Yale scientists discover how stress changes the brain to make memories stronger

 Stress does more than influence how we feel. It can also change what we remember, particularly when an experience is emotionally intense or personally meaningful. Scientists have long known that cortisol, a hormone released during stressful situations, can strengthen emotional memories. What has been less clear is exactly how this happens inside the brain.

Researchers at Yale University have now uncovered important clues. Their study reveals that cortisol strengthens emotional memories by changing how brain networks involved in emotion and memory function and communicate with one another. The findings offer a deeper understanding of why certain experiences leave such powerful impressions while others quickly fade.

"We all experience stress, and my lab is interested in understanding how stress can be helpful," said corresponding author Elizabeth Goldfarb, an assistant professor of psychiatry at Yale School of Medicine and of psychology in the Faculty of Arts and Sciences.

The findings were published in the journal Science Advances.

How Stress Hormones Influence Memory

Previous research involving both humans and rodents has shown that stress and cortisol can improve memory for emotional events. Scientists also know that certain brain regions, including the amygdala, play an essential role in this process. The amygdala is particularly important for processing emotions and identifying experiences that may be significant.

However, understanding precisely how cortisol strengthens memories has been challenging. Many brain regions participate in several mental functions, making it difficult to determine whether the hormone is influencing emotional responses, memory formation, or both.

"Forming memories for emotional experiences involves different processes in the brain: first, perceiving an experience as emotional or intense, and second, encoding that experience into long-term memory," said Goldfarb, who is also a member of Yale's Wu Tsai Institute, an interdisciplinary research initiative that explores cognition.

The researchers wanted to examine these processes separately to determine how cortisol affects the brain's ability to recognize emotional significance and preserve an experience as a lasting memory.

Watching the Brain Form Emotional Memories

To investigate, the Yale team conducted an experiment in which participants took a pill containing either hydrocortisone, a form of cortisol, or an inactive placebo. They then viewed a series of pictures while undergoing functional MRI (fMRI) scanning.

This imaging technique measures changes in blood flow and oxygen levels associated with brain activity, allowing researchers to identify which areas of the brain are more active during different tasks.

As participants examined the pictures, they reported their emotional reactions to each image. The following day, researchers tested how well they remembered what they had seen.

Each person completed the experiment twice, once after receiving hydrocortisone and once after receiving the placebo. The study used a double blind design, meaning neither the participants nor the experimenter knew which substance had been administered during a particular session.

This approach allowed the scientists to compare how the same person's brain responded with and without the additional cortisol.

A Five-Second Look at Brain Network Activity

One of the study's most important advances came from the way researchers analyzed the brain scans.

Scientists often study a measurement called functional connectivity, which describes how closely activity in different parts of the brain fluctuates together. When two regions show synchronized patterns of activity, it can indicate that they are participating in related processes.

Traditionally, examining these relationships requires several minutes of brain imaging data. The Yale team instead analyzed functional connectivity during individual trials lasting only around five seconds.

Using these brief snapshots, the researchers tested whether patterns of brain activity could predict two different outcomes: how emotionally intense participants found a picture and whether they would remember that picture the following day.

The approach worked for both. By identifying patterns associated with emotional intensity and memory formation separately, the scientists were able to examine how cortisol influenced each network and the interactions between them.

This gave the researchers a more detailed picture of the changing brain activity associated with emotional memory formation.

Source: ScienceDaily

Scientists uncover 3 key brain pathways linked to lasting depression relief

 Scientists at Mount Sinai have identified three important brain connections associated with long-term improvement in patients receiving deep brain stimulation (DBS) for severe depression that has not responded to conventional treatments. The discovery could help researchers make this experimental therapy more precise and effective.

Published October 1 in the American Journal of Psychiatry, the research examined the largest group of patients assembled across multiple independent cohorts to date who had received subcallosal cingulate deep brain stimulation (SCC DBS) for treatment-resistant depression.

The researchers found that lasting improvements were consistently associated with electrical stimulation reaching three specific white matter pathways: the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.

These findings strengthen the case for using detailed maps of the brain's connections to determine exactly where electrodes should be implanted, rather than choosing their positions based primarily on anatomical landmarks. Known as connectome-based targeting, this strategy has already helped shape the ongoing Abbott TRANSCEND clinical trial, a randomized, controlled study that uses individualized brain connectivity maps to guide SCC DBS treatment.

