By The Functional Medicine Report™

Originally published September 11, 2026 in Issue #009 of The Functional Medicine Report™

An Australian MRI study found a possible signal of altered brain clearance in ME/CFS. It tracked sleep disturbance and impaired concentration, but not fatigue severity. That distinction may matter more than the headline.

Key Takeaways

• In a small Australian study, 31 people with ME/CFS had a lower average DTI-ALPS index than 27 healthy controls.
• Lower values were associated with worse self-reported sleep disturbance and impaired concentration, but not fatigue severity.
• DTI-ALPS measures water-diffusion patterns. It does not directly show waste accumulation or establish the cause of ME/CFS.
• The study did not validate a diagnostic test or evaluate a treatment.
• The immediate practitioner takeaway is to assess symptom patterns, distinguish sleep from restoration and protect patients from post-exertional worsening.

The most revealing result in a new study of chronic fatigue may be the one its name makes easiest to overlook.

Researchers at Griffith University’s National Centre for Neuroimmunology and Emerging Diseases compared brain scans from 31 people with myalgic encephalomyelitis/chronic fatigue syndrome and 27 healthy volunteers. They found a lower MRI-derived index thought to reflect activity along the brain’s perivascular waste-clearance pathways.

Within the ME/CFS group, lower values were associated with worse sleep disturbance and impaired concentration.

They were not associated with fatigue severity.

That does not mean researchers have discovered a blocked brain-cleaning system behind ME/CFS. The study did not establish a cause, identify material accumulating in the brain, create a diagnostic test or point to a treatment. The imaging method itself is still being debated.

But it does sharpen a question patients have been describing for years: What if the problem is not simply being tired, sleeping poorly or struggling to think clearly, but failing to recover from the demands of being awake?

For functional medicine, that is an intriguing possibility. For now, it remains exactly that: a possibility worth following.

THE FINDING INSIDE THE FINDING

The study, published in Frontiers in Neuroscience in June 2026, used diffusion tensor imaging analysis along the perivascular space, known as DTI-ALPS. The technique looks at the direction of water diffusion in small regions of deep white matter. Higher values are generally interpreted as more efficient movement along perivascular pathways; lower values may suggest impairment.

The global DTI-ALPS index averaged 1.44 in the ME/CFS group and 1.51 among healthy controls, a difference that remained statistically significant after correction for multiple comparisons.

When researchers looked at the two sides of the brain separately, the right-sided index was lower in the ME/CFS group while the left-sided difference was not statistically significant. That finding is interesting, but not enough to support the idea that ME/CFS is somehow a right-sided brain-clearance disorder. The study’s formal measure of asymmetry did not differ significantly between groups, and the investigators could not explain the lateralization.

The symptom findings were more compelling.

Among participants with available symptom data, lower global DTI-ALPS values were moderately associated with worse sleep disturbance and impaired concentration. They were not associated with reported fatigue, illness duration, pain, physical function or a broader measure of cognitive impairment.

The concentration finding also came from a simple self-reported symptom rating rather than formal neuropsychological testing. Calling it proof that the scan measured “brain fog” would go farther than the study did.

The signal may still matter. Its meaning is simply narrower than the most exciting version of the headline.

The most interesting finding in a chronic fatigue study may be what did not track with fatigue.

THE BRAIN’S OTHER CIRCULATION

The brain produces metabolic waste while doing the work of thinking, sensing, regulating and keeping the body alive. Unlike most tissues, it does not contain a conventional lymphatic network running through the brain itself.

Research over the past decade has helped describe another route. Cerebrospinal fluid moves along spaces surrounding blood vessels, exchanges with fluid between brain cells and appears to participate in the movement and removal of solutes from brain tissue. Because glial cells and lymphatic-like clearance are involved, researchers began calling this the glymphatic system.

The metaphor that followed was irresistible: sleep helps the brain clean itself.

The biology is more complicated.

A landmark 2013 mouse study found greater cerebrospinal-fluid exchange and faster beta-amyloid clearance during sleep or anesthesia than during wakefulness. A 2024 mouse study using a different method reported the opposite, finding reduced clearance during sleep and anesthesia. The apparent disagreement may reflect differences in tracers, measurement methods and even what researchers mean by “clearance.”

