led by Jia Fumin at Fudan University’s Institute of Brain-Inspired Intelligence Science and Technology has developed a new generation of implantable brain-spinal interface devices for patients with spinal cord injuries. This innovation won the 2024 National Disruptive Technology Innovation Competition and is expected to undergo its first clinical trial by the end of the year, offering hope for spinal cord injury patients to stand and walk again.

These breakthroughs are not accidental; they are driven by profound underlying forces. By analyzing these driving forces, we can anticipate future trends. China’s early brain initiatives strategically invested in critical technologies such as neural modulation and BCIs, laying a strong foundation for future technological breakthroughs.

One clear trend from these initiatives is the move toward intelligent implantable deep brain stimulation technologies. The national strategic goal is to achieve a leading position in global competition, leveraging China’s strengths in medical industries and technology to achieve leapfrog development.

Another potential breakthrough lies in the decoding of neural activity. China has extensive resources in clinical research and data accumulation. With the launch of upcoming major national projects, progress in brain information decoding is expected to accelerate, paving the way for new advancements in BCI technology.

Question: If we gather enough brain data, is it possible to build a general brain model similar to ChatGPT?

Wang Shouyan: Large language models (LLMs) like ChatGPT have indeed provided us with significant inspiration. However, this question should be approached from two perspectives: the problem and the methodology. While LLMs offer a promising approach for understanding and decoding brain information, they are not the sole solution to the problem.

Although large data-driven models are disruptive and innovative, helping us better interpret and analyze brain data, relying solely on one approach in brain science research often leads to bottlenecks. Therefore, we advocate for a research paradigm that combines mechanisms and methodologies. For instance, optogenetics can help us better understand specific neural phenomena.

Currently, we are conducting research on integrating LLMs with large-scale EEG data modeling. The critical question is whether these models can genuinely help us address fundamental scientific questions. The future direction is likely to involve the convergence of data, mechanisms, and modeling. The ultimate value and significance of this technical approach depend on its ability to solve major scientific challenges.

Question: What research question are you most focused on?

Wang Shouyan: My primary focus is on how to effectively model under limited data conditions. In hospital-based research, we often cannot collect sufficient large-scale datasets, particularly when studying specific diseases. For example, in implantable device research, studies involving dozens of patients are already considered substantial, while those with over a hundred patients are extremely rare.

Does this mean that patients in such circumstances should not be studied? Or that they do not deserve treatment? These questions are not only scientific but also philosophical in nature. We must explore how to conduct effective research with limited data. Specifically, we are currently focused on leveraging large language models (LLMs) for precise modeling with small datasets. This approach aims to develop more personalized and intelligent strategies for neural modulation and brain-computer interaction.

Question: Are there valuable research cases in the application of small data?

Wang Shouyan: I can share some examples from our research on deep brain stimulation (DBS) for Parkinson’s disease. In China, over 100 hospitals are now offering this treatment, and tens of thousands of patients undergo this surgery every year. However, there are still hundreds of thousands of patients who need treatment, but only a small fraction have access to it. Our current focus is on how to use more precise neural modulation technologies to help a broader range of patients, especially those with significantly varied symptoms, benefit from treatment.

Additionally, we are collaborating with Huashan Hospital and Tiantan Hospital to study chronic pain patients. This includes those who have no effective pharmaceutical treatments or even patients in a vegetative state. Our goal is to use disruptive technologies to help these patients reconnect and communicate with their families. The core of these studies is leveraging small datasets to develop more precise and effective treatments.

Question: What challenges and difficulties do you see in the development of the Brain-Computer Interface (BCI) field?

Wang Shouyan: One of the biggest challenges in the broader scientific research landscape is interdisciplinary collaboration. Currently, China’s research evaluation system, with its emphasis on publishing papers and securing funding, often creates conflicts of interest. Consequently, institutional and systemic issues, particularly barriers to interdisciplinary collaboration, pose significant difficulties.

The root of these barriers lies in a value assessment system historically driven by metrics such as the number of publications and performance indicators. Researchers tend to focus on their specialized fields and are often reluctant to engage deeply with experts from other disciplines. Additionally, issues related to data sharing, especially disputes over authorship, frequently complicate collaborations. These evaluation criteria not only affect the publication of scientific results but also directly impact researchers’ year-end bonuses and personal assessments.

We are currently advocating for institutional innovation in the BCI field to break down these barriers. Chinese researchers are highly intelligent and hardworking, but overcoming these remaining challenges requires addressing systemic issues and establishing efficient collaborative teams. Adequate funding support and the creation of interdisciplinary platforms are essential. Other technical challenges can be resolved gradually in accordance with the natural progression of scientific development. Interdisciplinary collaboration is not an insurmountable scientific problem; instead, institutional obstacles represent the real bottleneck.

Question: What advice would you give to young scientists?

Wang Shouyan: BCI is a highly interdisciplinary field, making a broad knowledge base and the establishment of collaborative networks especially important. For young scientists, I have a few straightforward suggestions. First, read extensively and learn continuously. The old saying “read ten thousand books and travel ten thousand miles” remains relevant. Young scholars should visit and learn from different laboratories to broaden their horizons. Second, make friends and actively participate in academic conferences. Don’t hesitate to ask questions and engage in discussions during these events.

For students and postdoctoral researchers in the BCI field, stepping out of their narrow research focus is particularly critical. Understanding the scientific questions that other researchers are exploring will help them gain a broader perspective and achieve greater heights, ultimately making their work more forward-looking and practically meaningful. I hope everyone can gain something valuable from this process. Thank you.

]]> https://admin.next-question.com/people/interview-prof-wang-shouyan/feed/ 0 How Can We Determine If the Universe Is Not a Simulation? https://admin.next-question.com/features/universe-not-simulation/ https://admin.next-question.com/features/universe-not-simulation/#respond Wed, 01 Jan 2025 22:16:28 +0000 https://admin.next-question.com/?p=2692 On an ordinary evening, as you wrap up a day of work and sit down to start a game, the loading bar finishes, and a virtual world appears on the screen.