"This study underscores the importance of individualized surgical targeting for achieving optimal outcomes with deep brain stimulation for depression," said Helen Mayberg, MD, Mount Sinai Professor in Neurotherapeutics and founding Director of the Nash Family Center for Advanced Circuit Therapeutics at the Icahn School of Medicine at Mount Sinai. "In any randomized controlled trial of a neuromodulation treatment, precise lead placement and confirmation that the intended brain target has been engaged are essential first steps. We still have much to learn about which patients are most likely to benefit from stimulation of this particular target, but developing imaging-based signatures that can match patients to their optimal treatment remains a central goal of our research."

How Deep Brain Stimulation Targets Severe Depression

For people with treatment-resistant depression, standard therapies have failed to provide adequate relief. Researchers are investigating deep brain stimulation as a possible treatment for individuals living with severe, persistent symptoms.

The procedure involves surgically placing electrodes inside the brain to deliver controlled electrical signals to circuits involved in depression. However, positioning the electrodes correctly remains one of the greatest challenges.

Electrical stimulation does not simply affect the brain tissue closest to an implanted electrode. It can also influence larger networks through the white matter pathways that connect different brain regions. As a result, two patients with electrodes implanted in nearly identical locations may experience very different outcomes depending on which connections are actually stimulated.

Earlier research from Mount Sinai and Emory University helped establish the importance of these networks. In studies published between 2014 and 2023 in Biological Psychiatry, Molecular Psychiatry, and Nature, the teams identified white matter pathways associated with successful SCC DBS treatment and developed a method for planning electrode placement using brain connectivity maps.

The latest investigation sought to determine whether those connections were also important in patients treated at other research centers. Scientists also wanted to understand whether differences in the pathways reached by stimulation could help account for patients who did not benefit.

Three Brain Connections Linked to Lasting Improvement

To investigate, the researchers examined information from several clinical studies, including the BROADEN trial and a patient cohort at the University of Toronto, where SCC DBS was originally developed.

They used computer models of the electrical fields generated by implanted electrodes alongside maps of brain connectivity. This allowed them to estimate which pathways received stimulation and compare those patterns across different patient groups.

The results showed a consistent relationship between sustained improvement and stimulation of the cingulum bundle, forceps minor, and medial uncinate fasciculus/ventral amygdalofugal pathways.

One finding was especially notable. Across the study sites, patients who had not responded to treatment after two years showed a lack of stimulation engagement with the left cingulum bundle.

The researchers did not investigate whether moving electrodes to reach this pathway would improve those patients' symptoms. Nevertheless, the pattern offers a possible explanation for why apparently similar electrode placements can produce different results. An electrode might be positioned in the correct general region but still fail to activate all the connections associated with lasting improvement.

"This study addresses an important question in DBS: not simply which area of the brain to stimulate, but which connections within that area need to be engaged," said Brian Kopell, MD, Director of the Center for Neuromodulation at Mount Sinai. "For a network disorder such as depression, millimeters can determine whether stimulation reaches the pathways we intend to modulate. Identifying and reproducibly engaging those pathways gives us a more precise surgical target and a framework for understanding why otherwise similar electrode placements may produce different clinical outcomes."

Source: ScienceDaily

Breakthrough PTSD treatment achieves 68% remission rate in clinical trial

  A new approach to treating post-traumatic stress disorder (PTSD) has received FDA clearance, offering a personalized alternative for people who have not found sufficient relief through existing treatments. Developed by California-based Wave Neuroscience in collaboration with researchers at the Texas A&M Health Institute of Biosciences and Technology, the technology uses brain activity measurements to guide targeted magnetic stimulation.

Early clinical trial findings have been encouraging. According to Wave Neuroscience, patients experienced a 52% reduction in PTSD symptoms, while 68% achieved remission. The full findings are still being prepared for public release, but researchers believe the technology could significantly expand treatment options for millions of people.

The need for more effective PTSD care is substantial. In the United States, approximately 17.5 veterans die by suicide each day, and about 7% of veterans receive a PTSD diagnosis annually.

PTSD can develop after traumatic experiences such as military combat, serious accidents, natural disasters, or violence. An estimated 6% of Americans will experience PTSD during their lifetime, with higher rates among women and veterans.

Why Current PTSD Treatments Are Not Enough

Since PTSD was formally recognized as a diagnosis in 1980, treatment has largely centered on psychotherapy and medications known as selective serotonin reuptake inhibitors (SSRIs), including sertraline and fluoxetine.

