Article Central Autonomic Network Disturbance in People with ME: A Conversation with Dr. Mark Zinn

Central Autonomic Network Disturbance in People with ME:
A Conversation with Dr. Mark Zinn

Dr. Mark Zinn, along with his late wife Dr. Marcie Zinn, pioneered the use of advanced electro-encephalographic techniques to study myalgic encephalomyelitis. Image courtesy of Dr. Mark Zinn.

by Bronc

Dr. Mark Zinn and his late wife Dr. Marcie Zinn co-founded the NeuroCognitive Research Institute. He has expertise in quantitative and tomographic methods of electro-encephalographic analysis, in order to test theoretical premises in research involving neurocognitive disorders.

From 2011-2014 he served as research consultant at the Stanford University School of Medicine, where he studied cognitive impairment in infection-associated chronic diseases such as myalgic encephalomyelitis (ME).

In 2015, he and his wife went to work with Professor Leonard Jason at DePaul University. There they studied neuronal dysregulation within specific brain regions and brain systems, which contributes to brain network inefficiency in patients with ME.

Dr. Zinn’s ongoing research into the brain regions involved in the autonomic nervous system is an attempt to understand how brain dysregulation might underlie patient symptoms in people with neurocognitive diseases. He is the author of numerous research papers in the field of neurocognitive research.

Along with his wife, Dr. Zinn pioneered the use of advanced electro-encephalography (EEG) techniques in the study of ME. EEG is a non-invasive, inexpensive technique to record electrical brain activity using electrodes placed on the patient's scalp.

Specifically, he has used an advanced EEG analysis called exact low-resolution electromagnetic tomography (eLORETA), which produces three-dimensional images of electrical activity in the outer portions of the brain.

His latest research paper that he co-wrote with his late wife Marcie and Leonard Jason is the subject of the conversation below.

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Bronc:

How did you get involved in the field of myalgic encephalomyelitis research?

Dr. Mark Zinn:

I got involved in the research about 11 years ago, soon after my wife Marcie was diagnosed with herpes encephalitis. Fortunately, she came into contact with Dr. Jose Montoya at Stanford Medical Center and he diagnosed her with ME.​
He invited Marcie to be on the team for the newly formed Stanford ME/CFS Initiative to conduct a major research project involving quantitative EEG. I became involved in the project to help with analyzing the data using eLORETA, [which is] a three-dimensional analysis of EEG signals.​
The results were very promising and our presentation was well-received at the 2014 Stanford ME/CFS Symposium as well as the IACFS/ME Conference in San Francisco, where we first met Dr. Leonard Jason.​
Having finished our project at Stanford, Marcie and I decided to move to Chicago in 2015 to continue our work with Dr. Jason at DePaul University. I went on to get my PhD. in psychology with Dr. Jason as my mentor.​

Bronc:

ME is a disease of the central nervous system associated with neuroinflammation and dysfunction of the autonomic nervous system. There is a special need to understand the effects of physical activity on neurological processes in ME.
Your latest research examines the brain's central autonomic network (CAN) and its relationship to post-exertional malaise (PEM) in people with ME. Can you briefly explain what the "central autonomic network" is?

Dr. Mark Zinn:

The central autonomic network is a set of brain regions that work together in a tightly coordinated fashion to regulate our internal “steady state.” It is involved in everything you do throughout the day and night, controlling your body states by making adjustments like a thermostat.​
Depending upon momentary demands, it optimizes your blood circulation, heart rate, blood pressure, body temperature, digestion, sleep/wake cycle, cognition, and many other functions.​
Signs and symptoms of autonomic dysregulation include difficulty standing upright (orthostatic intolerance), debilitating fatigue, lightheadedness/ dizziness, nausea and GI symptoms, brain fog, irregular heartbeat, and shortness of breath.​

Bronc:
In your paper you note that a previous study of yours found abnormalities in brain regions that are part of the central autonomic network, thus implicating the central autonomic network as a prime target for further investigation. How does this relate to the main objective of your study?

Dr. Mark Zinn:

From the Stanford eLORETA study, we learned that certain brain regions with abnormal function were closely tied to autonomic function. The objective of the pilot study was to measure effects of physical exertion in the brain — but just targeting key regions known to be involved in maintaining and regulating the autonomic nervous system.​

Bronc:

How did you seek to measure post-exertional malaise in the participants of your pilot study?

Dr. Mark Zinn:

To study post-exertional malaise, we decided to record the participants’ EEG before and after performing moderately strenuous exercise involving a basic handgrip challenge.​
A defining aspect of PEM is that it often lasts 24 hours or more. So we had everyone come back the next day and measured their EEG again to assess for changes that might occur after a 24-hour period.​

Bronc:
Your study aimed to quantify the effects of physical exertion on central autonomic function in people with ME. What statistically significant findings did your study observe?

Dr. Mark Zinn:

In the patient group, we observed a significant reduction in brain activity immediately following the exercise and the reduction worsened after 24 hours. But in the control group, we observed a significant increase immediately after exercise, and a further increase after 24 hours.​
With the EEG, we were also able to look at brain rhythms and we found that certain frequencies predicted this change more than other frequencies.​
So, for example, frequencies involved in driving sensorimotor signaling during task performance predicted greater likelihood for autonomic dysregulation following exercise. Similarly, frequencies having to do with cognitive inhibition and attention also predicted greater likelihood for more autonomic dysregulation following exercise.​

Bronc:

In a previous pilot study, you found "support for all three networks of the triple network model, namely the central executive network (CEN), salience network (SN), and the default mode network (DMN) indicating hypo-connectivity [...] in patients with ME compared to controls."
How does hypo-connectivity in the triple network model relate to the CAN?

