Brain Imaging Validates Cognitive Problems After Lyme Disease Brain Imaging Validates Cognitive Problems After Lyme Disease

New imaging data show distinctive brain changes that appear to explain memory and cognitive problems following Lyme disease.

Using fMRI and diffusion tensor imaging (DTI) techniques, investigators found changes in white matter and other brain tissues in patients with posttreatment Lyme disease (PTLD) in comparison with healthy control persons who did not have a history of the disease.

“It is important for clinicians to know that PTLD leads to real, quantifiable brain changes and that patients’ cognitive complaints may be a direct consequence of these brain changes, rather than a side effect of other symptoms, such as fatigue, for example,” lead author Cheri Marvel, PhD, associate professor of neurology and psychiatry and behavioral sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, told Medscape Medical News.

“I think if patients heard this, they might feel validated that there is a biologic basis for their persistent symptoms, even if there is no good way to treat the cognitive difficulties yet — and this may be analogous to what is being reported in infection-associated persistent illnesses, such as long-haul COVID,” said Marvel, who is associated with the Cognitive Neuropsychiatric Research Laboratory at Johns Hopkins.

The study was published online October 26 in PLOS ONE.

Unknown Mechanisms

PTLD is a “chronic illness consisting of persistent or recurrent symptoms” in people who have been treated for Lyme disease, the authors write. Research into this condition is “relatively sparse,” and the underlying mechanisms of brain changes that may affect cognition are “largely unknown.”

“We were motivated by the persistent complaints of cognitive difficulties by patients who have been treated for their Lyme disease, with a lack of data to explain the reason behind these symptoms,” said Marvel.

“It seemed logical to us that if there were cognitive and neurological symptoms involved, then the brain may reveal something about this. Then we could begin to connect the dots between the patient experience and the underlying mechanisms driving them,” she added.

Previous studies had pointed to brain abnormalities in patients with PTLD, such as an increase in the number of white matter hyperintensities, but these studies “took a broader view of the brain than our approach did,” she said.

The researchers compared 12 male and female adults with PTLD (mean age [SD], 45.16 [13.62] years) to 18 adult control participants (mean age, 47.01 [13.10] years) who underwent fMRI scanning. Twelve control persons (mean age, 45.33 [13.76] years) were included in the DTI analysis.

PTLD participants completed a 36-item post-Lyme questionnaire of symptoms (PLQS), and the researchers correlated clinical variables with multimodal MRI findings. All participants performed a short-term working memory task in the MRI scanner.

The researchers identified functionally defined regions of interest (ROIs) for each participant’s scan and used DTI to investigate the potential relationship between PTLD and white matter structural integrity.

“Surprising” Findings

On the memory task, the PTLD group responded more slowly (but no less accurately) in comparison with the control participants (F[1,27] = 60.9; P < .001; ηp = .34). The PTLD group also showed “general motor slowing,” the authors note.

The control persons were found to have fMRI activations — increased blood oxygen level–dependent (BOLD) signal associated with verbal working memory in the frontal lobe, the premotor cortex, the caudate, the thalamus, the inferior parietal lobe, and the superior cerebellum. The PTLD group also showed increased BOLD signal in the frontal lobe, the premotor cortex, the caudate, and the precuneus but less activity in the premotor cortex, the thalamus, and the inferior parietal lobe.

The results suggested that group differences in the memory task “were due to the PTLD group showing hypo-activation (or not activating at all) in brain regions normally associated with the task, even though their accuracy was normal,” the authors note.

Conversely, “novel” activated regions were observed in the PTLD group but not in the control group. Increased task-related activity was observed in PTLD participants in comparison with the control persons primarily in three white matter regions of the frontal lobe: BA8, BA9, and BA6.

DTI analyses found regions of task-related activation that overlapped with the activity found on fMRI.

Area of task-related activation (ROI) Overlap with white matter
Left BA8 25.00%
Left BA9 anterior 22.35%
Left BA9 posterior 24.46%
Right BA6 13.46%

Whole-brain DTI analyses identified several frontal lobe regions that had higher axial diffusivity in the patients with PTLD, which were correlated with longer duration of illness. This higher axial diffusivity “correlated with fewer cognitive and neurological symptoms.”

In particular, axial diffusivity in the BA9 anterior ROI “negatively correlated” with all three clinical measures.

Clinical measure Correlation P value
Total r(12) = -.76 .004
Neurologic r(12) = -.78 .003
Cognitive r (12) = -.81 .001

“We found that the brains of PTLD patients had been altered by the disease — specifically, white matter function increased while performing a cognitive task, which is unusual to observe with the MRI methods we used, and we did not see such activity in the healthy control group,” said Marvel.

“We then looked more closely at the white matter in the PTLD group, and we were very surprised to find that axon diffusion — or ‘leakage’ from the white matter, which is usually considered to be pathological — was associated with better cognitive and neurologic outcomes in the PTLD patients,” she added.

“This led us to speculate that white matter changes are a healthy response to Lyme disease’s effects on the brain,” she said.

State-of-the-Art Methodology

Commenting for Medscape Medical News, John Keilp, PhD, associate professor of clinical psychology (in psychiatry), Vagelos College of Physicians and Surgeons, Columbia University, New York City, called the work an “important, carefully executed study that expands upon earlier brain imaging studies of patients with PTLD.”

Although the sample size was small, “the authors used rigorous methods to diagnose and characterize their patients and used state-of-the-art brain imaging and analysis methods,” said Keilp, who heads the neuropsychology laboratory within the Division of Molecular Imaging and Neuropathology, New York State Psychiatric Institute, and was not involved with the study.

The authors “have shown us a way forward to examine these patients and this disorder in greater detail as we attempt to unlock the uncertainties surrounding the physiological basis of these patients’ symptoms,” he said.

Funding for the study was provided by an anonymous donor. The authors and Keilp report no relevant financial relationships.

PLoS One. Published online October 26, 2022. Full text

Batya Swift Yasgur MA, LSW is a freelance writer with a counseling practice in Teaneck, NJ. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).

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