“The human brain displays a high degree of plasticity, and gray matter and white matter change throughout the life span.” Authors

Recently we saw that more intense connections from the one part of the brain  (prefrontal cortex) to another part of the brain (limbic system) appear to set the stage,  when the appropriate triggering event occurred, for a life of chronic pain for some people.


Does being in pain over long periods of time change the structure and functioning of the brain?

Other research indicates that the gray matter of the brain (the neuronal cell bodies)  tends to become reduced over time in people with chronic pain, and that those reductions occur areas of the brain associated with pain processing, cognition  and the emotions; the prefrontal cortex, the insula and the anterior cingulate.

This study asked if the brain becomes more affected by pain as we age. Specifically it asked if the pain processing centers of the brain were different in people in younger and older people with fibromyalgia.

Brain Changes Over Time

Before Fifty

It turns out the they were. The study, in fact,  found remarkable differences in the brains of younger and older  people with fibromyalgia.  The cutoff point seems to be around fifty years of age.

Before the age of fifty increased levels of gray matter were found  in pain processing regions like the insula, basal ganglia and prefrontal cortex relative to the healthy controls. This could be construed as a system gone berserk that is  slamming the body with pain signals, but it could also be interpreted as a system, under stress, that was  buffering itself to survive.

The fact that higher amounts of grey matter were inversely correlated with reduced catastrophizing suggested that the increased grey matter was adaptive, not maladaptive.  It appeared, at least in  the younger FM patients, that the  brain was doing it’s best to cope with the high demands its pain processing regions were under.

The pattern of connectivity between brain regions appeared to bear this out. The white matter portion of the study indicated that the connections between two important pain processing centers, the insula and the basal ganglia, had become  decoupled in the younger patients, perhaps in another effort to reduce their pain.

After Fifty

After fifty it’s a different story.  Perhaps due to ‘exhaustion’ or burnout (glutamate excitotoxicity?) , the grey matter in the pain processing region decreased  and was significantly lower than found in the healthy controls. The connectivity between the two insula and basal regions increased,  perhaps because of weakened myelin coverings on the nerves or damage to the axons which shoot out from the nerve bodies.


The brains of older people with fibromyalgia had less resilience than the brains of younger people with fibromyalgia

This suggested that not only was the grey matter in the pain processing regions of the brain not ‘buffered’, but had actually declined relative to controls, and the decoupling process to reduce pain had stopped.

This appeared to manifest itself in increased hypersensitivity to pain. While all patients had widespread pain, only the older patients demonstrated consistently increased hypersensitivity to pain  induced by the staff in the study.

This pattern of grey matter buffering followed by a kind of collapse  time also appears to occur in post-traumatic stress disorder, obsessive-compulsive disorder and bipolar disorder. It was only caught in fibromyalgia when researchers specifically differentiated older from younger patients.

Despite the fact that the older patients had experienced pain longer, it wasn’t clear that the  duration of pain produced these changes. (One aspect of the study suggested it did and another it didn’t). Neither were depression or anxiety implicated.

So what could be causing this? It could be a matter of an aging brain simply not being as adaptable as a younger brain or it could  be due to brain regions put on high alert,  that simply burnt themselves out over time.   Once that happens, the person becomes more hypersensitive to pain. (The authors did not think hormonal changes were responsible.).

The suggestion that younger brains try to adapt to and even reduce the amount of pain present suggests the source of the pain may be  coming from outside in; i.e. the problem could be more  in the body than in the pain processing centers of the brain.

This wasn’t great news for older patients, but the news wasn’t all bad. They were more hypersensitive to induced pain, but despite fact that their brains didn’t appear to be as effective at dealing with pain, their pain levels, interestingly enough, did not seem to be higher.

Chronic Fatigue Syndrome

Dr. Ian Lipkin – ‘Substantial Differences”

“there may be differences – substantial differences – in biomarkers: things that we may find in people who have had disease in 3 years or less and people who have had disease for more than 3 years.” Dr. Lipkin – CDC talk

In his recent CDC talk, Dr. Lipkin found dramatic differences in cytokine expression  and  immune cells in people who’d had ME/CFS for less than three years and for more than three years.  Interestingly, he didn’t set out to see if the immune systems of  recent onset vs later onset patients were operating differently, the data  just popped out at him.  He referred to these differences a ‘biomarkers’.

Do significant immune changes occur as early as three years into the illness?

Do significant immune changes occur as early as three years into ME/CFS?

The finding may just be the result of a very thorough research project. The questionnaire the patients filled out  had its oddities, but was nevertheless long and very thorough.  Lipkin is probably  one of the first researchers to take duration into account.

“We believe that this is going to be important” Dr Lipkin

The extent of the differences was unclear; Lipkin referred to a number of cytokines and only mentioned one, but we do know that people with ME/CFS for less than three years  appeared to have an increased allergic response and increased IL-17 levels.   (IL-17 was decreased in the other samples.)

Lipkin’s talk suggested that he also found marked differences in  immune markers  in the spinal fluid of more recent vs longer duration patients as well.

Doctors have long said that younger patients tend to respond better than older patients, but this finding reflected duration, not age.

Dr. Gordon Broderick:  the Menopause/Pregnancy Factor

Broderick’s data suggests both gender and duration of illness are producing  subsets in ME/CFS. During the Nova Southeastern Conference last year, Broderick talked  finding about distinct immune differences in young women with recent onset and older women with longer duration illness.

men and women

The more complex hormonal and immune systems in women could place them at more risk

Every man  knows how confusingly complex women can be at times (:)), but most don’t realize that that complexity has biological roots.  Broderick’s model of hormonal modeling for women is four times more complex than his is for men.  Researchers have as yet showed little interest in neuro-immune differences between men and women.  ( New York Times article pointed out that most lab rats are male – perhaps because they are simpler  – which means the real drug testing for woman mostly occurs not in the lab  but in real life.)

It’s possible that women’s more complex hormonal and the immune systems simply introduce more possibility of error.

That complexity gets magnified during during pregnancy and menopause – two changes men are never confronted with. The fact that some women watch their ME/CFS  symptoms dissipate or even disappear during pregnancy indicates these system are involved in ME/CFS.

Introducing More Complexity in FM and ME/CFS

As if these disorders need more complexity :).  The chronic fatigue syndrome findings could benefit younger patients, in particular, since they’re often buried in older cohorts and could benefit from targeted treatments that weren’t apparent until now. The older patients may benefit if Lipkin and others can come up with targeted treatments for them as well.


The mysterious rise and then decline of the anti-pathogenic cytokine IL-17 in ME/CFS could be illuminating

If these findings are validated they could also inform the disease process, giving researchers clues how these disorders develop.  Understanding the ‘events’ that occur early in the disease that turn it into a chronic illness could be very valuable.  The fact that IL-17 is a pro-inflammatory cytokine that is produced in response to extracellular pathogens is intriguing given the flu-like onset that is so common in ME/CFS.  Il-17 is also associated with an allergic response and it’s been linked with many immune/autoimmune diseases, yet Lipkin found that it declined over time in ME/CFS.

The changes in FM over time have negative consequences – a brain that appears to have less adaptability – but they could help target treatments that reduce the connectivity between different brain regions in older patients.  The researchers didn’t believe menopause affected their findings, but with Broderick suggesting it was a major factor in a significant immune shift in ME/CFS, that possibility must remain open.


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