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brainstem dysfunction and altered homeostasis

Discussion in 'Latest ME/CFS Research' started by kaffiend, Jun 26, 2011.

  1. kaffiend

    kaffiend Senior Member

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    This is my first time posting here. My apologies if a related thread already exists.

    This study appeared in NMR in Biomedicine. There's a lot of jargon in the abstract, but my field of research is (was) functional brain imaging, so I can unpack some of it if there are questions.

    A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis

    Barnden, L. et al, 2011.

    To explore brain involvement in chronic fatigue syndrome (CFS), the statistical parametric mapping of brain MR images has been extended to voxel?based regressions against clinical scores. Using SPM5 we performed voxel? based morphometry (VBM) and analysed T1? and T2?weighted spin?echo MR signal levels in 25 CFS subjects and 25 normal controls (NC). Clinical scores included CFS fatigue duration, a score based on the 10 most common CFS symptoms, the Bell score, the hospital anxiety and depression scale (HADS) anxiety and depression, and hemodynamic parameters from 24?h blood pressure monitoring. We also performed group hemodynamic score interaction regressions to detect locations where MR regressions were opposite for CFS and NC, thereby indicating abnormality in the CFS group. In the midbrain, white matter volume was observed to decrease with increasing fatigue duration. For T1?weighted MR and white matter volume, grouphemodynamic score interactions were detected in the brainstem [strongest in midbrain grey matter (GM)], deep prefrontal white matter (WM), the caudal basal pons and hypothalamus. A strong correlation in CFS between brainstem GM volume and pulse pressure suggested impaired cerebrovascular autoregulation. It can be argued that at least some of these changes could arise from astrocyte dysfunction. These results are consistent with an insult to the midbrain at fatigue onset that affects multiple feedback control loops to suppress cerebral motor and cognitive activity and disrupt local CNS homeostasis, including resetting of some elements of the autonomic nervous system (ANS). Copyright 2011 John Wiley & Sons, Ltd.
     
  2. kurt

    kurt Senior Member

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    Thanks for posting this, great to have a researcher in brain imaging here... This study has already been discussed here:
    http://phoenixrising.me/forums/show...brainstem-dysfunction-amp-altered-homeostasis. I can merge the threads if you like, or this could be a separate discussion (if we head a different direction...)

    Some questions from reading the abstract:

    So what are group x hemodynamic score interactions? Does that mean correlation between group scores and variables related to bloodflow? Or something else?

    What is T1-weighted MR and white matter volume?

    Are you familiar with neurofeedback to enhance midbrain or brainstem functions? Is that even possible?

    The astrocyte dysfunction is interesting given the vascular problems in CFS, might that be associated with the baroreceptor problems we have? (see: http://www.cfids-cab.org/MESA/cardiac-2.html)
     
  3. kaffiend

    kaffiend Senior Member

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    So what are group x hemodynamic score interactions? Does that mean correlation between group scores and variables related to bloodflow? Or something else?

    The subjects were normal controls and CFS patients who met both the Fukuda and Canadian criteria. The main findings were associations between pulse pressure and structural changes in the brainstem in CFS. White matter volume reductions in the midbrain were also correlated with fatigue duration in CFS.

    Pulse pressure = systolic - diastolic
    From wikipedia: "Theoretically, the systemic pulse pressure can be conceptualized as being proportional to stroke volume, or the amount of blood ejected from the left ventricle during systole and inversely proportional to the compliance of the aorta."

    The variance in the pulse pressure data look about the same for cfs group and the controls, suggesting that chronic changes in pulse pressure don't cause structural changes in the brainstem. The brainstem and hypothalamus send and receive signals from widespread regions in the central nervous system and the periphery. I find that brainstem/hypothalamic dysregulation accounts for all of my symptoms.

    What is T1-weighted MR and white matter volume?

    T1-weighting is a time needed for a certain type of contrast in magnetic resonance (MR). On T1 images, fluids (cerebral spinal fluid) shows up black, white matter shows up white and gray matter shows up gray. It has to do with how densely packed hydrogen protons are in each tissue type. The signal disappears at different rates based on such packing density, allowing for the contrast. It's like starting a race at time 0, then ending at T1, people with different speeds will be at different places.

    Are you familiar with neurofeedback to enhance midbrain or brainstem functions? Is that even possible?

