Is your Hypothalamus up the creek?

[Violeta]

It seems to be accepted now that the molecule that causes all of the symptoms of migraine is called Calcitonin gene-related peptide (CGRP) and is a 37-amino acid neuropeptide. Discovered 30 years ago, it is produced as a consequence of alternative RNA processing of the calcitonin gene. CGRP has two major forms (α and β). It belongs to a group of peptides that all act on an unusual receptor family (from Wiki).

Furthermore from Wiki regarding the new class of drugs specifically developed to treat migraine -

"Calcitonin gene-related peptide receptor antagonists are a class of drugs that act as antagonists of the calcitonin gene-related peptide receptor. Several monoclonal antibodies which binds to the CGRP receptor or peptide have been approved for prevention of migraine".

As a chronic migraine sufferer with almost daily migraines at times I have taken a particularl issue in this new combination of drugs but as I live in the UK we are not allowed to have these drugs (at least in my area of the south-east). It is so frustrating as they still throw old fashioned preventative medications for us to take which have huge side effects and I can never tolerate them. The only one that I can stick with is Propananol which also helps with the high blood pressure I have developed. But it always feels like my brain is on a knife edge as to whether it will switch over into migraine which usually lasts a few days if I cannot knock it out with Sumatriptan and paracetemol plus caffeine.

Hope my post hasn't taken things off topic.

Pam

Maybe you have already seen this, but:

Calcitonin gene-related peptide (CGRP) and nitric oxide are involved in the underlying pathophysiology of migraine and other diseases involving neurogenic inflammation.

So I am wondering if regulating nitric oxide would help.

Also from the paper:
CGRP promoter activity was also stimulated by nitric oxide donors and overexpression of inducible nitric oxide synthase (iNOS)

And then, of course, calcium channels:
nitric oxide action required extracellular calcium and likely involves T-type calcium channels.

Nitric oxide regulation of calcitonin gene-related peptide gene expression in rat trigeminal ganglia neurons
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC1486900/

 

[Violeta]

Maybe you have already seen this, but:

Calcitonin gene-related peptide (CGRP) and nitric oxide are involved in the underlying pathophysiology of migraine and other diseases involving neurogenic inflammation.

So I am wondering if regulating nitric oxide would help.

Also from the paper:
CGRP promoter activity was also stimulated by nitric oxide donors and overexpression of inducible nitric oxide synthase (iNOS)

And then, of course, calcium channels:
nitric oxide action required extracellular calcium and likely involves T-type calcium channels.

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC1486900/

To add to this, this study asks the question, which comes first the CGRP activity or the migraine.

https://journals.sagepub.com/doi/full/10.1177/03331024211042360
The chicken and egg problem: CGRP release due to trigeminal activation or vice versa?

"What comes first: trigeminal afferent activation or CGRP release? Is CGRP released from trigeminal afferents and drives the pain phase of migraine attacks, or is it just a bioindicator for vigorous activation of trigeminal afferents?"

 

[halcyon]

As a chronic migraine sufferer with almost daily migraines at times I have taken a particularl issue in this new combination of drugs but as I live in the UK we are not allowed to have these drugs (at least in my area of the south-east).

This is criminal. I hope this changes for you, and soon.

It seems to be accepted now that the molecule that causes all of the symptoms of migraine is called Calcitonin gene-related peptide (CGRP) and is a 37-amino acid neuropeptide.

It is definitely heavily involved, however I don't believe that it explains everything. Not to rub it in your face, but I have been taking one of the anti-CGRP monoclonals (Emgality) for close to 2 years. The drug absolutely halts the acute activation of the trigeminal nerve, and several of the worst migraine symptoms are downstream of this. However, despite this, I still continue to have many of the brain symptoms of migraine (and to bring it back around to the thread), including the hypothalamic symptoms (altered water metabolism, altered appetite, increased drowsiness, etc.).

 

[bertiedog]

To add to this, this study asks the question, which comes first the CGRP activity or the migraine.

From memory I am sure one of the experts, Dr Goasby who was involved in the CGRP trials said that in an experiment they could inject the CGRP molecule into a healthy control and it would cause a migraine like headache, hence the thinking that the release of CGRP is actually the cause of migraine. I could be wrong that it was actually Dr Goasby who said this but I listen every year to the Migraine Summit and definitely one of the experts explained this.

BTW for anybody who is interested the Migraine Summit is online and free from this Wednesday. It lasts for 8 days and is an excellent source of uptodate information on everything migraine related.

Pam

 

[bertiedog]

BTW for anybody who is interested the Migraine Summit is online and free from this Wednesday. It lasts for 8 days and is an excellent source of uptodate information on everything migraine related.

CORRECTION

Sorry I got the dates wrong regarding the Summit - should have said it runs from Wednesday 16 March to Thursday 24 March. My apologies,

Pam

 

[heapsreal]

I have empty Sella syndrome. Basically the box where the hypothalamus sits in, it is squashed flat. Discovered on an mri for headaches. And of course it has nothing to do with headaches but only in a small percentage. My headaches are supposedly migraines, which requires not black and white diagnostic, just an opinion.

