Central sensitization in fibromyalgia? A systematic review on structural and functional brain MRI

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Abstract

Objectives

The aim of the present study was to systematically review the literature addressing pain-induced changes in the brain related to central sensitization in patients with fibromyalgia (FM) using specific functional (rs-fMRI and fMRI) and structural (voxel-based morphometry—VBM) brain MRI techniques.

Methods

PubMed and Web of Science were searched for relevant literature using different key word combinations related to FM, brain MRI, and central sensitization. Full-text reports fulfilling the inclusion criteria were assessed on risk of bias and reviewed by two independent reviewers.

Results

From the 61 articles that were identified, 22 met the inclusion criteria and achieved sufficient methodological quality. Overall, eight articles examined structural brain (VBM) changes in patients with FM, showing moderate evidence that central sensitization is correlated with gray matter volume decrease in specific brain regions (mainly anterior cingulate cortex and prefrontal cortex). However, global gray matter volume remains unchanged. A total of 13 articles evaluated brain activity (fMRI) in response to a nociceptive stimulus. Findings suggest a higher but similar pattern of activation of the pain matrix in FM patients compared to controls. There is also evidence of decreased functional connectivity in the descending pain-modulating system in FM patients. Overall, two articles examined intrinsic brain connectivity in FM patients with rs-fMRI. In conclusion, there is moderate evidence for a significant imbalance of the connectivity within the pain network during rest in patients with FM.

Conclusions

The included studies showed a moderate evidence for region-specific changes in gray matter volume, a decreased functional connectivity in the descending pain-modulating system, and an increased activity in the pain matrix related to central sensitization. More research is needed to evaluate the cause–effect relationship.

Introduction

Chronic pain is a major health problem, affecting approximately 19% of the entire population in the Western world [1]. There is extensive evidence that abnormalities in central pain processing, rather than damage or inflammation of peripheral structures, play an important role in the development and maintenance of chronic pain in patients with FM, chronic fatigue syndrome (CFS), and chronic whiplash-associated disorders (WAD) [2], [3], [4], [5]. A common finding in these chronic pain syndromes is hyperalgesia and allodynia, which is an expression of disturbed pain processing in the central nervous system or central sensitization (CS). Central sensitization is defined as an increased responsiveness of the central nervous system to a variety of stimuli, e.g., pressure, temperature, light, and medication [4]. This central hyperexcitability causes hyperalgesia, allodynia, and referred pain across multiple spinal segments, leading to chronic widespread pain [2]. Temporal summation or wind up, dysfunctional descending inhibitory pathways, and increased facilitatory modulation are possible mechanisms contributing to sensitization of the central nervous system. Through research, CS has been demonstrated in a number of specific chronic pain populations, including fibromyalgia (FM) (for review see Clauw [6], Williams and Gracely [7], and Meeus and Nijs [2]).

Because of the large impact of chronic pain, multiple non-invasive structural and functional neuroimaging methods have recently been developed to enable rapid progress in understanding the processing of pain in the human brain and to provide insight into the previously unknown mechanisms underlying pain chronification [8].

Voxel-based morphometry (VBM) is the most commonly applied structural imaging technique. It is a statistical method of comparing the volume of gray and white matter in specific brain areas, which controls to a large extent for the variable shape of human brains by normalizing data to anatomical landmarks [9]. An increasing number of studies have reported macroscopic changes in gray matter volume in pain-processing brain regions [10].

Apart from structural reorganization, functional magnetic resonance imaging (fMRI) and resting-state functional magnetic resonance imaging (rs-fMRI) studies have contributed significantly to the knowledge on processing of pain in the human brain. The most common type of fMRI studies evaluates brain responses to an experimental stimulus in comparison to a baseline or control stimulus. This approach can be used to determine how healthy individuals respond to painful stimuli and how individuals with chronic pain respond to either noxious or innocuous stimuli [10]. fMRI provides an indirect measurement of brain activity via the blood oxygen level-dependent (BOLD) response, which is a measure of the amount of deoxygenated blood and blood volume in brain regions involved in the response to a stimulus [11]. Interestingly, recent evidence showed that the human brain is a functional network with different highly connected cortical regions [12]. As a consequence, functional connectivity MRI has evolved in which areas with correlating BOLD signal time courses are considered to be functionally connected. In addition, temporal correlations in spontaneous low-frequency fluctuations in BOLD signal while participants rest (rs-fMRI) also appears to be a reliable measure of brain connectivity [13], [14]. rs-fMRI examines intrinsic connectivity of the brain in the resting basal state and is a useful adjustment of fMRI as it is valuable for associating spontaneous pain with various brain network activities [15].

While it has already been shown that CS may be at the basis of the continuous pain associated with FM, so far there has been little standardized research, using this medical brain imaging, to unravel the neuroplastic brain changes in relation to chronic pain in patients with FM. Evidence for both structural and functional brain changes is existing, but up to now the results are somewhat inconclusive due to the different methodologies and the variety in brain regions of interest in different studies. In order to determine the present state of the art and to steer further research, a systematic review was performed to identify structural and functional changes in the brain of patients with FM related to CS using specific brain MRI techniques. The goal of this systematic literature review is to summarize the available evidence on structural and functional brain alterations measured with VBM analysis, fMRI, and rs-fMRI.

Section snippets

Information sources and search strategy

The search strategy had been executed in November 2013 in the electronic databases PubMed (http://www.ncbi.nlm.nih.gov/entrez) and Web of Science (http://isiwebofknowledge.com). The search request had been entered by J.S. and I.C. The full selection process was executed in attendance of both the reviewers under the supervision of M.M. The search strategy was based on a combination of Mesh terms and free text words derived from the PICO questions. The search request was based on synonyms of the

Study selection

The search for studies resulted in a total of 52 references and nine “hand-searched” articles. After deduplication and the two screening phases based on the selection criteria, 22 case–control studies remained. The screening process is presented in the Figure.

Risk of bias and level of evidence

The methodological quality was assessed according to the criteria shown in Supplementary Table S1. In most cases (93.8% or 107/114), there was an agreement between both the reviewers. During a consensus meeting, the seven differences were

Discussion

The goal of the present systematic study was to review the scientific literature addressing the use of functional (fMRI and rs-fMRI) and structural (VBM) brain MRI for identifying pain-induced neuroplastic changes related to CS in patients with FM.

It can be concluded that there is moderate evidence for structural changes in the brain of FM patients with CS. There is moderate evidence for a decrease in gray matter volume in the brain, mainly in regions related to pain processing (cingulate,

Conclusion

Based on this systematic review, there is moderate evidence for decreased gray matter volume in specific brain regions while the global gray matter volume remains unchanged. An increased activation of the pain matrix and lower pain thresholds are identified in patients with FM. Based on moderate evidence, patients with FM show less functional connectivity in the areas of the descending pain-modulating system and a unique pattern of temporal activation during application of a pain stimulus. In

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