    I've never seen results with this but I know it's done, particularly with EEG and ADHD. For me at least, the stress response to physical activity is way out of whack. Less than two years ago, I was doing 100 mile bike rides in Death Valley. Since a flu illness about 15 months ago, I get vertigo, palpitations, pounding heart and days of concentration problems from walking to the car too fast.

    I've recently got a handle on chronic immune problems, food sensitivities and other things that probably lead to/exacerbate my condition. I'm left with post-exertional malaise/fatigue that I believe is directly linked to deficient CRH or cortisol feedback onto the hypothalamus and brainstem. I don't have any substantial training in neuroendocrinology, so I'm just hypothesizing based on my symptoms and personal research. Since there's no obvious lesion (I had them elsewhere in my brain, but not in the brainstem) I think relaxation techniques, neurofeedback, meditation, and things of that nature might be useful. If chronic stress or infection can break the HPA axis, it's reasonable to think it can be brought back in line. Based on cognitive performance measures/fatigue ratings and other things I've been logging, I'm trying to tilt the axis with supplements that have an influence on cortisol metabolism (licorice root) and CRH release (fenugreek). Of course, I would love if I could just convince an endocrinologist to do a CRH stimulation test.

    The astrocyte dysfunction is interesting given the vascular problems in CFS, might that be associated with the baroreceptor problems we have?

    My cardiac problems seem the result of altered vagus nerve and sympathetic functioning. They only happen when I'm in the post-exertional fatigue state. What causes this is anyone's guess. Astrocytes are a principle energy source for neurons, so if they're dysfunctional, the neurons will hypo-function or die. The studies of brainstem hypo-perfusion might be showing this. This MRI study above doesn't measure direct pulse pressure or hemodynamic variables in the brain; it correlated pulse pressure taken outside of the MR scanner with the values from MR images. This is how one might find out if brain size is related to IQ, for example. Simplified, if a structure is atrophied or lesioned, the white and gray matter values will be lower and the cerebral spinal fluid values will be higher.

    Hope that helps!
     
  4. Enid

    Enid Senior Member

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    That is good to read kaffiend - this is an area which much interests - "high spots" (whatever my Neurologogist meant by that) were found by MRI in my own brain when almost totally incapacitated/ill - sometimes passing out. Pretty certain about brain stem involvement. My school biology suggests reticular activating formation as part of the problem along with normal homeostatic controls.
     
  5. kaffiend

    kaffiend Senior Member

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    The "high spots" are usually seen on a type of scan called T2. It basically reverses the contrast of a T1 image. On T2 images, fluids look bright and white matter looks dark. Edema, cerebral spinal fluid, and lesions in white matter show up as bright spots. B12 deficiencies can "mimic" MS, so I suspect problems with the methylation cycle can cause these lesions in CFS.

    The brainstem contains the cell bodies for every ascending and descending neurotransmitter system in the brain. Parkinson's disease, for example, is the loss of a tiny cluster of dopaminergic cells in a region called the substantia nigra (meaning dark stuff - it's somewhat blue-ish). When I wrote out all of my symptoms several months ago, I thought, "This is insane." I have symptoms appearing in every major bodily system. So, I'm either a complete hypochondriac or the structures controlling neuro-endocrine and homeostatic functions are disrupted. The latter seemed obvious to me.
     
  6. kurt

    kurt Senior Member

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    Thanks for the clarifications! Not sure what you imply about the baroreceptor problem, are you connecting those with cardiac problems? I was referring to the low blood volume (hypovolemia) that most CFS patients have, and the study showing baroreceptor problems, so was wondering whether astrocyte failure in a given brain region might explain that, such as in a region controlling baroreceptors.

    Regarding CRH stim test, I had a very good Endocrinologist the first few years of my CFS, and he did run that test for me. My cortisol would not suppress (it did not adjust overnight after the stim). And my CFS sounds very similar to yours, I was a swimmer, very active, and a researcher also (USAF) prior to the flu-like illness that started my CFS. Anyway, the result of the CRH stim really puzzled my Endo, he never did come up with an explanation, he scanned me for a cortisol-producing tumer (negative of course), that was the only theory he had. But of course, I realize that result was probably because of the CFS dysautonomia and brain dysfunction triggered by that flu.
     