Immersed in the game, you suddenly notice an ant crawling slowly on your monitor. In that instant, an image from the novel The Three-Body Problem comes to mind. The ant feels like a subtle reminder of something profound, sending a chill down your spine. A startling thought strikes you like lightning—what if each of our lives, or even this vast world, is nothing more than a simulation crafted by an advanced civilization?

At first, the idea may seem absurd. But consider this: the foundation of our existence, much like many major discoveries in human history, has been overturned repeatedly. Five hundred years ago, geocentrism was an unshakable belief. Two hundred years ago, proposing that humans evolved from apes could have branded someone a heretic. Humanity’s understanding of nature is a journey of realizing that we are not as exceptional as we once believed. This concept is embodied in the Copernican Principle, which asserts that no observer should regard themselves as uniquely special.


▷ The diagram “M” (Latin for Mundus) from Johannes Kepler’s Epitome of Copernican Astronomy illustrates this point: Earth is just one of countless stars, a stark reminder that humans, whether on Earth or within the solar system, are not privileged observers of the universe.

1. Ancestor Simulation

If you are familiar with the history of video games, you might recall how gaming has evolved dramatically over just a few decades—from the simple, pixelated graphics of ping-pong games to the lifelike environments of modern massively multiplayer online games. Looking to the future, with the rapid advancement of virtual reality, the scenarios depicted in the sci-fi series Black Mirror—such as uploading and downloading consciousness—seem almost within reach.

In this context, the notion that “we are virtual beings living in a simulation” begins to feel less far-fetched. After all, on a cosmic timescale, a few decades are barely a blink of an eye. And as the Copernican Principle reminds us, it is statistically improbable that humanity represents the pinnacle of civilization in the universe.

So, how likely is it that we are living in a simulation? Once you begin to think seriously about this question, you’ll realize you are not alone. Many physicists and philosophers have explored this possibility, sharing their thoughts through publications and public debates. In 2016, the American Museum of Natural History in New York hosted a panel where four physicists and a philosopher spent two hours discussing whether reality as we know it could be a simulation. Their estimates of the probability ranged widely, from as low as 1% to as high as 42%. That same year, Elon Musk famously declared in an interview that “we are most likely living in a simulation.”

However, following the crowd has never been your style. Determined to explore this question independently, you start gathering evidence. Could we, in fact, be living in a simulation? And if so, is there a way to break free from it?

The type of “simulation” discussed here is not a simple game like The Sims. Instead, it is a comprehensive model of the observable universe—what scholars refer to as an Ancestor Simulation. [1] This hypothesis proposes that a civilization with sufficiently advanced technology might create a simulation on an immense scale. While we cannot predict the exact capabilities of such future technologies, we can attempt to estimate their upper limits based on the physical laws of our observable universe.

If running a simulation of this magnitude would require energy and computational power beyond the constraints of physics, we could argue that such a civilization could not exist. In that case, the Ancestor Simulation hypothesis would be disproven—or, at the very least, humanity’s existence within such a simulation would become highly improbable.


▷ Source: Claire Merchlinsky

2. The Energy Required for Simulation

High-fidelity simulations necessitate immense information processing, which, with current technological capabilities, translates into extraordinarily high computational demands. In such scenarios, the state of every fundamental particle would need to be recorded and updated in real time, requiring computational resources on an astronomical scale. Furthermore, the energy needed to power these highly complex simulations would entail staggering demands. According to thermodynamic principles, extracting energy from cosmic background radiation to sustain computations of this magnitude would not only require overcoming theoretical physical limitations but also addressing significant practical challenges in technology.

These arguments suggest that, within our current technological and theoretical framework, energy constraints make it improbable that we are living in a simulated universe. However, such constraints may not represent an insurmountable barrier. For instance, a super-advanced civilization might bypass energy limitations by creating less precise simulations. Quantum mechanics, with its uncertainty principle—which prevents precise knowledge of an electron’s exact position—and the non-local effects of quantum entanglement, could serve as efficient methods to conserve computational resources during simulation construction.

If we are indeed part of a simulation, and its creators used resource-saving measures, we might uncover evidence of this illusion. One potential approach is to continuously increase the resolution of our observations to detect whether we encounter discrete, pixelated structures. This is similar to video games, where increasing the resolution can expose hidden inconsistencies or graphical artifacts. Interestingly, quantum mechanics already reveals that the world appears discontinuous at extremely small scales, lending some plausibility to the simulation hypothesis.

Moreover, in video games, wandering to the edges of the map often leads to graphical glitches or invisible “walls” that limit further exploration. By analogy, searching for similar anomalies could help determine whether we exist within a simplified ancestor simulation. However, in reality, humanity’s farthest-reaching probe, Voyager 1, has traversed the edge of the solar system without encountering any discontinuities or anomalies. Likewise, the Hubble Space Telescope has captured images of galaxies over 10 billion light-years away without uncovering any apparent anomalies. While these observations cannot definitively rule out the possibility that we are living in a simulation, they do significantly reduce its likelihood.


▷ Source: Staudinger + Franke

3. A Simulated Universe Does Not Require Full Brain Simulation

Beyond the vastness of the starry sky, the human mind is equally complex. The number of neural connections in the human brain is estimated to rival the number of stars in the observable universe. A 2024 study published in Science [2] conducted a nanoscale simulation of just 1 cubic millimeter of brain tissue, encompassing 57,000 cells and 150 million synapses. The resulting mapping data totaled 1.4 petabytes (Pb). When extrapolated to the full volume of the human brain, creating a static map of the entire brain would require 1.76 zettabytes (1 Pb = 1,024 terabytes [Tb], 1 Zb = 1,024 Pb). This vastly exceeds the parameter count of current open-source models, such as Llama 3.1, which had 405 gigabytes (GB) of parameters as of October 2024.