Although these approaches can help, many patients continue to experience symptoms despite receiving treatment.

A 2020 review of PTSD medications found that patients reported improvements ranging from 6.8 to 10.1 points on symptom assessments. However, remission rates reached only 10.9% at most.

Wave Neuroscience reported substantially stronger preliminary outcomes in its clinical trial. Erik Won, DO, the company's chief medical officer, described the results as a major advance over previously reported medication outcomes.

“In comparison to that study, our FDA trial reported a 52% reduction in symptoms, so more than a four-fold increase in efficacy,” Won said. “And more importantly, we saw 68% remission in our clinical trial. So, it’s really a quantum change, an inflection point in what we can offer to patients. From a clinical care perspective, that’s really meaningful.”

These findings are promising, although the results come from different studies and should not be interpreted as a direct comparison of treatment effectiveness.

How Personalized Brain Stimulation Works

The newly cleared system uses Magnetic e-Resonance Therapy (MeRT), a technology that combines measurements of brain activity with targeted magnetic stimulation.

First, an electroencephalogram (EEG) records the brain's electrical signals. This information helps guide a personalized treatment plan using transcranial magnetic stimulation, or TMS.

During TMS, a coil positioned against the scalp delivers magnetic pulses that stimulate brain activity. The technique has already been used for other psychiatric conditions, including treatment-resistant depression.

What distinguishes MeRT is its use of an AI-assisted algorithm to customize stimulation protocols based on each patient's brain activity rather than relying on a standardized approach.

“Transcranial magnetic stimulation, or TMS, was previously FDA cleared for treatment-resistant depression,” Won said. “By adding an augmented AI derived multivariate algorithm, we were able to personalize protocols that received FDA clearance for post-traumatic stress disorder, which should open up market access to about 13 million people who may be struggling with PTSD.”

Dr. Kenneth S. Ramos, a physician-scientist at Texas A&M Health with extensive experience in precision medicine, helped guide the research.

His work focuses on adapting medical care to the characteristics of individual patients instead of assuming that everyone will respond to the same treatment.

“Most clinical interventions for the treatment of PTSD do not work very well,” Ramos said. “So, this is a huge area where identifying interventions that could hopefully add quality of life to the people impacted by this disorder would be tremendously impactful.”

Wave Neuroscience CEO Fred Walke said Ramos was a natural fit for the project because of his expertise in personalized medicine.

Targeting PTSD With Greater Precision

Conventional TMS generally follows treatment protocols that are less individualized. MeRT builds on the same underlying technology but adjusts treatment according to the patient's specific brain activity.

Ramos emphasized that even small biological differences between people can have major implications for medical care. Humans are approximately 99.9% genetically alike, yet the remaining 0.1% contributes to differences that can influence how individuals respond to treatment.

Source: ScienceDaily

Poor sleep linked to migraine attacks

 A new study by researchers at the University of Arizona Health Sciences identified a link between poor sleep and migraine attacks that suggests improving sleep health may diminish migraine attacks in people with migraine.

Many people with migraine report having sleeping disorders, including insomnia, trouble falling or staying asleep, poor sleep quality, excessive daytime sleepiness, waking up from sleep and being forced to sleep because of a migraine headache. Until now, it was unknown whether migraine causes poor sleep or vice versa.

"It has been recognized for quite a long time that there is a relationship between sleep and migraine," said principal investigator Frank Porreca, PhD, research director for the Comprehensive Center for Pain & Addiction and professor of pharmacology at the UArizona College of Medicine -- Tucson. "The way it has been investigated in the past has been through patient-reported information, which is subjective. We quantitatively measured sleep in preclinical models and found that migraine-like pain does not influence sleep, but if you have disrupted sleep, your chances of having a migraine attack if you're a migraine patient are much higher."

Porreca led a research team that used preclinical mouse models to evaluate sleep disruption, as the sleep architecture of mice closely matches that of people, including cycles of deep sleep, REM sleep and light sleep. Sleep was assessed using electroencephalogram recordings and visual observations.

Researchers found that when mice were sleep deprived, they were more likely to experience migraine-like pain, but migraine-like pain did not disrupt normal sleep.

Porreca noted that sleep deprivation can happen for many reasons, including stress. For this study, the research team ensured they were studying the effect of sleep, and not stress, on migraine by giving mice novel objects to explore to keep them awake.

