Brain Fog and Neuroinflammation: The PET Scan Evidence

At a Glance

Brain Fog Is Not in Your Head — It Is in Your Brain

If you have Lyme disease and brain fog, you have probably been told some version of “your scans look normal” or “this is probably stress-related.” Standard MRI and CT imaging typically appear unremarkable in Lyme patients with cognitive dysfunction, leading to the dismissal of a symptom that patients describe as one of the most disabling features of their illness.

What I tell my patients is that standard brain imaging is not designed to detect neuroinflammation. An MRI shows structure. A normal MRI tells you the structure looks intact; it cannot tell you whether the brain is inflamed, because the tool is not sensitive to that. The research that changed this conversation came from Johns Hopkins.

The Johns Hopkins PET Scan Study

Researchers at the Johns Hopkins Lyme Disease Research Center used [11C]DPA-713 PET (positron emission tomography), a specialized imaging technique that detects translocator protein (TSPO) expression on activated microglial cells, to image the brains of patients with post-treatment Lyme disease syndrome (PTLDS) [1].

What They Found

Compared to healthy controls, PTLDS patients showed significantly elevated TSPO signal in multiple brain regions, indicating widespread microglial activation and neuroinflammation. The key findings:

• Widespread glial activation across multiple brain regions, not limited to a single area
• Correlation with symptoms: the severity of neuroinflammation correlated with the severity of self-reported cognitive symptoms
• Persistence after treatment: the neuroinflammation was present in patients who had completed standard antibiotic therapy, suggesting that the inflammatory process continues beyond active infection

This was the first study to provide direct neuroimaging evidence that brain fog in Lyme disease has a measurable biological correlate: neuroinflammation that can be seen and quantified.

Why This Matters

The significance of this research cannot be overstated for patients who have been told their cognitive symptoms are psychological:

1. Validation: Brain fog in Lyme disease has an identifiable neurobiological mechanism visible on appropriate imaging. Patients who were told it is imagined, exaggerated, or stress-related now have evidence otherwise.
2. Treatment direction: If brain fog is caused by neuroinflammation, treatment should target the neuroinflammation as well as the infection.
3. Persistence explanation: The continued presence of neuroinflammation after antibiotic therapy explains why brain fog often persists even when other Lyme symptoms improve.

The Mechanism: How Neuroinflammation Creates Brain Fog

Microglial Activation

Microglia are the resident immune cells of the central nervous system. In their resting state, they perform surveillance and maintenance functions. When activated by infection, injury, or biotoxins, they transform into a pro-inflammatory phenotype that produces TNF-alpha, IL-1beta, IL-6, reactive oxygen species, and nitric oxide [2].

In Lyme disease, microglia can be activated by:

• Direct Borrelia invasion of the CNS (neuroborreliosis)
• Borrelia outer surface proteins crossing the blood-brain barrier
• Systemic inflammatory mediators reaching the brain through a compromised blood-brain barrier
• Reactivated viruses with CNS tropism (particularly HHV-6)

Neurotransmitter Disruption

Activated microglia alter the kynurenine pathway, the primary metabolic route for tryptophan (the amino acid precursor to serotonin). Inflamed brain tissue shunts tryptophan away from serotonin and toward quinolinic acid, a neurotoxic metabolite that:

• Overstimulates NMDA receptors (excitotoxicity)
• Depletes serotonin (contributing to mood dysfunction)
• Generates free radicals (oxidative neuronal damage)
• Impairs synaptic plasticity (reducing learning and memory)

This shift explains why Lyme patients with brain fog often also experience mood changes, sleep disruption, and anxiety: they share a common neuroinflammatory mechanism.

Impaired Cerebral Blood Flow

Neuroinflammation impairs cerebral autoregulation, the brain’s ability to maintain consistent blood flow across varying blood pressures. This is compounded by the autonomic dysfunction common in chronic Lyme patients, which further impairs cerebral perfusion.

SPECT (Single Photon Emission Computed Tomography) imaging in Lyme patients has consistently shown regional hypoperfusion (areas of reduced blood flow) in the temporal and frontal lobes. These regions handle memory, executive function, and processing speed, the cognitive domains that brain fog affects.

White Matter Changes

While standard MRI may appear normal, advanced MRI techniques (diffusion tensor imaging, DTI) have detected white matter abnormalities in PTLDS patients, suggesting disruption of the myelinated pathways connecting different brain regions. This is consistent with both direct inflammatory damage and HHV-6 infection of oligodendrocytes (the cells that produce myelin).

The Evidence

What We Know (Human Data)

The Johns Hopkins PET scan study (Coughlin et al.) represents the strongest direct evidence for neuroinflammation in PTLDS. Additional supporting evidence includes:

• SPECT imaging studies documenting cerebral hypoperfusion in Lyme patients (Logigian et al., Fallon et al.)
• Neuropsychological testing consistently demonstrating processing speed, working memory, and executive function deficits in PTLDS patients [3]
• CSF biomarker studies showing elevated inflammatory markers (CXCL13, IL-6, neopterin) in neuroborreliosis patients
• Cognitive improvement with anti-inflammatory treatment in multiple case series

The evidence is moderate: consistent across multiple modalities, but limited by small sample sizes and the absence of large multicenter trials.

