Brain fluid dynamics key to migraine mysteries, new therapies

 New research describes for the first time how a spreading wave of disruption and the flow of fluid in the brain triggers headaches, detailing the connection between the neurological symptoms associated with aura and the migraine that follows. The study also identifies new proteins that could be responsible for headaches and may serve as foundation for new migraine drugs.

"In this study, we describe the interaction between the central and peripheral nervous system brought about by increased concentrations of proteins released in the brain during an episode of spreading depolarization, a phenomenon responsible for the aura associated with migraines," said Maiken Nedergaard, MD, DMSc, co-director of the University of Rochester Center for Translational Neuromedicine and lead author of the new study, which appears in the journal Science. "These findings provide us with a host of new targets to suppress sensory nerve activation to prevent and treat migraines and strengthen existing therapies."

It is estimated that one out of 10 people experience migraines and in about a quarter of these cases the headache is preceded by an aura, a sensory disturbance that can includes light flashes, blind spots, double vision, and tingling sensations or limb numbness. These symptoms typically appear five to 60 minutes prior to the headache.

The cause of the aura is a phenomenon called cortical spreading depression, a temporary depolarization of neurons and other cells caused by diffusion of glutamate and potassium that radiates like a wave across the brain, reducing oxygen levels and impairing blood flow. Most frequently, the depolarization event is located in the visual processing center of the brain cortex, hence the visual symptoms that first herald a coming headache.

While migraines auras arise in the brain, the organ itself cannot sense pain. These signals must instead be transmitted from the central nervous system -- the brain and spinal cord -- to the peripheral nervous system, the communication network that transmits information between brain with the rest of the body and includes sensory nerves responsible for sending information such as touch and pain. The process of communication between the brain and peripheral sensory nerves in migraines has largely remained a mystery.

Fluid Dynamics Models Shed Light on Migraine Pain Origins

Nedergaard and her colleagues at the University of Rochester and the University of Copenhagen are pioneers in understanding the flow of fluids in the brain. In 2012, her lab was the first to describe the glymphatic system, which uses cerebrospinal fluid (CSF) to wash away toxic proteins in the brain. In partnership with experts in fluid dynamics, the team has built detailed models of how the CSF moves in the brain and its role in transporting proteins, neurotransmitters, and other chemicals.

The most widely accepted theory is that nerve endings resting on the outer surface of the membranes that enclose the brain are responsible for the headaches that follow an aura. The new study, which was conducted in mice, describes a different route and identifies proteins, many of which are potential new drug targets, that may be responsible for activating the nerves and causing pain.

As the depolarization wave spreads, neurons release a host of inflammatory and other proteins into CSF. In a series of experiments in mice, the researchers showed how CSF transports these proteins to the trigeminal ganglion, a large bundle of nerves that rests at the base of the skull and supplies sensory information to the head and face.

It was assumed that the trigeminal ganglion, like the rest of the peripheral nervous system, rested outside the blood-brain-barrier, which tightly controls what molecules enter and leave the brain. However, the researchers identified a previously unknown gap in the barrier that allowed CSF to flow directly into the trigeminal ganglion, exposing sensory nerves to the cocktail of proteins released by the brain.

Migraine-Associated Proteins Double During Brain Wave Activity

Analyzing the molecules, the researchers identified twelve proteins called ligands that bind with receptors on sensory nerves found in the trigeminal ganglion, potentially causing these cells to activate. The concentrations of several of these proteins found in CSF more than doubled following a cortical spreading depression. One of the proteins, calcitonin gene-related peptide (CGRP), is already the target of a new class of drugs to treat and prevent migraines called CGRP inhibitors. Other identified proteins are known to play a role in other pain conditions, such as neuropathic pain, and are likely important in migraine headaches as well.

