The Pain Brain

hippocampus fibromyalgia

Reduced volume in the hippocampus is just the latest of many brain finding in fibronyalgia

Sometimes you’ve got to ask wonder where is it going to stop with fibromyalgia (FM) and the brain? Reductions in the volume of “gray matter” (the neuronal cell bodies and glial cells as opposed to the long nerve fibers) have been found in the insular, anterior cingulate cortices and the amygdala in the brains of FM patients. Other issues have been found in the thalamus, the basal ganglia, the  parahippocampal gyrus,  the premotor cortex, motor cortex, the somatosensory cortices and the prefrontal cortex in the brain. Other abnormalities have been found in the connections between various parts of the brain.

2015 Jan 30;8:47-52. doi: 10.2147/JPR.S71959. eCollection 2015. Fibromyalgia patients have reduced hippocampal volume compared with healthy controls.McCrae CS1, O’Shea AM1, Boissoneault J2, Vatthauer KE1, Robinson ME3, Staud R4, Perlstein WM5, Craggs JG1.

This Florida group was looking to add another brain region to the list: the hippocampus, a part of the limbic system that plays an important role in short-term memory (remember that?), long-term memory (generally thought to be intact) and “spatial navigation”.  The hippocampus isn’t directly involved in the production of pain but a breakdown in hippocampal functioning could lead to a “feed-forward” process that ends up disrupting the  limbic system and the pain networks in the brain.

Hippocampal problems could then conceivably result in discomfort, severe pain, anxiety and perhaps even the  mysterious and disturbing allodynia that some people with FM experience.

Some evidence of hippocampal atrophy exists in FM but this was the first time depression was controlled for in a study. Because hippocampal atrophy is also present in depression and because depression is fairly common in fibromyalgia, the atrophy could have been due to depression.

In this nice-sized (for a brain imaging study) 22 healthy controls and 40 fibromyalgia patients got into an MRI machine and had their hippocampal volumes analyzed. Rates of depression, pain disability, sleep efficiency were assessed as well.


You can another brain abnormality to the growing list. The hippocampus is made up of two hemispheres and hippocampal grey matter volumes were significantly reduced in both of them (p<.o8, p<.02).   Because the atrophy was independent of depression, it was coming from or contributing to fibromyalgia not depression.

Earlier studies buttressed the finding of reduced hippocampal volume.  Remarkably elevated NAA/Cho ratio’s in a 2008 study suggested that neuron damage had indeed occurred in the hippocampus.  A meta-analysis of magnetic resonance spectroscopy  findings concluded significant hippocampal NAA reductions are present in FM. A recent study linked cognitive problems in fibromyalgia with hippocampal dysfunction.

hippocampus fibromyalgia

Earlier findings suggested something had gone wrong with the hippocampus

The researchers inability to find correlations between levels of  pain and sleep efficiency, however, suggested that the smaller hippocampi in the FM patients was not significantly contributing to their symptoms.  (Despite the fact that the hippocampus plays a major role in cognition including short-term memory and cognition, they did not examine cognition. )

The fact that hippocampal atrophy was not associated with increased pain, symptom severity or decreased sleep efficiency suggested the atrophy found may have been secondary; i.e. it was the result of having FM rather than being the cause of it. More extensive symptom tests, might, however have found an association and that could change.

Whatever the symptom tests showed, the hippocampus is a major organ in the brain – not exactly something you want to have atrophy a bit. When the authors asked what could be causing the reduced hippocampal grey matter one of the usual suspects in FM showed up:  glutamate/GABA imbalance or nervous system burnout.

Glutamate/GABA and Nervous System Burnout

Nervous system “burnout” occurs when the excitatory part of the nervous system  triggers so much activity that nervous system cells get killed off.  Powered by glutamate and inhibited by GABA, several researchers have proposed that nervous system over excitation could be causing or contributing to the hypersensitive pain state found in FM.

There’s some evidence for this.  Increased glutamate levels or ratio’s appear to be widespread in FM having been found in the insula, thalamus and posterior gyrus and have been linked to increased pain in several studies. Increased glutamate ratio’s have also been found in restless leg syndrome, another disorder  apparently characterized by “over-excitation”.


Increased brain glutamate levels may be common in FM

Drugs that tamp down glutamate neurotransmission such as Lyrica, sodium oxybate and ketamine can be helpful for some patients. A recent study suggested transcranial direct stimulation (tDS) reduces pain  in FM by reducing brain glutamate and increasing brain GABA levels.

Dietary glutamate (MSG), intriguingly, was associated with increased symptom severity in FM in one study. A glutamate-free diet which includes avoid MSG, aspartame, soy, seaweed, yeast and other foods is a key part of Dr. Yasko’s protocol. On more anecdotal note, Marco – who has written several Health Rising blogs on glutamate/GABA –  recently received a comment from someone for whom a low FODMAPS/glutamate diet helped. (See Meg’s comment).

Prolonged Stress

Secondary or Primary Factor?

Because prolonged stress has been associated with hippocampal atrophy, the atrophy could simply result from the prolonged stress of having a painful illness. An a acute infection or otherwise stressful event could also kick off an atrophy in the hippocampus that helps to trigger FM. It’s also possible that people with FM are predisposed to having small hippocampi. A twin study found having a smaller hippocampus predisposed twins to come down with post-traumatic stress disorder after being exposed to a severe stressor.

The association between reduced hippocampus volume and prolonged stress suggests that interventions that impact the stress response and/or glutamate neurotransmission could be helpful. These could include behavioral modifications (mindfulness/meditation/yoga/CBT) and/or glutamate reducing drugs – some of which have been found useful in FM. A reduced glutamate diet is another, mostly untried, option.

The authors called the “neuroplasticity” of the hippocampus; e.g. it’s ability to respond to treatment an “unknown and exciting area”.

The hippocampus is now one of several brain regions implicated in fibromyalgia. How it will shake out in the end is unclear but it’s clear that the brain is heavily involved in producing the pain in FM. Whether that brain dysregulation is being driven by problems with the nerves or the immune system or pathogens or other factors in the body is a big question.

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