To create an ancestor simulation, it would be necessary to simulate not only every star in the sky but also the mental activities of every human who has ever lived. Attempting to replicate all neural activity from ancient times to the present on a supercomputer would demand energy that exceeds the physical limits of our universe, challenging the notion that we are living in a simulation [3].

However, one might argue that simulating mental activities does not always require extensive computation. A super-advanced civilization might only simulate minimal portions of the brain for most people, reserving significant computational resources for individuals engaged in deep thought. This raises an intriguing testable hypothesis: if billions of people simultaneously engage in reflective thinking, requiring full brain simulations, the computational load might overwhelm the simulation, causing delays reminiscent of frame rate drops in video games. Such anomalies could provide evidence supporting the simulation hypothesis.

Additionally, there are two counterarguments to the assertion that simulating human minds consumes excessive energy:

(1) On-Demand Rendering: In constructing an ancestor simulation, a super-advanced civilization might only render areas being actively observed. This is analogous to the “fog of war” in video games, where unobserved areas remain hidden, significantly reducing computational demands.

(2) Selective Simulation: The creators might simulate only the neural activities of “you,” ensuring your subjective experience feels authentic while generating others’ responses through simplified models. Current large-scale AI models can already simulate human-like interactions; for a civilization capable of ancestor simulations, this task would be trivial, drastically reducing energy consumption.


▷ Source: Mart Biemans

Beyond energy considerations, another way to evaluate the simulation hypothesis is to detect inevitable computational errors. If we live in a simulation, modeling inaccuracies would eventually accumulate, creating observable inconsistencies—similar to how The Matrix required regular reboots. In video games, prolonged gameplay often reveals modeling errors that necessitate developer patches to maintain consistency. By analogy, if we live in a simulation, changes in fundamental constants, such as the speed of light, could serve as evidence. However, the brevity of human history and our understanding of physics limits our ability to detect such long-term changes. It is possible that such patches exist but operate on timescales of tens of thousands or even millions of years. Therefore, even though we have not observed changes in physical constants, we cannot completely rule out the possibility that we are living in a simulation.

An additional counterargument is that a super-advanced civilization might prohibit ancestor simulations for ethical reasons. While less robust, this argument reduces the likelihood of such simulations existing. Similar to how the Drake Equation explores the probability of extraterrestrial civilizations’ existence—calculated by multiplying the number of stars in the universe by the probability of life arising on them and the probability that intelligent life is willing to communicate—thereby estimating the number of extraterrestrial civilizations capable of establishing communication.


▷ Source: University of Rochester
The Drake Equation, originally used to estimate the number of extraterrestrial civilizations, now includes:
N: The number of civilizations capable of creating simulations. R*: The rate of star formation in the Milky Way. fp: The fraction of stars with planetary systems. ne: The average number of habitable planets per system. fe: The fraction of habitable planets where life arises. fi: The fraction of life-bearing planets where intelligent life evolves. fc: The fraction of intelligent life willing to communicate or simulate. L: The time such civilizations remain active.

By adding two new factors to the Drake Equation—first, the probability that intelligent life advances to the point of being able to simulate a world; second, the probability that a super-advanced civilization would prohibit ancestor simulations for ethical reasons—we can use the modified equation, based on current technological and cultural development, to estimate the probabilities of these new factors. This allows us to assess the number of planets that might be willing to simulate worlds and, consequently, infer the probability that we are living in a simulation.

4. Three Possibilities for a Simulated World

In his 2003 paper Are You Living in a Computer Simulation?, philosopher Nick Bostrom redefined the debate by proposing three possibilities that cover all potential scenarios:

First, humanity or other intelligent beings go extinct before achieving simulation technology.
Second, super-advanced civilizations capable of creating ancestor simulations either lack the will or face prohibitions against using such technology.
Third, We are currently living in an ancestor simulation.

To evaluate which of the first two possibilities is more likely, two critical questions arise.The first question examines the probability of life successfully reaching the singularity. For example, before humanity develops general artificial intelligence, could it face extinction due to catastrophic events like runaway climate change or nuclear war? On this issue, the scientific community provides some predictions, though the outcomes remain uncertain.

The second question delves into the societal structures and moral frameworks of super-advanced civilizations—a nearly impossible task. Just as a gorilla cannot grasp the utility humans derive from advanced technology, we cannot envision the motivations or priorities of beings capable of ancestor simulations. Perhaps such civilizations lack the drive to undertake the creation of simulations that, once initiated, require no further involvement. Alternatively, ethical considerations or cultural values might prohibit such endeavors altogether. However, our complete lack of insight into their reasoning makes assessing this possibility extremely challenging.

At its core, if we ourselves do not believe we are living in a simulation, there is little reason to assume that future post-human civilizations would conduct large-scale ancestor simulations. Conversely, if we think humanity could one day simulate an entire world, why not accept the likelihood that we are already part of such a simulation?

One way to approach this paradox is through Occam’s Razor, which suggests that the simplest explanation is often more likely than a complex one. Believing we live in a simulation assumes the existence of a super-advanced civilization, thereby adding unnecessary complexity to the model. The maxim “entities should not be multiplied without necessity” thus provides a compelling framework for addressing the simulation hypothesis. However, Occam’s Razor is not absolute; in some cases, scientific consistency, predictive power, or internal logic may require adopting a more complex model.


▷ Source: Claudio Araos Marincovic

5. Why Is Speculative Thinking Meaningful?

Readers who have reached this point might wonder: “Like Zhuangzi dreaming of a butterfly or the butterfly dreaming of Zhuangzi, why should we concern ourselves with such abstract questions when life is already fraught with its own challenges?” This line of inquiry may seem akin to the philosophical stance of agnosticism—ultimately irresolvable. However, our concerns and curiosities drive exploration and foster awe for the universe’s diversity and mysteries. Throughout the history of science, many revolutionary discoveries have emerged from profound questions about the essence of existence.

