For years, patients with persistent symptoms after Lyme disease have faced a frustrating question: if standard tests are normal and antibiotics have already been given, could the remaining fatigue, pain, brain fog and neurological symptoms simply be psychological?
A growing body of research from the Johns Hopkins Lyme Disease Research Center argues that this explanation is inadequate.
In a May 2025 review of its research, Johns Hopkins stated that persistent symptoms associated with Lyme disease have an “identifiable biological basis,” pointing to evidence involving brain changes, inflammation, autonomic dysfunction, immune abnormalities and other measurable differences in patients with post-treatment Lyme disease. (Hopkins Lyme Research Center)
The significance goes beyond semantics.
It changes the scientific question from:
“Are these patients really sick?”
to:
“What biological processes are keeping them sick—and how do we identify and treat them?”
Some Patients Remain Sick Even After Early Treatment
One of the strongest pieces of evidence comes from a prospective Johns Hopkins study led by Lyme Disease Research Center director John Aucott, MD.
Researchers followed 234 patients with well-documented, early Lyme disease who received prompt standard treatment, comparing them with 49 healthy controls.
Six to twelve months later, approximately 14% of the treated Lyme patients had persistent symptoms severe enough to impair their functioning, compared with 4% of healthy controls.
Those symptoms included fatigue, pain and cognitive difficulties. The researchers specifically evaluated functional impairment rather than merely asking whether someone occasionally felt tired or achy. (Hopkins Lyme Research Center)
The Lyme group was approximately five times as likely to meet the study’s combined symptom and functional-impact criteria for post-treatment Lyme disease.
That finding matters because these patients were not selected from ambiguous cases with uncertain histories. They began with well-characterized Lyme disease and received conventional treatment.
Yet a subset did not return to their previous health.
This condition is commonly referred to in research as post-treatment Lyme disease, or PTLD.
Brain Fog Is Becoming Measurable
One of the most important developments has come from neuroimaging.
Patients with persistent Lyme symptoms frequently describe difficulty concentrating, slower thinking, impaired working memory and a sensation commonly called “brain fog.”
Historically, symptoms like these have been difficult to validate because a routine MRI may appear normal.
Johns Hopkins neurologist Cherie Marvel, PhD, and colleagues used more sophisticated imaging techniques to examine what was happening inside the brains of patients with PTLD.
In a peer-reviewed PLOS ONE study, researchers compared 12 carefully characterized PTLD patients with healthy controls while participants performed a working-memory task during functional MRI.
The PTLD patients responded more slowly, although their accuracy was preserved.
Their brains also behaved differently.
Researchers found altered activation patterns during the cognitive task, including reduced activity in some expected brain regions and recruitment of additional regions that the researchers suggested could represent compensatory activity.
Diffusion tensor imaging also identified unusual findings involving frontal-lobe white matter. (PLOS)
The study was small and needs replication in much larger populations. It is not a diagnostic test for an individual patient.
But it provides something Lyme patients have often lacked:
objective evidence that cognitive symptoms can correspond with measurable changes in brain function and structure.
The Autonomic Nervous System May Be Part of the Story
Another emerging area involves dysautonomia—dysfunction of the autonomic nervous system.
The autonomic nervous system regulates processes we ordinarily do not consciously control, including heart rate, blood pressure, digestion, sweating and temperature regulation.
When it malfunctions, symptoms can include:
- dizziness and lightheadedness
- rapid heart rate after standing
- exercise intolerance
- gastrointestinal problems
- fatigue
- palpitations
- temperature dysregulation
- cognitive problems or “brain fog”
These symptoms overlap strikingly with complaints reported by some patients after Lyme disease.
Johns Hopkins researchers have subsequently studied this directly. In research involving PTLD patients, investigators found substantially elevated autonomic symptoms and identified a subgroup with abnormal heart-rate increases while standing. In a cohort of 210 PTLD patients undergoing a 10-minute active stand test, about 4.3% demonstrated orthostatic tachycardia, while autonomic symptoms more broadly were common. (Hopkins Lyme Research Center)
Researchers are still determining precisely how Lyme disease might lead to these abnormalities.
Possible mechanisms under investigation across infection-associated chronic illnesses include immune dysregulation, autoimmune responses, inflammation, nerve injury and other post-infectious processes. (Johns Hopkins University)
The important point is that dizziness, racing heart, fatigue or brain fog need not automatically be interpreted as anxiety simply because routine testing fails to explain them.
Persistent Pain Can Have an Objective Biological Correlate
Pain creates a similar diagnostic problem.
If a patient’s joints hurt but there is no obvious swelling during a brief office examination, it can be tempting to conclude that the pain has no identifiable biological source.
