Brainstem Reduction and Deformation in the 4th Ventricle Cerebellar Peduncles in Long COVID Patients, 2025, Christof et al

https://www.medrxiv.org/content/10.1101/2025.04.08.25325108

Abstract
Post-COVID Syndrome (PCS), also known as Long COVID, is characterized by persistent and often debilitating neurological sequelae, including fatigue, cognitive dysfunction, motor deficits, and autonomic dysregulation (Dani et al., 2021). This study investigates structural and functional alterations in the brainstem and cerebellar peduncles of individuals with PCS using diffusion tensor imaging (DTI) and volumetric analysis.

Forty-four PCS patients (15 bedridden) and 14 healthy controls underwent neuroimaging. Volumetric analysis focused on 22 brainstem regions, including the superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP), periaqueductal gray (PAG), and midbrain reticular formation (mRt).

Significant volume reductions were observed in the SCP (p < .001, Hedges’ g = 3.31) and MCP (p < .001, Hedges’ g = 1.77), alongside decreased fractional anisotropy (FA) in the MCP, indicative of impaired white matter integrity. FA_Avg fractional anisotropy average tested by FreeSurfer Tracula, is an index of white matter integrity, reflecting axonal fiber density, axonal diameter and myelination.

These neuroimaging findings correlated with clinical manifestations of motor incoordination, proprioceptive deficits, and autonomic instability. Furthermore, volume loss in the dorsal raphe (DR) and midbrain reticular formation suggests disruption of pain modulation and sleep-wake cycles, consistent with patient-reported symptoms.

Post-mortem studies provide supporting evidence for brainstem involvement in COVID-19. Radtke et al. (2024) reported activation of intracellular signaling pathways and release of immune mediators in brainstem regions of deceased COVID-19 patients, suggesting an attempt to inhibit viral spread. While viral genetic material was detectable, infected neurons were not observed.

Matschke et al. (2020) found that microglial activation and cytotoxic T lymphocyte infiltration were predominantly localized to the brainstem and cerebellum, with limited involvement of the frontal lobe. This aligns with clinical observations implicating the brainstem in PCS pathophysiology. Cell-specific expression analysis of genes contributing to viral entry (ACE2, TMPRSS2, TPCN2, TMPRSS4, NRP1, CTSL) in the cerebral cortex showed their presence in neurons, glial cells, and endothelial cells, indicating the potential for SARS-CoV-2 infection of these cell types.

Associations with autoimmune diseases with specific autoantibodies, including beta-2 and M-2 against G-protein coupled alpha-1, beta-1, beta-2 adrenoceptors against angiotensin II type 1 receptor or M1,2,3-mAChR, among others, voltage-gated calcium channels (VGCC) are known (Blitshteyn et al. 2015 and Wallukat and Schminke et al. 2014).

These findings support the “Broken Bridge Syndrome” hypothesis, positing that structural disconnections between the brainstem and cerebellum contribute to PCS symptomatology. Furthermore, we propose that chronic activation of the Extended Autonomic System (EAS), encompassing the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system, may perpetuate these symptoms (Goldstein, 2020).

Perturbations in this system may relate to the elevation of toxic autoantibodies AABs (Beta-2 and M-2), specific epitopes of the COVID virus’s SPIKE protein and Cytokine storm of IL-1, IL-6, and IL-8 in their increased numbers (1,000->10,000)

Further research is warranted to elucidate the underlying neuroinflammatory mechanisms, EAS dysregulation, and potential therapeutic interventions for PCS.

Paragraphs added for readability.

 

They could have done with some proof reading of this paragraph.

I am not sure why changes in the cerebellum should have anything to do with autoantibodies.

 

These kind of studies and hypotheses are intriguing to me because this could also possibly explain why CCI/AAI surgery produces remission in some and possibly why LDA ie partial dopamine agonists significantly help others since the cerebellar peduncles play a very important role in the brain’s dopaminergic system.

 

The volume reduction in the SCP seem significant enough that you'd have expected it to be picked up in a previous study. Perhaps it has been.

 

Well there is this study, which found the exact opposite:

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1125208/full

All the volumes for different parts of the brainstem (including SCP) were lower than healthy controls.

 

Here's the thread for that paper:

Brainstem volume changes in myalgic encephalomyelitis/chronic fatigue syndrome and long COVID patients (2023, Frontiers in Autonomic Neuroscience)

 

The HCs in that study had lower SCP volumes than the LC patients in the above study (who had much lower SCP volumes than their controls). Not sure how that could happen.

 

That is odd. SCP in HC is over 50% larger in this study.

Study ____| Long COVID | HC
Christof __| 219.74 ______| 347.03
Thapaliya | 292.27 ______| 217.10

Sources:

 

Maybe it shows just how careful we have to be about interpreting these studies. I would need quite a lot to persuade me that volumes of brain areas were telling us something important about ME/CFS.

 

I agree, but also this study and possibly others found probable white matter track damage in these brain areas as well via fractional anisotropy DTI measurements.

 

Long COVID individuals found to have a disruption in the critical brain bridge linking the brainstem and cerebellum - Thailand Medical News

https://www.thailandmedical.news/ne...n-bridge-linking-the-brainstem-and-cerebellum

 

I'd like to share some info that made my spidey-sense tingle.

This study is associated with the German Prof Stark Institute. Actually this is what made me look this topic up, as recently this place has started popping up in my group as groundbreaking ME/CFS experts. Some hype is growing around them.

Here is the website. This is a private clinic for treating stress and fatigue. Prof Stark himself is a psychiatrist, specialising in psychosomatic medicine. (Although he personally was not involved in the research in this thread.)