 

[Violeta]

From memory I am sure one of the experts, Dr Goasby who was involved in the CGRP trials said that in an experiment they could inject the CGRP molecule into a healthy control and it would cause a migraine like headache, hence the thinking that the release of CGRP is actually the cause of migraine. I could be wrong that it was actually Dr Goasby who said this but I listen every year to the Migraine Summit and definitely one of the experts explained this.

BTW for anybody who is interested the Migraine Summit is online and free from this Wednesday. It lasts for 8 days and is an excellent source of uptodate information on everything migraine related.

Pam

Thank you, and did he say what causes CGRP to rise?

 

[bertiedog]

Thank you, and did he say what causes CGRP to rise?

TBH I don''t remember but they always stress that migraine is a brain disease and that there is a strong genetic component to it so I guess that is the main reason for this issue.

Both my parents had migraine but my Mum's was just menstrual whereas my father went on having migraines till he was in his 90s and as I am 74 on Friday it doesn't give me much hope!

Pam

 

[SWAlexander]

The latest on Cortisol.

Summary: The stress hormone cortisol reduces altruistic behaviors and alters brain activity in the dorsolateral prefrontal cortex in people with higher levels of empathy.

Source: SfN

Stress Hormone Reduces Altruistic Behavior in Empathetic People

The stress hormone cortisol reduces altruistic behavior and alters activity in brain regions linked to social decision making—but only in people who are better at imagining others’ mental states, according to new research published in The Journal of Neuroscience.

In a study from Universität Hamburg, participants decided how much money to donate to a selection of charities before and after completing a stressful public-speaking task while researchers monitored their brain activity with fMRI.

To simulate the personal cost of making an altruistic decision, the participants received a portion of the money they did not donate. Before the stressful task, people with higher mentalizing ability, or the ability to imagine others’ mental states, donated more money than people with low mentalizing ability.

In people with high mentalizing ability, increased levels of the stress hormone cortisol decreased donations; cortisol had no effect on people with low mentalizing ability.

The researchers could predict how high mentalizers would choose to donate based on activity in the dorsolateral prefrontal cortex (DLPFC), a brain region involved in social decision making. Yet higher levels of cortisol infringed on this pattern, indicating stress reduced the neural representation of donations in the DLPFC.

These results reveal cortisol might alter the activity of the DLPFC, which has a more pronounced effect on people who rely on mentalizing to make social decisions.
Article: https://neurosciencenews.com/cortisol-altrusim-empathy-20262/

 

[Jjnz]

And for anyone interested in a review of research into the Hypothalamic-Pituitary-Adrenal Axis in ME/cfs, there is the 2013 review by Cara Tomas, Julia Newton, and Stuart Watson:

A Review of Hypothalamic-Pituitary-Adrenal Axis Function in Chronic Fatigue Syndrome (Tomas, Newton, & Watson, 2013)
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4045534/
Excerpt:

I can not fir the life of me find where he said it or remember than name if the drug but warren Tait mentioned there was a trial of a new hypothalamus drug . If I find it ill post it

 

[Carnation4000]

Oh my gosh SWAlexander, thank you so much for posting this video! Just hearing him say such truth makes me feel better. The number one thing helping me with my CFS has been muscle testing (@Mary) but most folks seem to think communicating with your body is proof of insanity.

 

[pattismith]

Let's not forget Warren Tate's theory on the paraventricular nucleus of the hypothalamus:

:

This area of the hypothalamus is also involved in hypersomnia

Case Report: Dysfunction of the Paraventricular Hypothalamic Nucleus Area Induces Hypersomnia in Patients - PMC (nih.gov)
2022

Background

Hypersomnia is a common and highly impairing symptom marked by pathological excessive sleepiness, which induces suboptimal functioning and poor quality of life. Hypersomnia can be both a primary (e.g., hypersomnolence disorder) and secondary (e.g., tumors, and head trauma) symptom of disorders. However, its underlying mechanisms remain largely unknown.

Case Presentation
We report that three clinical cases with lesions around the paraventricular nucleus of the hypothalamus (PVH) area showed excessive daytime sleepiness and a prolonged nocturnal sleep lasting more than 20 h per day. Sleep architecture and subjective daytime sleepiness were examined by polysomnography.

These cases were presented with stroke,
myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders
and neuromyelitis optical spectrum disorder (NMOSD), respectively.

Magnetic resonance imaging (MRI) showed lesions around the PVH area in all these three patients. After treatment of their primary disorders, their excessive sleep decreased as the PVH area recovered.

Conclusion
Our findings suggest that the PVH may play an essential role in the occurrence of hypersomnia.

And this article makes even closer CFS/ME and idiopathic hypersomnia

Autonomic dysfunction in idiopathic hypersomnia: an overlooked association and potential management | Journal of Clinical Sleep Medicine (aasm.org)

2022 review

Nour Adra, BS, Manasa Reddy, MD, Hrayr Attarian, MD, Ashima S. Sahni, MD

ABSTRACT
There is a small yet robust body of literature regarding autonomic dysfunction in idiopathic hypersomnia as well as sleep disturbances in postural orthostatic tachycardia syndrome.
This review aims at summarizing the current literature and highlighting gaps in the current knowledge. This article additionally presents the personal experience of one of the authors at the sleep center.

