One of the most alarming discoveries I’ve found in this quest for answers without really knowing what questions I’m asking is the tissue change in the brain with long term chronic pain.  Cognitive disorders are commonly referred to, but somehow there has been a bit of a disconnect in my own brain (perhaps the result of a cognitive disorder called denial) that there are actual physical changes happening with fibromyalgia.  What these changes are seem pretty clear.  The consequences of these changes are not clear at all.

Neurological chemical imbalances in fibromyalgia patients, such as a deficiency of dopamine and serotonin, are very often mentioned as possible causes of fibromyalgia, but in looking further at the relationship between the brain and fibromyalgia, the chemicals are really the tip of the pain iceberg, and looking at possible reasons for the imbalance of chemicals is necessary. Unfortunately, the possible reasons seem to be fully submerged at the base of the iceberg, and the critical question, which comes first the pain disorder or the brain damage, remains unanswered.

It is an important question.  If the pain comes first, then it seems like there could be a potential for prevention of long term chronic pain.  Unfortunately, there is no clear cut answer, and there are contradictions in the research.  For example Cifre et al theorize that chronic pain leads to widespread brain dysfunction because the brain is unable to rest.  Robinson et al would concur, but possibly for different reasons.

On the other hand, other researchers (such as Cagnie et al) looking at decreased gray matter in the brain indicate that the decrease could cause widespread pain.  Diaz-Piedra et al would agree but add that it would also cause affective disorders, such as depression. Put both depression and chronic widespread pain together and there is a high likelihood of fibromyalgia diagnosis.

So far the cause for the decrease in gray matter volume is a bit elusive, and without that cause, there can be no definitive answer to the question. After all, it could be possible that chronic pain causes the decrease in gray matter, which then spirals into fibromyalgia (defining fibromyalgia as a “permanent” condition rather than “simply” chronic pain).  Furthermore, there is evidence that taking a medication like pregabalin will cause gray matter reduction and therefore give pain relief (see Puiu), which is exactly the opposite of other theories about the reduction of gray matter. Thus, possibilities are confusing, maybe because so many areas of the brain are affected.

It’s daunting to list the areas of the brain that are reportedly affected by gray matter volume reduction in patients with fibromyalgia/chronic pain.  The below is compiled from just one source, Wood (see library):

• amygdala
• anterior cingulate cortex
• bilateral inferior frontal gyri
• bilateral mid/posterior cingulum
• bilateral parahippocampal gyrus
• bilateral posterior thalami
• hippocampus
• insular cortex
• left mid-cingulate
• left parahippocampal gyrus
• left posterior thalamus
• left pregenual cortex
• left thalamus
• medial parietal cortex
• medial temporal cortex
• prefrontal cortex
• right dorsolateral prefrontal cortex
• right medial frontal cortex
• right medial temporal gyrus
• right mid-cingulate
• right superior temporal gyrus

Not surprisingly, the majority of the research indicates that reduction of gray matter in some of these regions may cause or exacerbate both pain and depression or other personality/mood disorders.

Kuchinad et al’s study (see library) pinpoints decreased gray matter as possibly caused by atrophy and that the atrophy, which is normal in aging brains, is accelerated in people with fibromyalgia.  So the brains in people with fibromyalgia may be actually aging faster than “normal” people.  The areas that seem significant to Kuchinad et al are the parahippocampal gyrus (which is related to stress) and the cingulate, insular, and prefrontal cortices (which are related to pain processing).  They point out that these regions are also related to cognitive function.  Looking at areas of the brain that are affected by “normal” aging (see Rajagopal et al), they do correspond with the cortex and hippocampus.  Furthermore, Rajagopal et al indicate that oxidative stress in the brain may be a factor in the aging process of the brain. Oxidative stress has been pointed to as a cause for fibromyalgia (see Cordero et al, Fatima et al, etc, in library), so there are definite parallels between the aging brain and the brain of fibromyalgia patients.

Interestingly, the parallel between aging and fibromyalgia doesn’t stop there.  There is an indication that people with fibromyagia are at an increased risk for age-related illnesses, as well as general physical and cognitive decline (see Hassett et al).  It would be interesting to look at the incidence of premature menopause, premature heart disease (such as atrial fibrillation, which is pretty inevitable in older people), and other “old people” disorders, such as bursitis and arthritis, in people with fibromyalgia.

