NIH_RFI_BCI

Responses must be submitted to BRAIN-CircuitPerturbation@nih.gov by August 1st, 2024. Responses should use the subject “RFI - Coordinated Neural Stimulating and Recording Efforts".

https://grants.nih.gov/grants/guide/notice-files/NOT-NS-24-080.html

Subject: RFI - Coordinated Neural Stimulating and Recording Efforts

Dear NIH BRAIN Initiative Team,

We commend the NIH for its commitment to advancing human neuroscience, as exemplified in the recent webinar on "Advancing Human Neuroscience through Neural Stimulation and Recording: Opportunities and Challenges for Coordinated Efforts." This event highlighted the critical need for both basic and invasive research to deepen our understanding of neural stimulation and recording technologies, including non-invasive methods. Our response emphasizes the crucial role of these research modalities in understanding brain-behavior relationships through coordinated efforts involving neural stimulation and recording.

Key Insights and Challenges in Understanding Brain-Behavioral Relationships

The potential of coordinated efforts using neural stimulation and recording to reveal new insights into fundamental brain functions is immense. These efforts can address questions about human network dynamics and brain function that are not possible under current constraints. Understanding the mechanisms of invasive and non-invasive stimulation approaches in high-throughput animal models is essential for probing these functions and developing theoretical and computational models. The integration of perturbations with animal models, theory, and modeling can elucidate how brain structure, function, and dynamics subserve human behavior.

The Importance of Basic and Invasive Research

Many of the gaps in knowledge and open questions highlighted in Session 1 of the webinar require basic mechanistic research that cannot be ethically conducted in human subjects. Basic research is essential for translational science, serving as the foundation for future therapeutic innovations. The concepts of parallel translation, reverse translation, and forward translation are key to this process. Parallel translation involves the simultaneous exploration of fundamental and applied research questions. Reverse translation refers to taking clinical observations back to the lab to uncover hidden mechanisms, refine or develop new models, and make fundamental discoveries for tomorrow’s treatments. Forward translation encompasses the application of these findings to develop new treatments or interventions.

In the context of non-invasive and invasive neural technologies, understanding the underlying mechanisms is crucial for effective application and further innovation. Invasive research often provides the necessary insights into these mechanisms, which cannot be fully explored in humans due to ethical and practical constraints. Such research includes the use of animal models and advanced techniques like viral vectors for introducing transgenic indicators, which are not permissible in human subjects.

High-Throughput Animal Research as a Critical Support for Human Research

High-throughput mechanistic research in animal models plays a vital role in supporting human research. It allows for the rapid testing of hypotheses and the exploration of complex neural circuits and behaviors under controlled conditions. These studies are essential for generating preliminary data that can guide human studies, helping to refine experimental designs and ensure that the most promising avenues are pursued. This approach maximizes the ethical use of human subjects by ensuring that we have exhausted other avenues of inquiry before involving them in research.

Ethical Considerations and Practical Challenges

Conducting human research ethically and responsibly requires that we maximize the knowledge gained from each subject, ensuring that we learn everything possible before enrolling new participants. Ethical guidelines must be strictly followed, especially given the limitations of human subject research, such as the inability to use certain invasive techniques. Moreover, the logistical challenges of human subject research further underscore the need for a strong basic research foundation. Human research is often slow, constrained by the health limitations and availability of participants, who may have difficulty with transportation, can only engage in studies for limited periods, fatigue quickly, require support for participating in studies, and have limited time availability for a large team of investigators. These factors, combined with the variability among human subjects, slow the pace of research and complicate data collection and analysis. This highlights the need for complementary high-throughput mechanistic studies in model systems.

Addressing Population Heterogeneity and Ensuring Generalizability

Recruiting inclusive and diverse samples is essential for ensuring the generalizability of findings. Methodological and phenotypic biases must be addressed to accurately interpret brain-behavior data. This includes strategies for determining minimal sample sizes that can establish reproducible brain-behavior associations, thereby enhancing the robustness and reliability of research findings. High-throughput statistical analyses in diverse animal models can identify key variables that affect neural and behavioral responses, allowing for more precise stratification and interpretation in human studies. By leveraging data from high-throughput mechanistic studies, researchers can better understand the range of normal and pathological variability, which is crucial for developing targeted and personalized interventions.

Practical Considerations for Coordinated Efforts

The complexity and scope of the problem that NIH seeks to address, and the tools and experimental models required to address them, requires a team of scientists with diverse expertise that can conduct parallel translational research. To enable large-scale, coordinated MPI efforts, critical practical challenges must be addressed. This includes developing standardized protocols and data-sharing frameworks, as well as providing incentives for key research partners. Establishing standardized protocols is particularly important in high-throughput research, where consistency and reproducibility are essential. Standardization ensures that data collected across different labs and studies can be aggregated and compared, enhancing the overall robustness of findings. Data-sharing frameworks facilitate the integration of diverse datasets, enabling comprehensive analyses that can uncover complex relationships between neural activity and behavior. Additionally, incentives such as funding, recognition, and collaborative opportunities are necessary to motivate key research partners, including those involved in high-throughput mechanistic studies, to contribute to large-scale efforts. These steps are necessary to facilitate collaboration and ensure that data collected is used responsibly and effectively.

Neuroethical Considerations and Research Gaps

Neuroethical considerations are paramount in designing studies and collecting data involving neurostimulation in humans. These considerations ensure that research is conducted responsibly, with the well-being of participants prioritized. Additionally, significant research gaps remain in understanding the mechanisms underlying non-invasive stimulation and recording technologies. Addressing these gaps through basic and invasive research will support the parallel, reverse, and forward translation of findings into practical applications for treating neurological and psychiatric disorders.

Conclusion and Call to Action

We urge the NIH to prioritize basic and invasive research alongside human studies to ensure a continuous and robust pipeline of scientific discovery. Other neurological and psychiatric conditions, such as multiple sclerosis (MS), Parkinson's disease, Alzheimer's disease (AD), stroke, and traumatic brain injury (TBI), benefit from a well-established pipeline of basic and translational research. This pipeline supports comprehensive studies that advance our understanding of these diseases, facilitating the development of effective therapies. A similar approach is needed for both invasive and non-invasive neural technologies, leveraging both basic and invasive research to drive forward translation and eventual clinical application.

Given these considerations, we strongly advocate for increased investment in basic and invasive research to support the parallel translation of non-invasive stimulation and recording technologies. Such investment is essential for uncovering the fundamental principles that govern these technologies, thereby enhancing their effectiveness and reliability in clinical settings. Additionally, reverse translation efforts can help refine our understanding of these mechanisms, while forward translation can facilitate the development of new interventions.

Thank you for considering our input. We look forward to the continued progress of the BRAIN Initiative and are eager to contribute to its success.

Sincerely,