Human evidence is also still developing. In 2024, investigators followed contrast material through perivascular channels in five patients already undergoing neurosurgical treatment for brain tumors. The study offered unusually direct evidence that cerebrospinal fluid can move through these pathways in the living human brain. It did not tell us how efficiently this system clears waste in healthy people, how it behaves in ME/CFS or whether changing it would improve symptoms.

The Australian ME/CFS study was even more indirect. It did not follow a tracer, scan glymphatic function during sleep or measure the removal of a specific waste product. It measured water diffusion during a standard MRI and used that pattern as an estimate of what might be happening around perivascular spaces.

That difference matters.

THE SCAN IS NOT THE SYSTEM

DTI-ALPS is appealing because it can be calculated from non-invasive diffusion MRI without placing contrast into the cerebrospinal fluid. Researchers have reported group differences using the technique in several neurological and systemic conditions, and it has increasingly been described as a possible marker of glymphatic function.

“Possible” is the important word.

The index depends on assumptions about the direction of white-matter fibers, small vessels and surrounding spaces. In 2025, researchers using high-resolution diffusion data showed that crossing fibers, axonal shape and other features of white-matter anatomy can influence the ALPS measurement.

Then, in 2026, a Radiology study compared DTI-ALPS with a more direct contrast-enhanced MRI method that followed cerebrospinal-fluid tracer movement over 48 hours. DTI-ALPS could distinguish participants with idiopathic normal-pressure hydrocephalus from reference participants, but it did not closely match the brain-wide tracer measures.

That does not make the ME/CFS result meaningless. The scans may still be detecting something important about perivascular dynamics, white-matter structure, vascular physiology or some combination of those processes.

It does change what the result can honestly be called.

A lower ALPS index is an imaging signal. It is not a picture of waste trapped in the brain.

WHY UNREFRESHING SLEEP MAY BE THE BIGGER CLUE

ME/CFS is often reduced to its most recognizable symptom: fatigue.

The actual syndrome is much more specific. The IOM/NAM criteria summarized by the CDC require a substantial loss of pre-illness function lasting more than six months, fatigue that is not substantially relieved by rest, post-exertional malaise and unrefreshing sleep. Cognitive impairment or orthostatic intolerance must also be present.

Unrefreshing sleep is not simply too few hours in bed. Patients may sleep through the night and still wake feeling as though restoration never happened. The diagnostic criteria specifically acknowledge that this can occur even when conventional sleep testing does not reveal an obvious abnormality.

That makes the Australian finding intriguing.

The imaging signal tracked with sleep disturbance and impaired concentration—two symptoms closely tied to the experience of waking without recovery. It did not track with the severity of fatigue itself.

One possibility is that altered perivascular or white-matter physiology contributes to a failure of sleep to restore cognitive function. Another is that disrupted sleep changes the imaging signal. A third is that both arise from some other part of the disease process.

The study cannot tell us which explanation is right.

There are also limits to how far the findings can be generalized. Participants with ME/CFS had been ill for an average of more than 14 years. This was a chronically affected group, not a picture of what happens near the beginning of illness. People with a history of COVID-19 were excluded, so the findings cannot automatically be applied to post-COVID ME/CFS. Several common comorbid conditions were also excluded.

The study may therefore have identified one feature of one carefully selected group at one moment in time.

Its strongest contribution may be the question it leaves behind:

What is different about sleep that happens without restoration?

A full night of sleep and a restored nervous system are not the same thing.

ONE MORE CLUE IN A MULTISYSTEM ILLNESS

ME/CFS has long occupied an uncomfortable place in medicine. It can be profoundly disabling, yet there is no single confirmatory diagnostic test. Symptoms overlap with many other conditions. Routine laboratory studies may be unrevealing. A patient can look well during a short appointment and pay for that effort with days of worsening afterward.

For too long, the absence of a simple biomarker was treated by some as evidence that the illness lacked a biological basis.

Research is making that position harder to sustain.

