Tag: neuroinflammation

Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome

Abstract:

BACKGROUND: Patients diagnosed with chronic fatigue syndrome (CFS) or fibromyalgia experience chronic pain. Concomitantly, the rat model of CFS exhibits microglial activation in the lumbar spinal cord and pain behavior without peripheral tissue damage and/or inflammation. The present study addressed the mechanism underlying the association between pain and chronic stress using this rat model.

METHODS: Chronic or continuous stress-loading (CS) model rats, housed in a cage with a thin level of water (1.5 cm in depth), were used. The von Frey test and pressure pain test were employed to measure pain behavior. The neuronal and microglial activations were immunohistochemically demonstrated with antibodies against ATF3 and Iba1. Electromyography was used to evaluate muscle activity.

RESULTS: The expression of ATF3, a marker of neuronal hyperactivity or injury, was first observed in the lumbar dorsal root ganglion (DRG) neurons 2 days after CS initiation. More than 50% of ATF3-positive neurons simultaneously expressed the proprioceptor markers TrkC or VGluT1, whereas the co-expression rates for TrkA, TrkB, IB4, and CGRP were lower than 20%. Retrograde labeling using fluorogold showed that ATF3-positive proprioceptive DRG neurons mainly projected to the soleus. Substantial microglial accumulation was observed in the medial part of the dorsal horn on the fifth CS day. Microglial accumulation was observed around a subset of motor neurons in the dorsal part of the ventral horn on the sixth CS day. The motor neurons surrounded by microglia were ATF3-positive and mainly projected to the soleus. Electromyographic activity in the soleus was two to three times higher in the CS group than in the control group. These results suggest that chronic proprioceptor activation induces the sequential activation of neurons along the spinal reflex arc, and the neuronal activation further activates microglia along the arc. Proprioceptor suppression by ankle joint immobilization significantly suppressed the accumulation of microglia in the spinal cord, as well as the pain behavior.

CONCLUSION: Our results indicate that proprioceptor-induced microglial activation may be a key player in the initiation and maintenance of abnormal pain in patients with CFS.

Source: Yasui M, Menjyo Y, Tokizane K, Shiozawa A, Tsuda M, Inoue K, Kiyama H. Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome. J Neuroinflammation. 2019 Mar 30;16(1):67. doi: 10.1186/s12974-019-1456-x. https://jneuroinflammation.biomedcentral.com/articles/10.1186/s12974-019-1456-x (Full article)

Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is the label given to a syndrome that can include long-term flu-like symptoms, profound fatigue, trouble concentrating, and autonomic problems, all of which worsen after exertion. It is unclear how many individuals with this diagnosis are suffering from the same condition or have the same underlying pathophysiology, and the discovery of biomarkers would be clarifying.

The name “myalgic encephalomyelitis” essentially means “muscle pain related to central nervous system inflammation” and many efforts to find diagnostic biomarkers have focused on one or more aspects of neuroinflammation, from periphery to brain. As the field uncovers the relationship between the symptoms of this condition and neuroinflammation, attention must be paid to the biological mechanisms of neuroinflammation and issues with its potential measurement.

The current review focuses on three methods used to study putative neuroinflammation in ME/CFS: (1) positron emission tomography (PET) neuroimaging using translocator protein (TSPO) binding radioligand (2) magnetic resonance spectroscopy (MRS) neuroimaging and (3) assays of cytokines circulating in blood and cerebrospinal fluid. PET scanning using TSPO-binding radioligand is a promising option for studies of neuroinflammation. However, methodological difficulties that exist both in this particular technique and across the ME/CFS neuroimaging literature must be addressed for any results to be interpretable.

We argue that the vast majority of ME/CFS neuroimaging has failed to use optimal techniques for studying brainstem, despite its probable centrality to any neuroinflammatory causes or autonomic effects. MRS is discussed as a less informative but more widely available, less invasive, and less expensive option for imaging neuroinflammation, and existing studies using MRS neuroimaging are reviewed. Studies seeking to find a peripheral circulating cytokine “profile” for ME/CFS are reviewed, with attention paid to the biological and methodological reasons for lack of replication among these studies.

We argue that both the biological mechanisms of cytokines and the innumerable sources of potential variance in their measurement make it unlikely that a consistent and replicable diagnostic cytokine profile will ever be discovered.

