Scientists have observed distinctive patterns in the electrical activity of neuron groups in healthy brains. Networks of neurons move through states of similar behavior (synchronization) and dissimilar behavior (desynchronization) in a process that is associated with memory and attention. But in a brain with a neurological disorder like epilepsy, synchronization can grow to a dangerous extent when a collection of brain cells begins to emit excess electricity. “Synchronization is thought to be important for information processing,” Jennifer Creaser of the University of Exeter said. “But too much synchronization — such as what occurs in epileptic seizures or Parkinson’s disease — is associated with disease states and can impair brain function.”

Measurements of epileptic seizures have revealed that desynchronization in brain networks often occurs before or during the early stages of a seizure. As the seizure progresses, networks become increasingly more synchronized as additional regions of the brain get involved, leading to high levels of synchronization towards the seizure’s end. Understanding the interactions between the increased electrical activity during a seizure and changes in synchronization is an important step towards improving the diagnosis and treatment of epilepsy.

Jennifer Creaser, Peter Ashwin (University of Exeter), and Krasimira Tsaneva-Atanasova (University of Exeter, Technical University of Munich, and Bulgarian Academy of Sciences) explored the mechanisms of synchronization that accompany seizure onset in a paper that published in December in the SIAM Journal on Applied Dynamical Systems. In their study — which took place at the Engineering and Physical Science Research Council’s Centre for Predictive Modelling in Healthcare at the University of Exeter and University of Birmingham — the researchers used mathematical modeling to explore the interplay between groups of neurons in the brain that leads to transitions in synchronization changes during seizure onset. “Although this is a theoretical study of an idealized model, it is inspired by challenges posed by understanding transitions between healthy and pathological activity in the brain,” Ashwin said.

The authors utilize an extended version of an existing mathematical model that represents the brain as a network connecting multiple nodes of neuron groups. The model network consists of bistable nodes, meaning that each node is able to switch between two stable states: resting (a quiescent state) and seizure (an active and oscillatory state). These nodes remain in their current state until they receive a stimulus that gives them a sufficient kick to escape to the other state. In the model, this stimulus comes from other connected nodes or appears in the form of “noise” — outside sources of neural activity, such as endocrine responses that are associated with an emotional state or physiological changes due to disease.

The influence between neighboring nodes is governed by a coupling function that represents the way in which the nodes in the network communicate with each other. The first of the two possible types of coupling is amplitude coupling, which is governed by the “loudness” of the neighboring nodes. The second is phase coupling, which is related to the speed at which the neighbors are firing. Although the researchers needed to utilize a simple formulation on a small network to even make their analysis possible — a more complex and realistic system would be too computationally taxing — they expected their model to exhibit the same types of behaviors that clinical recordings of real brain activity have revealed.

The nodes in the modeled system all begin in the healthy resting state. In previous research, the authors found that adding a small amount of noise to the system caused each node to transition to the active state — but the system’s geometry was such that returning to the resting state took much longer than leaving. Because of this, these escapes can spread sequentially as a “domino effect” when a number of nodes are connected. This leads to a cascade of escapes to the active state — much like a falling line of dominos — that spreads activity across the network.

Creaser, Ashwin, and Tsaneva-Atanasova’s new paper builds upon this previous research on the domino effect to explore the transitions into and out of synchrony that occur during cascades of escapes. The team used their model to identify the circumstances that bring about these changes in synchrony and investigate how the type of coupling in a network affects its behavior.

When the model incorporated only amplitude coupling, it exhibited a new phenomenon in which the domino effect could accelerate or decelerate. However, this effect had no bearing on synchronization changes in the network; all of the nodes started and remained synchronized. But when the model incorporated more general amplitude and phase coupling, the authors found that the nodes’ synchrony could change between consecutive escapes during the domino effect. They then determined which conditions would cause changes in synchrony under phase-amplitude coupling. This change in synchrony throughout the sequence of escapes was the study’s most novel result.

The results of this work could facilitate further studies on seizures and their management. “The mathematical modeling of seizure initiation and propagation can not only help to uncover seizures’ complex underlying mechanisms, but also provide a means for enabling in silico experiments to predict the outcome of manipulating the neural system,” Tsaneva-Atanasova said. Understanding the interplay between synchronized and desynchronized dynamics in brain networks could help identify clinically-relevant measures for seizure treatment. For example, Creaser and Tsaneva-Atanasova recently served as the lead and senior author, respectively, on a paper that utilized a simpler version of the model to classify patterns of seizure onset that were recorded in a clinical setting. In the future, these kinds of modeling studies may lead to the personalization of seizure identification and treatment for individuals with epilepsy.

