By Laurel White
Dane Cook has spent decades studying diseases some believe don’t even exist.
Those diseases, which fall under the medical community’s broad category of “chronic multisymptom illness,” include fibromyalgia, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), Gulf War Illness, and — a new addition to the pack — long COVID.
“Most of these diseases have lived in the shadows for a long time,” says Cook, a professor in the School of Education’s Department of Kinesiology.
Cook says the primary reason for skepticism surrounding this particular group of illnesses comes down to the lack of a specific biomarker for each. A biomarker is a measurable substance that indicates the presence of a disease, infection, or environmental exposure. Cook says all of the diseases he, his colleagues, and his students study in his labs have biomarkers — including changes to the immune system, organs, gut, and central nervous system — but the problem is, they aren’t specific enough.
“For many physicians, these conditions are clinically indistinguishable,” he says.
But for individuals who have been diagnosed with diseases like ME/CFS, fibromyalgia, Gulf War Illness, and long COVID, the symptoms are very real.
People suffering from ME/CFS report extreme exhaustion after physical or mental exertion, memory loss, and joint pain. Fibromyalgia symptoms include constant, dull, full-body aches. Veterans with Gulf War Illness report persistent pain, fatigue, and difficulties with concentration and memory that greatly interfere with their day-to-day lives.
The social stigma of these conditions is also formidable.
A 1992 study published in Medical Anthropology Quarterly found 90% of self-diagnosed chronic fatigue syndrome patients reported negative and delegitimizing experiences with physicians. And a 2005 study in Psychology & Health outlined how doubt and lack of support following diagnosis can fracture personal relationships with loved ones.
As the co-director of the Exercise Psychology Laboratory in the School of Education’s Department of Kinesiology and director of the Exercise Science Laboratory at the William S. Middleton Memorial Veterans’ Hospital in Madison, Cook is leading work aimed at deepening the scientific community’s understanding of these illnesses.
Creating a better picture of brain health in chronic multisymptom illness
In high school, Jacob Ninneman was captain of the football team. As an undergraduate studying kinesiology at UW–Madison, he was an offensive lineman for the Badgers. And after graduation, during what he calls a “gap year,” he worked as a strength and conditioning coach. During each of these eras, he saw a fair number of head injuries.
“I’d seen some times when concussion care wasn’t the best,” Ninneman says. “So I asked myself, ‘Do I want to contribute to continuing this system? What can I do to improve it?’”
So he returned to UW–Madison to begin a master’s program in kinesiology. He joined Cook’s lab and set out to advance scientific understanding of brain health. Specifically, he wanted to study how head injuries might lead to negative behaviors later in life, and how physical activity might mitigate some of those consequences.
“My interests have since broadened and revolve around using neuroimaging to understand behavior in chronic multisymptom illnesses,” Ninneman explains. “But I have maintained a focus on how lifestyle factors, such as being physically active, might work as a treatment for some of these illnesses.”
In layperson’s terms, Ninneman’s research revolves around doing a lot of imaging scans of the brain, particularly brains of people with chronic multisymptom illnesses. Through those scans, he hopes to build a better, more comprehensive understanding of brain composition — grey matter and white matter — and function.
“The big goal is to combine all of those different metrics into a singular model to better understand brain health,” he says.
In 2022, Ninneman published a study in the journal JNeurosci that found Gulf War veterans who experience chronic pain have larger pain-processing regions and smaller pain regulation regions in their brains than their healthy peers. The finding — which shows pain symptoms are associated with the structure of the central nervous system, rather than issues with nerves or pain receptors — could help researchers create more effective pain treatments.
For his dissertation, which he hopes to complete this year, Ninneman is comparing brain inflammation after exercise in individuals who have self-diagnosed with a number of chronic multisymptom illnesses.
Cook says Ninneman’s approach is a promising model for better understanding these illnesses.
