The Brainstem

The brainstem – a small area at the base of the brain that contacts the spinal cord – has become of ever more interest in chronic fatigue syndrome (ME/CFS). Barnden’s studies suggest brainstem involvement is present. VanElzakker believes brain scans focused on upper areas of the brain have missed a crucial aspect of ME/CFS.

Has the “Reptilian Brain” Gone Haywire in ME/CFS? Back to the Brainstem We Go.

Then there’s craniocervical instability (CCI). Surgical procedures that stopped the skull from impinging on the brainstem in some people with ME/CFS have led to recoveries – which have made it clear that brainstem issues have the potential to produce every symptom found in ME/CFS.

We know the brainstem is heavily involved in the regulation of basic processes that we need to survive, including autonomic nervous system functions such as heart rate, breathing, sleep and in conveying sensory and other signals to the brain. It turns out, though, that the a small area of the brainstem called the parabrachial nucleus also plays a role in chronic pain.

The finding that the brainstem matters in chronic pain illuminates two things: (a) how complex a process pain production is; and (b) how much researchers are learning about it. Several years ago, Alan Light, PhD noted that he aimed to do for the production of fatigue what we already knew about the production of pain. We know quite a bit about how pain in fibromyalgia (FM) is produced.

Wound up, Overheated and Tweaked: A Look at the Fibromyalgia Brain and Nervous System.

We know, for instance, that two kinds of small nerve fibers in the body that transmit pain signals to the spine, and ultimately the brain, have become hyperactivated in FM. We know that another process called “windup” results in other nerve fibers becoming hypersensitive to pain. We know that several neurotransmitters that upregulate pain production are increased in FM, that the pain inhibitory pathways are underperforming in the disease, and that areas of the brain that produce pain have become hyperactive.

So much is going on that it seemed as if every aspect of the pain producing process has gone sideways in FM, but researchers are not done learning about how pain is produced – not all.

Parabrachial Nucleus (PBN)

“This tells us that chronic pain is manufactured by the brain. It’s not a one-way process driven by something coming up from the periphery; the brain is not a passive recipient. To me that’s what’s exciting: The brain is actively constructing a chronic pain state in part by this recurring circuit.” Mary Heinricher

Another part of the brain that has not been assessed in fibromyalgia may play a key role in the pain found in the disease.


Pain and other signals get passed up the spinal cord to a part of the brainstem called the parabrachial nucleus.

Recent animal studies indicate that the brainstem also plays a role in pain production. Pain starts off as a sensory signal that gets interpreted by the brain. Because pain usually denotes some sort of injury, the brain has given pain signals a special emotional resonance to do something about the situation. So while a pain signal starts off as a kind of sensory signal, over time it becomes more than that. The first place the process of turning a pain signal into a complex response starts is at the parabrachial nucleusin the brainstem.

Studies have shown that PBN has a windup problem of its own: i.e. in chronic pain, nerves in the PBN remain active and ready to punch out pain signals long after they’ve calmed down in non-pain states. That suggested that some sort of inhibitory pain control had been lost.

The main excitatory neurotransmitters in the brain – glutamate – were lacking in the part of the PBN involved in pain production. Careful studies indicated that projections from the amygdala – generally known as the fear center of the brain – were responsible. They weren’t the projections that the researchers expected, though. Through its interactions with PBN, the amygdala was turning down pain – not ramping it up.


In a switch the amygdala – long known as the fear center of the brain – was actually sending calming signal to the brainstem.

While it’s mostly known for producing sensations of fear, the amygdala was shooting calming signals straight to the PBN in the brainstem. It was also doing it using different neurotransmitters such as dynorphin and somatostatin. Surprisingly, it was the loss of amygdala signaling that was leaving the PBN in a hyperactive state – and the subject in more pain.

In fact, one animal study, which painstakingly stimulated nerves known to carry inhibitory pain and hunger signals from the hypothalamus to other parts of the brain, found that only the activation of nerves leading to the PBN reduced pain behaviors.

Once again, but in a new way, we can see how vitally important pain inhibition process is to our experience. The researchers had found a new way to heighten pain signals – and create a chronic pain state.

Going Defensive

The twitchy PBN wasn’t producing just pain, though. Researchers have thought that the brain does most of the emotional processing, but it turns out that the PBN – the main processing center of pain signals coming from the body and up the spine – is doing some emotional processing of its own. The PBN determines whether brain regions involved in escape or aversive behaviors (yelling, hitting, getting angry) are alerted or not. Above all, the PBN is involved in defensive reactions; e.g. aversion.

Nerve projections to other parts of the brain indicate that the PBN plays a key role in our emotional responses to pain. In fact, it and the amygdala appear to be the two general alarm centers of the brain.  A recent review called the PBN “a ‘hub’ for pain and aversion” that responds to any potentially dangerous situation. Not surprisingly, PBN neurons have been associated with the “freeze response”. One researcher likened the PBN to a home alarm:

“The alarm goes off while you’re away, and you don’t know if it’s a broken window, an intruder, or a fire—you just know that something bad has happened.”

Interestingly, given the possibility produced by Bob Naviaux that people with chronic fatigue may exist in a kind of hibernation-like metabolic state, the vast convergence of different sensory inputs (cardiovascular, respiratory, metabolic, and pain) at the PBN appears to give it a key role in determining whether an organism enters into hibernation. Inhibiting the activity of some PBN neurons prevented anorexia (e.g. the starvation phenotype) and malaise in laboratory animals.

It’s connected with several brain areas associated with FM, including the hypothalamus, insula and the periaqueductal gray area. The PBN also regulates autonomic nervous system functioning (respiration, blood pressure, heart rate, water balance).


Once again we see a part of the brain that has been largely ignored possibly playing a major role. The PBN used to be thought of as a passive relay center for sensory signals, but it’s clearly not. Not only does it determine to some extent how the brain will react to pain signals – with aversion or escape – but it’s also at the tail end of an inhibitory pain process.

alarm clock

The PBN and the amygdala are the two alarm centers of the brain. (Image by Sarah-Richter from Pixabay)

We don’t know if the parabrachial nucleus in the brainstem plays a role in the pain in fibromyalgia, but it’s hard to imagine that it doesn’t. As the PBN discovery fleshes out our understanding of how pain is produced, it also illuminates how complex the process of pain production is – and helps us understand why producing a good pain drug has been so difficult. (I was unable to find any drug associated with the PBN.)

We know that the pain in FM is associated with numerous issues in pain processing, neurotransmitter production and brain activation but we still don’t know what starts the process off. Even so, it’s good to know that researchers are continuing to produce new insights into how pathological pain (i.e. inappropriate pain) is being produced. Given that FM occurs in some people after an infectious event, it’ll be interesting to see if the research into the COVID-19 long haulers provides some insights in chronic pain.


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