"We have identified a new signaling pathway and several molecules that activate sensory nerves in the peripheral nervous system. Among the identified molecules are those already associated with migraines, but we didn't know exactly how and where the migraine inducing action occurred," said Martin Kaag Rasmussen, PhD, a postdoctoral fellow at the University of Copenhagen and first author of the study. "Defining the role of these newly identified ligand-receptor pairs may enable the discovery of new pharmacological targets, which could benefit the large portion of patients not responding to available therapies."

The researchers also observed that the transport of proteins released in one side of the brain reaches mostly the nerves in the trigeminal ganglion on the same side, potentially explaining why pain occurs on one side of the head during most migraines.

Source: ScienceDaily

New drug to prevent migraine may start working right away

 A drug recently approved to prevent migraine may start working right away, according to a study published in the December 23, 2024, online issue of Neurology®, the medical journal of the American Academy of Neurology. The study looked at the drug atogepant, which is a calcitonin gene-related peptide (CGRP) receptor antagonist taken by mouth.

"With many current drugs to prevent migraine, it takes time to find the right dosage for the individual and it can take weeks or even months for it to be most effective," said study author Richard B. Lipton, MD, of Albert Einstein College of Medicine in the Bronx, New York, and a Fellow of the American Academy of Neurology. "Some people give up and stop taking the drugs before they reach this point. Plus, many people experience side effects with current treatments. Developing a drug that works both effectively and quickly is critical."

In the study, people taking the drug atogepant were less likely to have a migraine on the first day of taking the drug compared to those taking a placebo. They also had fewer migraines per week during each of the first four weeks of the study and fewer migraines during the study overall than those taking a placebo.

For this study, researchers looked at the data from three trials on the safety and effectiveness of atogepant over 12 weeks to focus on how rapidly improvements appeared. The ADVANCE trial, which enrolled people with episodic migraine, had 222 people taking the drug and 214 taking placebo. The ELEVATE trial, which enrolled people with episodic migraine who had previously not responded well to other oral preventive treatments, had 151 on the drug and 154 on placebo. The PROGRESS trial, which enrolled people with chronic migraine, had 256 on the drug and 246 on placebo.

People with episodic migraine experience up to 14 migraine days per month. People with chronic migraine experience at least 15 days with headache per month, with at least eight days being characteristic of migraine.

On the first day of the study, 12% of those taking the drug in the first trial, the ADVANCE trial had a migraine, compared to 25% of those taking placebo. In the second trial, the ELEVATE trial, the numbers were 15% and 26%. For the third trial, the PROGRESS trial, the numbers were 51% and 61%.

When researchers adjusted for other factors that could affect the rate of migraine, they found that people taking the drug were 61% less likely to have a migraine in the first trial, 47% less likely in the second trial, and 37% less likely in the third trial.

For the first two trials, the people taking atogepant had an average of one fewer day with migraine per week, compared to an average of less than one-half day fewer per week for those taking the placebo. For the third trial, average migraine days per week declined by about 1.5 days for those taking the drug compared to about one day for those taking the placebo.

The people taking atogepant also showed improvement on assessments of how much migraine impaired their activities and their overall quality of life compared to people taking the placebo.

"Migraine is the second-leading cause of disability in the overall population and the leading cause of disability in young women, with people reporting negative effects on their relationships, parenting, career and finances," Lipton said. "Having a treatment that can act quickly and effectively addresses a key need."

A limitation of the study is that it involved mostly female and white participants, so the results may not apply to the overall population.

The study was supported by AbbVie, the maker of atogepant.

Source: ScienceDaily

Propranolol may reduce ischemic stroke risk in women with migraines

 A medication often used to treat high blood pressure and prevent migraines was associated with a reduction in ischemic stroke risk among women using the drug for migraine prevention, according to a preliminary study to be presented at the American Stroke Association's International Stroke Conference 2025. The meeting is in Los Angeles, Feb. 5-7, 2025, and is a world premier meeting for researchers and clinicians dedicated to the science of stroke and brain health.

Propranolol, a beta blocker medication used for treating high blood pressure and preventing migraines, had a stronger protective effect for ischemic stroke risk in women with migraine, particularly those without aura. However, the medication did not have the same protective effect on men.