Dr. Mark Zinn:

There is some overlap of the CAN with regions of the three networks of the triple network model (DMN, CEN, SN) and the current study results could be interpreted from the perspective of these networks.​
As with the CAN, these three networks are involved in adapting our thoughts and behaviors to rapidly changing circumstances. Hypo-connectivity or disconnection of these networks suggests that the networks are unable to keep up with situational demands and there are fewer resources available to [compensate for] the effects of neuronal injury, possibly due to tissue loss.​
We see this pattern in patients with white-matter injury who may present a mixture of hyper/hypo-connected networks but when a critical threshold of tissue loss is reached, the networks become completely hypo-connected and there is significant loss of function.​
For example, in multiple sclerosis, we know that patients with visual and sensorimotor symptoms show a pattern of hypo-connectivity involving visual and sensorimotor regions.​
However, I would argue that disturbance to these networks is also partly due to underlying disturbance to central autonomic processing.​

Bronc:

If the findings of your study are confirmed by further research, how might this be of use to the diagnosis, treatment and understanding of ME?

Dr. Mark Zinn:

Overall reduced activation within the central autonomic network may serve as a neurobiological indicator for PEM, which is the most debilitating feature of this illness. Our research protocol could be used in the clinic for measuring subtle changes in brain function triggered by moderate exercise in order to capture features of PEM.​
In the ME research field, there has been a lot of mixed and contradictory findings, but there may be more agreement within the context of the central autonomic network.​
In addition, patients with severe ME may have a difficult time with performing maximal cardiopulmonary exercise tests, and this is a practical method that could be done on most patients, even at the bedside.​
Quantitative EEG adds sensitivity for confirming neurological aspects of PEM and monitoring treatment effectiveness over time. More research is needed to sort all the diagnostic and treatment implications, but these results are promising.​

Bronc:

What further actions are needed by public health authorities to help improve the life outcomes for people with ME?

Dr. Mark Zinn:

The healthcare system and general public need to be made aware of reasons for the wide-ranging autonomic symptoms reported by patients with ME. When there are no major indications on routine tests, patients are typically told there is nothing wrong, but there may be follow-up tests for autonomic dysfunction from post-viral/immune responses in the brain, resulting in extreme fatigue.​
People with ME may look fine on the outside while their body is failing to maintain steady-state on the inside. Objective findings of PEM validate the illness while demonstrating that worsening symptoms are due to an underlying neurological condition that needs to be taken seriously.​
There needs to be funding set aside for the intensive study of the central autonomic network in relation to nearly all aspects of this debilitating disease.​

Bronc:
Do you have plans for any future ME research that would follow up your study of the central autonomic network?

Dr. Mark Zinn:

I plan to make the CAN the main focus of my research, adding heart-rate variability as a peripheral autonomic measure to study mind-heart interactions.​
Our NIH grant application for conducting a much larger study on CAN functioning in ME was dismissed by the ME/CFS special interest panel, sadly. Getting funding has been difficult and this pilot study was done without any funding whatsoever.​
We've submitted another grant application to the NIH to study neurological factors in neuro-COVID symptoms in older and younger people, as well as adolescents. This will involve collaborations with researchers at Northwestern University and Lurie Children's Hospital in Chicago.​

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Learn more:

The research discussed is published here:

Mark Zinn, Marcie L. Zinn, Leonard A. Jason DePaul University, Central Autonomic Network Disturbance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Pilot Study, 2021-06-30, Neuro Regulation 8(2) 73-86.

Dr. Marcie Zinn was a dedicated researcher and advocate with ME. Tragically, she passed away unexpectedly on December 28, 2019, after the manuscript for this paper was completed.

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Bronc is a former historian who is active in his local ME support group. He enjoys interviewing scientists involved in ME research to help himself and others better understand their illness.
 
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Comments

To study post-exertional malaise, we decided to record the participants’ EEG before and after performing moderately strenuous exercise involving a basic handgrip challenge.A defining aspect of PEM is that it often lasts 24 hours or more. So we had everyone come back the next day and measured their EEG again to assess for changes that might occur after a 24-hour period.
In the patient group, we observed a significant reduction in brain activity immediately following the exercise and the reduction worsened after 24 hours. But in the control group, we observed a significant increase immediately after exercise, and a further increase after 24 hours.
Overall reduced activation within the central autonomic network may serve as a neurobiological indicator for PEM, which is the most debilitating feature of this illness. Our research protocol could be used in the clinic for measuring subtle changes in brain function triggered by moderate exercise in order to capture features of PEM.
In addition, patients with severe ME may have a difficult time with performing maximal cardiopulmonary exercise tests, and this is a practical method that could be done on most patients, even at the bedside.
I think what people find most interesting about this work is the possibility that it could be used to develop a cheap, safe, and objective test to detect the presence of both physical and cognitive PEM. Such a test could become part of a more comprehensive diagnostic strategy.

Although the 2-day CPET is a very important tool, it's not perfect: it only looks at physical impairment, and can be dangerous for people with severe ME.