The study’s findings, published October 26 in the journal PLOS ONE, substantiate and help validate that memory, and other cognitive difficulties experienced long-term by individuals with post-treatment Lyme disease, are linked to functional and structural changes in the brain.

Lyme disease, whose early symptoms may include a characteristic rash, flu-like aches and fever, joint pain, and fatigue, is treated using a rigorous course of antibiotics, which usually clears the illness.

However, in those considered long-haul patients for whom Lyme symptoms continue after completion of antibiotics, the condition is a chronic illness that can be marked by fatigue, muscular pain, insomnia, depression and cognitive difficulties, such as trouble with concentration and memory. Such individuals generally have no obvious clinical or laboratory evidence of ongoing issues.

In a bid to identify what they suspect are long-term changes in brain function that may be causing certain persistent Lyme disease symptoms, researchers from Johns Hopkins Medicine’s departments of neurology and psychiatry and behavioral sciences, in collaboration with the Lyme Disease Research Center, used functional MRI (fMRI) scans of the brain, a technology that detects changes in brain blood flow. These scans allow investigators to track changes in the brain in real time.

“Objective biologic measures of post-treatment Lyme symptoms typically can’t be identified using regular MRIs, CT scans, or blood tests,” says researcher John Aucott, M.D., director of the Johns Hopkins Lyme Disease Clinical Research Center and associate professor of medicine at the Johns Hopkins University School of Medicine. “We needed to expand our methods of evaluation,” he adds.

Spearheaded by lead author Cherie Marvel, Ph.D., the team recruited 12 male and female post-treatment Lyme disease patients, and 18 participants without a history of Lyme, to undergo fMRI scans while performing a short-term memory task.

The imaging tests revealed unusual activity in the frontal lobe, an area of the brain responsible for cognitive tasks such as memory recall and concentration. Participants were asked to memorize and recall capital and lowercase letters, as well as the alphabetical order of multiple letters.

Notably, the researchers say, the images showed differences in their frontal lobe activity between the two groups in the white matter of the brain, which normally does not show up in fMRI scans, as this tissue operates with less blood flow than gray matter. White matter is crucial for moving information around the brain, acting like train tracks that help deliver information to the train depot, or gray matter.

“We saw certain areas in the frontal lobe under-activating and others that were over-activating, which was somewhat expected,” says Marvel, an associate professor of neurology. “However, we didn’t see this same white matter activity in the group without post-treatment Lyme.”

To confirm this finding, researchers used a second form of imaging called diffusion tensor imaging (DTI) on all 12 participants with Lyme and 12 of the 18 non-Lyme participants. DTI detects the direction of water movement within brain tissue. This unique approach corroborated their fMRI findings and revealed new findings: Water was diffusing, or leaking, along the patients’ axons — the extensions of neurons that carry electrical signals to other neurons — within the same white matter regions identified in the fMRI.

Surprisingly researchers also found that axonal leakage in white matter correlated with fewer cognitive deficits and better outcomes among the post-treatment Lyme disease patients they studied.

The researchers believe the increased activity they saw in white matter may reflect a helpful immune response in the post-treatment Lyme patients, as it correlated with better disease outcomes. However, this finding was also correlated to the patients with post-treatment Lyme needing longer periods of time to complete the memory task. The researchers say this is indicative that the white matter response could be an adaptive one, but that the white matter’s physiology and function have been changed, which could come at a cost.

“Approaching this problem collaboratively with experts in different fields is what gave us these novel findings, and will hopefully answer our remaining questions, specifically about the role of axonal leakage and white matter activation in post-treatment Lyme disease,” she says.

Marvel and Aucott say this research may help illuminate underlying mechanisms and potential therapeutic targets for neurologic Lyme disease. Their findings may also have relevance to other kinds of infection-associated chronic illnesses, including long COVID and chronic fatigue syndrome.

Funding for the project was provided by an anonymous donor to John Aucott.

The research team also includes Kylie Alm, Deeya Bhattacharya, Alison Rebman, Arnold Bakker, Jason Creighton, Erica Kozero, Arun Venkatesan, and Prianca Nadkarni of Johns Hopkins Medicine; as well as Owen Morgan who is now at Cornell University.

The authors declare no competing interests.

Led by Simone Schürle, Professor of Responsive Biomedical Systems, the ETH Zurich researchers chose to work with bacteria that are naturally magnetic due to iron oxide particles they contain. These bacteria of the genus Magnetospirillum respond to magnetic fields and can be controlled by magnets from outside the body.

Exploiting temporary gaps

In cell cultures and in mice, Schürle and her team have now shown that a rotating magnetic field applied at the tumour improves the bacteria’s ability to cross the vascular wall near the cancerous growth. At the vascular wall, the rotating magnetic field propels the bacteria forward in a circular motion.

