No differences in locus coeruleus MR measured neuromelanin contrast in fibromyalgia
Poster No:
1767
Submission Type:
Abstract Submission
Authors:
Marilena DeMayo1, Clifford Cassidy2, Cheryl McCreary1, Tuan Trang1, Ashley Harris1, Alexander McGirr1
Institutions:
1University of Calgary, Calgary, Alberta, 2SUNY Stony brook, New York, NY
First Author:
Co-Author(s):
Introduction:
Fibromyalgia is a chronic pain condition that affects approximately 2-3% of the population (McNally, Matheson, & Bakowsky, 2006). It is characterized by ongoing, widespread pain, along with accompanying symptoms such anxiety, mood, disrupted sleep, and cognitive difficulties (Hauser et al., 2015). Noradrenergic dysfunction is posited as one possible mechanism to explain the core pain and associated symptoms of fibromyalgia (Clauw, 2009).
The primary source of noradrenaline in the central nervous system is the locus coeruleus (LC; Benarroch, 2018; Schwarz & Luo, 2015), a midbrain nucleus that sends projections throughout the brain and spinal cord. LC activity plays a critical role in both nociception and non-pain related symptoms associated with fibromyalgia, including anxiety, mood, sleep, and cognition (Wolfe et al., 2010).
A novel approach to studying LC noradrenaline function makes use of a paramagnetic by product of catecholamine synthesis, neuromelanin, using magnetic resonance imaging (MRI). Neuromelanin signal in the LC is considered a proxy measure of lifetime noradrenaline synthesis (Keren et al., 2015), We hypothesized that fibromyalgia patients would have a greater lifetime synthesis of noradrenaline as quantified by neuromelanin MRI (i.e., greater LC-neuromelanin signal intensity) and investigated associations between LC-neuromelanin in fibromyalgia and anxiety, mood, and sleep.
The primary source of noradrenaline in the central nervous system is the locus coeruleus (LC; Benarroch, 2018; Schwarz & Luo, 2015), a midbrain nucleus that sends projections throughout the brain and spinal cord. LC activity plays a critical role in both nociception and non-pain related symptoms associated with fibromyalgia, including anxiety, mood, sleep, and cognition (Wolfe et al., 2010).
A novel approach to studying LC noradrenaline function makes use of a paramagnetic by product of catecholamine synthesis, neuromelanin, using magnetic resonance imaging (MRI). Neuromelanin signal in the LC is considered a proxy measure of lifetime noradrenaline synthesis (Keren et al., 2015), We hypothesized that fibromyalgia patients would have a greater lifetime synthesis of noradrenaline as quantified by neuromelanin MRI (i.e., greater LC-neuromelanin signal intensity) and investigated associations between LC-neuromelanin in fibromyalgia and anxiety, mood, and sleep.
Methods:
Twenty-four participants and 24 healthy controls were recruited for a cross-sectional characterization of LC-neuromelanin contrast. Data was collected on a 3T General Electric Discovery MR750 scanner. A T1-weighted anatomical scan (TR=8.1 ms, TE=3.2ms, 1mm isotropic voxels) was collected to prescribe the neuromelanin acquisition and for coregistration purposes. The neuromelanin was a 2D gradient echo acquisition (TR=475ms, FA=50 degrees, TE=4.7ms, 0.47 x 0.47 x 1.5 mm voxels reconstructed, 5 averages, 16 slices with a 1200ms magnetization transfer pulse). Participants completed the Revised Fibromyalgia Impact Questionnaire (Bennett et al., 2009), as well as measures of anxiety, depression and sleep.
Data was processed using a custom-built, semi-automated, MATLAB algorithm (Cassidy et al., 2022). Briefly, using the coregistration with ANTS toolbox (Avants et al., 2011) an overly inclusive mask of LC region is registered from MNI space to each participant's unprocessed NM-MRI image. This mask acts as a search region for a "funnel-tip" search method, with the starting point of the most intense voxel within the mask interpreted to represent the greatest neuromelanin signal within the LC. Five contiguous voxels for each identified LC slice are designated to be a part of the LC. Each mask was visually inspected to ensure accuracy. The neuromelanin signal was calculated as a ratio between the LC and a central pons reference region.