In 2024, an intensive National Institutes of Health study of people with post-infectious ME/CFS reported differences across immune function, autonomic regulation, metabolism and brain activity. That study was also small and exploratory, but it reinforced the idea that ME/CFS may not be explained by one organ system or one pathway.

The glymphatic study belongs in that larger picture. It does not replace immune, autonomic, vascular, metabolic, mitochondrial or neuroendocrine hypotheses. It adds another possible relationship—this time among fluid dynamics, white-matter structure, sleep and cognition.

That is more useful than asking one mechanism to explain the entire disease.

For patients, even early biological findings carry weight. Many have spent years being told that normal routine tests mean nothing is wrong, that more rest should fix the problem or that their limitations reflect motivation rather than physiology.

An MRI group difference cannot diagnose an individual patient. But studies like this help move the conversation away from whether ME/CFS is biologically real and toward the much more useful question of which mechanisms are driving it.

For practitioners, the opportunity is to stay curious without moving faster than the evidence.

The study may have found a clue to restoration, not an explanation for the whole disease.

WHEN A MECHANISM BECOMES A TREATMENT TARGET

A new mechanism can become a treatment idea very quickly.

This study is not there yet.

Researchers did not measure retained waste products in the brain, test a treatment or show that changing the ALPS index changes symptoms. They did not establish a clinical reference range, determine whether the measurement can distinguish ME/CFS from other fatiguing illnesses or show that it can be used to monitor response.

No participant received a therapy designed to change glymphatic function.

That does not make the finding clinically irrelevant. It means the immediate value lies in sharpening the questions we ask while researchers determine what the imaging signal actually represents.

Even familiar health advice needs context. The paper discusses physical activity as one factor that may influence glymphatic function, drawing in part from animal research. That does not support prescribing more exercise to someone with ME/CFS. Post-exertional malaise is a defining feature of the illness, and activity that exceeds an individual patient’s energy limits can produce substantial delayed worsening.

Sleep deserves careful attention for the same reason. Practitioners can take a detailed sleep history, screen for treatable conditions such as sleep apnea or restless legs syndrome, review medications and substances, and address pain or other factors that disrupt sleep. Those interventions may improve quality of life.

They do not prove that glymphatic dysfunction caused the patient’s ME/CFS or that improving sleep will repair it.

ME/CFS has generated many plausible theories over the years. The important question is which ones hold up when they are tested repeatedly.

For now, this study should change the questions before it changes the treatment plan.

WHAT SHOULD CHANGE ON MONDAY?

Start by asking what the patient means by “fatigue.”

Is the dominant problem sleepiness, physical weakness, cognitive slowing, post-exertional worsening, orthostatic symptoms, pain, sensory overload or the feeling that sleep never restores them? Those experiences are not interchangeable, and using one word for all of them can hide clinically useful patterns.

Then separate time asleep from restoration. Ask how the patient feels when they wake, whether cognition improves or worsens after sleep, what interrupts the night and whether more sleep actually produces more function. When the history suggests a treatable sleep disorder, evaluate it without assuming it explains the whole syndrome.

Timing matters too. Brain fog that follows exertion may tell a different story from cognitive difficulty that follows poor sleep or prolonged upright posture. Because post-exertional malaise can emerge 12 to 48 hours after activity, a same-day symptom review can miss the relationship entirely.

Above all, protect the patient from mechanism-driven overexertion. No emerging theory about circulation, lymphatics or brain clearance overrides the need to recognize post-exertional malaise and keep activity within an individually tolerable energy envelope.

And do not order or market DTI-ALPS as a clinical ME/CFS test. The evidence does not yet support using it to confirm a diagnosis, select a treatment or monitor response.

The responsible response is not to dismiss the imaging result.

It is to keep it where it belongs for now: as a research finding that helps us ask better questions.

PATTERN BEFORE PATHWAY

Does the clinical pattern fit?

Document loss of function, post-exertional malaise, unrefreshing sleep, cognitive symptoms and orthostatic intolerance rather than relying on the word “fatigue.”

What remains treatable now?

Evaluate sleep disorders and other contributors without assuming one finding explains the entire syndrome.

