Forty US diplomats who experienced bizarre sensory episodes and developed a constellation of neurological symptoms while stationed in Cuba have slight differences in their brain structures and connectivity compared with healthy controls, according to an analysis of advanced brain imaging published Tuesday in JAMA.

The imaging adds a fuzzy new clue to the mysterious episodes, which US officials have dubbed “health attacks.” From the start, the phenomenon has evoked the idea of an international cloak-and-dagger operation involving clandestine weaponry that has eluded all scientific explanation and hatched countless conspiracy theories.

Beginning in late 2016, diplomats in Havana began reporting puzzling episodes of irritating directional sounds, vibrations, and pressure before falling ill with an array of symptoms. They experienced dizziness, nausea, headaches, balance problems, ringing in the ears (tinnitus), nosebleeds, difficulty concentrating and recalling words, hearing loss, and speech problems.

Most of the staff at the embassy has been called back to the US, while various theories on the phenomenon have circulated. Theories range from the existence of a dubious sonic weapon, to mass psychogenic illness, to infectious agents, chemical exposure, malfunctioning surveillance equipment, and a mix of stress and crickets. But no clear explanation for the diplomats' experiences or their symptoms have been found. And in the meantime, diplomats in China began reporting similar episodes and symptoms and have been evacuated.

Early last year, a team of medical experts at the University of Pennsylvania published a preliminary clinical evaluation of 21 individuals affected. They conducted extensive evaluations of the individuals and concluded that, overall, they seemed to have suffered “injury to widespread brain networks without an associated history of head trauma.”

The report bolstered concern over the odd cases but also generated criticism. Some neurologists said that the team had made their criteria for a few of the neurological problems overly broad—finding disabilities when there, perhaps, were none. The team responded, telling reporters that they had more data than what the US government allowed them to include in the initial report and that the criteria were “more nuanced.” Instead of using standard cut-offs, they used what was considered normal for each patient.

The new brain imaging analysis—published by the same team at Penn—is unlikely to resolve any disputes. In fact, it only raises new questions.

Blurry picture

For the new analysis, the team used three types of imaging techniques to get detailed information about the brains of 40 individuals affected in Cuba. The first technique was standard 3D fluid-attenuated inversion recovery (FLAIR) imaging that allowed the team to calculate the volume of white and gray matter throughout each patient’s brain. The second was Diffusion Tensor Imaging (DTI), which uses the diffusion of water molecules in brain tissue to glean information about tissue integrity and microstructures. The last was resting-state Functional Magnetic Resonance Imaging (fMRI), which uses changes in blood-flow in the brain while a person is not performing any specific tasks to assess basal activity in functional connections, that is networks involved in things like hearing, visual perception, and executive functions.

The team then compared the brain imaging findings in the 40 patients to two sets of healthy controls: a set of 21 healthy individuals who matched the education levels and professional status of the 40 patients, as well as demographic information, such as age and ethnicity; and a group of 27 healthy individuals who had a broader spectrum of education and skills.

Overall, the researchers found that the 40 patients had, on average, slightly smaller volumes of total white matter in their brains compared with that of the healthy groups. White matter is tissue made up of bundles of nerve fibers—axons—that connect neurons in different brain regions, forming functional circuits. Gray matter, on the other hand, is the pinkish-gray tissue rich in neuronal cell bodies.

In particular, the researchers found smaller volumes of white matter neighboring the patients’ cerebellums, a structure at the lower back of the brain involved in motor control and balance. The DTI results also found differences in the tissue diffusion and microstructures in this region. Some of these differences seemed to link up to the patients' scores on sensory and clinical tests—the bigger the differences the worse their scores. Last, the rs-fMRI found reduced connectivity in the patients' auditory and visuospatial networks compared with controls. But this finding didn’t correlate with the patients’ clinical symptoms.

Brain teaser

Overall, the researchers found an array of differences that they couldn’t explain. The pattern of changes didn’t match those seen in any other brain injury or disorder known. If the differences are real, it would appear to be a wholly unique set of brain changes.

Still, while intriguing, the team at Penn was cautious in their conclusions, writing that, given the “relatively weak correlations observed for some metrics, and the absence of correlation with functional connectivity metrics entirely, the clinical implications of the neuroimaging differences remain uncertain.”

The researchers also noted that the study has significant limitations: it has just 40 affected adults, and the team had no information on the state of their brains before the reported episodes. They also couldn’t determine how much exposure each individual had to the offending phenomenon. There were also different amounts of time since each patients’ exposure, providing varying opportunities for recovery from any potential brain injuries. And of course, the various imaging techniques used in the analysis have their own limitations and error rates.

In an accompanying editor’s note, two high-level editors at JAMA echo the authors' uncertainty about whether the differences they found are clinically relevant. But they acknowledge that the mystery remains, writing: “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.”

JAMA, 2019. DOI: 10.1001/jama.2019.9269 (About DOIs).