In their recent study published in PLOS ONE, Dr. John Aucott and Cherie Marvel found that unexpected white matter activity in the brain, a symptom normally considered pathological, was found to be correlated with better outcomes in patients with post-treatment Lyme disease (PTLD).
PTLD occurs in patients who have received treatments for Lyme disease but have yet to fully recover. Persistent complaints about cognitive difficulty are one of the symptoms.
Aucott is an associate professor in the Division of Rheumatology at the School of Medicine. He is also the director of the Lyme Disease Clinical Research Center and a clinical-translational researcher in Lyme disease with a focus on PTLD.
He stressed that PTLD affects 10% to 20% of patients who were previously diagnosed with and treated for Lyme disease in an interview with The News-Letter.
“Post-treatment Lyme disease is not a trivial problem. It is a problem that should be noticed,” he said.
Marvel is a cognitive neuroscientist and an associate professor of Neurology at the School of Medicine. She has been using brain imaging methods to look at different cognitive and motor functions, primarily in clinical populations.
In an interview with The News-Letter, Marvel noted that the complaints of PTLD patients did not align well with the standard cognitive or neuro-psychological testing.
“So we thought we should look inside the brain. The way we can do that non-invasively is through functional MRI,” she said.
Participants were asked to perform working memory tasks while their brain activity was recorded by functional magnetic resonance imaging (fMRI). fMRI measures brain activity by detecting increased oxygen level in areas of activation.
Aucott highlighted that the decision to use an fMRI test for the study was intentional.
“The mystery behind post-treatment Lyme disease is whether there is something biological going on. Tests that are normally available to clinicians, such as regular MRI or CT, scans can’t identify these,“ he said. “So we hypothesized that stress tests under fMRI would be more sensitive to any biological changes.”
All participants performed two tasks. The easier task, which was the control condition, required participants to remember two letters for a short duration. After, the screen would show a new letter, and the participant would need to evaluate whether it was one of the two letters previously shown.
The harder task, which was the experimental condition, required participants to count two alphabetical letters forward of the same two letters and remember the new letters. Then, they were asked if a newly-appeared letter was one of the two new letters.
Marvel explained the reason for choosing this experimental design.
“Doing this allowed us to control for variables such as visual stimuli, so the net effect was just the cognitive aspect of holding and manipulating information in mind,” she said.
With fMRI, the researchers found expected brain activity in the gray matter. Surprisingly, the fMRI also detected unusual activity in the white matter, which was not in their original hypothesis.
The central nervous system, responsible for cognitive functions, consists of two types of tissue: the gray matter and the white matter. Cells in the gray matter have larger neuronal bodies that are specialized for processing electrical signals from all parts of the body. Cells in the white matter have longer axons, which are specialized for communicating signals between gray matter.
According to Marvel, the researchers decided to further examine the unexpected finding.
“It was already one year into the study. We kept detecting white matter activity; we thought it was an accident initially. We eventually decided to add [diffusion tensor imaging] (DTI), a special MRI sequence that looks more closely at white matter activities such as leaking,” she said.
The researchers discovered axial diffusivity in the white matter where the fMRI detected activation signals. In axial diffusivity, water leaks along the axon, which is a part of neurons that relay electrical signals to each other. They also found that increased axial diffusivity was correlated with better outcomes and fewer symptoms in patients, which was surprising to the team.
Aucott described that axial diffusivity would normally be considered pathological. However, in in this case, it seemed to be the body’s compensatory response to maintain slower but accurate cognitive functions in patients with PTLD.
“It is like a positive response to an injury. Just like how our immune system responds to infections, our brain is trying to repair itself from this insult,” he said.
The finding on white matter axial diffusivity corresponds with patients’ complaints about slow mental processes and “brain fog.” White matter is the bridge that helps gray matter communicate. Leakages in white matter prevent neuron communication from proceeding as quickly and fluidly as it should.
Cognitive complaints in PTLD resemble those observed in people with chronic fatigue and long-haul COVID. Further research can explain the shared influences of these infection-related chronic illnesses on cognitive functions.
Marvel emphasized that the researchers want to continue their work by following patients longitudinally to examine the temporal onset of white matter axial diffusivity and its changes over time. They are also interested in looking for markers of inflammatory activities through cerebrospinal fluid samples.
“Participants in this study had post-treatment Lyme disease symptoms for a while, so we don’t know at what point in their illness the white matter changes happened,“ she said. “We want to understand the development of white matter axial diffusivity and how it is shown the symptoms.”