"Mice are compelled to explore novel objects. They just have to go and look," Porreca said. "It reminds me of how teenagers are often sleep deprived because they're on their phones. Anybody who studies sleep will tell you that from a sleep hygiene point of view, you don't want any devices in your bedroom where you're trying to sleep."

For people with migraine, limiting the use of electronic devices before bedtime and following other sleep health tips could be an easy way to limit the likelihood of migraine attacks.

"Early morning is one of the most common times people experience migraine attacks," Porreca said. "Migraine is highly female prevalent -- it's 3 to 1, women to men -- and almost all the women are of childbearing age. Many people with migraine probably have children. They wake up with a migraine attack and are immediately stressed. They don't have time to take care of themselves, they have to get the kids ready for school and they have to get ready for work. That migraine attack is happening in the worst time of the day for function. Improved sleep is critically important and probably would diminish the frequency of migraine attacks."

The American Migraine Foundation estimates more than 39 million people in the U.S. live with migraine, though that number is probably higher due to the number of people who do not get a diagnosis or treatment.

Source: ScienceDaily

Do astronauts experience 'space headaches'?

 Space travel and zero gravity can take a toll on the body. A new study has found that astronauts with no prior history of headaches may experience migraine and tension-type headaches during long-haul space flight, which includes more than 10 days in space. The study was published in the March 13, 2024, online issue of Neurology®, the medical journal of the American Academy of Neurology.

"Changes in gravity caused by space flight affect the function of many parts of the body, including the brain," said study author W. P. J. van Oosterhout, MD, PhD, of Leiden University Medical Center in the Netherlands. "The vestibular system, which affects balance and posture, has to adapt to the conflict between the signals it is expecting to receive and the actual signals it receives in the absence of normal gravity. This can lead to space motion sickness in the first week, of which headache is the most frequently reported symptom. Our study shows that headaches also occur later in space flight and could be related to an increase in pressure within the skull."

The study involved 24 astronauts from the European Space Agency, the U.S. National Aeronautics and Space Administration (NASA) and the Japan Aerospace Exploration Agency. They were assigned to International Space Station expeditions for up to 26 weeks from November 2011 to June 2018.

Prior to the study, nine astronauts reported never having any headaches and three had a headache that interfered with daily activities in the last year. None of them had a history of recurrent headaches or had ever been diagnosed with migraine.

Of the total participants, 22 astronauts experienced one or more episode of headache during a total of 3,596 days in space for all participants.

Astronauts completed health screenings and a questionnaire about their headache history before the flight. During space flight, astronauts filled out a daily questionnaire for the first seven days and a weekly questionnaire each following week throughout their stay in the space station.

The astronauts reported 378 headaches in flight.

Researchers found that 92% of astronauts experienced headaches during flight compared to just 38% of them experiencing headaches prior to flight.

Of the total headaches, 170, or 90%, were tension-type headache and 19, or 10%, were migraine.

Researchers also found that headaches were of a higher intensity and more likely to be migraine-like during the first week of space flight. During this time, 21 astronauts had one or more headaches for a total of 51 headaches. Of the 51 headaches, 39 were considered tension-type headaches and 12 were migraine-like or probable migraine.

In the three months after return to Earth, none of the astronauts reported any headaches.

"Further research is needed to unravel the underlying causes of space headache and explore how such discoveries may provide insights into headaches occurring on Earth," said Van Oosterhout. "Also, more effective therapies need to be developed to combat space headaches as for many astronauts this a major problem during space flights."

Source: ScienceDaily

A third of women experience migraines associated with menstruation, most commonly when premenopausal

 A third of the nearly 20 million women who participated in a national health survey report migraines during menstruation, and of them, 11.8 million, or 52.5%, were premenopausal. The analysis was conducted by researchers at Georgetown University Medical Center and Pfizer, Inc., which makes a migraine medication.

Because of the underuse of medications to help treat or prevent menstrual migraines, investigators wanted to understand how common menstrual migraines were and which groups of women could most benefit from potential therapies. The study will be presented April 16, at the American Academy of Neurology 2024 Annual Meeting in Denver.

"The first step in helping a woman with menstrual migraine is making a diagnosis; the second part is prescribing a treatment; and the third part is finding treatments patients are satisfied with and remain on to reduce disability and improve quality of life," says the study author, Jessica Ailani, MD, professor of clinical neurology at Georgetown University School of Medicine and director of the MedStar Georgetown Headache Center at Medstar Georgetown University Hospital.