Migraine headaches are common in the general population, but they occur three times more often in women than in men. This debilitating condition is associated with an increased risk of stroke. While the beta blocker propranolol can be used to prevent migraines, its effectiveness in reducing overall stroke risk is still uncertain.

"Migraine is an often-ignored risk factor for cardiovascular issues. Until recently, preventive treatments for people who have migraines were not available," said lead study author Mulubrhan Mogos, Ph.D., M.Sc., FAHA, an assistant professor at Vanderbilt University School of Nursing in Nashville, Tennessee. "Many women suffer from migraines, and it's important to note that propranolol may be beneficial for these women, particularly those who experience migraine without aura. This is an important discovery for those dealing with migraines."

Mogos also noted that migraine disproportionately affects women from historically under-resourced communities, and this disparity may impact the ability to achieve education goals or maintain stable employment, creating a vicious cycle. While new treatments have proven effective, they may not be accessible to women in these groups due to high costs.

For the study, researchers reviewed more than 3 million electronic health records from two large databases. In separate analyses, researchers identified people with migraine who developed stroke and those with migraine who did not develop stroke (control group). They then assessed whether the individuals were treated with propranolol for migraine and whether that treatment had impacted stroke risk.

"We initially looked at overall stroke and then ischemic stroke specifically. We refined our analysis further by controlling for possible confounders and found the association is significant and stronger for ischemic stroke," Mogos said.

After adjusting for potential variables, such as demographics (age, sex, race), other conditions (high blood pressure, diabetes, etc.) and hormonal factors (use of birth control, pregnancy -- considered separately for each woman) that might affect results the analysis found:

• Propranolol was significantly associated with a reduced risk of ischemic stroke in women with migraine, particularly in those without aura. The risk of developing a stroke was 52% lower for women taking the medication in one database analysis and 39% lower in the other. No stroke risk reduction was seen in men in either analysis group.
• The protective effect of propranolol was stronger for ischemic stroke and in women with migraine without aura. Migraine aura can include disturbances, such as flashing lights, blind spots, zigzag patterns or seeing colored spots. Other symptoms include tingling or numbness in the face or hands, difficulty speaking, dizziness or confusion.
• Secondary analyses showed lower overall stroke rates in women taking propranolol at multiple time points in both databases.

"Our findings indicate that women and health care professionals should discuss the advantages of preventive migraine interventions. For under-resourced individuals who bear a greater burden from this condition and may lack access to new treatments, we must ensure these treatments are available to them. This approach can help reduce health disparities," Mogos said.

"Migraine without aura may often be overlooked as a risk factor for stroke, especially in women, in whom previous literature has demonstrated that migraine is a stronger, more important risk factor compared with men. The study's findings are not surprising since we have strong evidence that medications similar to propranolol used to treat blood pressure reduce stroke risk substantially. The findings are potentially quite helpful, though, for women living with frequent migraine, as they suggest we have a good medication option that helps to prevent both migraines and strokes. This study is a great example of the important information that can be gained by studying women and men separately -- we can take advantage of known sex differences in stroke risk factors and move towards more personalized care," said Tracy E. Madsen, M.D., Ph.D., chair of the American Heart Association Clinical Cardiology (CLCD)/Stroke Women's Health Science Committee and associate professor of emergency medicine at The Robert Larner, M.D. College of Medicine at The University of Vermont. Madsen was not involved in the study.

Source: ScienceDaily

Scientists created a tiny device that can control your nerves to treat chronic pain

 A miniature medical device small enough to be delivered through a standard needle could change how doctors treat chronic pain and movement disorders. Developed by scientists at NYU Abu Dhabi in partnership with Cleveland Clinic Abu Dhabi, the technology can regulate nerve activity without surgical implantation, batteries, or connecting wires.