  7. kurt

    kurt Senior Member

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    Have you studied the cellular hypoxia hypothesis for CFS (Dr Bell and Marty Pall)? A cellular-level disease is another viable explanation for the broad base of symptoms. How would the neuro-endo and homeostasis functions adjust to cellular hypoxia? That is one of the complicating factors of CFS in my opinion, the fact that if this is a cellular disease homeostatic autonomic mechanisms will get disrupted, and if it is a dysautonomia creating depletions then cellular functions will get disrupted. A chicken and egg problem (and classic systems dilemma)

    There are also simple explanations for the mass of symptoms, ongoing B12 depletion, or chronic Lyme, for example, each can manifest a multitude of symptoms.
     
  8. Enid

    Enid Senior Member

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    @ kaffiend
    Many thanks for your reasoning reply on brain scans. This is your field so will know more - but I did come to the same conclusion "symptoms appearing in every major bodily system" = controlling structures in the brainstem/hypothalamus (to put it crudely). Mine a clear infection onset (throat/glands etc). There has been some talk about pathogens (?) crossing the blood brain barrier. Lots to ponder here - thanks so much for your input. (and kurt)
     
  9. kurt

    kurt Senior Member

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    Here is an older but very interesting study that suggests a connection between NO pathologies (such as what Marty Pall proposes for CFS) and decline in white matter in the brain:

    This seems consistent with both the reduced white matter finding in the MR study and Marty Pall's hypothesis about NO/ONOO in CFS and the role of iNOS. Also, how interesting an Astrocytes pathology was induced by the elevation of NO (which is what the MR study found in CFS patients). Another interesting corelary is that the ATP levels in the brain were reduced by the NO excess in the brain. Also, the fact that steady low level increase in NO is more harmful than rapid high dose is interesting, given that iNOS increase could be due to a metabolic error (the vicious cycle Pall describes), something that would more likely produce a steady low level exposure than sudden spikes.

    In a round-about way, this new Barnden MR study of CFS brains may have confirmed some elements of the Pall NO/ONOO hypothesis, if one considers this rat study, which admittedly was in vitro, but still, maybe this is a way to connect some dots ...
     
  10. merylg

    merylg Senior Member

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    Hi Kaffiend,
    Thanks for this thread. I am most interested as I am soon to have a functional Brain MRI as well as a Cervical/Upper Thoracic MRI on 13th July, 2011. I have had CFS since having an enteric virus (? Norovirus) back in 1995. I have also had MCS getting worse since then, including many food chemical sensitivities, intolerances and allergies.

    Just in last year I have had more severe symptoms. My activity level is about 3 now. I have recently had my arthritis diagnosed as Psoriatic arthritis. I have also had numerous severe Angioedema gastric & breathing reactions to chemicals inhaled and prescribed drugs.

    I will let you know results of my MRIs. Maybe you can help me interpret/understand them.
    I already had a Carotid Doppler Ultrasound that was normal...no blockages! (Have family history of Vascular Dementia on Father's side) However, he was a smoker.

    Thanks again...
     
  11. Enid

    Enid Senior Member

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    Thanks kurt - "dots" beginning to connect - though joining the "real" world - perceptually that is - and going back over "experiences" personally I'm convinced of deep brain (stem/hypothalamus inc RAF) insult - probably viral. Memory returns so not dementia as we know it.
     
  12. kaffiend

    kaffiend Senior Member

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    Realities are always more complex, but the most parsimonious explanation for the symptoms of viral onset type CFS is permeable blood brain barrier that allows for peripheral cytokines to attack latent herpesvirus in the brainstem and hypothalamus. Inflammatory cytokines would then produce iNOS and massive oxidative stress to areas controlling gut motility, heart-rate/blood pressure, HPA axis. Once the functions of the brainstem are sufficiently damaged from oxidative stress, regulatory and negative feedback for just about everything gets dampened and the physiological stress response is broken or slowed. This is where drugs/supplements that inhibit the pro-inflammatory cytokine TNF-alpha might be useful. Bupropion (Wellbutrin) and vinpocetine are examples.
     
  13. Jenny

    Jenny Senior Member

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  14. kaffiend

    kaffiend Senior Member

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    I've fortunately never had any depression, but I find it helps with post-exertional malaise. Bupropion inhibits TNF-alpha and a few classes of nicotinic receptors in addition the dopamine uptake activity through which it may alleviate depression.

