Feinstein Institutes Uncover Ancient Reflex Linked to Future Brain Injury Therapies
Researchers at Northwell Health’s Feinstein Institutes for Medical Research have uncovered the molecular mechanism behind one of the body’s oldest survival responses—the diving reflex—providing new insights that could transform the treatment of neurological diseases such as dementia, stroke, traumatic brain injury, and other conditions linked to reduced oxygen supply or oxidative stress.
The findings, recently published in the journal Free Radical Biology and Medicine, explain for the first time how the diving reflex activates a sophisticated network of protective pathways in the brain. By identifying the biological signals responsible for this natural defense mechanism, the research team believes it may be possible to develop therapies that safely reproduce these protective effects without requiring actual underwater immersion.
The study was led by Chunyan Li, PhD, Associate Professor in the Institute of Bioelectronic Medicine at the Feinstein Institutes. According to the researchers, understanding the molecular “blueprint” of the diving reflex could pave the way for innovative pharmaceutical and bioelectronic treatments designed to activate the body’s own protective systems on demand.
An Ancient Survival Mechanism
The diving reflex is one of the body’s most remarkable natural defense mechanisms and has evolved over millions of years across numerous species, including marine mammals and humans.
When a person holds their breath and submerges their face—particularly in cold water—the body automatically initiates a series of physiological changes intended to conserve oxygen. Heart rate slows, blood flow is redirected toward essential organs such as the brain and heart, and oxygen consumption is reduced.
These adaptations help maximize survival during periods of limited oxygen availability.
While scientists have long understood the physiological effects of the diving reflex, the precise molecular processes responsible for its protective benefits have remained largely unknown.
The new study provides the first comprehensive explanation of how this ancient response protects brain tissue at the cellular level.
Decoding the Brain’s Protective Switch
According to the investigators, the diving reflex functions as a master regulator of the brain’s antioxidant defense system.
Rather than simply conserving oxygen, the reflex initiates a cascade of molecular events that actively protect neurons from damage caused by oxidative stress, inflammation, and reduced blood supply.
The researchers discovered that activation of the diving reflex begins with stimulation of the trigeminal nerve, a major sensory nerve located in the face.
When triggered, this nerve releases a signaling molecule known as calcitonin gene-related peptide (CGRP) into the brain.
CGRP then activates Nrf2, a protein widely recognized as one of the body’s primary regulators of antioxidant defense and cellular protection.
Once activated, Nrf2 turns on numerous protective genes that help cells resist injury, repair damage, and neutralize harmful reactive oxygen species.
This coordinated response effectively strengthens the brain’s natural ability to withstand stress and injury.
A Different Approach from Conventional Drug Therapy
One of the study’s most important findings is that activation of Nrf2 through the diving reflex differs fundamentally from many currently available drug-based approaches.
Existing pharmacological strategies often attempt to stimulate antioxidant pathways indirectly, but some can inadvertently increase cellular stress before protective mechanisms become fully active.
By contrast, activation through the diving reflex appears to enhance antioxidant defenses naturally without placing additional stress on brain cells.
The researchers believe this physiological approach could potentially provide a safer method for protecting vulnerable neural tissue.
Because the body itself initiates the protective response, therapies based on this mechanism may offer a more balanced and biologically compatible method of treatment.
Promising Results in Dementia Models
To evaluate the therapeutic potential of the diving reflex, the research team conducted experiments using laboratory models of vascular dementia, one of the most common forms of cognitive decline.
Vascular dementia develops when reduced blood flow damages brain tissue over time, leading to progressive memory loss and cognitive impairment.
The investigators found that activation of the diving reflex produced several encouraging outcomes.
Among the observed benefits were:
- Restoration of damaged brain cells
- Replenishment of antioxidant reserves
- Improved cellular resistance to oxidative stress
- Significant improvements in memory and cognitive performance
These findings suggest that therapies based on the diving reflex may help protect brain tissue while also supporting recovery following injury.
Although additional research will be needed before human clinical applications become available, the early results demonstrate considerable promise.
Two Layers of Protection
The study also revealed that the diving reflex operates through a sophisticated two-stage protective process.
Immediate Response
The first stage occurs rapidly.
Within approximately 30 minutes of activation, antioxidant-related genes begin increasing their activity, allowing brain cells to mount an immediate defense against injury.
This rapid response may prove particularly valuable during acute medical emergencies such as stroke or traumatic brain injury, when minimizing early cellular damage is critical.
Long-Term Protection
The second stage develops over a longer period.
