Excessive Brain Activity Linked to Shorter Life Span

Video: New research links excess neural activity — the flickering light seen in this image — to reduced longevity. Credit: Yankner lab, Harvard Medical School.

The brain’s neural activity — long implicated in disorders ranging from dementia to epilepsy — also plays a role in how long we live.

The study, led by scientists in the Blavatnik Institute at Harvard Medical School and based on findings from human brains, mice, and worms, suggests that excessive activity in the brain is linked to shorter life spans, while suppressing overactivity can extend life.

Neural activity refers to the constant flicker of electrical currents and transmissions in the brain. Excessive activity, or excitation, could manifest in numerous ways, from a muscle twitch to a change in mood or thought, according to the researchers.

“An intriguing aspect of our findings is that something as transient as the activity state of neural circuits could have such far-ranging consequences for physiology and life span,” said study senior author Dr. Bruce Yankner, a professor of genetics and co-director of the Paul F. Glenn Center for the Biology of Aging.

Neural excitation appears to act along a chain of molecular events famously known to influence longevity — the insulin and insulin-like growth factor (IGF) signaling pathway, the researchers explain.

The key in this signaling cascade appears to be a protein called REST, previously shown by researchers in the Yankner Lab to protect aging brains from dementia and other stresses.

Study results could lead to the design of new therapies for conditions that involve neural overactivity, such as Alzheimer’s disease and bipolar disorder, the researchers said.

The findings also raise the possibility that certain medicines, such as drugs that target REST, or certain behaviors, such as meditation, could extend life span by modulating neural activity, they said.

Human variation in neural activity might have both genetic and environmental causes, which would open future avenues for therapeutic intervention, Yankner added.

The researchers began their investigation by analyzing gene expression patterns — the extent to which various genes are turned on and off — in donated brain tissue from hundreds of people who died at ages ranging from 60 to over 100.

The information was collected through three separate research studies of older adults. Those analyzed in the current study were cognitively intact, meaning they had no dementia, the researchers noted.

The researchers immediately noticed a striking difference between the older and younger study participants, Yankner said. The longest-lived people — those over 85 — had lower expression of genes related to neural excitation than those who died between the ages of 60 and 80.

Next came the question that all scientists confront: Correlation or causation? Was this disparity in neural excitation merely occurring alongside more important factors determining life span or were excitation levels directly affecting longevity? If so, how?

To answer these questions, the researchers conducted a barrage of experiments, including genetic, cell, and molecular biology tests in the model organism Caenorhabditis elegans, analyses of genetically altered mice, and additional brain tissue analyses of people who lived for more than a century.

These experiments revealed that altering neural excitation does indeed affect life span and illuminated what might be happening on a molecular level, the researchers said, noting all signs pointed to the protein REST.

REST, which is known to regulate genes, also suppresses neural excitation, the researchers found.

Blocking REST or its equivalent in the animals led to higher neural activity and earlier deaths, while boosting REST did the opposite.

The researchers also discovered that people who lived to 100 and beyond had significantly more REST in the nuclei of their brain cells than people who died in their 70s or 80s.

“It was extremely exciting to see how all these different lines of evidence converged,” said study co-author Dr. Monica Colaiácovo, a professor of genetics at Harvard Medical School, whose lab collaborated on the C. elegans work.

The researchers found that from worms to mammals, REST suppresses the expression of genes that are centrally involved in neural excitation, such as ion channels, neurotransmitter receptors, and structural components of synapses.

Lower excitation activates a family of proteins known as forkhead transcription factors. These proteins have been shown to mediate a “longevity pathway” via insulin/IGF signaling in many animals. It’s the same pathway that scientists believe can be activated by caloric restriction, according to the researchers.

In addition to its emerging role in staving off neurodegeneration, discovery of REST’s role in longevity provides additional motivation to develop drugs that target the protein, the researchers said.

Although it will take time and many tests to determine whether such treatments reduce neural excitation, promote healthy aging, or extend life span, the concept has captivated some researchers.

“The possibility that being able to activate REST would reduce excitatory neural activity and slow aging in humans is extremely exciting,” said Colaiácovo.

The study was published in Nature.

Source: Harvard Medical School

 

Slower Walkers Have Older Brains and Bodies at 45

A new study shows that people with a lower walking speed at the age of 45 have accelerated aging of both their bodies and their brains.

Using a 19-measure scale, researchers at Duke University found that in slower walkers, their lungs, teeth and immune systems tended to be in worse shape than the people who walked faster. MRI exams showed several indications that their brains were also older.