    One of the arms of the immune system shown to be up-regulated in CFS after exercise is complement. If I had grant money and research facilities, I would look at the complement immune system and the cholinergic anti-inflammatory pathway first thing.

    http://en.wikipedia.org/wiki/Cholinergic_anti-inflammatory_pathway

    http://en.wikipedia.org/wiki/Complement_system

    Licorice root (Glycyrrhiza specifically) has demonstrated anti-complement properties, as well as blocking cortisol metabolism (which would be anti-flammatory).
    http://www.ncbi.nlm.nih.gov/pubmed/12761187
     
  15. Esther12

    Esther12 Senior Member

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    I'm not really capable of understanding the particulars to all this but...

    I've read other things about migraines being possibly related to physical irritation of the brainstem/spinal cord. It's thought that strengthening core muscle strength could be helpful here.

    This could also explain why connective tissue disorders have increased incidence of CFS and migraine (more dependent upon muscular support to protect brainstem/spinal column).

    This is all a bit speculative but... should I be focusing my energy on something like Pilates to improve core muscle strength? What does anyone think?
     
  16. mellster

    mellster Marco

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    Wow Kaffiend,

    The analysis in his thread seems to be the most plausible explanation so far - for the symptoms throughout the whole body vs just isolated, for the trouble arising only in post-exertional state, for the cytokine response to viral illness penetrating the blood-brain barrier and so on. 80-90% of the symptomatic presentation I can find in myself. I have long speculated that once certain damage is done and cytokines are upregulated that the autonomous system is not able to distinguish stressors and exercise is definitely a stressor, albeit supposedly a beneficial one in the long term. It also might explain strong reactions to minor stressors such as noise or emotional issues that seem to amplify when in a malaised state and also attribute for that sometimes somewhat anxious feeling (a stress response as well). Needless to say most of the tests with specialists were done in a resting state and the stress test was done once and never repeated (since outperformed). Apart from supplements pacing seems the only viable option to reduce heightened stress responses and cytokine inflammation after workout. Another trick is to do the workout 10-20 bpm below the target heart rate and only perform in the target heart rate or higher for a reduced amount of time. It seems somewhat that for each minute you workout at let's say 150 bpm you can workout 20 mninutes at 120 bpm (just an example), there seems to be a roughly inverse logarithmic function describing the increase in allowed exercise time on the x-axis over the lowering of the HR on the y-axis (where 0 is approx. your resting/sitting/normal activity HR). Just an idea, no data to back this up ;)
     
  17. kaffiend

    kaffiend Senior Member

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    I can't figure out if it's heart-rate or intensity more generally. The threshold is somewhat of a moving target as well.

    Exercise is a stressor, but it also elicits a large immune response. If the negative feedback on that response is broken (cortisol?) then it keeps going.

    This is interesting: http://www.ncbi.nlm.nih.gov/pubmed/20145562
     
  18. mellster

    mellster Marco

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    I noticed improvement from taking NAC and D-ribose, no theanine in the mix yet. I had slightly elevated cortisol levels (although still in range for the reference range of other labs) and I think it has to do with pain response and also the fact that the pain is more prevalent on the left side. I don't know what kind of exercise the test subjects were doing but I used to kickbox 3-4 times a week and that was too much to sustain and I got weaker in the long run until I crashed (due to lack of sleep and stress as well). Also, the HR might just be one factor, I also noticed that exercising on the stationary bike at the same HR levels is less taxing than jogging (with changing incline) outdoors at the same HR. This is probably because jogging/running (as kickboxing) is a jarring type of exercise where a big part of your body is in motion and needs proper oxygenation and more muscles are worked, whereas with stationary cycling the torso is mostly still. Also, the lungs are more affected by pollution and extreme (hot or cold) weather.
     
  19. taniaaust1

    taniaaust1

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    Pilates can be good (as its laying down) as long as one doesnt get the heart rate at too much (many dont realise that this can be quite intense).. so go carefully.

    Improving muscle strength is, if you arent going to overdo it good. (helps stop us be more prone to injury.. those core muscles also help protect your back etc). I once ended up in hospital for a week after my muscles all became weak so hence then I injured my back (weak muscles from lack of use after a long bedbound phase).
     

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