During this adaptive phase, the brain gradually builds sustained levels of protective proteins that provide ongoing resilience against future injury and chronic disease.
This long-lasting response may have important implications for slowly progressive neurological disorders such as vascular dementia and other neurodegenerative conditions.
Together, these two complementary phases provide both immediate protection and long-term support for brain health.
Inspiration from Nature
Dr. Chunyan Li explained that although scientists have recognized the diving reflex for decades, the biological mechanisms responsible for its neuroprotective effects had remained largely unexplained.
She noted that the team’s findings now provide a detailed molecular roadmap showing how this natural survival response functions.
According to Dr. Li, the discovery extends beyond basic scientific knowledge and offers a practical framework for developing entirely new therapeutic strategies.
Rather than attempting to invent artificial protective mechanisms, researchers can now focus on learning how to activate one that nature has already perfected through evolution.
She emphasized that the ultimate goal is to develop treatments capable of switching on these protective pathways whenever patients need them.
A Potential Breakthrough in Neuroprotection
Kevin J. Tracey, MD, President and CEO of the Feinstein Institutes for Medical Research and Karches Family Distinguished Chair in Medical Research, described the findings as a potentially transformative advance.
He noted that the ability to deliberately activate the body’s own defense systems could fundamentally change how many neurological diseases are treated.
According to Dr. Tracey, Dr. Li’s research has successfully transformed the diving reflex from a fascinating biological phenomenon into a clearly defined therapeutic pathway that may eventually support targeted medical interventions.
The work also reflects the growing field of bioelectronic medicine, which seeks to treat disease by precisely modulating neural circuits rather than relying exclusively on pharmaceuticals.
Building on Earlier Discoveries
The latest findings build upon previous research conducted by Dr. Li and her colleagues.
In earlier studies published last year, the team demonstrated that abnormalities involving vasoactive neuropeptides contribute to microvascular dysfunction in vascular cognitive impairment (VCI).
They also showed that stimulating the diving reflex could restore blood vessel function and improve cognitive performance in experimental models.
The current study extends those observations by identifying the precise molecular signaling pathway responsible for these beneficial effects.
By linking trigeminal nerve activation, CGRP release, and Nrf2 signaling into one integrated mechanism, the researchers have established a comprehensive explanation for how the diving reflex protects the brain.
Future Therapeutic Possibilities
Understanding the molecular basis of the diving reflex opens several exciting avenues for future research and drug development.
Potential strategies include:
- Development of medications that selectively activate CGRP-mediated protective pathways
- Bioelectronic devices designed to stimulate the trigeminal nerve and safely trigger the diving reflex
- Combination therapies integrating pharmaceutical and neurostimulation approaches
- Preventive interventions for individuals at high risk of stroke or neurodegenerative disease
Researchers believe these approaches could eventually be adapted to treat not only vascular dementia but also traumatic brain injury, ischemic stroke, and potentially other neurological disorders characterized by oxidative stress and impaired blood flow.
Because the protective mechanisms are naturally present within the body, therapies designed around this pathway may offer significant advantages in both safety and biological compatibility.
The discovery of the molecular blueprint underlying the diving reflex represents a significant advance in neuroscience and bioelectronic medicine. By revealing how an ancient survival mechanism activates the brain’s antioxidant defenses through the trigeminal nerve, CGRP signaling, and Nrf2 activation, researchers at the Feinstein Institutes have provided new insight into one of the body’s most powerful natural protective systems.
While additional studies will be necessary before these findings can be translated into clinical therapies, the research establishes a strong scientific foundation for future innovations aimed at protecting the brain from both acute injury and chronic neurodegenerative disease. As scientists continue exploring ways to harness this naturally evolved defense mechanism, the diving reflex may ultimately become the basis for a new generation of treatments capable of improving outcomes for patients with dementia, stroke, traumatic brain injury, and other challenging neurological conditions.
About the Feinstein Institutes
The Feinstein Institutes for Medical Research is the home of the research institutes of Northwell Health, the largest health care provider and private employer in New York State. Encompassing 50+ research labs, 3,000 clinical research studies and 5,000 researchers and staff, the Feinstein Institutes raises the standard of medical innovation through its six institutes of behavioral science, bioelectronic medicine, cancer, health system science, molecular medicine, and translational research. We are the global scientific leader in bioelectronic medicine – an innovative field of science that has the potential to revolutionize medicine. The Feinstein Institutes publishes two open-access, international peer-reviewed journals Molecular Medicine and Bioelectronic Medicine. Through the Elmezzi Graduate School of Molecular Medicine, we offer an accelerated PhD program.