When we explore the possibility of a simulated universe, we are not only questioning the nature of reality but also sparking deeper discussions about technology, ethics, and existence itself. For example, this inquiry intersects with advancing technologies such as virtual reality (VR) and mixed reality (MR), raising questions about how we treat virtual beings powered by AI-driven models. As we approach the advent of general artificial intelligence (AGI), such discussions also highlight concerns about losing control over intelligent agents and whether these agents might attempt to escape the simulated environments we create for them. Speculating on whether we are living in a simulation inspires research into AI alignment while also deepening our understanding of existence.

In the future, as technology advances and humanity’s understanding of the universe grows, we may approach these questions with entirely new perspectives. More detailed observations, refined data analyses, and novel technological methods could help us test these hypotheses. Yet, in the pursuit of truth, maintaining curiosity and humility toward the unknown remains among the most enduring values in scientific inquiry.

]]> https://admin.next-question.com/features/universe-not-simulation/feed/ 0 Hearing the Silent Soul: Consciousness in Vegetative State Patients https://admin.next-question.com/features/hearing-the-silent-soul-consciousness-in-vegetative-state-patients/ https://admin.next-question.com/features/hearing-the-silent-soul-consciousness-in-vegetative-state-patients/#respond Wed, 01 Jan 2025 21:33:33 +0000 https://admin.next-question.com/?p=2683 Introduction: Using advanced neuroimaging technologies such as fMRI and EEG, scientists have identified subtle signs of consciousness in patients previously diagnosed with a “vegetative state” (VS). This breakthrough not only challenges the traditional understanding of the vegetative state but also highlights the concept of “covert consciousness” or “cognitive-motor dissociation.”

In Edward Yang’s film Yi Yi, an elderly woman falls into a coma following an accidental fall. Her caregiver advises the family to talk to her daily to aid recovery. But does speaking to a comatose individual truly make a difference? Can such patients actually hear, or even retain any degree of consciousness?

1. Conscious Responses in the “Vegetative State”

The question of whether comatose individuals retain consciousness has sparked debate since the 1990s.

Modern medicine traditionally defines the vegetative state as a condition characterized by a lack of conscious awareness and unresponsiveness. Yet, research indicates that 13–19% of patients diagnosed with VS or coma exhibit conscious responses to external stimuli.


▷ Owen, Adrian M., et al. “Detecting awareness in the vegetative state.” science 313.5792 (2006): 1402-1402.

A groundbreaking 2006 study published in Science (Owen et al., 2006) reported a compelling case [1]: a 23-year-old female patient in a vegetative state following a traffic accident demonstrated neural activity indistinguishable from that of healthy individuals when exposed to linguistic stimuli. Strikingly, when presented with sentences containing ambiguity, her left ventrolateral prefrontal cortex displayed neural responses typical of language comprehension.

Even more remarkably, the patient exhibited evidence of “imaginative behavior.” When instructed to imagine specific actions such as playing tennis or walking (motor imagery), her neural activity was indistinguishable from that of healthy controls.


▷ The study monitored the activity of the supplementary motor area (SMA) in both the patient and a control group of 12 healthy volunteers during the process of imagining playing tennis. When imagining moving around her home, the researchers detected neural activity in the parahippocampal gyrus (PPA), posterior parietal cortex (PPC), and premotor cortex (PMC).

Despite meeting the clinical criteria for a vegetative state, her ability to comprehend and follow instructions suggested a preserved awareness of herself and her environment. This study underscored that neural activity in response to stimuli can serve as a marker of consciousness, while its absence does not necessarily confirm unconsciousness.

Previously, it was widely believed that comatose patients either progressed to brain death or transitioned into a vegetative state—both thought to lack consciousness entirely. However, Adrian Owen’s findings introduced the possibility of intermediary states, such as the “minimally conscious state” (MCS) or “covert consciousness.”

This raises a profound question: how can we accurately determine whether a person, especially one unable to communicate verbally or behaviorally, retains consciousness?

2. Determining the Presence of Consciousness

To assess the presence of consciousness in individuals with severe neurological conditions, it is crucial to first understand the classifications of death. Death is generally divided into two main categories: legal death (the cessation of legal personhood) and natural death, which itself encompasses three progressive stages: clinical death, brain death, and biological death [2].


The vegetative state (VS) is a condition that resembles these stages but retains certain physiological functions. According to the Merck Manual of Diagnosis and Therapy [3]:

The vegetative state is a chronic condition in which patients can sustain blood pressure, respiration, and cardiac functions but lack higher cognitive abilities. While the hypothalamus and medullary brainstem functions remain intact to support cardiopulmonary and autonomic systems, the cortex suffers severe damage, eliminating cognitive function. Despite this, the reticular activating system (RAS) remains functional, allowing wakefulness. Midbrain or pontine reflexes may or may not be present. Typically, such patients lack self-awareness and interact with their environment only via reflexive responses.

However, findings from Owen’s team demonstrate that patients diagnosed as being in a vegetative state may indeed possess self-awareness and can even interact with their environment autonomously through neural activity. For example, patients have been shown to imagine actions, such as playing tennis, in response to instructions from clinicians. This neural activity, which can be detected using fMRI or EEG, indicates the presence of consciousness despite the absence of observable physical behavior. This phenomenon is referred to as “covert consciousness.”

3. Cognitive-Motor Dissociation: A New Understanding of Consciousness

Building on Adrian Owen’s groundbreaking research, subsequent studies have confirmed the phenomenon of “covert consciousness” in patients previously classified as being in a vegetative state. These findings, often based on motor imagery techniques, have identified a condition termed Cognitive-Motor Dissociation (CMD).

CMD describes a state in which patients demonstrate measurable neural responses to external stimuli, including motor imagery comparable to that of healthy individuals. However, due to motor system impairments, they are unable to execute corresponding physical actions.


