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The received wisdom about the pain in fibromyalgia (FM) is that it’s being produced in the central nervous system. That idea was amplified very early in “Altered Pain in the Brainstem and Spinal Cord of Fibromyalgia Patients During the Anticipation and Experience of Experimental Pain” when the authors stated:

“Most evidence to date suggests that the abnormal pain responses in FM may be the result of central sensitization.”

brainstem

The brainstem sits at the bottom of the brain – making it difficult to capture with top-down MRI’s. Recent research suggests it may play a role in FM, chronic pain and ME/CFS.

Then came a caveat, though. Those nice imaging studies that demonstrated that FM patients’ brains are amping pain signals have tended to miss a rather significant part of the brain. As VanElzakker noted in a paper on ME/CFS, standard MRI studies don’t get a good picture of the brainstem. That’s a shame in a number of ways. For one, the brainstem determines how many pain signals the brain is going to get smacked with. For another, it’s a powerful regulator of the autonomic nervous system.

These authors recently demonstrated that blood flows and pain signals in the spinal cord and brainstem are being adjusted all the time – even in healthy participants. When healthy people were told they were going to experience some pain, blood flow moved a region of the brainstem that tamps down pain signals. The same thing happened when the pain was applied, and afterward.

Importantly, the study also showed, though, that the pain signals in the brainstem and spinal cord were changing continuously even when no stimulus was expected; i.e. there was a kind of background level of brainstem activity that was being continuously modulated. They weren’t sure what was causing it, but given the brainstems’ ability to constantly fine-tune blood flows, these subtle background modulations have something to do with what we’re involved in at the moment; e.g. what we’re devoting our attention to, what our mood is, what we’re anticipating, etc.

Being able to sustain one’s attention on something is one way to reduce pain. In fact, the process of reducing pain by paying attention to something else or engaging in cognitive activity (reading, crossword puzzles, etc.) is called “attentional analgesia”.

A recent study found – to the researchers’ surprise – that the brainstem pathways that support attentional analgesia are still intact in FM. It’s hard to know what to make of that in a disease in which attention-deficit problems appear to run rampant. It appears that producing attentional analgesia is possible – but probably not easy in FM.

ADHD (Attention Deficit Hyperactivity Disorder) May Be Common in Fibromyalgia

Next, the research team moved on to people with fibromyalgia. The same general study protocol was used. The subjects were given trials in which they received a small painful stimulus (heat applied to the hand) which were interspersed with trials in which no pain stimulus was given. As that was happening, blood flows in the brainstem and spinal cord were assessed. Special attention was given to regions of the brainstem involving autonomic nervous system regulation.

Pain and autonomic nervous system functioning was also assessed using various assessment tools (total FIQR and function, impact and symptom subscales), measures of autonomic function (total COMPASS and all subscales), and pain inventory scores (total MPQ).

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Results

The expected parts of the brainstem became activated in both the healthy controls and FM patients, but the brainstems of the people with FM went further – parts of the brainstem that are generally associated with autonomic nervous system functioning were also activated. One connection, in particular – to the rather vividly named nucleus gigantocellularis or NGc – shot up in the people with FM.

Gigantic Neurons Activated

Gigantocellularis neurons

The gigantocellular neurons in the brainstem. (From the Rockefeller University and Donald Pfaff)/

This “gigantocellularis” nucleus is aptly named as it contains some of the largest – and potentially most important – neurons in the brain. The connections this nucleus has to unusually large parts of the brain underscores just how significant it is. The authors didn’t mention it, but the NGc’s could impact arousal, pain sensitivity, autonomic nervous system activity, movement, and brain blood flows in FM.

Donald Pfaff, the leader of the Laboratory of Neuroscience and Behavior at The Rockefeller University in New York City, has said that the generalized arousal that the NGc’s trigger “is what wakes us up in the morning and keeps us aware and in touch with ourselves and our environment throughout our conscious hours”. Different parts of the NGc help to “awaken” also play a role with sleep, and assist with movement as well.

