A systematic review of neurological impairments in myalgic encephalomyelitis/chronic fatigue syndrome using neuroimaging techniques

leokitten

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This is a pretty well done and thorough review paper, makes for a good reference to find papers you might've read long ago on particular neuroimaging studies of ME.

While most, if not all, the neuroimaging studies in ME had fairly small sample sizes (due to abysmal ME funding!) and most used Fukuda criteria because CCC and ICC didn't become mainstream for ME research until after many of these studies were published, seeing all the papers again in one document shows that there were indeed multiple replicated results, with some being replicated in a number of papers. Though of course there were also inconsistent results between some papers, so hopefully with CCC criteria selected patients and larger sample sizes (increased funding for ME research) that future neuroimaging studies can produce more highly statistically significant findings and possible markers of ME.

My first pleasant surprise about this review, and I didn't realize this about ME until I saw this with all the results in one place, is wow the cingulate cortex brain region appears to very implicated in ME. It was found to have abnormalities/impairments in cerebral blood flow studies, neuroinflammation and other PET studies (i.e. lower SERT transporter density, glucose hypometabolism), functional connectivity studies, EEG studies, and cognitive function fMRI and SPECT studies (and possibly a couple types I missed). And many of these cingulate cortex findings are replicated by multiple papers. Of course there are other brain regions with abnormalities discussed in the review that are important, but the cingulate cortex appeared to me to stand out as it has been implicated in almost all the different study modalities.

The cingulate cortex is a key brain region that has a lot of important and coordinating functions.

From Neuroanatomy, Cingulate Cortex:
As seen from the extensive neural pathways it shares with other brain regions, the cingulate cortex can be considered, in a sense, a connecting hub of emotions, sensation, and action. Some of these pathways are those involved in motivational processing, which is apparent through the connections with the orbitofrontal cortex, basal ganglia, and insula, which together make up the reward centers of the brain. Also, the cingulate cortex projects pathways to the lateral prefrontal cortex which is involved in executive control, working memory, and learning. Pathways between cingulate cortex and motor areas like the primary and supplementary motor cortices, spinal cord, and frontal eye fields, suggest an important role in motor control. Moreover, the cingulate cortex, frontal and parietal lobes comprise a neural network for orienting attention, and expectedly, injury to any of these areas is known to cause hemineglect. The neural circuits cingulate cortex shares with the hippocampus and amygdala suggest a role in consolidating long-term memories and processing emotionally-relevant stimuli, respectively.
The cingulate cortex is also involved in regulation of autonomic and neuroendocrine responses and pain perception.


A systematic review of neurological impairments in myalgic encephalomyelitis/chronic fatigue syndrome using neuroimaging techniques
Maksoud et al. PLOS One April 2020

Abstract

Background
Myalgic encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS) is a multi-system illness characterised by a diverse range of debilitating symptoms including autonomic and cognitive dysfunction. The pathomechanism remains elusive, however, neurological and cognitive aberrations are consistently described. This systematic review is the first to collect and appraise the literature related to the structural and functional neurological changes in ME/CFS patients as measured by neuroimaging techniques and to investigate how these changes may influence onset, symptom presentation and severity of the illness.

Methods
A systematic search of databases Pubmed, Embase, MEDLINE (via EBSCOhost) and Web of Science (via Clarivate Analytics) was performed for articles dating between December 1994 and August 2019. Included publications report on neurological differences in ME/CFS patients compared with healthy controls identified using neuroimaging techniques such as magnetic resonance imaging, positron emission tomography and electroencephalography. Article selection was further refined based on specific inclusion and exclusion criteria. A quality assessment of included publications was completed using the Joanna Briggs Institute checklist.

Results
A total of 55 studies were included in this review. All papers assessed neurological or cognitive differences in adult ME/CFS patients compared with healthy controls using neuroimaging techniques. The outcomes from the articles include changes in gray and white matter volumes, cerebral blood flow, brain structure, sleep, EEG activity, functional connectivity and cognitive function. Secondary measures including symptom severity were also reported in most studies.

Conclusions
The results suggest widespread disruption of the autonomic nervous system network including morphological changes, white matter abnormalities and aberrations in functional connectivity. However, these findings are not consistent across studies and the origins of these anomalies remain unknown. Future studies are required confirm the potential neurological contribution to the pathology of ME/CFS.
 
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Wishful

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I wonder if any of the ME research organizations are keeping track of research that has shown significant results and which need replication and/or larger studies. Completely novel research isn't necessarily going to find the one true answer, brightly lit with banners flying and a marching brass band. An important part of ME may already be found, but is sitting on a shelf gathering dust, because it lacked the waving banners. It might just need a bit of cleaning and polishing.
 

leokitten

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Unfortunately in ME research you also see a lot of one-offs by labs which do a very good first study and then you never see another ME publication from them again. It's quite uncommon in other research areas and I believe it's due to the lack of money in ME research. Labs can usually find enough money for one project on their own, but the issue is that technical and other knowledge about protocols etc doesn't build.
 
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Pyrrhus

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My first pleasant surprise about this review, and I didn't realize this about ME until I saw this with all the results in one place, is wow the cingulate cortex brain region appears to very implicated in ME.
Interestingly, the Anterior Cingulate Cortex (ACC) in the cortical brain also figures prominently in research studies on Attention Deficit Disorder (ADD).[1] One reason why the ACC may be critical for maintaining attention is its connections with the thalamus in the sub-cortical brain.[2] The thalamus is the part of the subcortical (autonomic) brain that is most closely connected to the cortical (conscious) brain.