To better understand the mechanism to cross the vessel wall works, a detailed look is necessary: The blood vessel wall consists of a layer of cells and serves as a barrier between the bloodstream and the tumour tissue, which is permeated by many small blood vessels. Narrow spaces between these cells allow certain molecules from the to pass through the vessel wall. How large these intercellular spaces are is regulated by the cells of the vessel wall, and they can be temporarily wide enough to allow even bacteria to pass through the vessel wall.

Strong propulsion and high probability

With the help of experiments and computer simulations, the ETH Zurich researchers were able to show that propelling the bacteria using a rotating magnetic field is effective for three reasons. First, propulsion via a rotating magnetic field is ten times more powerful than propulsion via a static magnetic field. The latter merely sets the direction and the bacteria have to move under their own power.

The second and most critical reason is that bacteria driven by the rotating magnetic field are constantly in motion, travelling along the vascular wall. This makes them more likely to encounter the gaps that briefly open between vessel wall cells compared to other propulsion types, in which the bacteria’s motion is less explorative. And third, unlike other methods, the bacteria do not need to be tracked via imaging. Once the magnetic field is positioned over the tumour, it does not need to be readjusted.

“Cargo” accumulates in tumour tissue

“We make use of the bacteria’s natural and autonomous locomotion as well,” Schürle explains. “Once the bacteria have passed through the blood vessel wall and are in the tumour, they can independently migrate deep into its interior.” For this reason, the scientists use the propulsion via the external magnetic field for just one hour — long enough for the bacteria to efficiently pass through the vascular wall and reach the tumour.

Such bacteria could carry anti-cancer drugs in the future. In their cell culture studies, the ETH Zurich researchers simulated this application by attaching liposomes (nanospheres of fat-like substances) to the bacteria. They tagged these liposomes with a fluorescent dye, which allowed them to demonstrate in the Petri dish that the bacteria had indeed delivered their “cargo” inside the cancerous tissue, where it accumulated. In a future medical application, the liposomes would be filled with a drug.

Bacterial cancer therapy

Using bacteria as ferries for drugs is one of two ways that bacteria can help in the fight against cancer. The other approach is over a hundred years old and currently experiencing a revival: using the natural propensity of certain species of bacteria to damage tumour cells. This may involve several mechanisms. In any case, it is known that the bacteria stimulate certain cells of the immune system, which then eliminate the tumour.

Multiple research projects are currently investigating the efficacy of E. coli bacteria against tumours. Today, it is possible to modify bacteria using synthetic biology to optimise their therapeutic effect, reduce side effects and make them safer.

Making non-magnetic bacteria magnetic

Yet to use the inherent properties of bacteria in cancer therapy, the question of how these bacteria can reach the tumour efficiently still remains. While it is possible to inject the bacteria directly into tumours near the surface of the body, this is not possible for tumours deep inside the body. That is where Professor Schürle’s microrobotic control comes in. “We believe we can use our engineering approach to increase the efficacy of bacterial cancer therapy,” she says.

E. coli used in the cancer studies is not magnetic and thus cannot be propelled and controlled by a magnetic field. In general, magnetic responsiveness is a very rare phenomenon among bacteria. Magnetospirillum is one of the few genera of bacteria that have this property.

Schürle therefore wants to make E. coli bacteria magnetic as well. This could one day make it possible to use a magnetic field to control clinically used therapeutic bacteria that have no natural magnetism.

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Materials provided by ETH Zurich. Original written by Fabio Bergamin. Note: Content may be edited for style and length.

Americans die younger than people in most other high-income countries and within the United States life expectancy differs markedly across geographic areas. In 2019, it ranged from 74.4 years in Mississippi to 80.9 years in Hawaii.

In the new work, the researchers used data from the 1999-2019 National Vital Statistics System to calculate state-level age-adjusted mortality rates for deaths from all causes and from cardiovascular disease (CVD), alcohol, suicide and drug poisoning among adults ages 25 to 64. They merged that data with annual state-level data on eight policy domains, where each state’s policies were scored on a 0-to-1 conservative-to-liberal continuum.

The analysis revealed that more liberal policies on the environment, gun safety, labor, economic taxes and tobacco taxes were associated with lower mortality in each state. However, for marijuana, more conservative policies were associated with lower mortality. Particularly strong associations were found between gun safety policies and suicide mortality among men; between labor policies and alcohol-induced mortality; and between economic and tobacco tax policies and cardiovascular disease mortality. Simulations suggested that changing all policies in all states to a fully liberal orientation could have saved 171,030 lives in 2019, while changing them to a fully conservative orientation may have cost 217,635 lives.

The authors conclude that the emergence of more conservative state policies in several domains and shifts in the share of the population living in states with these policies provide a partial explanation for the high and rising mortality among working-age Americans and the overall mortality disadvantage of the US compared to other high-income countries.

The authors add: “U.S. state policies in recent decades may have contributed to the high and rising mortality rates of working-age adults. Changing state policies could prevent thousands of deaths every year from cardiovascular disease, suicide, alcohol, and drug poisoning.”

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Materials provided by PLOS. Note: Content may be edited for style and length.