▷ Schiff, Nicholas D. “Cognitive motor dissociation following severe brain injuries.” JAMA neurology 72.12 (2015): 1413-1415.

In 2015, Nicholas D. Schiff’s team used advanced imaging techniques such as Dynamic Causal Modeling (DCM) and Diffusion Tensor Imaging (DTI) to assess the functional integrity of brain networks supporting motor imagery in these patients. Their research aimed to uncover the neural mechanisms underlying Cognitive-Motor Dissociation [4].

The study revealed that in healthy individuals, excitatory coupling between the thalamus and motor cortex is critical for executing motor behaviors. However, in patients with covert consciousness, analyses using DCM and DTI demonstrated a selective disruption of this coupling. This disruption explains the dissociation between preserved motor imagery and absent skeletal movement. It is akin to operating the mechanical arm of an excavator when the circuit between the control panel and the arm is severed—you can still issue commands, but the arm cannot carry out the movements.

*DCM: A neuroimaging technique that examines causal relationships and connectivity between brain regions, providing insights into their functional interactions.
DTI: An MRI-based method for mapping the direction and integrity of white matter tracts, offering a detailed view of brain structural connectivity and its changes.

4. Research on the Prevalence of Cognitive-Motor Dissociation

Patients with Cognitive-Motor Dissociation (CMD) are often misdiagnosed as being in a vegetative state. However, there is currently no standardized method for accurately identifying CMD. The mechanism identified by Schiff’s team, discussed earlier, may not apply universally to all CMD cases. Moreover, previous studies on CMD have generally been small-scale, fragmented, and lacking consistency, with limited sample sizes. Under these conditions, developing a globally applicable standard for patient assessment is challenging, let alone designing targeted treatment approaches for CMD.

To address this issue, the paper titled “Cognitive Motor Dissociation in Disorders of Consciousness”, [5] supported by the Tianqiao Chen Institute-MGH Research Scholar Award, offers a potential solution. This study, published in The New England Journal of Medicine in August 2024, features Chen Scholar Brian L. Edlow as a key participant.


▷ Bodien, Yelena G., et al. “Cognitive motor dissociation in disorders of consciousness.” New England Journal of Medicine 391.7 (2024): 598-608.

This study recruited patients from diverse settings, including intensive care units, rehabilitation centers, nursing homes, and community populations. A unified inclusion criterion was applied: participants had no prior history of neurological or psychiatric disorders and were physiologically capable of undergoing brain imaging techniques, including MRI and EEG.

The research analyzed 353 adult patients diagnosed with disorders of consciousness using motor imagery tasks assessed via fMRI and EEG. Among these, 241 patients were classified as being in a coma, a vegetative state, or a minimally conscious state (MCS) based on the internationally recognized Coma Recovery Scale-Revised (CRS-R). Notably, 25% (60 patients) of this group exhibited CMD, characterized by task-based neural responses despite the absence of behavioral responses. Additionally, 112 patients were diagnosed as being in an MCS+ state or as having recovered from MCS. Among this subgroup, 43 patients (38%) exhibited observable task-based responses to commands detected via fMRI, EEG, or both.

*Minimally conscious states are further categorized as MCS− and MCS+, based on language processing abilities: MCS+ patients demonstrate simple command-following, intelligible verbal expression, or conscious but non-functional communication. MCS− patients exhibit more limited behaviors, such as visual pursuit, localization to noxious stimuli, or basic spontaneous activities like grasping bedsheets.

This study reported a higher prevalence of CMD (25%) than previous research, which estimated that 10–20% of patients with disorders of consciousness exhibit CMD symptoms. While traditional behavioral metrics like CRS-R offer valuable insights into assessing patient consciousness and responsiveness, task-based neuroimaging technologies significantly enhance diagnostic accuracy. Notably, the combined use of EEG and fMRI further improves measurement precision. These findings suggest that the prevalence of CMD may have been underestimated in prior studies.

5. The Significance of Measuring Consciousness in the Vegetative State

Imagine being aware of everything around you—the hum of medical equipment by your bedside, the whispers of family and friends—yet being unable to speak, move, or respond in any way. This state of isolation and helplessness could lead one to abandon even the faintest will to live. Although the phenomenon of “living dead” occurs in only a minority of vegetative state patients, every individual, no matter how rare their condition, represents a unique and precious life.

Whether driven by technological advancement or humanistic ethics, we need a measurement method that is more accessible, precise, and cost-effective to determine the consciousness state of comatose patients. The research conducted by Y.G. Bodien and colleagues stands out by integrating patient data from multiple locations and unifying measurement methodologies through brain imaging techniques. This unprecedented approach has maximized the accuracy of identifying Cognitive-Motor Dissociation (CMD) patients and pointed the way forward for future medical technologies and treatments. Most importantly, it offers a renewed sense of hope to those trapped in a silent world.

]]> https://admin.next-question.com/features/hearing-the-silent-soul-consciousness-in-vegetative-state-patients/feed/ 0 Why Can’t Musk’s “Blind Vision” Surpass Natural Sight? https://admin.next-question.com/uncategorized/blind-sight-surpass/ https://admin.next-question.com/uncategorized/blind-sight-surpass/#respond Fri, 27 Dec 2024 05:03:34 +0000 https://admin.next-question.com/?p=2668 Perhaps I can best illustrate by imagining what I should most like to see if I were given the use of my eyes, say, for just three days. And while I am imagining, suppose you, too, set your mind to work on the problem of how you would use your own eyes if you had only three more days to see. If with the oncoming darkness of the third night you knew that the sun would never rise for you again, how would you spend those three precious intervening days? What would you most want to let your gaze rest upon?
—— Helen Keller

In our vibrant world, we often lament Helen Keller’s blindness and are deeply moved by her longing for the beauty she could never see. However, the reality is that over 2.2 billion people suffer from visual impairment or blindness worldwide. Advances in visual cortex restoration technologies, particularly visual cortical prosthetics, offer a glimmer of hope for these individuals. Yet, even if partial vision is restored, can we truly understand what their world looks like?