The Gist

  • The brainstem is difficult to assess and most MRIs -which take a top-down approach – fail to capture it. Yet the brainstem controls the pain and sensory signals coming into the brain is an autonomic nervous system regulator, and clearly plays a role in pain. It’s even been called the “pain conductor” in the brain.
  • In fact, the brainstem is such a fine-tuned instrument that it appears to be constantly modulating the blood flows within it – possibly reacting to our thoughts as we go through our day.
  • Not many brainstem studies have been done in fibromyalgia (FM). This study used a series of trials – some involving a painful stimulus – and others not – to assess blood flows.
  • It found that contrary to the healthy people the brainstems of people with FM were activated even when they were at rest. The FM patient’s brainstems also sent blood to areas of the brainstem involved in autonomic nervous system functioning – potentially linking this deep, primordial part of the brain to the autonomic nervous system problems found in FM. That’s a potentially important link as the autonomic nervous system is looking more and more like a key player in chronic pain.
  • The FM brainstems also sent blood to an unusual part of the brainstem called the gigantocellularis neurons; huge neurons that connect to unusually large portions of the brain.
  • These neurons play a big role in arousal and wakefulness, pain sensitivity and blood flows in the brain. They play such a powerful role in arousal that researchers have been able to quickly pull laboratory animals out of a chemically-induced coma by activating them.
  • It’s not known why these neurons are being activated in FM but they play such a critical role in the brain that their appearance in FM is nothing if not interesting.
  • Other studies have found brainstem issues in FM. One even suggested that the wind-up phenomenon which causes the nerves to accelerate pain sensitivity over time instead of reducing it may originate in the brainstem. Others have found the brainstem connecting more actively with areas of the brain known to produce pain.
  • Seemingly every part of the pain processing pathways – from the small nerves in the skin, to the neurons in the dorsal horn outside the spinal cord, to the brainstem, to the pain processing centers in the brain have taken a hit FM. In fact, one wonders if any parts of the pain processing system have NOT been deranged in this disease. If the brainstem – in its role as the main conduit between the spinal cord and the brain, plays a major in FM, deep brain modulating techniques might help.
Interestingly given the idea that people with ME/CFS/FM may exist in a kind of hibernation-like state, researchers were recently able to rouse mice from a chemically induced deep coma state simply by activating part of their NGc. The NGc seems more effective at “arousal” than any other part of the brain.

When Pfaff’s team assessed the genes being expressed in these giant neurons, they were shocked to find genes that regulate brain blood flows popping up – a potentially interesting connection given reductions in brain blood flows seen in FM and ME/CFS. Apparently, these are the only neurons in the brain known to express these genes.

Reduced blood flows in the brain could be causing some unusual mischief. For instance, mice injected with a substance that knocks out these genes had trouble calming down after being exposed to with novel scents. – an interesting finding given the problems with scents, light, and other stimuli often found in these diseases. It’s no wonder that the NGc has been called “a central integrator for pain and cardiovascular-related functions“.

Why these huge neurons have become activated in FM is unclear, however. Is the brainstem is trying to get the NGc to wake up or something else? We’ll see in an upcoming blog that the big problem with the autonomic nervous system in FM may be that it’s fallen asleep.

Back to the Study

Getting back to the first paper, the striking thing was how amplified the brainstem circuits of FM patients were before the pain stimulus was ever applied. While the anticipation of pain further heightened activity in these circuits in people with FM, those circuits were already amplified at rest. The outcome was the opposite seen in the healthy controls; their brainstem blunted their pain levels, but the brainstem activity in the FM patients left them in more pain.

Plus, connections to parts of the brainstem involved in producing pain and regulating the autonomic nervous system (locus coeruleus, parabrachial nuclei, and hypothalamus) were particularly activated as well. Their increased COMPASS (ANS symptom) scores suggested that the brainstem-autonomic nervous system connection the imaging study found in FM was valid, and that the autonomic nervous system had been dragged into the pain amplification process. It was at the brainstem the authors proposed that a “convergence of autonomic regulation and pain modulation systems” was producing problems.

An earlier study found that the brainstems of FM patients were communicating more actively with pain-producing regions of the brain (insula, anterior cingulate cortex, anterior prefrontal cortex) that also, interestingly, regulate autonomic nervous system activity. The more communication, the greater the pain.

Connectivity between brain regions may also influence how effective drugs are. Milnacipran was effective in FM patients whose brainstems were connecting less with the insular cortex but not effective in patients whose brainstems were communicating more with that region. The drug was apparently not powerful enough to overcome that stream of signals.

A recent “windup” study amplified how important the brainstem may be. It traced how pain signals get amplified in FM (instead of being ratcheted down) and examined activity up and down the spinal cord in conjunction with pain. The brainstem was the only region to show accelerated activity.

While not a lot of work has been done on the brainstem in FM, it is increasingly been seen as playing a central component in chronic pain. Imaging advances are allowing us to study the brainstem in much greater detail. It’s recently been shown, for instance, that the placebo effect may originate in the brainstem.

A recent review article called it “the pain conductor” and proposed that our understanding of its role will lead to “better optimized pain-relief strategies”. Those might include the new forms of “deep brain stimulation” that get down to the bottom of the brain, and are being tested now. in movement disorders like Parkinson’s Disease.

That another pain processing center has gone awry in FM shouldn’t come as a surprise. With similar findings in nerves leading to the spinal cord, in the brainstem, and in several pain processing pathways in the brain, we have to wonder if there are any places pain signals are NOT getting amplified in FM.

 

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