What is the time relationship?

Track sleep, cognition, activity, posture and delayed worsening across days.

What could cause harm?

Avoid recommendations that ignore post-exertional malaise, medication sensitivity or the patient’s current capacity.

What does the evidence permit?

Use DTI-ALPS as a research measure, not a diagnostic label or treatment target.

WHAT WOULD MAKE THIS PRACTICE-CHANGING?

The next step is not simply a larger version of the same study.

The finding needs to be replicated in independent and more diverse groups. Researchers need more standardized imaging methods and better ways to account for differences in white-matter anatomy, sleep position, vascular health and other factors that may influence the measurement.

It would also help to pair the imaging with objective sleep assessment and more direct measurements of fluid movement. That could begin to answer whether the ALPS signal relates to sleep architecture, circadian timing, perivascular flow or something else entirely.

Longitudinal studies are especially important. Researchers need to know whether the signal appears early in the illness, changes with severity, predicts the course of disease or moves when patients improve.

Comparisons with other conditions—including sleep disorders, depression, fibromyalgia, multiple sclerosis and long COVID—would help determine whether the finding is specific enough to become clinically useful.

Eventually, an intervention study would need to show more than a change on a scan. It would need to improve outcomes that matter to patients without worsening post-exertional malaise.

Only then could DTI-ALPS begin to move from an interesting research measure toward a useful biomarker or treatment target.

For now, the study gives us something more modest and still valuable. It identifies a group-level imaging difference associated with sleep disturbance and impaired concentration. It reinforces that ME/CFS cannot be reduced to ordinary tiredness. And it gives researchers a new lead worth following.

The goal is not to be first to name the next root cause. It is to notice a promising clue, stay curious and wait for the science to tell us how much that clue really means.

ME/CFS patients have been describing sleep without restoration and thought without clarity for years. This study does not explain why.

It may help science ask the question with greater precision.

That is how an early clue becomes useful: not as proof, but as a better place to look next.

DR. Z’S TAKE

I think the word fatigue has confused the conversation around ME/CFS for years.

Fatigue sounds familiar. Everyone has been tired. You work too hard, sleep too little, push through a stressful week, then rest and recover.

That is not what many ME/CFS patients are describing.

There is tired, and then there is a body that no longer seems able to recover from what you ask of it. You sleep, but you do not wake restored. You exert yourself and feel worse later. Your thinking slows. Your nervous system becomes less resilient. Your body can feel as though it never fully resets.

I have experienced both. They are not remotely the same thing.

That is why this study is interesting to me. The MRI finding did not track with fatigue severity. It tracked with sleep disturbance and impaired concentration. And yes, I do think the lymphatic and glymphatic systems matter. If fluid movement, waste clearance or perivascular function is impaired, that deserves attention.

But I would not stop there.

In functional medicine, we are always asking what may be driving the loss of resilience underneath the symptom. In patients with ME/CFS, I often think about persistent or reactivated infections, autoimmune activity, immune dysregulation, autonomic dysfunction, mitochondrial stress, vascular changes and the downstream inflammatory effects that can connect all of those systems.

Sometimes an infection may be the beginning of the story. Sometimes the immune response that follows becomes the bigger problem. Sometimes both are still active. And sometimes the damage is less about one single pathway and more about several systems that no longer recover normally together.

That is why I would never look at a finding like this and say, “The glymphatic system is the root cause.”

I would say, this may be one more place where we can see the consequences of a larger biological problem.

The better clinical question is not simply, “Why is this patient tired?”

It is: Why is this patient not recovering?

What happens after sleep? What happens after physical or mental exertion? What happens 12, 24 or 48 hours later? Does upright posture worsen symptoms? Are there signs of immune activation, infection, autoimmunity or autonomic dysfunction? What pattern keeps showing up?

Maybe altered brain clearance turns out to be part of that picture. I think it very well may be.

But the value of this research is not that it gives us one more mechanism to chase. It gives us one more reason to look at ME/CFS as what it is: a complex biological illness involving systems that are supposed to restore, regulate and recover — and in these patients, often do not.

That is the clue I would follow.

Sources

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