Currently, three clinical trials of visual cortical prosthetics are underway. One uses surface electrodes (the Orion device by Second Sight Medical Products 1,2), while the other two employ deep electrodes 3,4. However, predicting the extent of restored vision remains a challenge. Furthermore, the field of neural implants heavily depends on intuition and experience, which introduces the risk of perceptual biases due to subjective interpretations.

A recent article in Scientific Reports 5 by Ione Fine and Geoffrey M. Boynton from the University of Washington introduces a “virtual patient” model grounded in the architecture of the primary visual cortex (V1). This model accurately predicts perceptual experiences reported in various studies on human cortical stimulation. Simulations reveal that increasing the number of smaller electrodes does not always improve visual restoration. In the near term, the quality of perception provided by cortical prosthetics seems more constrained by the visual cortex’s neurophysiological structure than by technological limitations.
 

1. Advances and Challenges in Vision Restoration Technologies

Vision restoration technologies are advancing rapidly worldwide, with at least eight teams developing retinal electronic implants. Among these, two devices have been approved for patient use 6-12, while others are currently in clinical trials 13. Another promising approach is optogenetics, which has shown limited but encouraging results in early clinical trials. Gene therapy, particularly for conditions like Leber congenital amaurosis, has already received clinical approval, and many additional gene therapies are under active development. Furthermore, retinal pigment epithelium and stem cell transplantation are progressing, with several phase I/II trials ongoing. Many other promising therapies are also being explored.

However, these approaches are limited to retinal interventions and cannot address conditions like retinal detachment or diseases causing irreversible damage to retinal ganglion cells or the optic nerve, such as congenital childhood glaucoma. This limitation has driven significant interest in vision restoration by directly targeting the brain’s cortical visual centers. Since 2017, three clinical trials for visual cortical prosthetics have been initiated. These trials, grounded in decades of research on cortical stimulation (see Table 1), have examined both short-term and long-term effects. However, the findings so far are primarily descriptive.


▷ Table 1: Studies describing perceptual effects of human cortical electrical stimulation.

Predicting the level of vision restoration achievable with visual cortical prosthetics before human implantation remains a significant challenge. The field of neural implants continues to rely heavily on experience and assumptions. For example, it seems logical that increasing the number of smaller electrodes would enhance resolution. But is this assumption valid?

A team led by Ione Fine 14 developed a computational “virtual patient” model based on the neurophysiological structure of the primary visual cortex (V1). This model accurately predicted perceptual outcomes from electrical stimulation, including the position, size, brightness, and spatiotemporal shape of elicited visual perceptions. Such predictions provide a valuable tool for anticipating the perceptual effects of visual cortical prosthetic implants before their application in humans.
 

2. Addressing Data Shortage with a “Virtual Patient” Model

Building on previous models of retinal prosthetic stimulation, Ione Fine’s team has developed an innovative theoretical framework. The model integrates currents from cortical implants over time, converting them into neural signal intensities. The resulting perception from neuronal stimulation is based on a linear summation of each cell’s receptive field, adjusted by the neural signal intensity at each specific location and moment. Despite its mathematical simplicity and lack of complex parameters, the model accurately predicts a range of data on cortical stimulation.


▷ Fine, Ione, and Geoffrey M. Boynton. “A virtual patient simulation modeling the neural and perceptual effects of human visual cortical stimulation, from pulse trains to percepts.” Scientific Reports 14.1 (2024): 17400.

(1) Temporal Conversion from Pulse Trains to Perceptual Intensity

To design the model, Ione Fine’s team first employed a rapid temporal integration phase, capturing the immediate response of cells to current as a measure of “spike activity intensity.” They also introduced a refractory period, positing that cells require a brief interval after activation before they can respond to subsequent stimuli. This phase is followed by a slower integration process, incorporating a compressive non-linear relationship, as shown in Figure 1.

▷ Figure 1. Schematic of the conversion from pulse trains to perceptual intensity over time

The team implemented this process using a straightforward single-stage leaky integrator. In this model, the depolarization rate depends on both the current depolarization level and the input current, meaning that variations in current directly influence the rate of depolarization. In the model’s first phase, the “spike response intensity” reflects the collective recruitment of spikes from various cell populations with differing activation thresholds. The compressive non-linear function not only accounts for saturation effects in these populations but also mirrors complex cortical gain control mechanisms.

(2) Visual Dominant Columns, Orientation Pinwheels, and Receptive Fields

The primary visual cortex (V1) contains complex, structured neural arrangements that influence how visual information is perceived and processed. Building on the work of Rojer and Schwartz, Figure 2 illustrates these simulated structures. The orientation columns (Figure 2B), sensitive to visual direction, were generated by band-pass filtering random white noise to reflect neurons’ directional preferences. Fine’s team further enhanced the model by incorporating visual dominant columns (Figure 2C), which add directional gradients to the same noise signal, resulting in orthogonally arranged visual and orientation columns. These structures closely mimic maps observed in both macaques and humans.

A single receptive field (Figure 2F) is the basic unit in the visual system responsible for receiving and processing light signals. It is generated using a simple model through the additive combination of “ON” and “OFF” subunits, with the spatial separation of subunits derived from a unimodal distribution. The same band-pass filtered white noise used to generate orientation and visual dominant maps was also used to create controls for the separation of “ON” and “OFF” receptive fields (δ_on–off) and the relative strength of “ON” and “OFF” receptive fields (w_on–off).

Predicted phosphenes are produced by summing receptive field contours at each cortical location, with intensity weighted according to the level of electrical stimulation. Consequently, the stimulation intensity at an electrode directly influences the perceived phosphene’s brightness and size.


