Hippocampal Dysfunction in Fibromyalgia Syndrome

The symptoms of Fibromyalgia Syndrome (Fibro) may be explained by the dysfunction of an area of the brain called the Hippocampus, according to recent research.

In May, an article was published in the American Journal of Neuroradiology describing a study evaluating the cerebral metabolism of patients with Fibro using Proton MR spectroscopy. [1] The study was carried out by a team of researchers at the University of Michigan Hospitals, Michigan, USA, which included FibroAction Professional Advisory Board (PAB) member Daniel Clauw MD.

The study was carried out in order to test the hypotheses:

1. Widespread pain sensitivity in patients with Fibro suggests a central nervous system (CNS)-processing problem.
2. Therefore, it is conceivable that metabolic alterations exist in pain-processing brain regions of people with Fibro compared with healthy controls and that such metabolic data could correlate with clinical symptoms.

Twenty-one patients with Fibro and 27 healthy controls underwent conventional structural MR imaging (MRI) and additional 2D-chemical shift imaging (CSI) MR-spectroscopy sequences. [1]

For the 2D-CSI spectroscopy, larger volumes of interest were centered at the level of the basal ganglia and the supraventricular white matter (i.e. the white brain matter above the ventricles). Within these larger areas, 16 smaller voxels were placed in a number of regions previously implicated in pain processing. N-acetylaspartate (NAA)/Creatine(Cr), Choline (Cho)/Creatine(Cr) and -acetylaspartate (NAA)/Choline (Cho) ratios were calculated for each voxel, these substances being metabolites of the brain. Study participants also underwent clinical and experimental pain assessment. [1]

The average metabolite ratios and the ratio variability were analysed for each region and correlations between clinical symptoms and metabolite ratios were assessed. [1]

The researchers found that Cho/Cr variability in the right dorsolateral prefrontal cortex (a specific area of the brain) was significantly different in the 2 groups. A significant correlation between Cho/Cr in this location and clinical pain was also found to be present in the Fibro patients group. It was also found that the evoked pain threshold correlated significantly with NAA/Cho ratios in the left insula and left basal ganglia. [1]

The researchers concluded that:

"Our data suggest that there are baseline differences in the variability of brain metabolite relative concentrations between patients with [Fibro] and [healthy controls], especially in the right [dorsolateral prefrontal cortex]. Furthermore, there are significant correlations between metabolite ratios and clinical and experimental pain parameters in patients with [Fibro]." [1]

In July, an article was published in the Journal of Rheumatology describing a study, by a team of reseachers from Cairo University Hospital, Egypt, that used proton magnetic resonance spectroscopy to investigate hippocampal metabolism in patients with Fibro. [2]

The study aimed to:

1. investigate dysfunction of hippocampus in patients with Fibro using proton magnetic resonance spectroscopy (1H-MRS), and to compare these findings with healthy controls.
2. correlate levels of metabolites obtained with aspects of cognition, depression, and sleep symptoms in the patient group.

The study participants were 15 female patients, who met American College of Rheumatology criteria for the classification of Fibro, and 10 healthy age-matched female controls. Participants were receiving no medications known to affect cognitive functioning or central nervous system metabolites before their participation in the study. [2]

In all patients and controls, 1H-MRS was used to assess N-acetylaspartate (NAA), choline (Cho), creatine (Cr), and their ratios from both hippocampi, with levels of these metabolites and their ratios being determined and the findings compared between the groups. All patients and controls underwent psychological assessment to assess cognitive function and depression, and had a structured sleep interview with sleep diary. The Fibromyalgia Impact Questionnaire (FIQ), the number of tender points, and the visual analog scale (VAS) for pain were also assessed in all patients. [2]

The researchers found that the NAA levels of the right and left hippocampi differed significantly between patients and controls. Cho levels in the right hippocampus were also higher in the patient group than in controls, but no differences were found with respect to Cr levels in both hippocampi. Analysis also showed that the NAA/Cho and NAA/Cr ratios differed significantly between patients and controls, while the Cho/Cr ratio showed no differences. Significant correlations were found between language score and right Cho and right Cr levels, but no significant correlations were found between metabolites and their ratios with FIQ, VAS for pain, or the number of tender points. [2]

The researchers concluded that:

"The hippocampus was dysfunctional in patients with [Fibro], as shown by lower NAA levels compared to controls, representing neuronal or axonal metabolic dysfunction. As the hippocampus plays crucial roles in maintenance of cognitive functions, sleep regulation, and pain perception, we suggest that metabolic dysfunction of hippocampus may be implicated in the appearance of these symptoms associated with this puzzling syndrome." [2]

This month, an article was e-published ahead of print in the Journal of Pain describing a study by a team of researchers including FibroAction Professional Advisory Board (PAB) member Patrick Wood MD. [3]

For this study, the researchers investigated the bilateral hippocampus of 16 female Fibro patients in comparison to 8 age- and gender-matched healthy control subjects using single voxel proton magnetic resonance spectroscopy. [3]

They found that there was a significant reduction in the ratio of N-acetylaspartate to creatine (NAA/Cr) in Fibro patients versus matched control subjects, specifically in the right temporal lobe from a voxel centered on the right hippocampus. [3]

Moreover, correlation analysis demonstrated a significant negative correlation between patient scores on the Fibromyalgia Impact Questionnaire and NAA/Cr ratio within the right hippocampus - i.e. as the NAA/CR ratio decreased, the Fibro had more of an impact on patients.

The researchers concluded that:

"Our results indicate that [Fibro] is associated with brain metabolite abnormalities within the right hippocampus that correlate with patient symptoms." [3]

All these studies have demonstrated an abnormality in hippocampal brain metabolites in patients with Fibro. The correlation between the patients' experiences of symptoms and altered ratios of these metabolites suggests a role for the hippocampus in the pathology of Fibro.

Although the pathology of Fibro is poorly understood, a growing body of evidence suggests involvement of the central nervous system.

The hippocampus is a brain center that is sensitive to the effects of stress exposure, when talking about stress as physical stressors, which can be related to either physical trauma, mental stress or both, and the hippocampus has been demonstrated to be affected in a variety of disorders whose onset, like Fibro, are associated with stressful experience. [3]

The hippocampus plays major roles in short term memory and spatial navigation, so its role in the pathology of Fibro would explain two of the previously less well understood symptoms of Fibro: cognitive difficulties (including memory problems) and clumsiness.

References:

1. Petrou M, Harris RE, Foerster BR, McLean SA, Sen A, Clauw DJ, Sundgren PC. Proton MR spectroscopy in the evaluation of cerebral metabolism in patients with fibromyalgia: comparison with healthy controls and correlation with symptom severity. AJNR Am J Neuroradiol. 2008 May;29(5):913-8. Epub 2008 Mar 13.
2. Emad Y, Ragab Y, Zeinhom F, El-Khouly G, Abou-Zeid A, Rasker JJ. Hippocampus dysfunction may explain symptoms of fibromyalgia syndrome. A study with single-voxel magnetic resonance spectroscopy. J Rheumatol. 2008 Jul;35(7):1371-7. Epub 2008 May 15.
3. Wood PB, Ledbetter CR, Glabus Deceased MF, Broadwell LK, Patterson JC 2nd. Hippocampal Metabolite Abnormalities in Fibromyalgia: Correlation With Clinical Features. J Pain. 2008 Sep 2. [Epub ahead of print]