“The thing that’s really striking is that this is in 45-year-old people, not the geriatric patients who are usually assessed with such measures,” said lead researcher Line J.H. Rasmussen, a post-doctoral researcher in the Duke University Department of Psychology and Neuroscience.

“Doctors know that slow walkers in their seventies and eighties tend to die sooner than fast walkers their same age,” said senior author Terrie E. Moffitt, the Nannerl O. Keohane University Professor of Psychology at Duke University, and Professor of Social Development at King’s College London. “But this study covered the period from the preschool years to midlife and found that a slow walk is a problem sign decades before old age.”

The data come from a long-term study of nearly 1,000 people who were born during a single year in Dunedin, New Zealand. The 904 research participants in the current study have been tested, quizzed, and measured their entire lives, mostly recently from April 2017 to April 2019 at age 45.

Researchers note that neurocognitive testing that these individuals took as children predicted who would become slower walkers. At age 3, their scores on IQ, understanding language, frustration tolerance, motor skills, and emotional control predicted their walking speed at age 45, according to the researchers.

MRI exams during their last assessment showed the slower walkers tended to have lower total brain volume, lower mean cortical thickness, less brain surface area and higher incidence of white matter “hyperintensities,” small lesions associated with small vessel disease of the brain. In short, their brains appeared somewhat older, they said.

Adding insult to injury, the slower walkers also looked older to a panel of eight screeners who assessed each participant’s “facial age” from a photograph, the researchers reported.

Walking speed has long been used as a measure of health and aging in geriatric patients, but what’s new in this study is the relative youth of these study subjects and the ability to see how walking speed matches up with health measures the study has collected during their lives, the researchers explained.

“It’s a shame we don’t have gait speed and brain imaging for them as children,” Rasmussen said. (The MRI was invented when they were five, but was not given to children for many years after.)

Some of the differences in health and cognition may be tied to lifestyle choices these individuals have made, the researchers noted.

But the study also suggests that there are already signs in early life of who would become the slowest walkers, Rasmussen said.

“We may have a chance here to see who’s going to do better health-wise in later life.”

The study was published in JAMA Network Open.

Source: Duke University

Photo: A long-term study has found that signs of aging may be detected by a simple walking test at age 45, and that the brains of slower walkers were different at age 3. Credit: Duke University Communications.

Two-Year-Olds From Poor Neighborhoods More Likely to Have Language Difficulties

Two-year-olds from disadvantaged backgrounds are three times more likely to develop difficulties with language than those from more affluent areas, according to a new Scottish study published in the journal JAMA Network Open.

Researchers say the findings highlight the need for policy makers to address the social factors that can hinder speech, language and communication (SLC) development.

Failing to do so means children might not fully develop the language skills necessary for emotional development, wellbeing and educational and employment opportunities.

“Growing up in a disadvantaged neighbourhood where there is poverty and reduced access to services is closely associated with problems with preschool language development,” said Professor James Boardman of Neonatal Medicine at the University of Edinburgh’s MRC Centre for Reproductive Health.

“These results suggest that policies designed to lessen deprivation could reduce language and communication difficulties among pre-school children.”

For the study, a research team from the University of Edinburgh and NHS Lothian in Scotland looked at more than 26,000 records of children who had received a routine health review between 27 and 30 months between April 2013 and April 2016.

The findings show that two-year-olds living in the most economically deprived neighborhoods were three times more likely to have SLC concerns compared to those brought up in better-off areas.

It is believed that growing up in neighborhoods with low income and unemployment — which is related to problems with education, health, access to services, crime and housing — can increase the risk of setbacks.

The researchers also discovered that being born prematurely had an impact on language issues. The findings show that each week a child spent in the womb from 23 to 36 weeks was associated with an 8.8% reduction in the likelihood of the children having an SLC concern reported at 27 months.

A pregnancy is considered full term between 39 weeks and 40 weeks, 6 days, while preterm birth is defined as delivery before 37 weeks of gestation. Socioeconomic disadvantage has also been associated with a greater risk for preterm birth.

Although the research team looked at birth data from children born in the Lothians, experts say similar results might be expected across the United Kingdom.

Source: University of Edinburgh

Thrashing Sleep More Common Among Veterans With PTSD

Military veterans with post-traumatic stress disorder (PTSD) or concussion are much more likely to develop REM sleep behavior disorder (RBD) — a thrashing form of sleep behavior — compared to the general population, according to a new study published in the journal SLEEP.

Next, the researchers from the VA Portland Health Care System and Oregon Health & Science University (OHSU) want to investigate whether RBD might provide an early signal of neurodegenerative conditions such as Parkinson’s disease.