Roughly the size of a small seed, the device is injected into the body and positioned close to a specific nerve. Once in place, it sends carefully controlled electrical signals that alter the nerve's activity. Power is supplied wirelessly from outside the body, allowing doctors or patients to adjust the stimulation in real time.

The findings, published in Science Advances, describe a potentially less invasive way to deliver precise nerve stimulation. Rather than replacing existing treatments, which can include medications and surgically implanted devices, the technology could provide another option tailored to individual medical needs.

"This work represents a shift in how we think about treating nerve-related conditions," said Prof. Khalil Ramadi, Assistant Professor of Bioengineering at NYU Abu Dhabi and NYU Tandon and the study's senior author. "By creating a device that can be injected rather than surgically implanted, we are making these therapies simpler, safer, and more accessible, while still maintaining precise control over nerve activity."

Wireless Nerve Stimulation Without Surgery

One of the device's key advantages is that doctors can locate and monitor it using familiar imaging techniques, including ultrasound and computed tomography (CT) scans. These methods help guide placement near the intended nerve and allow the device's position to be checked afterward.

The implant also provides programmable electrical stimulation. This means the signals it delivers can be adjusted to suit a patient's needs, potentially giving healthcare providers greater flexibility in managing conditions that involve abnormal or unwanted nerve activity.

"This collaboration with NYU Abu Dhabi reflects our commitment to advancing innovative, clinically relevant research that translates into meaningful improvements in patient care," said Dr. Sawsan Abdel-Razig, Chief Academic Officer at Cleveland Clinic Abu Dhabi. "By bringing together multidisciplinary expertise, this work highlights how academic partnerships can accelerate the development of safer, less invasive therapies and expand access to advanced treatments for patients."

Promising Early Results for Chronic Pain Treatment

The researchers evaluated the technology through laboratory experiments and preclinical testing. Their results showed that the miniature device could deliver precise nerve stimulation while maintaining consistent performance under conditions designed to resemble real-world use.

Source: ScienceDaily

Eating olive oil before carbs has a surprising effect on blood sugar

 The order in which you eat different foods may have a surprising effect on blood sugar levels. Research in mice suggests that consuming fat before carbohydrates can reduce the sharp rise in blood sugar that typically follows a meal. The findings also reveal how hormones and nerve signals work together to influence this response.

Keeping blood sugar from rising too high after eating is an important part of diabetes management. Previous clinical studies have shown that eating vegetables, protein, or fat before carbohydrates can help limit these increases. This suggests that changing the sequence of foods during a meal could offer a practical, sustainable way to improve blood sugar control without eliminating entire food groups.

Scientists have generally explained this effect through two main mechanisms. The first is slower gastric emptying, which means food moves from the stomach into the small intestine more gradually. The second involves increased release of hormones called incretins, including GLP-1, which help the body regulate blood sugar.

However, researchers have not fully understood how hormones produced by the gut and pancreas interact with the nervous system to produce these effects. To investigate, an international research team examined how consuming fat before or after glucose influences blood sugar, hormone activity, and the speed at which the stomach empties.

"Our group has long been interested in practical dietary approaches that people can continue in everyday life," says corresponding author Daisuke Yabe of Kyoto University. "Meal-sequencing is appealing because it merely changes how a meal is eaten rather than requiring people to avoid entire food groups."

Testing How Olive Oil Changes Blood Sugar Levels

The researchers conducted a series of experiments in mice to determine whether the timing of fat consumption affected how the body processed glucose.

After an overnight fast, the mice were assigned to three groups. One group received water followed by glucose. A second group was given olive oil, followed 15 minutes later by glucose. The third group received glucose first, with olive oil administered 15 minutes afterward.

The scientists then measured blood glucose levels and several hormones involved in blood sugar regulation, including insulin, glucagon, GIP, and GLP-1. Glucagon is normally associated with increasing blood sugar, while GIP and GLP-1 help regulate glucose levels after eating.

To determine how quickly material was leaving the stomach, the researchers also administered acetaminophen, a common pain reliever. By measuring how much of the drug appeared in the bloodstream after oral administration, they could estimate the rate of gastric emptying.

