Researchers with the National Institutes of Health published a pair of studies on Monday that found few clinical differences between patients with a mysterious ailment known as “Havana syndrome” and healthy comparison groups.

In one study, NIH researchers took a closer look at the brains of people who were believed to have Havana syndrome and found no consistent evidence of brain injury and no significant differences between that group and a healthy comparison group.

In the second study, scientists ran a battery of tests on 86 US government staff and family members who reported Havana syndrome, comparing them with 30 people who had similar jobs but had no such symptoms, and found that by most clinical and biomarker measures, the two groups were the same.

The mysterious illness first emerged in late 2016, when a cluster of diplomats stationed in the Cuban capital of Havana began reporting symptoms consistent with head trauma, including dizziness and extreme headaches. In subsequent years, there have been cases reported around the world, including clusters of at least 60 incidents in Bogota, Colombia, and Vienna, Austria. There have been about 1,500 reported cases across the US government in 96 different counties, officials said last year, but the number of reported incidents has dropped significantly in recent years.

Despite longstanding speculation that the illness could have been the result of a targeted campaign by an enemy of the US, the US intelligence community said last year that it cannot link any cases to a foreign adversary, ruling it unlikely that the unexplained illness was the result of a targeted campaign by an enemy of the US.

But the illness — and its cause — have remained frustratingly opaque to both the intelligence community and the medical community.

Dr. David Relman, a professor of microbiology and immunology at Stanford who worked on earlier investigations of people with Havana syndrome, argued in an editorial published alongside the research Monday that while the study involving brain scans may appear to show that “nothing, or nothing serious” happened with these cases, coming to this conclusion “would be ill-advised.”

Earlier work found evidence of abnormalities, he said, and the same is true for the study that did a wider variety of tests. Because the condition can look different in each person, he said, doctors don’t have specific tests that can fully determine what is wrong with them.

“Clearly, new, sensitive, standardized, non-invasive tests of nervous system function, especially involving the vestibular system, are needed, such as more specific blood markers of different forms of cellular injury,” Relman wrote.

‘Institutional failures’ contributed to outcomes, expert says

One problem facing the medical community is that there is still not a clear definition of Havana syndrome — or what the government terms “anomalous health incidents” or AHIs. These tests were done, in some cases, long after symptoms began, making it harder to understand what physically happened.

In 2022, an intelligence panel investigating the cause of AHIs said that some of the episodes could “plausibly” have been caused by “pulsed electromagnetic energy” emitted by an external source.

But Relman noted that there is a relative lack of information about the biological effects of electromagnetic and acoustic energy on the brain, even if this is what actually triggered the problems in people with Havana syndrome.

Some current and former CIA officers have raised concerns that a CIA task force in charge of investigating Havana syndrome soft-pedaled its investigation, CNN has previously reported.

And some patients and former officials have said they were treated with skepticism and in some cases outright dismissal by the Trump administration in the months and years following the appearance of the first cases.

Despite the uncertainty surrounding the condition, Congress in 2021 passed legislation mandating compensation for CIA and government victims, which the agency began disbursing in 2022.

Relman noted that as with any kind of highly publicized clinical syndromes, such as Gulf War syndrome and now Havana syndrome, it is difficult for scientists to deal with “uncertainty, complexity, the need for transdisciplinary approaches, insufficient information or misinformation, and a topic that is politically charged and divisive.”

“Going forward, we must address the underlying institutional failures and vulnerabilities that contributed to these outcomes,” Relman writes. He argued for surveillance systems designed to detect early cases across government agencies and objective independent panels to review emerging data.

“Prejudice and poorly supported assumptions must be set aside,” he wrote.

What the new studies found

The neuroimaging study compared the brains of 81 people thought to have Havana syndrome and those of 48 people who had no such health complaints. Twenty-nine members of the comparison group had similar employment as the 81 in the patient group.

To look for differences in the participants’ brains, the scientists used imaging known as high-quality diffusion MRI, which doctors typically use to check for conditions such as a stroke, a brain tumor, multiple sclerosis and epilepsy. This kind of MRI can visualize white matter fibers in the brain and determine whether the brain matter is normal or if there are problems.

When the researchers compared the two groups, they found no significant differences in the structures and measurements of the brains.

“These findings suggest that the origin of the symptoms of participants with AHIs may not be linked to an MRI-identifiable injury to the brain,” the study concluded.

There are limitations to this research, however. The control group was small and not perfectly matched to those with Havana syndrome. The earliest scans were also conducted within 14 days after the person said they experienced the event that triggered their symptoms, and the results may have been different if done at a different time.

The study results differ from previous imaging studies that found evidence of some brain abnormalities, but past studies were done on smaller number of participants.

In the second study, researchers tested hearing, balance, eyesight and neuropsychological state, and they looked at blood biomarkers, in the two groups.

There were no significant clinical differences between the two groups when it came to their hearing or vision, nor were there differences when the researchers tested the inner ear or checked the blood for certain biomarkers. Cognitive tests were also similar.

There were some differences in self-reported symptoms, however, including fatigue, depression, post-traumatic stress, imbalance and some neurobehavioral issues.

Headache was a common concern among the participants with Havana syndrome. Most developed daily persistent headaches, the study said, but only eight were diagnosed with new-onset migraines.

“While we did not identify significant differences in participants with AHIs, it’s important to acknowledge that these symptoms are very real, cause significant disruption in the lives of those affected and can be quite prolonged, disabling and difficult to treat,” Dr. Leighton Chan, lead author on one of the papers and acting chief scientific officer of the NIH Clinical Center, said in a news release.

The authors of the study noted several limitations to their research, including the fact that some of the assessments, though sensitive, are not specific, and some are not used clinically, so it is unclear exactly how impactful they are.

There were also no psychiatric evaluations performed. Anxiety, depression pain and fatigue can affect balance, hearing and cognitive testing, so abnormalities can be difficult to interpret.

The study concluded that whatever caused Havana syndrome seems to create symptoms “without persistent or detectable physiologic changes. A lack of evidence for a brain injury does not necessarily mean that no injury is present or that it did not occur at the time of the AHI.”

“Alternatively, the ‘attack’s’ physiological effects might be so varied and idiosyncratic that they cannot be identified with the current methodologies and sample size,” the study said.