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U.S. Embassy personnel in Havana who had neurological symptoms after a mysterious sensory exposure subsequently showed differences in brain tissue and connectivity compared to healthy individuals, a retrospective analysis of advanced MRIs found.

Whole brain white matter volume, regional gray and white matter volume, cerebellar tissue microstructural integrity, and functional connectivity in auditory and visuospatial networks all differed significantly in 40 U.S. workers in Cuba potentially exposed to the widely reported but unknown phenomena -- occurring from late 2016 to May 2018 and manifesting subjectively as pressure, sound, or vibration -- versus several dozen matched controls, reported Ragini Verma, PhD, of the University of Pennsylvania in Philadelphia, and co-authors, in .

The clinical implications of these findings are uncertain, but they do "provide some tangible evidence that there really is something -- a change in the brain -- that could explain the symptoms" these people have reported, co-author Douglas Smith, MD, director of Penn's Center for Brain Injury and Repair, said in an interview with 乌鸦传媒.

"These are real neurological findings, very complex findings," he added. "We suspected this was what we call a 'stealth pathology.' In concussion, for example, symptoms reflect the function of the brain networks: you're not getting an electrical signal from one part of your brain to another fast enough. When these patients came in, it became clear they had this type of network issue."

In late 2016, in Havana reported various neurological symptoms after experiencing strange sounds that were associated with a sensation described as pressure-like or vibratory. Nearly all said they had immediate neurological symptoms associated with the noise, but it was (and still is) unclear how the symptoms and phenomena may have been linked. Initial symptoms appeared to be auditory related and led to a triage program centered on otolaryngology evaluations at the University of Miami.

In 2017, the State Department convened an expert panel which concluded that the triage findings most likely were related to neurotrauma and recommended further study. A by Penn researchers documented neurological symptoms of 21 people who had reported exposure to the mysterious phenomena; these patients had visual and balance problems, headache, sleep problems, and deficits in working memory, sustained attention, and concentration.

"This is really concussion without concussion," . Speculation on the cause included some type of sonic or microwave weapon, although experts said neither was plausible.

In the current analysis, researchers looked at brain imaging of 40 potentially-exposed patients and 48 healthy, demographically similar controls. Of the 40 patients, 12 had a history of remote concussion with resolved symptoms. Patients averaged about age 40; 23 were men and 17 were women.

As part of their evaluation, patients had advanced neuroimaging before they received any comprehensive rehabilitation treatment. Imaging was obtained a median of 188 days (range 4-403) after the reported exposure and included structural, diffusion, and functional MRI.

The researchers used group-based analysis to identify differences in total and regional brain volume, cerebellar tissue microstructure (mean diffusivity), and functional subnetwork connectivity. Compared with controls, patients showed:

• Smaller mean whole brain white matter volume (542.22 cm³ vs 569.61 cm³; P<0.001), with no significant difference in whole brain gray matter volume
• Significantly greater volume ventral diencephalon and cerebellar gray matter volumes, but significantly lower volumes in frontal, parietal, and occipital white matter
• Lower mean diffusivity in the inferior vermis of the cerebellum (7.71 × 10^-4 mm²/s vs 8.98 × 10-⁴ mm²/s; P<0.001)
• Lower mean functional connectivity in the auditory subnetwork (0.45 vs 0.61; P=0.003) and visuospatial subnetwork (0.30 vs 0.40; P=0.002), but not in the executive control subnetwork

Differences persisted even when people with some history of brain injury were excluded from the analysis.

"These findings may represent something not seen before," Smith observed.

The cerebellar findings "are notable, given that a number of the patients evaluated exhibited abnormalities in balance and the coordinated movement of the eyes, both of which are associated with cerebellar dysfunction in the brain," Penn co-author Randel Swanson, DO, PhD, said in a statement.

"These unique data provide additional information and contribute to a growing evidence base that may help in understanding the neurological signs and symptoms experienced by this group of individuals," wrote JAMA senior editor Christopher Muth, MD, of Rush University Medical Center in Chicago, and executive editor Phil Fontanarosa, MD, MBA, in an .

"However, despite the differences in advanced neuroimaging metrics between patients and controls reported in this study, the clinical relevance of these differences is uncertain, and the exact nature of any potential exposure and the underlying etiology of the patients' symptoms still remain unclear," Muth and Fontanarosa added.

The study had several limitations, the researchers noted. It was not designed as a research study but was conducted retrospectively. It was not possible to use a control group of unaffected personnel similar to those deployed in Cuba. The analysis involved high heterogeneity in a small sample and only group-level statistical differences could be assessed. Perhaps most important, pre-exposure brain scans were not available for the embassy personnel.

"We don't know anything about the natural history of this disorder," Smith said. Some individuals have recovered; some have symptoms that wax and wane, he noted: "It will be important for us to follow these patients and to work with others who have subsequently examined the same patient group as well."

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