Although the thalamus is best known as a relay station that provides all the body's sensory information to the cortical brain, the cortical brain also provides "feedback" to the thalamus, allowing the thalamus to suppress certain sensory information. It is thought that this cortical "feedback" is how the conscious brain decides which sensory information to pay attention to, and which sensory information to ignore, a phenomenon called "sensory gating". If there is a problem with this "feedback", then the conscious brain may be inundated with too much sensory information.

References
[1] https://pubmed.ncbi.nlm.nih.gov/23713508/
[2] https://pubmed.ncbi.nlm.nih.gov/23371564/
 

Pyrrhus

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Interestingly, the Anterior Cingulate Cortex (ACC) in the cortical brain also figures prominently in research studies on Attention Deficit Disorder (ADD).[1] One reason why the ACC may be critical for maintaining attention is its connections with the thalamus in the sub-cortical brain.[2] The thalamus is the part of the subcortical (autonomic) brain that is most closely connected to the cortical (conscious) brain.
I forgot to mention that, in addition to the thalamo-cortical circuits, there are also basal ganglia-thalamus-cortical circuits:
https://en.m.wikipedia.org/wiki/Cortico-basal_ganglia-thalamo-cortical_loop

A rough diagram:
E56D65BD-5560-4EF7-9E00-E4BF41755BA6.png
Connectivity diagram showing excitatory glutamatergicpathways as red, inhibitory GABAergic pathways as blue, and modulatory dopaminergicpathways as magenta. (Abbreviations: GPe: globus pallidus external; GPi: globus pallidus internal; STN: subthalamic nucleus; SNc: substantia nigra pars compacta; SNr: substantia nigra pars reticulata)

Hope this helps.
 

Pyrrhus

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It might be interesting to compare the conclusions from this review of neuroimaging by Staines & Marshall-Gradisnik with this other review of neuroimaging, by Michael Van Elzakker:
https://forums.phoenixrising.me/thr...-a-critical-review-of-research-methods.76890/

Donald Staines & Sonya Marshall-Gradisnik's review:
  • "A total of 55 studies were included in this review."
  • "Out of the 55 papers, 43 relied on the Fukuda criteria to classify ME/CFS patients."
  • "Out of the 55 studies: 16 studies utilised MRI, 17 used functional MRI (fMRI), five used PET scans and 11 used EEG. The remaining studies used magnetic resonance spectrometry (MRS)."
  • "The articles reported on multiple outcomes including brain structure, cerebral blood flow (CBF), gray and [white matter (WM)] volumes, sleep and EEG, and [functional connectivity (FC)]."
  • "The results suggest widespread disruption of the autonomic nervous system network including morphological changes, white matter abnormalities and aberrations in functional connectivity."
  • "However, these findings are not consistent across studies and the origins of these anomalies remain unknown."
  • "The search for definitive cerebral signatures for ME/CFS remains difficult. The lack of reproducibility of the studies and low sample size also contribute to the inability to arrive at a consensus regarding potential neurological markers for ME/CFS. There are, however, consistent examples of altered brain health, e.g. an increase in neuroinflammation suggestive of a neuroimmune mechanism and reduced functional efficiency."

Michael Van Elzakker's review:
  • "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."
  • "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."
  • "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."
  • "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."
  • "Kraynak et al. (19) conducted a useful meta-analysis of this basic neuroimmunology research. They synthesized results from studies that performed neuroimaging during peripheral immune activation by either an immune stimulating antigen (e.g., lipopolysaccharide [LPS]) or proinflammatory cytokines (e.g., interferon alpha [IFN-α]). [...] Consistent activation occurred in basal ganglia (bilateral striatum), limbic structures (right amygdala, bilateral hippocampus, and hypothalamus), brainstem/pons, and neocortex (right anterior insular cortex, right temporal and left parahippocampal gyri, subgenual and dorsal anterior cingulate cortex [sgACC and dACC], and dorsomedial and ventromedial prefrontal cortex [dmPFC and vmPFC])."
  • "The dACC (which would be considered anterior midcingulate cortex [aMCC] by some anatomists) [...] was consistently activated and therefore could also be considered an a priori region of interest in neuroinflammation studies. Given the role of dACC in attention and cognitive control, we suggest that its function in ME/CFS could be considered particularly important for “brain fog” symptoms."
  • "Furthermore, Kraynak et al. (19) reported that the thalamus was also consistently detected across multiple study designs, but not in a way that demonstrated functional connectivity. However, we consider thalamus an important region of interest in ME/CFS given its detection by Nakatomi et al. (8) and given the role of thalamus in sensory filtering, a likely mechanism for the common symptom of sensory sensitivity."
  • "The current gold standard for in vivo imaging of neuroinflammation is PET scanning using a translocator protein-binding radioligand."
  • "Nakatomi et al. (8) conducted the first case-control study using PET to measure [translocator protein (TSPO)] expression in the central nervous system of ME/CFS patients vs. healthy controls. [...] Nakatomi et al. (8) remains an important, groundbreaking study that should be replicated with complementary methods."
  • "The ME/CFS research field has been stuck in a somewhat defensive posture, with a focus on demonstrating “this is a real condition” by showing significant biological differences between patients and controls. [...] The field is ready to move past proving “this is a real condition” and to start elucidating the specific relationship of ME/CFS symptoms to neuroinflammation."