“We’re hoping to find out if neuroinflammation is one of the reasons people with these conditions feel worse after exercise,” Cook explains. “There’s evidence that there’s dysregulation in multiple systems when people suffer from these conditions, and we think the throughline is inflammation.”
Ninneman says his motivation to enter academia to improve health and the lives of others has, in some ways, already been achieved.
“In the scientific community, we have understood these illnesses for a long time, but many individuals don’t know about them,” he says. “It’s almost gratifying for people suffering from these illnesses to see what they’re experiencing is normal. They have this moment of, ‘Holy cow, someone understands me.’ It’s good to be able to provide that.”
Bringing passion for veterans’ health to study of Gulf War Illness
Doctoral student Alex Boruch’s motivation to study chronic multisymptom illnesses is deeply personal. Boruch’s father, a veteran, suffered from severe health challenges following his deployment, as did many of the men in his unit.
“I’ve always been really passionate about veterans’ health,” Boruch says. “Seeing the consequences of deployment, that was really eye opening for me. A lot of these people are really stoic. The training is to push through.”
Boruch’s research in Cook’s lab focuses on Gulf War Illness. Specifically, he aims to increase understanding of the roots and effect of the disease in the body, also known as its pathophysiology. He hopes to better understand that pathophysiology by bringing insight from the field of epigenetics. Epigenetics studies how environmental exposures — like Gulf War veterans’ exposure to sarin gas, for example — can affect how genes are expressed.
For his master’s thesis, Boruch researched how exercise may affect gene expression and symptom responses in Gulf War Illness. He found that vigorous exercise induced change in gene expression in the body’s inflammatory and adrenal systems, but that gene expression alone does not explain the sharp uptick in symptoms after exertion.
He has continued that work, recently publishing a study in the journal Brain, Behavior, and Immunity on the responses of symptoms and inflammatory markers to different doses of exercise in Gulf War veterans. He was also involved in a study of brain, autonomic, and behavioral interactions when veterans experience extreme fatigue after physical exertion, and an effort to better understand symptom burden for the illnesses before and after exercise.
Boruch says the wide range of approaches to chronic multisymptom illnesses in Cook’s lab, from investigating brain composition and function to epigenetics and much more, creates a rich and exciting scientific environment.
“It’s such a wealth of data we have access to, it builds this comprehensive view of these conditions,” he says. “It’s a unique opportunity for our lab, and it culminates in a great opportunity for better scientific understanding of these illnesses.”
Surge in long COVID research funding shines a light on other illnesses
For the community of researchers studying chronic multisymptom illnesses, the emergence of long COVID has been hugely important.
Cook says he, his colleagues, and his students have seen a surge in research funding opportunities available from organizations including the U.S. Department of Veterans Affairs and the National Institutes of Health. Those organizations and many others are keenly interested in unearthing answers about long COVID, which is similar in complexity and scope to the multisymptom illnesses Cook has studied for years.
“Unfortunately for the world, COVID is here,” Cook says. “But for other chronic multisymptom illnesses, because the United States has invested in long COVID research, our hope is that it will help us better understand those other illnesses.”
Ninneman calls it a “blossoming of opportunities.”
“It’s almost reinvigorated the interest in other chronic multisymptom illnesses, like chronic fatigue syndrome, which is researched less often,” he says. “It’s brought more attention to it.”
Cook says he and other senior scholars in the chronic multisymptom illness research community have taken it upon themselves to offer advice, support, and hard-won lessons to less experienced researchers entering the field.
“We want the long COVID researchers to not make the same mistakes we’ve made over the years studying chronic multisymptom illnesses — we want to keep the national consciousness about it up,” he says.
Acknowledging the darkness of the pandemic and all it inspired, Cook says the potential to learn more about chronic multisymptom illnesses is an emergent silver lining. Research breakthroughs enabled by a surge in public interest, public support, and plentiful funding could benefit millions of people suffering from debilitating and marginalized illnesses.
“We’re going to learn so much,” Cook says.
And it’s time to shine a light.