Why can thinking feel harder, mental stamina shrink, and mood change long after an illness or other health disruption?

An immune response that remains active is one possible explanation. In a conversation on the FMP Essentials Show, Dr. Robert Rountree and Dr. Yousef Elyaman explore how inflammation outside the brain and stress within brain cells may contribute to a continuing cycle.

The important question becomes: what is still feeding that response?

The Brain Is Part of the Immune Conversation

When you get sick, immune cells release cytokines, signaling proteins that coordinate the body’s defenses. These signals can also influence the brain, helping explain why illness may leave you mentally drained, less motivated, or unusually low. Dr. Rountree describes these changes as “cytokine sickness.”

In a randomized study, healthy volunteers received either a small dose of bacterial endotoxin to temporarily activate inflammation or a placebo. Those receiving endotoxin reported greater depressed mood and feelings of social disconnection, demonstrating that immune activity can affect emotional experience.

The blood-brain barrier regulates movement between the bloodstream and brain tissue. Formed by specialized cells lining brain blood vessels, it provides protection while allowing essential communication. Immune signals can influence cells at this interface without an infection entering the brain.

The brain also has resident immune cells called microglia, which help detect threats, respond to injury, and clear debris. Together, these systems allow the brain to respond to what is happening throughout the body. This protective activity becomes a concern when it remains active or poorly regulated.

What If the Signals Keep Coming?

An acute illness provides a recognizable reason for immune activation. But ongoing inflammatory conditions may continue to generate signals, sometimes without the obvious symptoms of an acute infection.

Periodontal infections, gut disturbances, and persistent infections elsewhere in the body are among the potential contributors discussed in the episode. Several may coexist, creating multiple sources of immune stimulation.

Oral health deserves attention alongside gut health. Periodontal disease can persist for years, and bleeding gums or gaps in dental care may reveal an overlooked inflammatory source. In the ARIC study, severe periodontal disease was associated with a modest increase in dementia risk over long-term follow-up. This association does not establish that gum disease causes dementia or that treating it prevents cognitive decline.

Persistent symptoms may also involve changes in how the brain and body interact. A 2024 human imaging study found increased blood-brain barrier permeability in people with long COVID and brain fog compared with recovered participants and those with long COVID without brain fog.

These findings suggest that ongoing immune stimulation and altered blood-brain barrier function deserve investigation. They also raise another question: could stress within cells help sustain the response?

When Cellular Stress Adds Fuel

Mitochondria produce much of the energy cells need and participate in immune signaling. In the mechanism described during the episode, mitochondrial damage generates danger signals that can contribute to activation of the NLRP3 inflammasome.

An inflammasome is a protein complex that helps activate inflammatory cytokines. NLRP3 acts as a cellular danger sensor. When this pathway is activated, it promotes inflammatory signaling through cytokines including interleukin-1β and interleukin-18.

This creates a potential connection between impaired energy production and inflammation: cellular damage may promote immune activity, while continued inflammatory stress may further compromise cellular function.

Identifying an infection or another trigger may therefore explain how a response began without fully explaining why it continues.

What Helps the Response Resolve?

Reducing an inflammatory trigger and supporting recovery are related, but they are not necessarily the same task. An ongoing infection may need treatment, while disrupted sleep, chronic stress, and metabolic dysfunction may also require attention.

Sleep supports more than daytime energy. It is closely linked with the glymphatic system, which participates in fluid exchange and waste clearance in the brain. Poor sleep can also affect concentration and mood, adding to the symptoms that brought attention to brain health in the first place.

Chronic stress adds another layer. Allostatic load describes the cumulative physiological burden of repeated or prolonged demands on the body. Together with sleep disruption and other health problems, this burden may complicate recovery.

The original trigger may explain how symptoms began. Understanding what continues to challenge the body may help explain why they persist. These connections belong within a thorough evaluation, since cognitive and mood symptoms have multiple possible causes.

References

Eisenberger NI, Inagaki TK, Mashal NM, Irwin MR. Inflammation and social experience: An inflammatory challenge induces feelings of social disconnection in addition to depressed mood. Brain, Behavior, and Immunity. 2010. Article

Greene C, Connolly R, Brennan D, et al. Blood–brain barrier disruption and sustained systemic inflammation in individuals with long COVID-associated cognitive impairment. Nature Neuroscience. 2024;27:421–432. Article

Demmer RT, Norby FL, Lakshminarayan K, et al. Periodontal disease and incident dementia: The Atherosclerosis Risk in Communities Study (ARIC). Neurology. 2020;95(12)–e1671. Article