▷ Figure 2. Schematic of the cortical model (A) Transformation from visual space to cortical surface. (B) Orientation pinwheel map. (C) Visual dominant columns. (D) Spatial separation of ON and OFF subunits. (E) Relative strength of ON and OFF. (F) Receptive field size.

(3) Phosphene Thresholds and Brightness as Functions of Electrical Stimulation Temporal Characteristics

Ione Fine’s team compared the model’s predictions with data on current amplitude thresholds and brightness ratings measured across various pulse sequences. The model accurately described how pulse sequences are converted into perceptual intensity, successfully predicting phosphene thresholds and brightness ratings across different pulse parameters, electrode locations, and electrode sizes. This suggests that the model can reliably estimate patients’ perceptual experiences regardless of changes in stimulation frequency, pulse width, or the specific location and size of electrodes.

*Phosphene threshold refers to the minimum current intensity required to produce a visible phosphene, while brightness rating is patients’ subjective evaluation of the phosphene’s brightness.

(4) Relationship Between Phosphene Size, Current Amplitude, and Eccentricity

Additionally, the model developed by Ione Fine’s team 1 successfully predicted how phosphene size varies with current amplitude and visual field eccentricity. The study found that as current amplitude increases, phosphene size also increases, closely aligning with patient perception data. This indicates that current amplitude is a key factor in determining phosphene size. Furthermore, the model demonstrated that phosphene size grows with visual field eccentricity, meaning that electrical stimulation at the periphery produces larger phosphenes than those in the central area.

(5) Shape Recognition

In the study, the team compared perceptual experiences generated by simultaneous versus sequential electrode stimulation. The results showed that when multiple electrodes were stimulated simultaneously, the model failed to correctly recognize complete letter shapes, mirroring patients’ actual experiences. However, when electrodes were stimulated sequentially in the order of writing, the model accurately recognized letter shapes. This highlights a critical point: simultaneous stimulation makes it difficult to group and interpret phosphenes correctly, whereas sequential stimulation facilitates the formation of recognizable shapes.

This phenomenon may arise from the absence of the Gestalt effect in the model. Gestalt psychology posits that the whole is greater than the sum of its parts, meaning our perceptual system integrates dispersed phosphenes into meaningful wholes. However, since the model does not account for electric fields or complex neural spatiotemporal interactions, phosphenes cannot be effectively grouped during simultaneous stimulation, leading to challenges in shape recognition. Sequential stimulation, by temporally separating stimuli, reduces interference between phosphenes and allows the perceptual system to better integrate information and recognize shapes accurately.

(6) Using “Virtual Patients” to Predict Perceptual Outcomes of New Devices

The ability of Ione Fine’s team’s model to replicate extensive data suggests it can provide insights into the potential perceptual experiences of new technologies—one of the primary uses of the “virtual patient” model.


Figure 3 examines the perceptual experiences produced by different electrode sizes using the “virtual patient” model. In Figure 3A, the simulated array employs extremely small electrodes (tip areas ranging between 500-2000 μm²). The model predicts visual phosphenes that align with preliminary experimental data: phosphenes from adjacent electrodes cannot be clearly distinguished. This matches patients’ pre-experimental observations, indicating that when electrode stimulation intervals range from 0.4 to 1.85 millimeters, both single and multiple electrode stimulations produce irregularly shaped phosphenes. This implies that extremely small electrodes may simultaneously stimulate neuronal populations tuned to similar directions, resulting in elongated or complex phosphene structures.

Figures 3B and 3C further explore the impact of electrode size on patient perception. For small electrodes with limited current diffusion (cortical tissue stimulation radius less than 0.25 millimeters), the model predicts complex phosphene structures, as shown in the upper part of Figure 3B. At this stage, electrode size has minimal impact on phosphene appearance or size. When the electrode radius ranges from 0.25 millimeters to 1 millimeter, phosphenes begin to resemble “Gaussian blobs,” but their size is still primarily determined by receptive field size rather than the stimulated area. Only when the electrode radius exceeds 1 millimeter does electrode size significantly influence phosphene size.

Crucially, the model indicates that throughout the visual field, receptive fields impose a physiological “lower limit” on phosphene size. Specifically, reducing the stimulation area’s radius below 0.5 millimeters may not significantly enhance vision and might instead render phosphenes difficult to interpret.


▷ Figure 3. Using “Virtual Patients” to Predict Perceptual Outcomes
(A) Simulated perception with very small deep electrode arrays. The lower left panel shows electrode positions and sizes in the array. The upper right panel displays example perceptions from three individual electrodes. The lower panel shows predicted outcomes when electrode pairs are stimulated simultaneously. (B, C) Simulated predicted phosphene shapes and sizes under different electrode sizes and cortical locations. The narrow shaded area in panel C represents the 5–95% confidence interval.

Similarly, the question arises: does having more electrodes lead to better vision restoration?

Ione Fine’s team simulated perceptual outcomes for three different electrode array configurations through Figure 4, revealing the complexity of this issue.

Figure 4A shows electrodes arranged in a regular pattern within the visual space. This arrangement produces sparse, small phosphenes in the foveal region (the retina area responsible for high-resolution vision), significantly underestimating its perceptual capability. This means that despite an increased number of electrodes, the phosphene distribution in the foveal region is not dense enough to fully utilize its high-resolution potential.


▷ Figure 4. Comparison of Simulated Electrode Array Configurations
(A) Regularly spaced electrodes in the visual field. (B) Regularly spaced electrodes on the cortical surface. (C) ‘Optimal’ spacing.

Figure 4B shows electrodes arranged regularly on the cortical surface. This configuration leads to an excessive concentration of electrodes in the foveal region, causing significant overlap between receptive fields. Consequently, these overlapping receptive fields do not substantially improve resolution. In fact, electrodes near the foveal region almost project to the same visual spatial location, making it difficult for patients to perceive positional changes even with slight electrode movements. This finding challenges the traditional view that the extensive expansion of the foveal region in V1 supports higher spatial sampling capabilities.