Source: Michael B. VanElzakker, Sydney A. Brumfield and Paula S. Lara Mejia. Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods. Front. Neurol., 10 January 2019 | https://doi.org/10.3389/fneur.2018.01033 https://www.frontiersin.org/articles/10.3389/fneur.2018.01033/full?fbclid=IwAR3KxhofUaLakZRPNiyBliNHSlJvUOdsVqVf5cED_i6o5gF9MCbWxpeS298#h7 (Full article)

Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy

Abstract:

Previous neuroimaging studies have detected markers of neuroinflammation in patients with Myalgic Encephalomyelitis /ChronicFatigue Syndrome (ME/CFS). Magnetic Resonance Spectroscopy (MRS) is suitable for measuring brain metabolites linked to inflammation, but has only been applied to discrete regions of interest in ME/CFS. We extended the MRS analysis of ME/CFS by capturing multi-voxel information across the entire brain.

Additionally, we tested whether MRS-derived brain temperature is elevated in ME/CFS patients. Fifteen women with ME/CFS and 15 age- and gender-matched healthy controls completed fatigue and mood symptom questionnaires and whole-brain echo-planar spectroscopic imaging (EPSI). Choline (CHO), myo-inositol (MI),lactate (LAC), and N-acetylaspartate (NAA) were quantified in 47 regions, expressed as ratios over creatine (CR), and compared between ME/CFS patients and controls using independent-samples t-tests. Brain temperature was similarly tested between groups.

Significant between-group differences were detected in several regions, most notably elevated CHO/CR in the left anterior cingulate (p < 0.001). Metabolite ratios in seven regions were correlated with fatigue (p < 0.05). ME/CFS patients had increased temperature in the right insula, putamen, frontal cortex, thalamus, and the cerebellum (all p < 0.05), which was not attributable to increased body temperature or differences in cerebral perfusion. Brain temperature increases converged with elevated LAC/CR in the right insula, right thalamus, and cerebellum (all p < 0.05). We report metabolite and temperature abnormalities in ME/CFS patients in widely distributed regions. Our findings may indicate that ME/CFS involves neuroinflammation.

Source: Christina Mueller, Joanne C. Lin, Sulaiman Sheriff, Andrew A. Maudsley, Jarred W. Younger. Evidence of widespread metabolite abnormalities in Myalgic encephalomyelitis/chronic fatigue syndrome: assessment with whole-brain magnetic resonance spectroscopy. Brain Imaging and Behavior. https://link.springer.com/epdf/10.1007/s11682-018-0029-4?author_access_token=rNZAi4Qn9MGbc1YywGoHCve4RwlQNchNByi7wbcMAY4otkELpwVAg-M9CJyul_kO-cT6SC717CxfcGOGfesdx7f1AhmYrPeCJukInpp-Dq7L6ew7TkRsW7LllmoDMoo7GAglGA7edR1iMan4xy8-LA%3D%3D (Full article)

VIDEO: Jarred Younger, PhD | How Brain Inflammation Causes ME/CFS

Jarred Younger studied Psychophysiology at the University of Tennessee in Knoxville in 2003. He then completed postdoctoral fellowships in pain medicine and neuroimaging at Arizona State University and Stanford University before joining the faculty at Stanford in 2009. In 2014, he transferred to the University of Alabama at Birmingham, where he currently directs the Neuroinflammation, Pain and Fatigue Laboratory. His lab uses neuroimaging, immune monitoring, and clinical trial techniques to develop new diagnostic tests and treatments for pain and fatigue disorders.

You can read the full transcript HERE.

A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS

[Editor’s comment: While nicely explored in this article, the idea that the limbic system is the main driver behind ME/CFS symptoms is hardly new. Jay Goldstein in his 286-page book, Chronic Fatigue Syndromes: The Limbic Hypothesis (June 1993), examines the important role of the limbic system, and in particular the hypothalamus, in ME/CFS pathophysiology. The authors of this article fail to give him a mention.]

Abstract:

A neuroinflammatory paradigm is presented to help explain the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The hypothalamic paraventricular nucleus (PVN) is responsible for absorbing and processing multiple, incoming and convergent ‘stress’ signals, and if this cluster of neurons were affected (by neuroinflammation), the ongoing hypersensitivity of ME/CFS patients to a wide range of ‘stressors’ could be explained. Neuroinflammation that was chronic and fluctuating, as ‘inflammatory-marker’ studies support, could reflect a dynamic change in the hypothalamic PVN’s threshold for managing incoming ‘stress’ signals.