Here is an excerpt from the website to get an idea about what they do (translated by Google):

The info about ME/CFS on their website sounds very compassionate and mentions that the disease is not taken seriously by doctors and they misdiagnose it as somatization etc. And they also mention their research about finding a biomarker.

He has some other websites where you can find more info about his self-help treatment program, like https://www.prof-stark-fatigue-zentrum.de/online-selbsthilfe or https://mind-and-health.com/cfs/

It is mostly brain retraining:

There is also a paywalled article in German media about their research, the one in this thread. I cannot access it due to the paywall but the text was posted in my group and also posted on the CFS subreddit. I'm going to just copy the English version from the subreddit here so you can see:

As you can see, there are lots of big words here, groundbreaking research, breakthrough, international sensation, whatnot. We are talking about a paper posted on a preprint server and they are calling the preprint server prestigious, as if posting it there was a huge achievement.

As I said, my spidey-sense is tingling.

 

I found some stuff about the Energy Barrel thingy here:
https://prof-stark.com/praxis-prof-dr-stark-2-2-2/prof-dr-stark-e/prof-stark-method/energiemodelle/

There is a lot of stuff on that site, to the point that it probably warrants a thread of its own if we don’t have one already.

 

I think I had an account pushing some “prof stark” stuff follow me on bluesky but I didn’t really have the energy to check what it’s all about.
Urgh.

It sounds especially ridiculous to me for some reason given the name. Like “stark” in german means “strong”.

So it’s like the “Prof Stark Methode”, the “professor strong method”. Sound like something out of a cartoon.

 

https://archive.ph/ea6sQ

Hundreds of thousands of people affected by long-term COVID-19 in Germany alone are pinning all their hopes on research, as there are currently no approved medications or even a cure. This is especially true for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the most severe form of long-term COVID-19 . Hope now comes from a small team of researchers at the Professor Stark Institute at Schlump Hospital in Hamburg-Eimsbüttel.

Specifically, it concerns a study that has already been published in advance due to the significant national and international interest. The Hamburg scientist Dr. Christof Ziaja, who led the study, calls it a "breakthrough." "Based on the findings we have gained, we believe we have found a biomarker that essentially proves the clinical picture," says the 49-year-old. This finding is "groundbreaking," especially given that many affected individuals are suspected of having a mental illness .

Post Covid: What the results of the Hamburg study mean for those affected
In an interview with the Abendblatt, Dr. Ziaja explains how the study is structured, what was discovered and what the new findings mean for those affected.

Hamburger Abendblatt: How was the study designed, and what was the initial hypothesis?
Dr. Christof Ziaja: Initially, we essentially wanted to replicate a previously completed study at Stanford University. This study examined patients using a so-called functional MRI – a special and rare scanner that can reveal more changes than a conventional MRI. Since the UKE has such a device, we wanted to take a closer look at it to better understand the disease. The findings we obtained were, in a sense, not based on any theory. It was a purely incidental finding.

What did it look like specifically? What did you see?
In the 90 patients, some of whom were severely affected and bedridden, whom we examined repeatedly over several years using functional MRI, I initially believed the imaging was a visual error. But that wasn't the case. As the disease progressed, we saw that a certain part of their brain had shrunk massively. I immediately discussed this with my colleagues at Stanford University, and they also saw what I had found. From then on, we worked closely together.

Brain parts that disappear? That sounds very threatening
Specifically, it involves a connection between the brain stem, the cerebellum, and the cerebral medulla, the so-called fourth ventricle, which is relevant for essential things like recovery, sleep-wake rhythm, heartbeat, vitality, and much more. This connection—a kind of bridge (the roof of the so-called rhomboid fossa)—is, in a sense, broken in those affected. And that explains many symptoms. For example, the fact that patients can no longer recover and wake up completely exhausted in the morning. These new findings naturally concern us. But that's not all. Because we can derive a lot from this knowledge that helps us understand the disease. It's basically like a biomarker that proves: This is an organic finding, not psychological.

Is there any clarity about what triggers this process?
Clarity is still lacking, but we're understanding more and more. We currently assume that spike proteins of the coronavirus cause the immune system to produce toxic autoantibodies that drive inflammatory processes in the cerebrospinal fluid. We also found this fluid in the affected brain regions. The study authors further assume that the changes we also observed in the so-called white matter may be associated with damage along the nerve fiber tracts.

What is the significance of the study results?
The significance is enormous. Many researchers, including myself, have been arguing for years against those who still claim the disease doesn't exist. In light of the current findings, I've even had doctors approach me and say, "You're right. We can now understand it." In professional circles, ME/CFS is now referred to by many as an 'MS-like disease,' meaning a condition similar to multiple sclerosis. This condition, too, is not yet fully understood, but it is recognized, and there are treatments available.

Medication is the key word. Hundreds of thousands of patients are waiting for it in Germany alone. Can your findings advance the search for suitable medications?
Absolutely. We've made a huge step forward. And this new insight is important for drawing parallels to other, broadly similar diseases that are treatable with medication. The list of potential off-label medications is long. Now we know more precisely what we're looking for.

What happens next?
Following the preliminary publication on the renowned portal medRxiv, which is operated by Yale University, among others, we now plan to officially complete and present the study soon. We essentially have all the relevant data, but to meet scientific criteria, the control group of healthy individuals needs to be larger. We expect this to happen in the summer. Before then, however, I will be presenting our study at specialist conferences. For example, in May I'm invited to speak at the ME/CFS Conference 2025 in Berlin.

 

I have to say that at this point, I'm going to ignore anyone who even so much as uses the word 'hope' in this context. In the rare possibility where it's used correctly, it probably still works 99% of the time anyway. I don't think I've ever once seen a relevant use of it. And I'm aware that OMF uses it as a tagline.

We need answers and solutions, not hope. Hope can feck off, it's almost always hype anyway.