What I See in Practice

In our clinical experience, brain fog is one of the most common complaints among our chronic Lyme patients. It is also consistently the symptom that persists longest, often remaining after joint pain, fatigue, and other systemic symptoms have improved.

What I observe in practice is that brain fog responds to a different treatment approach than the systemic infection. Anti-Borrelia therapy reduces the upstream trigger but often does not fully resolve the neuroinflammation. The patients who experience the most complete cognitive recovery are those who receive targeted neuroinflammation treatment in addition to antimicrobials.

I also observe that brain fog severity correlates strongly with two factors:

1. Duration of illness: patients sick for years have more entrenched neuroinflammation than those treated within months
2. Viral co-reactivation: patients with reactivated EBV and/or HHV-6 have significantly worse brain fog than those without viral reactivation

Practical Application

Diagnosing Neuroinflammation

Standard neurological workup (MRI, EEG, basic neuropsych) will typically be normal or mildly abnormal. More sensitive approaches:

• Neuropsychological testing: quantifies processing speed, working memory, and executive function deficits
• SPECT imaging: detects cerebral hypoperfusion patterns
• TSPO PET (research setting only, not widely available): direct neuroinflammation imaging
• CSF (cerebrospinal fluid) analysis, if lumbar puncture is clinically indicated: CXCL13, white cell count, protein, Borrelia antibody index

Treatment Strategy for Neuroinflammation-Mediated Brain Fog

1. Treat the upstream trigger

• Continue anti-Borrelia therapy
• Address viral co-reactivation (EBV, HHV-6)
• Address mold/CIRS if present
• Optimize the vagus nerve pathway to modulate neuroinflammation

2. Direct anti-neuroinflammatory therapy

• Low-dose naltrexone (LDN) 1.5-4.5mg nightly: evidence for microglial modulation in neuroinflammatory conditions
• Curcumin (bioavailable form): crosses the blood-brain barrier (BBB), inhibits NF-kB, reduces microglial activation
• Omega-3 fatty acids (high-dose EPA): precursors of specialized pro-resolving mediators that actively resolve neuroinflammation
• N-acetylcysteine (NAC): reduces oxidative stress and quinolinic acid-mediated excitotoxicity
• Palmitoylethanolamide (PEA): endogenous anti-neuroinflammatory lipid; 600mg twice daily

3. Neuromodulation approaches

• Transcranial Pulse Stimulation (TPS): single ultrashort acoustic shock-wave pulses, distinct from focused ultrasound. It is the neuromodulation approach we use most for neurological recovery, but the evidence is still emerging: a 2025 sham-controlled trial in Alzheimer’s disease did not meet its primary endpoint (PMID: 40009384)
• Vagus nerve stimulation: activates the cholinergic anti-inflammatory pathway
• PEMF therapy: evidence for reducing neuroinflammation and promoting neuronal recovery
• Neurofeedback: retrains brainwave patterns disrupted by chronic neuroinflammation

4. Cerebrovascular support

• Ginkgo biloba: evidence for improving cerebral perfusion (EGb 761 standardized extract)
• Vinpocetine: enhances cerebral blood flow and oxygen utilization
• Exercise: the most evidence-supported intervention for improving cerebral perfusion (start with vagus nerve exercises if autonomic dysfunction prevents traditional exercise)

5. Brain fog recovery timeline: set realistic expectations. Neuroinflammation resolves over months, not weeks.

Safety and Considerations

• Low-dose naltrexone is generally well-tolerated but should not be used with opioid medications. Start at 1.5mg and titrate to 4.5mg over 2-4 weeks.
• Not all brain fog is neuroinflammation. Sleep deprivation, medication side effects, hormonal dysfunction, nutritional deficiencies, and primary psychiatric conditions should be evaluated.
• Of the nutritional deficiencies worth evaluating, vitamin D deficiency is among the most consequential: calcitriol is a direct suppressor of microglial NF-κB signalling and is depleted at an accelerated rate in neuroinflammatory states. See our article on Vitamin D as a Neuroimmune Signal for protocol details.
• Neuropsychological testing provides objective measurement of cognitive deficits, useful both for diagnosis and for tracking treatment response.
• Brain fog recovery takes time. Patients should expect gradual improvement over 3-12 months, not rapid resolution. Neuroinflammation that has been present for years does not resolve in weeks.
• The PET scan findings from Johns Hopkins are promising but based on a small cohort. Larger replication studies are needed to confirm and expand these findings.

The Bottom Line

Brain fog in Lyme disease has a measurable neuroinflammatory basis that is visible on appropriate imaging and increasingly well understood. The Johns Hopkins PET research showed, in a small cohort, that microglial activation persists in PTLDS patients, providing biological validation for a symptom that patients have been told is “in their head.” Treatment must go beyond antimicrobials: targeted anti-neuroinflammatory therapy, neuromodulation, cerebrovascular support, and addressing viral co-reactivation are essential for cognitive recovery. In my clinical experience, patients who receive comprehensive neuroinflammation-directed treatment achieve significantly better cognitive outcomes than those treated with antimicrobials alone.