The team extended the experiments to additional groups of mice, including animals with type 2 diabetes and others that lacked the receptor needed to respond to GLP-1.

They also performed experiments that blocked glucagon or GLP-1 signaling, surgically interrupted the vagus nerves below the diaphragm on both sides, and examined whether different dietary fats produced similar results. The vagus nerve is an important communication pathway between the brain and digestive system, helping coordinate functions such as digestion and hormone release.

Eating Fat First Slows Blood Sugar Spikes

The results showed a clear difference depending on when the mice received olive oil.

When olive oil was given before glucose, the initial rise in blood sugar was smaller than when the oil was administered afterward. The earlier fat intake also slowed gastric emptying, delaying the movement of glucose from the stomach into the intestine.

At the same time, consuming fat before glucose stimulated an early increase in several hormones, including glucagon, GIP, and GLP-1.

Importantly, these effects were also observed in mice with type 2 diabetes and severe insulin deficiency. This suggested that the response could still function even when normal insulin regulation was significantly impaired.

A Surprising Role for a Blood Sugar Hormone

One of the most unexpected findings involved glucagon, a hormone generally known for raising blood sugar by stimulating the liver to release stored glucose.

The researchers discovered that blocking glucagon signaling alone did not eliminate the blood sugar lowering effect of consuming olive oil before glucose. Blocking GLP-1 signaling by itself also failed to remove the benefit.

However, when both signaling pathways were blocked simultaneously, the beneficial effect was reduced.

This finding suggests that glucagon and GLP-1 work together as part of a more complex system that helps moderate blood sugar after fat is consumed before carbohydrates. It also reveals that glucagon, despite its familiar role in increasing blood sugar, can contribute to a response that ultimately limits the rise in glucose after eating.

Source: ScienceDaily

A plastic once thought harmless may be fueling fatty liver disease

 Microplastics have spread into nearly every corner of the environment. These tiny plastic particles have been found in ocean water, drinking water, and even inside the human body. Although their presence is well documented, scientists are still working to understand what prolonged exposure could mean for human health.

Researchers at the Texas A&M College of Veterinary Medicine and Biomedical Sciences (VMBS) have now identified a potential health concern involving polyethylene, one of the most widely used plastics in the world. Their findings suggest that polyethylene microplastics may contribute to fatty liver disease, particularly when exposure occurs alongside an unhealthy diet.

Polyethylene accounts for approximately one-third of plastic production worldwide. It is used in numerous everyday products, including food wrappers, storage containers, plastic packaging, and the linings of beverage cups. Despite its widespread use, scientists have devoted relatively little attention to its potential effects on the liver compared with other types of microplastics.

"No studies have really looked into polyethylene's effect on liver health, and it's the most widely produced plastic," said Dr. Adi Joshi, associate professor in VMBS' Department of Veterinary Physiology and Pharmacology. "What we now know is that these microplastics, especially polyethylene, affect our liver's natural defense and repair mechanisms."

Common Microplastics May Contribute to Fatty Liver Disease

To investigate the possible health effects of polyethylene, Joshi and his colleagues examined whether exposure to this common plastic could promote fatty liver disease.

The condition develops when excessive fat accumulates inside liver cells. According to the American Liver Foundation, it affects approximately 25% of people worldwide, making it a major global health concern.

The researchers discovered that polyethylene exposure increased indicators of fatty liver disease even without the added influence of an unhealthy diet. When the plastic was combined with a diet rich in fat, fructose, and cholesterol, the signs of liver disease became more severe.

These results suggest that exposure to environmental pollutants and poor dietary habits may reinforce each other's harmful effects, potentially worsening liver damage.

"Those who have a more Western-style diet, including foods like burgers and sodas, may have a greater chance of progressing to fatty liver disease if they are also exposed to polyethylene," Joshi said.