Data was processed using a custom-built, semi-automated, MATLAB algorithm (Cassidy et al., 2022). Briefly, using the coregistration with ANTS toolbox (Avants et al., 2011) an overly inclusive mask of LC region is registered from MNI space to each participant's unprocessed NM-MRI image. This mask acts as a search region for a "funnel-tip" search method, with the starting point of the most intense voxel within the mask interpreted to represent the greatest neuromelanin signal within the LC. Five contiguous voxels for each identified LC slice are designated to be a part of the LC. Each mask was visually inspected to ensure accuracy. The neuromelanin signal was calculated as a ratio between the LC and a central pons reference region.
Results:
An independent groups t-test revealed no differences in LC-neuromelanin contrast between participants with fibromyalgia and healthy controls, (t(45)=-0.26, p=0.40). For the participants with fibromyalgia, partial correlations accounting for age showed no association between LC-neuromelanin and time since fibromyalgia diagnosis (r(20)=0.14, p=0.54), fibromyalgia symptom severity (r(20)=-0.14, p=0.54), anxiety (r(20)=-0.03, p=0.79), depression (r(20)=-0.06, p=0.79), or insomnia (r(20)=-0.02, p=0.94). Almost 90% of participants with fibromyalgia had been exposed to medications targeting noradrenergic function limiting the interpretability of these data.
·Average neuromelanin signal in the locus coeruleus for participants with fibromyalgia and healthy controls
Conclusions:
Neuromelanin accumulation in the LC as measured by MR did not distinguish participants with fibromyalgia and healthy controls. Further, LC neuromelanin sensitive signal did not associate with core fibromyalgia pain symptoms or associated symptoms. Dynamic measures of noradrenergic function may be required to understand noradrenergic contributions to fibromyalgia.
Disorders of the Nervous System:
Psychiatric (eg. Depression, Anxiety, Schizophrenia) 2
Neuroanatomy, Physiology, Metabolism and Neurotransmission:
Transmitter Systems 1
Keywords:
ADULTS
DISORDERS
Neurotransmitter
Noradrenaline
Norpinephrine
Pain
1|2Indicates the priority used for review
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Provide references using APA citation style.
Benarroch, E. E. (2018). Locus coeruleus. Cell and Tissue Research, 373(1), 221-232. doi:10.1007/s00441-017-2649-1
Bennett, R. M., et al. (2009). The Revised Fibromyalgia Impact Questionnaire (FIQR): validation and psychometric properties. Arthritis Research & Therapy, 11(4), R120. doi:10.1186/ar2783
Cassidy, C. M., et al. (2022). Association of locus coeruleus integrity with Braak stage and neuropsychiatric symptom severity in Alzheimer's disease. Neuropsychopharmacology, 47(5), 1128-1136. doi:10.1038/s41386-022-01293-6
Clauw, D. J. (2009). Fibromyalgia: an overview. The American Journal of Medicine, 122(12 Suppl), S3-S13. doi:10.1016/j.amjmed.2009.09.006
Hauser, W., et al. (2015). Fibromyalgia. Nature Reviews Disease Primers, 1, 15022. doi:10.1038/nrdp.2015.22
Keren, N. I., et al. (2015). Histologic validation of locus coeruleus MRI contrast in post-mortem tissue. Neuroimage, 113, 235-245. doi:10.1016/j.neuroimage.2015.03.020
McNally, J. D., et al. (2006). The epidemiology of self-reported fibromyalgia in Canada. Chronic diseases in Canada, 27(1), 9-16. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/16672135
Schwarz, L. A., et al. (2015). Organization of the locus coeruleus-norepinephrine system. Current Biology, 25(21), R1051-R1056. doi:10.1016/j.cub.2015.09.039
Wolfe, F., et al. (2010). The American College of Rheumatology preliminary diagnostic criteria for fibromyalgia and measurement of symptom severity. Arthritis Care Research, 62(5), 600-610. doi:10.1002/acr.20140