The researchers used the 2021 U.S. National Health and Wellness Survey, conducted by the National Center for Health Statistics, to analyze responses from women who reported their current migraine treatments, frequency and disabilities via the Migraine Disability Assessment Test (MIDAS), a five-question survey. A migraine headache can cause severe throbbing pain or a pulsing sensation, usually on one side of the head. It's often accompanied by nausea, vomiting, and extreme sensitivity to light and sound.

"Discrepancies in the incidence of who gets migraine attacks associated with menses is likely due to premenopausal women having more regular menstrual cycles and thus more menstrual-related migraines," says Ailani. "Additionally, as women move into their 40's and become peri-menopausal, there tends to be a greater shift through the month in hormone levels also leading to frequent migraine attacks."

The survey found that for all women during their menstrual periods, migraine attacks occurred as frequently as 4.5 times and that monthly only migraine headaches lasted 8.4 days, on average; 56.2 % of women had moderate-to-severe migraine-specific disabilities that ranked highest on the MIDAS scale.

When looking at treatments women in the survey used to help control their migraine symptoms, 42.4% used over-the-counter medications while 48.6% used prescription medications. Of the 63.9 % of women who used migraine treatments for acute symptoms, the most commonly used were triptans, a class of drugs developed in the 1990s to quiet overactive nerves associated with migraines and cluster headaches.

Source: ScienceDaily

Could preventative drug be effective in people with migraine and rebound headache?

 A drug used to prevent migraine may also be effective in people with migraine who experience rebound headaches, according to a new study published in the June 26, 2024, online issue of Neurology®, the medical journal of the American Academy of Neurology.

People with chronic migraine who overused pain medication had fewer monthly migraine and headache days and fewer days using pain medication when taking the migraine prevention drug atogepant.

"There is a high prevalence of pain medication overuse among people with migraine as they try to manage what are often debilitating symptoms," said study author Peter J. Goadsby, MD, PhD, of King's College London and a member of the American Academy of Neurology. "However, medication overuse can lead to more headaches called rebound headaches, so more effective preventive treatments are needed. Our findings are encouraging, suggesting atogepant may help reduce the need for pain medication among people with chronic migraine."

The study involved 755 participants who had chronic migraine, defined as having 15 or more headache days per month with eight or more qualifying as migraine.

Of this group, 66% met the criteria for medication overuse defined as taking pain medications such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen for 15 or more days in a month, triptans or ergots for 10 or more days a month, or any combination for 10 or more days.

At the start of the study, average monthly migraine days ranged from 18 to 19, and average monthly pain medication days ranged from 15 to 16.

For 12 weeks, participants were either given 30 milligrams (mg) of atogepant twice daily, 60 mg once daily, or a placebo. Atogepant is a calcitonin gene-related peptide receptor antagonist, or CGRP inhibitor. CGRP is a protein that plays a key role in starting the migraine process.

Participants recorded their migraines and headaches in an electronic diary, noting characteristics including duration and intensity, whether they experienced aura or nausea, and if they took other medications.

Researchers found for participants with medication overuse, those taking atogepant twice daily had an average of three fewer migraine days a month and three fewer headache days when compared to those taking placebo. Those taking the drug once a day had two fewer migraine days a month and two fewer headache days compared to placebo. Both groups also had three fewer days of taking pain medications to treat their symptoms when compared to placebo. Researchers say similar reductions were found among participants without medication overuse.

In those with medication overuse, 45% of those taking the drug twice daily and 42% of those taking it once a day had a 50% or more reduction in average monthly migraine days compared to 25% taking the placebo.

The number of people meeting the criteria for medication overuse also declined by 62% among those taking the drug twice daily and by 52% among those taking it once a day.

"Based on our findings, treatment with atogepant may potentially decrease the risk of developing rebound headache by reducing the use of pain medications," said Goadsby. "This could lead to an improved quality of life for those living with migraine."

Goadsby noted more studies are needed to evaluate the long-term safety and effectiveness of atogepant, as well as to assess the potential risk of medication overuse relapse among people with migraine.

A limitation of the study was that participants recorded their headaches and medication use in electronic diaries, so it is possible some participants may not have recorded all information accurately.

The study was funded by AbbVie, the maker of atogepant. Goadsby reported that he received personal fees from AbbVie during the study.

Source: ScienceDaily