The results were especially unexpected because polyethylene has traditionally been regarded as a relatively biologically inert material. In other words, scientists generally considered it less likely to interact with biological systems than more reactive substances.

However, the findings indicate that polyethylene may influence liver function in ways that were previously overlooked. Its effects appeared both independently and alongside dietary risk factors, raising important questions about how this common plastic interacts with the body's metabolism and protective mechanisms.

Scientists Pinpoint How Microplastics Affect the Liver

Understanding where and how polyethylene causes biological changes could help explain its potential role in liver disease.

To investigate these effects in greater detail, the Texas A&M team partnered with scientists at the University of Oklahoma and applied a powerful technique called spatial transcriptomics.

This technology allows researchers to study gene activity while preserving information about where individual cells are located within a tissue. Rather than simply measuring which genes are active, scientists can identify precisely where biological changes are occurring.

Using this approach, the team mapped areas of liver damage associated with polyethylene exposure and identified molecular pathways that may help explain the effects.

One important finding involved PPAR-alpha, a protein that helps regulate fat metabolism in the liver. The researchers found that polyethylene activated this protein, suggesting that it plays a significant role in the liver's response to microplastics.

They also identified ANXA2, a gene associated with tissue repair, as another possible contributor to the disease process.

Together, these discoveries provide a more detailed picture of how polyethylene may interfere with the liver's normal functions, including the mechanisms involved in protecting and repairing damaged tissue.

Joshi believes that understanding these biological pathways could eventually help researchers identify potential treatments that reduce the harmful effects of microplastic exposure.

Source: ScienceDaily

The eye has a hidden cleanup system scientists never knew existed

 Scientists have uncovered a previously unknown cleanup system at the back of the eye, revealing a hidden route that allows fluid and waste to escape into the body's lymphatic system. The discovery challenges long-standing assumptions about how the eye functions and could eventually lead to new approaches for treating serious conditions that cause blindness.

Glaucoma, age-related macular degeneration, and several other major causes of permanent vision loss are associated with the accumulation of fluid, metabolic waste, and inflammatory material in the back of the eye. Until now, researchers have struggled to explain exactly how this sensitive region removes unwanted substances.

A team from the University of British Columbia (UBC) and the University of Toronto has identified a previously unrecognized drainage route called the posterior ocular lymphatic outflow, or POLO pathway. The system appears to carry fluid and waste away from the back of the eye and into the lymphatic network, which helps the body maintain fluid balance, remove waste, and support immune defenses.

The finding, demonstrated in mice, offers scientists a new way to investigate how the eye protects its delicate tissues and what happens when waste removal is disrupted.

"The retina is one of the most metabolically active parts of the body, constantly generating byproducts that need to be cleared," said Dr. Neeru Gupta, professor and head of UBC's department of ophthalmology and visual sciences. "This discovery helps explain how the eye flushes this waste and promises to transform how we think about and treat a range of eye conditions."

A Hidden Eye Drainage System Could Open New Paths to Treatment

The retina, the light-sensitive tissue at the back of the eye, requires substantial energy to convert incoming light into signals the brain can interpret. This constant activity produces metabolic byproducts that must be removed to keep the surrounding tissues functioning properly.

When fluid and waste accumulate, they can contribute to conditions that damage the eye. Glaucoma, macular degeneration, and other retinal disorders are associated with changes in fluid regulation, cellular waste buildup, tissue stress, and inflammation.

Age-related macular degeneration alone affects approximately 2.5 million Canadians, highlighting the potential importance of understanding the processes that keep the retina healthy.

The newly identified POLO pathway suggests that the back of the eye has a natural mechanism for moving unwanted material out of this vulnerable region. If scientists can determine how that mechanism works and whether it can be strengthened, it could provide a new target for therapies designed to protect vision.

"This gives us a whole new framework for understanding these diseases and a potential target for therapeutics," said Dr. Gupta. "The question now is: How can we enhance or exploit this cleanup system to treat or even prevent disease."

Source: ScienceDaily