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Materials provided by Society for Industrial and Applied Mathematics. Original written by Jillian Kunze. Note: Content may be edited for style and length.

“Over the years, many labs, including mine, have identified important roles for astrocytes in promoting neurological diseases,” said corresponding author Francisco Quintana, PhD, of the Ann Romney Center for Neurologic Diseases at the Brigham. “This is the first case in which we’re showing that at least a subset of these cells (astrocytes) can prevent inflammation. The reason we haven’t seen this before was because we were studying these cells as if they were uniform, or one single cell type. But now we have the resolution to see the differences between these cells.”

The researchers used refined gene- and protein-analysis tools to identify the novel astrocyte subset. The astrocyte population resides close to the meninges (the membrane enclosing the brain) and expresses a protein called LAMP1, along with a protein called TRAIL, which can induce the death of other cells. These features help the LAMP1+TRAIL+ astrocytes limit CNS inflammation by inducing cell death in T-cells that promote inflammation.

To determine what mechanism controls LAMP1+TRAIL+ astrocytes in the brain, the researchers performed a series of tests using the gene-editing tool CRISPR-Cas9. They found that a particular signaling molecule, called interferon-gamma, regulates TRAIL expression. Moreover, they found that the gut microbiome induces the expression of interferon-gamma in cells that circulate through the body and ultimately reach the meninges, where they can promote astrocyte anti-inflammatory activities.

Understanding the mechanisms driving the anti-inflammatory functions of LAMP1+TRAIL+ astrocytes could enable researchers to develop therapeutic approaches to combat neurological diseases, like multiple sclerosis. For example, they are exploring probiotic candidates that can be used to regulate the astrocytes’ anti-inflammatory activity. Additionally, the research team’s more recent data indicates that certain brain tumors exploit this pathway to evade the body’s immune response. The investigators are therefore developing cancer immunotherapies to retaliate against the tumors’ attacks.

“Finding microbiome-controlled anti-inflammatory subsets of astrocytes is an important advance in our understanding of CNS inflammation and its regulation,” Quintana said. “This is a very novel mechanism by which the gut controls inflammation in the brain. It guides new therapies for neurological diseases, and we believe that this mechanism could contribute to the pathogenesis of brain tumors.”

Quintana’s lab identified the only other subset of astrocyte known to be regulated by the gut microbiome in 2016, but the investigators believe that there are likely others. “It’s becoming clear that the gut flora are important in many diseases,” he said. “We’re lucky that we’ve been leading the charge to identify different subsets of astrocytes and the mechanisms that control them. We have a list of other populations of astrocytes, and we’re working to see how the gut flora may control them.”

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Materials provided by Brigham and Women’s Hospital. Note: Content may be edited for style and length.

They hurt. Veins can burst, or even roll — like they’re trying to avoid the needle, too.

Oftentimes, doctors use blood samples to check for biomarkers of disease: antibodies that signal a viral or bacterial infection, such as SARS-CoV-2, the virus responsible for COVID-19; or cytokines indicative of inflammation seen in conditions such as rheumatoid arthritis and sepsis.

These biomarkers aren’t just in blood, though. They can also be found in the dense liquid medium that surrounds our cells, but in a low abundance that makes it difficult to be detected.

Until now.

Engineers at the McKelvey School of Engineering at Washington University in St. Louis have developed a microneedle patch that can be applied to the skin, capture a biomarker of interest and, thanks to its unprecedented sensitivity, allow clinicians to detect its presence.

The technology is low cost, easy for a clinician or patients themselves to use, and could eliminate the need for a trip to the hospital just for a blood draw.

The research, from the lab of Srikanth Singamaneni, the Lilyan & E. Lisle Hughes Professor in the Department of Mechanical Engineering & Material Sciences, was published online Jan. 22 in the journal Nature Biomedical Engineering.

In addition to the low cost and ease of use, these microneedle patches have another advantage over blood draws, perhaps the most important feature for some: “They are entirely pain-free,” Singamaneni said.

Finding a biomarker using these microneedle patches is similar to blood testing. But instead of using a solution to find and quantify the biomarker in blood, the microneedles directly capture it from the liquid that surrounds our cells in skin, which is called dermal interstitial fluid (ISF). Once the biomarkers have been captured, they’re detected in the same way — using fluorescence to indicate their presence and quantity.