Figure 4C presents an “optimal” electrode configuration, where electrode spacing is designed so that the center-to-center distance of stimulated phosphenes maintains a fixed ratio with phosphene size. Since receptive field size increases linearly with visual field eccentricity and cortical magnification changes logarithmically, this configuration results in a more dispersed electrode distribution in the foveal region compared to peripheral areas. The results indicate that electrodes should be more sparsely arranged in the foveal region rather than densely packed, contrary to common intuition.

The simulation results from Ione Fine’s team demonstrate that excessively dense electrode arrangements in the foveal region do not enhance perceptual resolution. Instead, based on neurophysiological constraints, appropriately distributing electrode positions and spacing is essential to maximize the perceptual efficacy of visual cortical prosthetics.
 

3. Insights from the “Virtual Patient” Model

The “virtual patient” model tackles a fundamental challenge in vision restoration: predicting patients’ perceptual experiences before device implantation. This model enables researchers to evaluate how different electrode designs and stimulation parameters might impact visual perception, all without actual implantation.

Additionally, the model challenges a common misconception: increasing electrode numbers or reducing their size does not necessarily improve visual perception and may actually complicate perceptual experiences.

Ione Fine’s model identifies three main factors limiting the spatial resolution of cortical implants: cortical magnification, receptive field structure, and electrode size. Receptive field size is strongly linked to cortical magnification. In most cortical areas, the receptive field area is roughly to the -2/3 power of cortical magnification. This relationship supports prior findings by Bosking and colleagues, who noted that patient-drawn phosphene sizes could be predicted by cortical magnification. In the foveal region, where cortical magnification peaks, receptive fields are smallest, with radii ranging from 0.02 to 0.5 degrees.

Data and simulations show that for a fixed electrode size, phosphene size increases linearly with eccentricity. When electrode radii are smaller than 0.25 millimeters, this relationship primarily reflects the increase in receptive field size with eccentricity. For larger electrodes, both cortical magnification and the size of the stimulated cortical area become significant factors in determining phosphene size.

With smaller electrodes, receptive field size primarily limits visual acuity. If neurons with very small receptive fields could be selectively stimulated, closer electrode spacing in the foveal region could enhance spatial resolution. However, human vision can resolve details far finer than a single receptive field width. This fine discrimination depends on interpreting complex response patterns across neuron populations with diverse receptive fields, rather than on individual neurons alone.

In summary, Ione Fine’s simulations suggest that, in the near future, the spatial resolution of visual cortical prosthetics will likely be constrained more by the neurophysiological structure of the visual cortex than by engineering limits. This implies that enhancing vision restoration outcomes will require a deeper understanding and application of visual cortex neurophysiology, rather than simply increasing electrode numbers or reducing their size.
 

4. Current Limitations of the “Virtual Patient” Model

The advent of the “virtual patient” model has transformed our understanding of retinal implant surgeries. While modeling techniques have long simulated the effects of electrical stimulation on local tissues, such as current diffusion from electrodes, predicting perceptual outcomes requires expanding virtual models to include core physiological principles.

The “virtual patient” model developed by Ione Fine’s team has effectively predicted a range of perceptual outcomes from cortical electrical stimulation, suggesting it may serve as a useful approximation for future retinal or cortical implants. This model could guide future research using more reliable subject data.

Despite its utility, the current model has several limitations. First, it uses current amplitude as an input parameter, though a more precise approach would employ current density (current intensity divided by electrode area) to better capture current distribution and its effects within tissue.

Second, the model assumes that electrodes are perfectly aligned with the cortical surface. In reality, electrodes may not sit flush, and even slight tilts can result in only the edges driving neural responses effectively.

Third, the model serves only as an approximation and may not be suitable for long-term stimulation protocols. Fourth, it excludes electric fields and nonlinear neural interactions. Fifth, it assumes perception is a simple average across receptive fields. An alternative could involve representing each neuron by its “optimal reconstruction filter”—the cell’s specific role in reconstructing natural images within the neural network.

Finally, the current model only includes the V1 cortical area. Due to the cortical surface’s configuration, electrode implantation is much easier at higher-level visual areas, such as V2 or V3. Many components of the model, including the transformation from visual space to the cortical surface, could be easily extended to these higher visual areas. The model could also be expanded to incorporate the receptive fields of V2 or V3 neurons. However, the complexity of V2-V3 receptive field structures, combined with a lack of cortical stimulation data from V2 or V3 electrodes, means that any such extension of the model remains highly speculative at present.

5. Future Outlook

In the future, “virtual patient” models may serve multiple critical functions. For researchers and companies, they can quantitatively evaluate our level of understanding of this technology. Given the difficulties in collecting behavioral and cortical data, model-driven approaches can help guide experiments to produce the most meaningful insights, thereby optimizing the allocation of research resources.

Another important application is predicting the visual quality a specific implant might provide. In this study, Ione Fine’s team used qualitative assessments of perceptual quality to evaluate different array configurations. A more rigorous approach might involve subjective interpretation; for example, asking visually normal individuals to perform perception tasks with simulated prosthetic vision. Alternatively, simulations could serve as inputs for decoders trained to reconstruct the original image. Recent cortical simulators display characteristics similar to those in more complex models.

Finally, “virtual patients” can guide the development of new technologies. The current model, for example, suggests that small electrode sizes and dense implantation in the foveal region provide limited advantages. Additionally, “virtual patients” could help generate optimized training sets for deep learning-based prosthetic vision, aiding in the identification of optimal stimulation patterns for existing implants. Similar retinal stimulation models are currently used to simulate and enhance prosthetic vision in virtual reality environments by generating preprocessed training data for deep learning.

For agencies like the FDA and insurance providers, these models can inform essential visual tests for device evaluation, helping to establish scientific standards that ensure the safety and effectiveness of new vision restoration technologies. Finally, for surgeons and patients’ families, these models provide more realistic expectations for perceptual outcomes.

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