This may not only be a mechanism underpinning the characteristic feature of ME/CFS, post-exertional malaise, and its associated debilitating relapses, but could also be responsible for mediating the long-term perpetuation of the disease. Triggers (sustained physiological ‘stressors’) of ME/CFS, such as a particular viral infection, toxin exposure, or a traumatic event, could also target the hypothalamic PVN, a potentially vulnerable site in the brains of ME/CFS susceptible people, and disruption of its complex neural circuitry could account for the onset of ME/CFS. In common with the different ‘endogenous factors’ identified in the early ‘neuroinflammatory’ stages of the ‘neurodegenerative’ diseases, an as yet, unidentified factor within the brains and central nervous system (CNS) of ME/CFS patients might induce both an initial and then sustained ‘neuroinflammatory’ response by its ‘innate immune system’.

Positron emission tomography/magnetic resonance imaging has reinforced evidence of glial cell activation centred on the brain’s limbic system of ME/CFS patients. Neuroinflammation causing dysfunction of the limbic system and its hypothalamus together with a consequently disrupted autonomic nervous system could account for the diverse range of symptoms in ME/CFS relating, in particular to fatigue, mood, cognitive function, sleep, thermostatic control, gastrointestinal disturbance, and hypotension.

Source: Angus Mackay, Warren P Tate. A compromised paraventricular nucleus within a dysfunctional hypothalamus: A novel neuroinflammatory paradigm for ME/CFS. International Journal of Immunopathology and Pharmacology. First Published December 6, 2018. https://doi.org/10.1177/2058738418812342  https://journals.sagepub.com/doi/full/10.1177/2058738418812342 (Full article)

Brain Science on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. A variety of studies have been performed to establish objective biomarkers of the disease, including positron emission tomography (PET) molecular imaging and neuro-functional imaging using magnetic resonance imaging (MRI) and magnetoencephalogram (MEG). In this chapter, we summarize the results from PET, MRI, and MEG imaging.

Regional cerebral blood flow and glucose utilization rates are decreased in patients with ME/CFS as compared with age- and sex-matched healthy subjects. Acetyl-L-carnitine uptake into the releasable pool of glutamate and serotonin transporters densities are decreased in a few specific brain regions, mostly in the anterior cingulate in the patients. Although it is hypothesized that brain inflammation is involved in the pathophysiology of ME/CFS, there was no direct evidence of neuroinflammation in patients.

Our recent PET study successfully demonstrated that neuroinflammation is present in widespread brain areas in ME/CFS patients, and is associated with the severity of neuropsychological symptoms. Evaluation of neuroinflammation in patients with ME/CFS may be essential for understanding the core pathophysiology, as well as for developing objective diagnostic criteria and effective medical treatments for ME/CFS. By using specific neurological features of these patients such as prefrontal cortical atrophies and the over-guarding phenomenon were found using MRI and functional MRI, respectively. We here describe related pathophysiological findings and topics in order to aid in the development of future therapies for ME/CFS patients.

Source: Watanabe Y. Brain Science on Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain Nerve. 2018 Nov;70(11):1193-1201. doi: 10.11477/mf.1416201164. [Article in Japanese]  https://www.ncbi.nlm.nih.gov/pubmed/30416112

Research teams find widespread inflammation in the brains of fibromyalgia patients

A study by Massachusetts General Hospital (MGH) researchers – collaborating with a team at the Karolinska Institutet in Sweden – has documented for the first time widespread inflammation in the brains of patients with the poorly understood condition called fibromyalgia. Their report has been published online in the journal Brain, Behavior and Immunity.

“We don’t have good treatment options for fibromyalgia, so identifying a potential treatment target could lead to the development of innovative, more effective therapies,” says Marco Loggia, PhD, of the MGH-based Martinos Center for Biomedical Imaging, co-senior author of the report. “And finding objective neurochemical changes in the brains of patients with fibromyalgia should help reduce the persistent stigma that many patients face, often being told their symptoms are imaginary and there’s nothing really wrong with them.”

