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Check out Geoff’s narration:

The GIST

The Blog

 

THE GIST

  • Check out Geoff’s narration of the GIST at the top of the blog.
  • Major Takeaway – researchers find a circuit in the brain that turns on and off the inflammatory response that characterizes so many chronic illnesses, including ME/CFS and long COVID. It could also explain how stress impacts inflammation. 
  • Twenty years ago, our idea of how the immune system works changed radically when Kevin Tracey discovered that an “inflammatory reflex” produced by the brain in conjunction with the vagus nerve. Instead of inflammation being produced locally, it quickly became clear that the brain was in control of how much inflammation was present in the body.
  • Meanwhile, over in chronic fatigue syndrome (ME/CFS) and fibromyalgia land, the low heart rate variability and dysautonomia found made the vagus nerve – the chief regulator of the parasympathetic nervous system – of interest.
  • Recently, a widely lauded paper, “A body-brain circuit regulating body inflammatory responses,” identified a master immune switch in the brain that is able to turn off and turn on inflammation in the body. Yale immunologist Ruslan Medzhitov called the finding a “black swan event”; i.e. a rare and unpredictable event that made perfect sense once it was found. Medzhitov stated the study indicated, “there is a whole layer of biology that we haven’t even anticipated”.
  • The study identified neurons associated with the vagus nerve in the brainstem that are able to turn on or off the inflammatory or innate immune response in the body. The authors called the circuit between the neurons the inflammation “rheostat” of the brain, which regulates the amount of inflammation occurring in the body.
  • These neurons were found in the caudal nucleus of the solitary tract (cNTS) in the brainstem – which transmits oceans of sensory, chemical, autonomic and immune data to the brain.
  • Because the nucleus also integrates emotional data with the other data and has strong ties to brain organs like the amygdala and insular cortex – which regulate autonomic nervous system, movement and emotional data – the authors proposed that the finding could also illuminate psychosomatic symptoms which show up during stressful states.
  • In short, the cNTS is the place in the brain where body and mind and physiological and emotional stressors meet. It’s been described as: “the brain’s primary sensory nucleus for visceral sensations relevant to symptoms in medical and psychiatric disorders and as “a key node in the “mind-body” characteristics of several medical and psychiatric diseases.”
  • Finding a master regulator of the innate immune system was no mean feat and the study was widely hailed for the new possibilities it promises to rein in in autoimmune and inflammatory diseases, as well mysterious conditions such as long COVID.
  • Trinity College biochemist Dan O’Neil stated: “if we could target these circuits very precisely, then there’s great potential to block the inflammation response for many diseases”.
  • Now that they have a starting place (specific neurons in the cNTS), researchers will track down how these neurons in the brainstem are able to affect the immune system across the body; i.e. what cells they’re interacting with and how they’re interacting with them to do that. That should open up more treatment possibilities.
  • For its part, the brainstem seems more fraught with possibility than ever. I took part in a small study that assessed the effects of what I called the “zapper” on the brainstem. The device was designed to reduce inflammation in other parts of the body. I was only able to get in two sessions of the zapper, but after the second session, I felt distinctly clearer, calmer, and more focused.
  • Plus, work on manipulating the vagus nerve continues. Kevin Tracey’s work has shown that invasive vagus nerve stimulators can have profound effects on autoimmune and inflammatory diseases, and billions of dollars have recently been poured into developing electroceutical devices that can stimulate the vagus and other nerves in the body.
  • The study was done on mice – not humans – but the basic anatomy is similar. Given the toll the chronic autoimmune and inflammatory diseases take – not to mention diseases like ME/CFS, FM, and long COVID – finding a potential on-off switch for the innate immune system will undoubtedly unleash a torrent of studies to validate and broaden the finding and find new ways to treat disease.

Twenty years ago, our idea of how the immune system changed radically when Kevin Tracey found that cutting the connection of the vagus nerve – the big nerve that sends immune signals from the body to the brain – dramatically affected the innate immune response. No longer could we think of the immune system as some localized response to infection or injury; after Tracey’s finding, it became clear that the interplay between the brain and the vagus nerve in what came to be called “the inflammatory reflex” played a major role in the inflammatory innate or early immune response.

