Synopsis

Keywords: White Matter, Diffusion Tensor Imaging

The relationship between abnormal pain sensation and alterations in the central nervous system of fibromyalgia patients is unknown. In this study, diffusion tensor imaging was used to systematically investigate the alterations in white matter tracts of the pain modulatory pathways. The findings revealed the altered integrity of spinothalamic tract-thalamus, thalamus-insula tracts, tracts connected thalamus, midbrain and pons, were associated with the physical and psychological dysfunction in patients with fibromyalgia.

Introduction

Fibromyalgia (FM) is the most frequent cause of persistent, widespread musculoskeletal pain, together with fatigue, sleep, memory, and mood problems¹.Researches showed the abnormal pain sensation of FM was caused by altering the way the brain and spinal cord process pain, further giving rise to the related mental disorder of FM patients². There are three distinct but interconnected pathways in the anatomical processing of chronic pain. The sensory aspects of pain, including location, characteristics, and intensity, are encoded via the lateral pathway. The affective-motivational components of pain are transmitted through the medial pathway. In addition to the two ascending pathway, the descending pain inhibitory pathway represents the ability to suppress pain and regulates context-dependent pain perception such as placebo analgesia³. Diffusion tensor imaging (DTI) is frequently used to analyze the white matter (WM) architecture in the brain non-invasively and provide clues of disease progress and clinical consequences⁴. The change of WM integrity in the brain regions related to pain processing with DTI metrics, such as corpus callosum, cingulum, and thalamus, which was associated with clinical pain intensity and pain perception in FM patients^5-7. However, there is no systematic analysis on how WM microstructures are altered through the three specific pain pathways in FM patients. Thus, we hypothesized alterations of WM integrity in pain modulatory pathways was related to process of abnormal pain sensation and alterations in the central nervous system of FM patients.

Methods

Thirty-eight FM patients (4 males / 34 females, mean age = 48.95±11.13 years) and forty-one healthy control participants (HC) (5 males / 36 females, mean age = 47.17±12.79 years) were included. Patients were confirmed by experienced rheumatologists and met the American College of Rheumatology criteria for FM⁸. Whole brain images were obtained using a 3 Tesla MRI (Siemens, Prisma, Munich, Germany). DTI was acquired using the spin-echo EPI method with a b value of 1000 s/mm² for each of 64 diffusion encoding directions, and one b₀ image set, (TR/TE=7000/65 ms, FOV=196×196mm², Matrix:128×128×63, 3-mm slice thickness). The in-plane resolution was 1.53125 mm. To acquire the spin distribution function, the diffusion data were reconstructed by using q-space diffeomorphic reconstruction in the MNI space. The targeted tracts were reconstructed using DSI Studio (http://dsi-studio.labsolver.org). The WM integrity in each targeted tract was measured by fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD) values. Regions of interests (ROIs) in both hemispheres shown in Figure 1 were selected according to the three pain pathways according to previous study³. FA, MD, AD, RD, and demographic were compared between patients with FM and HC group using independent two-sample t-test. P values (2-tailed) under 0.05 were regarded as significant. Data are presented as mean ± standard error of the mean. All calculations were performed with SPSS V.26 (Armonk, NY: IBM Corp).

Results

No significant difference of demography between the FM patients and the HC group. Significant higher AD and RD were found in the left spinothalamic tracts (STT) to thalamus in the lateral and medial pathway in the FM group compared with the HC group (Figure 2). In the medial pathway, FA in right thalamus-insula, MD and AD in left thalamus-insula significantly decreased in the FM group (Figure 3). As compared to the HC group, significant higher MD, AD, and RD were revealed in the left thalamus-midbrain-pons of the inhibitory pathway (Figure 4).

Discussion

Significantly higher RD were found in the left STT-thalamus of the FM group. Elevated RD is associated with demyelination⁹. Demyelinated axons may discharge action potentials spontaneously¹⁰ and were associated with the pain of multiple sclerosis¹¹. Studies show multiple sclerosis lesions that grow in the spinothalamic tract of the cervical and thoracic spinal cord cause central extremity pain, therefore suggesting the spinothalamic tract is where extremities neuropathic pain originates¹².
Significantly lower MD and AD were found in the left thalamus-insula of the FM group, and significantly lower FA was found in the right thalamus-insula. Neuronal damage and loss, which cytotoxic edema is associated with the decrease of MD and axonal loss correlates to decreased AD, possibly indicated hampered connections with the insular cortex^{13, 14}. Insula is considered a limbic-related cortex, and anterior insula directly corresponds with all emotional feelings and subjective physical sensations¹⁵. The axonal pathology along the WM tracts from thalamus to insula is correlated with abnormal affective regulation processes such as bipolar disorder and obsessive-compulsive disorder^{16, 17}. Similar psychological alterations such as anxiety and depression can be seen on FM patients^{18, 19}.
Significantly higher MD, AD and RD were found in the left thalamus-midbrain-pons of the FM group. In the inhibitory pathway, the periaqueductal gray (PAG) of the midbrain is a crucial structure in the propagation and modulation of pain²⁰. PAG has been shown to have an antinociceptive role with inhibitory connections to the trigeminal sensory nucleus and the dorsal horn of the spinal cord²¹. Chronic pain such as FM is associated with the result of deficiency in activation of the pain inhibitory pathway³.

Conclusion

In this study, we successfully investigated the WM microstructure in three pain modulatory pathways in FM patients has shown difference compared with HC group, which might be a potential neural substrate in fibromyalgia.

Acknowledgements

This work is financially supported by Ministry of Science and Technology of Taiwan under Contract numbers of MOST 110-2314-B-038-052, 108-2314-B-038-101-MY2, and 110-2314-B-038-074. We also are grateful for support from Imaging Center for Integrated Body, Mind and Culture Research, National Taiwan University.

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