Characterized by symptoms including chronic widespread pain, sleep problems, fatigue, and problems with thinking and memory, fibromyalgia affects around 4 million adults in the U.S., according to the Centers for Disease Control and Prevention. Previous research from the Karolinska group led by Eva Kosek, MD, PhD, co-senior author of the current study, suggested a potential role for neuroinflammation in the condition – including elevated levels of inflammatory proteins in the cerebrospinal fluid – but no previous study has directly visualized neuroinflammation in fibromyalgia patients.

A 2015 study by Loggia’s team used combined MR/PET scanning to document neuroinflammation – specifically activation of glial cells – in the brains of patients with chronic back pain. Hypothesizing that similar glial activation might be found in fibromyalgia patients as well, his team used the same PET radiopharmaceutical, which binds to the translocator protein (TSPO) that is overexpressed by activated glial cells, in their study enrolling 20 fibromyalgia patients and 14 control volunteers.

At the same time, Kosek’s team at Karolinska had enrolled a group of 11 patients and an equal number of control participants for a similar study with the TSPO-binding PET tracer. Since that radiopharmaceutical binds to two types of glial cells – microglia and astrocytes – they also imaged 11 patients, 6 who had the TSPO imaging and 5 others, and another 11 controls with a PET tracer that is thought to bind preferentially to astrocytes and not to microglia. At both centers, participants with fibromyalgia completed questionnaires to assess their symptoms. When the MGH team became aware of the similar investigation the Karolinska group had underway, the teams decided to combine their data into a single study.

The results from both centers found that glial activation in several regions of the brains of fibromyalgia patients was significantly greater than it was in control participants. Compared to the MGH team’s chronic back pain study, TSPO elevations were more widespread throughout the brain, which Loggia indicates corresponds to the more complex symptom patterns of fibromyalgia. TSPO levels in a structure called the cingulate gyrus – an area associated with emotional processing where neuroinflammation has been reported in patients with chronic fatigue syndrome – corresponded with patients reported levels of fatigue. The Karolinska team’s studies with the astrocyte-binding tracer found little difference between patients and controls, suggesting that microglia were primarily responsible for the increased neuro-inflammation in fibromyalgia patients.

“The activation of glial cells we observed in our studies releases inflammatory mediators that are thought to sensitize pain pathways and contribute to symptoms such as fatigue,” says Loggia, an assistant professor of Radiology at Harvard Medical School. “The ability to join forces with our colleagues at Karolinska was fantastic, because combining our data and seeing similar results at both sites gives confidence to the reliability of our results.”

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The co-lead authors of the Brain, Behavior and Immunity report are Daniel Albrecht, PhD, MGH Martinos Center and Department of Radiology, and Anton Forsberg, PhD, Karolinska Institutet. Support for the study includes U.S. Department of Defense grant W81XWH-14-1-0543; National Institutes of Health grants R01 NS094306-01A1, R01 NS095937-01A1 and R21 NS087472-01A1; an International Association for the Study of Pain Early Career Award, and funding from the Stockholm County Council the Swedish Research Council, the Swedish Rheumatism Association and the Fibromyalgia Association of Sweden.

Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH Research Institute conducts the largest hospital-based research program in the nation, with an annual research budget of more than $900 million and major research centers in HIV/AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, genomic medicine, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, photomedicine and transplantation biology. The MGH topped the 2015 Nature Index list of health care organizations publishing in leading scientific journals and earned the prestigious 2015 Foster G. McGaw Prize for Excellence in Community Service. In August 2018 the MGH was once again named to the Honor Roll in the U.S. News & World Report list of “America’s Best Hospitals.”

Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is characterized by chronic, profound, disabling, and unexplained fatigue; cognitive impairment; and chronic widespread pain. By using positron emission tomography, our study demonstrated neuroinflammation in the brain of patients with ME/CFS. Neuroinflammation was found to be widespread in the brain areas of the patients with ME/CFS and was associated with the severity of their neuropsychological symptoms. The ongoing research would lead to the establishment of objective diagnostic criteria and development of an appropriate therapy.

Source: Nakatomi Y1, Kuratsune H, Watanabe Y. Neuroinflammation in the Brain of Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Brain Nerve. 2018 Jan;70(1):19-25. doi: 10.11477/mf.1416200945. [Article in Japanese] https://www.ncbi.nlm.nih.gov/pubmed/29348371