Johns Hopkins researchers report evidence that some people with persistent pain following Lyme disease have subtle ongoing joint inflammation detectable using musculoskeletal ultrasound, even when inflammation is not readily apparent by conventional examination. (Hopkins Lyme Research Center)
Again, this does not mean that every case of persistent pain after Lyme has the same cause.
It demonstrates that deeper investigation can uncover abnormalities that conventional assessments may miss.
Being Told “It’s Anxiety” Has Consequences
Perhaps one of the most revealing Johns Hopkins studies looked not at the bacteria or immune system, but at the experience of patients navigating the medical system.
Researchers studied 80 rigorously characterized patients with PTLD.
Approximately 51% reported that a healthcare provider had doubted that their illness was real, while nearly one-third reported being told that their condition was due entirely or substantially to psychological causes such as anxiety or depression.
Greater medical invalidation was associated with greater symptom severity, poorer quality of life and lower trust in physicians. (Hopkins Lyme Research Center)
This does not mean anxiety and depression are irrelevant.
Chronic illness can profoundly affect mental health.
A person who suddenly loses the ability to work, exercise, think clearly, sleep normally or participate in ordinary life may understandably develop anxiety or depression.
The critical distinction is between psychological symptoms occurring as part of chronic illness and assuming that psychological factors are the primary explanation for the entire illness.
Johns Hopkins researchers argue that the accumulating biological evidence makes the latter assumption increasingly difficult to defend. (Hopkins Lyme Research Center)
What This Research Does—and Does Not—Prove
Scientific credibility requires an important distinction.
Evidence that PTLD is biologically mediated does not automatically prove that every patient with persistent symptoms has an ongoing, actively replicating Borrelia infection.
Those are separate questions.
Researchers are investigating several potentially overlapping mechanisms, including:
- persistent immune activation
- inflammatory responses
- autonomic nervous system dysfunction
- changes in brain function
- residual microbial antigens
- tissue injury
- altered immune regulation
- metabolic and microbiome changes
- and, in some research models, questions surrounding microbial persistence
Different mechanisms may operate in different patients.
The Hopkins findings also do not establish that prolonged antibiotic therapy is appropriate for every patient with persistent symptoms.
What they do establish is something more fundamental:
Persistent illness following Lyme disease is a legitimate biomedical research problem.
The absence of an explanation on a standard laboratory panel does not mean the absence of disease biology.
Lyme Disease May Be Part of a Larger Post-Infectious Puzzle
Perhaps the most intriguing implication of this research is its resemblance to other infection-associated chronic illnesses.
Long COVID, ME/CFS and PTLD can share symptoms such as profound fatigue, cognitive dysfunction, exercise intolerance, sleep abnormalities, pain and autonomic problems.
Johns Hopkins researchers have explicitly raised the possibility that some of these conditions may share biological pathways involving inflammation, immune dysregulation or autonomic nervous system dysfunction. (Hopkins Lyme Research Center)
That creates an opportunity much larger than the Lyme field alone.
Instead of classifying patients solely by the infection that preceded their illness, researchers may increasingly be able to classify them by the biological systems that remain dysfunctional afterward.
One patient might primarily exhibit autonomic dysfunction.
Another might show abnormal immune signaling.
Another might have persistent neuroinflammation.
Another could have musculoskeletal inflammation.
And some may have several abnormalities simultaneously.
That approach could eventually transform both diagnosis and treatment.
The Next Question Is Not Whether Patients Are Sick
For decades, much of the Lyme debate has been consumed by terminology: chronic Lyme disease, post-treatment Lyme disease syndrome, persistent Lyme disease and other competing definitions.
Those debates are unlikely to disappear soon.
But the scientific center of gravity may be moving.
Advanced imaging can identify altered brain activity.
Ultrasound can uncover subtle inflammation.
Autonomic testing can identify physiological abnormalities.
Researchers are finding differences in immune activity, metabolism, microbiome composition and gene regulation.
And prospective studies show that a measurable subset of appropriately treated Lyme patients remain functionally impaired months later. (Hopkins Lyme Research Center)
The question therefore should no longer end with:
“Your standard tests are normal. Could this all be psychological?”
A more productive question is:
“What have we not yet measured?”
That distinction matters enormously for patients.
Validation alone is not a treatment. Biological abnormalities still have to become reproducible biomarkers, clinically useful diagnostics and ultimately effective therapies.
But recognition is the beginning of better science.
As the Johns Hopkins Lyme Disease Research Center puts it, meaningful progress starts with listening to patients. (Hopkins Lyme Research Center)
For people who have spent years being told that persistent fatigue, neurological symptoms, pain or cognitive dysfunction were simply “in their head,” the emerging research carries a straightforward message:
The symptoms deserve investigation. The biology deserves study. And the patient deserves to be taken seriously.
Telos Lyme provides research and educational information and does not provide individual medical diagnosis or treatment. Patients should discuss symptoms, testing and treatment decisions with qualified healthcare professionals.