There is more to consider with reduced gray matter volume and fibromyalgia, however.  The brain is kind of like a fuse box and the body a house.  All the circuits in the house merge together in the fuse box, and its functionality depends on the strength of connections, wires, etc.  With fibromyalgia and the changes in the brain, there is imbalance in the circuitry.  Again, it makes for a daunting list, the below compiled from one source, Cifre et al:

• reduced connectivity of the posterior cingulate cortex with superior temporal sulcus
• reduced connectivity between amygdala and periaqueductal gray  matter
• reduced connectivity between thalamus and insula
• reduced connectivity between insula and putamen
• reduced connectivity between periaqueductal gray  matter and caudate
• reduced connectivity of the globus pallidus and caudate
• reduced connectivity of the secondary somatosensory area and primary motor cortex
• reduced connectivity of the secondary somatosensory area and posterior cingulate cortex
• increased connectivity between anterior cingulate cortex and insula
• increased connectivity of the primary motor cortex with supplementary motor area
• increased connectivity of the secondary somatosensory area and caudate
• increased connectivity of the globus pallidus with the amygdala and superior temporal sulcus
• increased connectivity of the medial prefrontal cortex with the posterior cingulate cortex and caudate

There is a strong parallel between the list of affected areas of the brain and affected connections and those areas being part of the pain processing networks, as well as cognitive and motor function.

There’s a bottom line somewhere, but I’m not sure I can find it.  The chickens are glaring at the eggs at this point.  And the eggs are just smug.  There is really only one thing that everyone seems to agree on.  There are physical changes in the brain with chronic pain, including with fibromyalgia.  The longer a person endures the stress of chronic pain, the more pronounced the changes.  To me this indicates that the changes are caused by chronic pain.  However, there are other indications that the changes induce the chronic pain.  Medications such as pregabalin that work directly with brain mechanisms do have a positive impact on fibromyalgia symptoms by changing those affected areas, which then would make me think that the changes in the brain would be the cause of the pain.  The parallels between aging and the changes that occur in patients with fibromyalgia add a different dimension to the question.  So here are what seem to me to be the options:

1. Long term chronic pain causes changes in the brain, particularly in the pain network
2. Changes in the brain, particularly in the pain network, cause long term chronic pain
3. Fibromyalgia is caused by premature aging of the brain – people with fibromyalgia are actually “elderly” in a way.

My personal favorite: extended periods of pain train the brain to be oversensitive.  It becomes an involuntary habit, kind of like an addiction, and is “cemented” into the brain tissues themselves, affecting how the brain areas talk to each other. Unfortunately, there isn’t a 12-step program for fibromyalgia.

Regions of the Brain Involved in Pain Regulation (yep, source is Wikipedia, sorry…)

insula (INS) or insular cortex – linked to emotion, regulation of the body’s homeostasis; functions include perception, motor control, self awareness, cognitive function, interpersonal experience LOCATION: folded in the lateral sulcus

anterior cingulate cortex (ACC) – plays a role in autonomic functions, regulating blood pressure and heart rate; also higher-level functions, reward anticipation, decision-making, impulse control, emotion LOCATION: frontal part

posterior cingulate cortex (PCC) – prominent role in pain and episodic memory retrieval LOCATION: upper part of the limbus lobe

basal ganglia – associated with control of voluntary motor movements, procedural learning, routine behaviors or habits, eye movements, cognition and emotion LOCATION: base of the forebrain, strongly interconnected w/cerebral cortex, thalamus, brainstem

thalamus (THA) – relays sensory and motor signals to the cerebral cortex, regulates consciousness, sleep, alertness LOCATION: between the cerebral cortex and midbrain

periaqueductal gray (PAG) matter – primary control center for descending pain modulation. Enkephalin-producing cells that suppress pain LOCATION: cerebral aqueduct within the tegmentum of the midbrain

medial prefrontal cortex (mPFC) – implicated in planning complex cognitive behavior, personality expression, decision making, moderating social behavior.  “The orchestration of thoughts and actions in accordance with internal goals”

superior temporal sulcus (STS)

primary somatosensory area (SI) – complex system of nerve cells – touch, proprioception, haptic perception

secondary somatosensory area (SII) – light touch, pain, visceral sensation, tactile attention

somatosensory area LOCATION: postcentral gyrus

primary motor cortex (M1) – works with other motor areas to plan and execute movement

supplementary motor area (SMA) – contributes to the control of movement

amygdala (AMYG) – processing of memory, decision-making, emotional reactions LOCATION: temporal lobes

globus pallidus – involved in the regulation of voluntary movement. LOCATION: sub-cortical

caudate (CAU) – caudate nucleus, associated with motor processes, also procedural learning, associative learning, executive function, etc. part of the cortico-basal ganglia-thalamic loop LOCATION: part of the dorsal striatum which is part of the basal ganglia