Meanwhile, over in chronic fatigue syndrome (ME/CFS) and fibromyalgia land, the low heart rate variability and dysautonomia found made the vagus nerve – the chief regulator of the parasympathetic nervous system – of interest. That nerve got even more interesting when eleven years ago, Michael VanElzakker proposed that infections of the vagus nerve were causing it to transmit signals to the brain, which resulted in a chronic case of “sickness behavior”; i.e. pain, fatigue, cognitive, and sleep issues in ME/CFS.

A “Black Swan” Event

Recently, a widely lauded paper, “A body-brain circuit regulating body inflammatory responses,” identified a master immune switch in the brain that is able to turn off and turn on inflammation in the body.

Yale immunologist Ruslan Medzhitov called the finding a “black swan event”; i.e. a rare and unpredictable event that made perfect sense once it was found. Medzhitov stated the study indicated “there is a whole layer of biology that we haven’t even anticipated”.

That switch was found in that complicated and vital piece of central nervous system real estate called the brainstem – another big area of interest in ME/CFS, fibromyalgia, and long COVID.

First, the researchers infected mice with a bacterial toxin called LPS known to activate the immune system. (In a small study, Jarred Younger recently found that the same toxin, when given to people with fibromyalgia, may have triggered an abnormal neuroinflammatory response in their brains.) Using precise imaging techniques, they found that vagus nerve neurons in the brainstem lit up with activity as soon as the toxin was introduced.

It soon became clear that these neurons were controlling immune activity – not in the brain – but in the body. One set of neurons in the brainstem was in charge of damping down immune activity, while another set was in charge of amping it up. Turning off the first set of neurons resulted in a dramatic (300% increase) increase in pro-inflammatory activity and a similar decrease in anti-inflammatory activity was seen. Turning off the second set turned inflammation down by 70%.

Further testing indicated that glutamateric and GABA-ergic neurons found within the caudal nucleus of the solitary tract (cNTS) in the brainstem were controlling the immune response. The authors called this circuit the inflammation “rheostat” of the brain, which regulates the amount of inflammation occurring in the body. (A rheostat controls the flow of electrical current).

Plus, the researchers found a place where the vagus nerve triggers some of the flu-like symptoms found in “sickness behavior”. Immune factors called cytokines triggered sensory neurons in a part of the vagus nerve called the nodose ganglia.

The cNTS – an Inflammatory, Sensory and Psychosomatic Hub?

nucleus solitarius

The nucleus solitarius (shown here in tan) is connected to the caudal nucleus of the solitary tract. (Image by Bhimj, Creative_Commons_NHCBI)

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The caudal nucleus of the solitary tract (cNTS) is where it all happens. The solitary tract is so named because it consists of vagus nerve fibers that end in a bundle of nerve cells. The solitary tract connects the vagus nerve to the brainstem and tracks many different factors including sensory information, chemical changes (glucose, leptin and angiotensin II), changes in blood pressure, blood pH, breathing, heart rate and gut motility.  (The team that authored this study came to it in part through their prior research linking taste sensations to the nCTS). In short, one review called it:

“the primary brain region to receive and process rapid, neuro-chemical information regarding the internal environment of the body.”

One of the lead researchers, Dr. Jin, made an interesting statement:

“A lot of psychosomatic effects could actually be linked to brain circuits telling your body something,”

That came out of the blue. How did a tract of neurons in the brainstem that are associated with inflammation get linked up with “psychosomatic symptoms ”.

To the public, psychosomatic connotes an illness that is made up, but the term psychosomatic does not necessarily define a made-up illness at all. Psychosomatic is defined as “(of a physical illness or other condition) caused or aggravated by a mental factor such as internal conflict or stress” i.e. it could be construed as being caused by problems with the stress response.

The cNTS is where sensory information inflammation, autonomic nervous system functioning, and emotional states collide. In other words, it’s potentially an excellent place to explain diseases characterized by lots of strange body sensations and pain, dysautonomia, inflammation and psychological distress that often ramps up symptoms.

Brainstem

It’s all part of some very crowded real estate in the brainstem. (Image: Nadezdha_Wikimedia_Commons.)

It’s connected to regions of the brain that regulate autonomic nervous system functioning and the emotions. Neurons, for instance, from the insular and medial prefrontal cortex, amygdala and hypothalamus connect to the cNTS.