ISF is a rich source of biomolecules, densely packed with everything from neurotransmitters to cellular waste. However, to analyze biomarkers in ISF, conventional method generally requires extraction of ISF from skin. This method is difficult and usually the amount of ISF that can be obtained is not sufficient for analysis. That has been a major hurdle for developing microneedle-based biosensing technology.

Another method involves direct capture of the biomarker in ISF without having to extract ISF. Like showing up to a packed concert and trying to make your way up front, the biomarker has to maneuver through a crowded, dynamic soup of ISF before reaching the microneedle in the skin tissue. Under such conditions, being able to capture enough of the biomarker to see using the traditional assay isn’t easy.

But the team has a secret weapon of sorts: “plasmonic-fluors,” an ultrabright fluorescence nanolabel. Compared with traditional fluorescent labels, when an assay was done on microneedle patch using plasmonic-fluor, the signal of target protein biomarkers shined about 1,400 times as bright and become detectable even when they are present at low concentrations.

“Previously, concentrations of a biomarker had to be on the order of a few micrograms per milliliter of fluid,” Zheyu (Ryan) Wang, a graduate student in the Singamaneni lab and one of the lead authors of the paper, said. That’s far beyond the real-world physiological range. But using plasmonic-fluor, the research team was able to detect biomarkers on the order of picograms per milliliter.

“That’s orders of magnitude more sensitive,” Ryan said.

These patches have a host of qualities that can make a real impact on medicine, patient care and research.

They would allow providers to monitor biomarkers over time, particularly important when it comes to understanding how immunity plays out in new diseases.

For example, researchers working on COVID-19 vaccines need to know if people are producing the right antibodies and for how long. “Let’s put a patch on,” Singamaneni said, “and let’s see whether the person has antibodies against COVID-19 and at what level.”

Or, in an emergency, “When someone complains of chest pain and they are being taken to the hospital in an ambulance, we’re hoping right then and there, the patch can be applied,” Jingyi Luan, a student who recently graduated from the Singamaneni lab and one of the lead authors of the paper, said. Instead of having to get to the hospital and have blood drawn, EMTs could use a microneedle patch to test for troponin, the biomarker that indicates myocardial infarction.

For people with chronic conditions that require regular monitoring, microneedle patches could eliminate unnecessary trips to the hospital, saving money, time and discomfort — a lot of discomfort.

The patches are almost pain-free. “They go about 400 microns deep into the dermal tissue,” Singamaneni said. “They don’t even touch sensory nerves.”

In the lab, using this technology could limit the number of animals needed for research. Sometimes research necessitates a lot of measurements in succession to capture the ebb and flow of biomarkers — for example, to monitor the progression of sepsis. Sometimes, that means lot of small animals.

“We could significantly lower the number of animals required for such studies,” Singamaneni said.

The implications are vast — and Singamaneni’s lab wants to make sure they are all explored.

There is a lot of work to do, he said: “We’ll have to determine clinical cutoffs,” that is, the range of biomarker in ISF that corresponds to a normal vs. abnormal level. “We’ll have to determine what levels of biomarker are normal, what levels are pathological.” And his research group is working on delivery methods for long distances and harsh conditions, providing options for improving rural healthcare.

“But we don’t have to do all of this ourselves,” Singamaneni said. Instead, the technology will be available to experts in different areas of medicine.

“We have created a platform technology that anyone can use,” he said. “And they can use it to find their own biomarker of interest.”

We don’t have to do all of this ourselves

Singamaneni and Erica L. Scheller, assistant professor of Medicine in the Division of Bone and Mineral Disease at the School of Medicine, worked together to investigate the concentration of biomarkers in local tissues.

Current approaches for such evaluation require the isolation of local tissues and do not allow successive and continuous inspection. Singamaneni and Scheller are developing a better platform to achieve long term monitoring of local biomarker concentration.

Working together

Srikanth Singamaneni, the Lilyan E. Lisle Hughes Professor in the Department of Mechanical Engineering & Materials Science, and Jai S. Rudra, assistant professor in the Department of Biomedical Engineering, worked together to look at cocaine vaccines, which work by blocking cocaine’s ability to enter the brain.

Current candidates for such a vaccine don’t confer long-lasting results; they require frequent boosting. Singamaneni and Rudra wanted a better way to determine when the effects of the vaccine had waned. “We’ve shown that we can use the patches to understand whether a person is still producing the necessary antibodies,” Singamaneni said. “No blood draw necessary.”