Another syndrome with Hypersomnia + Dysautonomia

Kleine-Levin syndrome: report of a case with marked dysautonomic features | Journal of Clinical Sleep Medicine (aasm.org)

2022

Abstract

Kleine-Levin syndrome (KLS) is a rare neurologic disorder of unknown etiopathogenesis, characterized by abrupt onset and remission of attacks of hypersomnia and cognitive dysfunctions. Psychiatric symptoms are frequently present, ranging from disinhibited sexual behavior and eating disorders to hallucinations, anxiety, mood alterations, and derealization.

A vast range of attack-related dysautonomic signs and symptoms are reported, but remain poorly described.

We describe a KLS patient with sleep attacks dominated by marked dysautonomic features.

We briefly review similar clinical cases and suggest that the hypothalamus may play a central role in the genesis of autonomic dysfunction in KLS.

 

[Pyrrhus]

This area of the hypothalamus is also involved in hypersomnia

Case Report: Dysfunction of the Paraventricular Hypothalamic Nucleus Area Induces Hypersomnia in Patients - PMC (nih.gov)
2022

Very interesting! Thanks for sharing!

 

[pattismith]

Very interesting! Thanks for sharing!

This area of the hypothalamus is also involved in hypersomnia

Case Report: Dysfunction of the Paraventricular Hypothalamic Nucleus Area Induces Hypersomnia in Patients - PMC (nih.gov)
2022

I am currently doing an interesting trial Methylphenidate + minocycline (to target my sleepiness/drowsiness/brain fog), and I must say I am much more active than usual.

Here a recent study linking PVN (paraventricular Nucleus of Hypothalamus) and minocycline activity:

Frontiers | Minocycline Reduces Hypothalamic Microglia Activation and Improves Metabolic Dysfunction in High Fat Diet-Induced Obese Mice (frontiersin.org)

In High Fat Diet fed mice, minocycline attenuated body mass and adiposity without altering food intake suggesting enhanced energy expenditure.

Minocycline also attenuated hyperinsulinemia and improved insulin sensitivity in HFD mice.

Increased microglial activation and autophagy gene network changes were observed in the paraventricular nucleus (PVN) of the hypothalamus of HFD mice, which was prevented by minocycline treatment.

Contrary to PVN findings, there were no significant effects of either HFD or minocycline on microglia activation in the hypothalamic arcuate nucleus or central amygdala.

Together, these findings suggest that minocycline improves HFD-induced weight gain and insulin resistance in part by reducing inflammatory processes in the PVN, a key hypothalamic region regulating metabolic function.

 

[Violeta]

I am currently doing an interesting trial Methylphenidate + minocycline (to target my sleepiness/drowsiness/brain fog), and I must say I am much more active than usual.

Here a recent study linking PVN (paraventricular Nucleus of Hypothalamus) and minocycline activity:

Frontiers | Minocycline Reduces Hypothalamic Microglia Activation and Improves Metabolic Dysfunction in High Fat Diet-Induced Obese Mice (frontiersin.org)

@pattismith , do you think it's safe to jump to the conclusion that the minocycline helps this because it's caused by a pathogen?

 

[pattismith]

@pattismith , do you think it's safe to jump to the conclusion that the minocycline helps this because it's caused by a pathogen?

@Violetta,
research says minocycline helps because it's a brain microglia inhibitor. It means that minocycline is efficient against brain neuroinflammation.

The pathway that target minocycline may involved CCL11, P2X7R ...(edit: target seems also TNF-alpha)

I have not read studies saying that minocycline is inhibiting microglia via its anti pathogen activity....

 

[hapl808]

I am currently doing an interesting trial Methylphenidate + minocycline (to target my sleepiness/drowsiness/brain fog), and I must say I am much more active than usual.

Had you tried Ritalin before on its own without minocycline? One thing I haven't really tried is stimulants, but it's been on my list. Curious about your experience.

 

[pattismith]

Had you tried Ritalin before on its own without minocycline? One thing I haven't really tried is stimulants, but it's been on my list. Curious about your experience.

Yes I use low dose Ritalin since I had an aggravation of my brain fog/sleepiness/Attention Deficit in october 2020, after a flu vaccine. I couldn't tolerate more than 15 mg per day, and got not better result with a bigger dose.
With Minocycline addition, Ritaline is working better, I can take a bit more, and I feel much energetized, with no side effects.

 

[Consul]

Looks like Komaroff thinks mecfs is caused by problems in the Hypothalamus now, Cort Johnson has written about it here. I would scroll down to headline "The Cause" and read from there. Its also mentioned another researcher that has written a paper about this theory. Must say i like this idea.

 

[Arius]

That's a very inspiring article. An undiscussed implication: cortisol damages the hypothalamus, which would explain why so many driven type A folks end up with CFS/ME. It also means that stress reduction is an important part of healing, (although I think we probably all know that already and that would be true of any healing process).