The insular cortex processes sensory information, coordinates movements, monitors the body’s internal state, and regulates the emotional response to situations. Sensations emanating from the throat, chest, and abdomen get translated by the loop from the insular cortex to the cNTS. Indeed, stimulating the insular cortex has been shown to produce sensations in the throat, chest, and abdomen (as well as altering gut motility and breathing). On its end, the medial prefrontal cortex is responsible for attention, concentration, motivation and movement.

Nerves going to the fear center of the brain, the amygdala, as well as the hypothalamus permeate the cNTS as well. Once again, we find this intriguing connection between parts of the brain involved in emotional states and autonomic nervous system functioning.

Interestingly, neurons in the cNTS are the only cells in the brain that respond to aldosterone – a part of the RAAS complex that maintains (or in the case of POTS and ME/CFS is supposed to maintain – see the RAAS paradox) blood volume. One review article proposed another way to mess with emotional regulation in these diseases – alterations in aldosterone. That’s an interesting finding given anecdotal reports that increasing blood volume in ME/CFS can reduce anxiety.

In short, the cNTS is the place in the brain where physiological and emotional stressors meet. It’s been described as:

“the brain’s primary sensory nucleus for visceral sensations relevant to symptoms in medical and psychiatric disorders and as “a key node in the “mind-body” characteristics of several medical and psychiatric diseases.”

Given the connections between the sensory system, inflammation, and the emotions, it’s no surprise that Dr. Jin proposed that this new finding could shed light on what’s going on with so-called psychosomatic symptoms.

Importance

Finding a master regulator of the innate immune system was no mean feat and the study was widely hailed for the new possibilities it promises to rein in autoimmune and inflammatory diseases, as well mysterious conditions such as long COVID.

Trinity College biochemist Dan O’Neil stated:

“if we could target these circuits very precisely, then there’s great potential to block the inflammation response for many diseases”.

Now that they have a starting place (specific neurons in the cNTS), researchers can begin to track down how these neurons in the brainstem are able to affect the immune system across the body; i.e. what cells they’re interacting with and how they’re interacting with them to do that. That will open up more treatment possibilities.

For its part, the brainstem seems more fraught with possibility than ever. I took part in a small study that assessed the effects of what I called the “zapper” on the brainstem. The device was designed to reduce inflammation in other parts of the body. I was only able to get in two sessions of the zapper, but after the second session, I felt distinctly clearer, calmer, and more focused.

Plus work on manipulating the vagus nerve continues. Kevin Tracey’s work has shown that invasive vagus nerve stimulators can have profound effects on autoimmune and inflammatory diseases.

In 2011 Tracey proposed that conditions characterized by low heart rate variability – such as ME/CFS, POTS, fibromyalgia and now long COVID – might respond well to vagus nerve stimulation.  Dr. Natelson – who is studying non-invasive vagus nerve stimulation – reported on an remarkable story of a woman with very severe fibromyalgia who responded well to invasive vagus nerve stimulation.

“Reborn” – Reversing Fibromyalgia with Vagus Nerve Stimulation

The NIH and the drug companies have caught on. From NIH’s SPARC initiative to major investments from pharmaceutical companies, billions are dollars are being invested in finding ways to electronically stimulate the vagus and other nerves to improve health.

Good-bye to Drugs? Kevin Tracey MD on the Bioelectronics Revolution at the Dysautonomia International Conference

Wrap Up

The study was done on mice – not humans – but the basic anatomy is similar. Studies will have to assess if the same inflammatory regulator is working in the same way in humans. Since we’re dealing with the most primitive part of the immune system which works similarly in many organisms – my guess is that a similar process is taking place.

This finding came about because of technical advances that allowed the research team to very precisely find where in these very small nerve passages the activity was occurring. This kind of very detailed work is being done across the vagus nerve and could provide much help in the future. The NIH’s SPARC Initiative, for instance, is focusing in precisely defining the anatomy and functional connectivity of the vagus nerve (SPARC-V), in order to support the development of neuromodulation devices and “facilitate the development of new best-in-class bioelectronic medicine therapies.” Let it be so – and as quickly as possible :).

Given the toll the chronic autoimmune and inflammatory diseases take – not to mention diseases like ME/CFS, FM, and long COVID – finding a potential on-off switch for the innate immune system will undoubtedly unleash a torrent of studies to validate and broaden the finding and find new ways to treat disease.

Thanks to Susan for the link to this most interesting finding!

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