Symptoms are Nothing to Sneeze At
After examining syncope and sepsis, dangerous and dire medical states, respectively, in our last two installments, let’s keep this one lighter and broadly relatable. Coughing and sneezing are ordinary phenomena familiar to every human on earth. Could there be specific and identifiable neural circuits for such common symptoms too? According to recent neuroscience, yes! In summer 2024, researchers at University of Michigan reported in Nature Neuroscience a detailed mapping of a “vagal-brainstem pathway” for coughing.
This study was covered by a Transmitter article, which recounted how it began with the initial observation by senior author Peng Li that mice appeared to cough, contrary to most prior literature. It described the methodologies used to map the vagal-brainstem pathway following that spark of discovery. As with syncope and sepsis, a small neural population was identified within the lower brain regions with microscopic and molecular precision. And as with sepsis, the brain cell population was isolated within the solitary tract nucleus known as NTS, and it was also shown to be necessary and sufficient to elicit a cough-like phenomenon in mice.
I noticed the similarities and realized I could now have a (friendly!) Oxford comma debate with my editor while reasonably claiming: advanced neuroscience is now “routinely” capable of fine-scale vagal-brainstem mapping as shown for syncope, sepsis, and coughing. Moreover, all the stories to date point to an element of control within the lower brainstem: the medical effects could be elicited artificially, such as with optogenetics or chemogenetics. This suggests the NTS and medulla are not just a passive map of visceral sensations but also likely an active site of innate physiological control and potentially a site of future medical interventions.
In fall 2024, another specific body-brain neural circuit, again with fine-scale molecular and microscopic precision, was reported in Cell by Washington University researchers for the symptom of sneezing. This is when I realized: today’s neuroscience may not only be ready for new medical frontiers “behind the scenes”, but that it was possible to share outside of scientific circles. I began discussing the idea of specific neural circuits for specific symptoms, while naming the familiar experiences of coughing and sneezing, with non-scientists. I noticed a level of understanding and curiosity beyond what I experienced years ago, when explaining the general concepts of micro-scale brain imaging to lay audiences as the founder of an early US BRAIN Initiative spinout. Digging a little into the literature, I’ve since learned that a third familiar symptom–nausea–was similarly mapped to a fine-scale brainstem neural circuit in 2022 by Harvard-based researchers. So I can happily use an Oxford comma again to group the recent “neurally-mapped” symptoms of coughing, sneezing, and nausea for conversations out “on the street”.
You might have noticed that I used the phrase “body-brain circuit” for the sneezing study versus repeating “vagal-brainstem pathway” from the coughing study. While the vagus nerve, also known as the tenth cranial nerve, carries most of the body’s signals to the brainstem, the sneezing circuit turns out to run through the trigeminal nerve, aka the fifth cranial nerve. I prefer to call these cranial nerve bundles, since recent studies are identifying individual “wires” within these gross anatomy structures. Even when research “only” delineates specific-function small neural populations in the brainstem (e.g., the nausea and coughing studies), we can surmise that identifiable wires exist for their input cranial nerves.
Cranial nerves, such as “the” vagus nerve, are really nerve bundles with “wires” each carrying specific information recently identifiable with microscopic and molecular technologies
Like the coughing study before, it was interesting to read the scientists explain their surprise. They anticipated that interoceptive circuitry for coughing would be largely replicated in a different body location, i.e., nose versus lung. While both pathways do converge in the same NTS brainstem nucleus, the similarities end there. They have distinct neural populations in the brainstem, traveling via distinct cranial nerves, and with distinct molecular signatures for the peripheral nerve endings that ultimately trigger the symptom. These nerve endings further surprised them in a couple of ways:
Nasal sensory neurons showed a wide range of molecular barcodes, but only one (expressing the gene MrgprC11 but not MrgprA3) triggered sneezing
Lung sensory neurons included a set with this same barcode, yet do not trigger coughing
While rather detailed, such commentary illustrates that body-brain neural circuit mapping is highly fertile ground for many new and surprising discoveries. From a scientific standpoint, this is fascinating stuff, and indeed brain-body communication emerged as a popular topic for early-career neuroscientists in 2024.
The fundamental science excites me, but my predicament compels me to reach more people. Last fall, I took an opportunity to rehearse the idea of scaling up symptom-to-circuit mapping at a Speculative Technologies Brainstem workshop, with many people from quite different fields. One workshop attendee gave me feedback that I was proposing to “build a dictionary”. During the following weeks, I sketched out this entity-relationship diagram based on their insight:
While the recent studies we’ve covered use advanced (aka nontrivial) technologies, the 1:1 mappings of specific symptoms to specific neural circuits struck me as evidently simpler than the other one-to-many (1:N) and many-to-many (N:N) connections that complicate medical research today, which is largely focused on both ends of this “semantic chain”: root causes and disease labels. The workshop encouraged ambitious proposals, and mine landed on a platform that, if you will, extends from the Oxford comma triads described above to a broader directory of neural circuits explaining as many as possible of the hundreds of common symptoms defined today in, say, the Oxford English dictionary (or: the ICD-10 medical classification listing). Not to mention several uncommon symptoms now lacking a definitive word or clinical classification. One can even imagine a future day where neural circuits drive the definitions used in everyday language.
As we’re thinking of a certain university in England, it’s worth noting the current British medical chief and his colleagues seem to also sense a broad opportunity: that wide swaths of medicine may have nexus with neuroscience. But they take a fundamentally different tack by focusing on the mind which is, needless to say, much more multi-faceted. Ansyme is anchored as much by engineering as science, and aims to support research into the “utility closet” of the lower nervous system. Carefully mapping the countable and identifiable wires and controllers there gives biomedical research a clear set of new targets for interventions. Furthermore, today’s neuroscience can then trace back from such well-defined targets to upstream root causes; one pioneering study of this type will be explored in a future post.