Typically, during REM (rapid eye movement) sleep, a person’s muscles are effectively paralyzed. In cases of RBD, however, the brain’s control of muscle paralysis is impaired, resulting in people acting out their dreams, sometimes causing injuries to themselves or their partners.

RBD is estimated to affect less than 1% of the general population. However, the researchers found that 9% of the 394 veterans in this study had RBD, and this number increased to 21% among those with PTSD.

“This is important because, in the general population, RBD has been linked to Parkinson’s disease, and RBD often precedes classic symptoms of Parkinson’s by years,” said senior author Miranda Lim, M.D., Ph.D., a staff physician at the VA and assistant professor of neurology, medicine and behavioral neuroscience in the OHSU School of Medicine.

“We don’t know whether veterans who have PTSD and higher rates of RBD will go on to develop Parkinson’s, but it is an important question we need to answer.”

Researchers suspect chronic stress on the brain may play a role in causing the sleep disorder in veterans with PTSD, as many veterans have been exposed to concussion which potentially accelerates neurodegenerative processes.

Each participant underwent an overnight sleep study at the VA Portland Health Care System between 2015 and 2017 to determine the presence of dream enactment during episodes of REM sleep. Muscle activity was monitored constantly during the 8 hours of the study in order to diagnose RBD. The findings show that participants with PTSD had over 2-fold increased odds of RBD compared to veterans without PTSD.

“RBD seems to be highly prevalent in veterans with a history of trauma,” said lead author Jonathan Elliott, Ph.D., a research physiologist at the Portland VA and assistant professor of neurology in the OHSU School of Medicine.

Doctors involved in the study, including co-authors Kristianna Weymann, Ph.D., R.N., a clinical assistant professor in the OHSU School of Nursing, and Dennis Pleshakov, a student at the OHSU School of Medicine, will continue to track research participants with RBD, looking for early signs of Parkinson’s or other neurodegenerative conditions.

Although there are several approaches to ease certain Parkinson’s symptoms, including tremor and fatigue, there is no definitive therapy to prevent the condition.

Clinical trials for promising therapies are usually conducted well after patients have been diagnosed with Parkinson’s, at a stage which may be too late to reverse the symptoms. Lim said that identifying patients with RBD presents an opportunity to identify people earlier in the disease course, and potentially provides a more viable window to test promising interventions.

“By the time a patient shows classic symptoms of Parkinson’s, it may be too late,” Lim said. “If you could intervene when people first start to show RBD, maybe you could prevent later symptoms of Parkinson’s.”

Source: Oregon Health & Science University

 

Brain Scans May Predict Suicide Risk

New research has identified brain circuitry differences that might be associated with suicidal behavior in individuals with mood disorders.

The study provides a promising lead toward tools that can predict which individuals are at the highest risk for suicide, according to researchers at the University of Utah Health and the University of Illinois at Chicago.

Suicide rates are rising steadily among young adults, especially those with mood disorders, such as depression. More than half of individuals who commit suicide saw a health professional within the past 30 days, but they did not necessarily seek care for mood problems, the researchers note.

“At present, we have very few tools to identify individuals who may be at high risk for suicide-related behavior,” said Dr. Scott Langenecker, a professor of psychiatry at the University of Utah Health and senior author on the study. “Right now, we go on self-report and clinician judgment. Those are good, but they’re not great.”

Previous studies identified brain circuits associated with mood disorders: The cognitive control network (CCN), which is involved in executive function, problem-solving and impulsivity; the salience and emotional network (SEN), which is involved in emotion processing and regulation; and the default mode network (DMN), which is active when individuals are engaged in self-focused thought.

However, these studies focused primarily on depression, according to the researchers.

“This is one of the first studies to try to understand brain mechanisms that may be relevant to suicide risk,” said Dr. Jonathan Stange, an assistant professor of psychiatry at the University of Illinois at Chicago and first author on the study.

The study used resting-state functional MRI (fMRI), which captured brain images while participants were rested and calm, to assess the connectivity of these circuits in 212 young adults at the University of Illinois at Chicago and the University of Michigan.

“For risk factors involved in suicide, the tasks we have to measure are pretty nonspecific and inexact,” Langenecker said. “If we go to the level of the resting-state networks, we’re actually asking the brain to tell us which brain networks and connections are most relevant.”

The study included individuals with mood disorders and a history of suicide attempts, those with mood disorders and a history of suicidal thoughts, those with mood disorders and no history of suicidal behavior or thoughts, and healthy controls. All study participants with mood disorders were in remission, the researchers noted.

Compared with other study participants — even those with mood disorders and a history of suicidal thoughts — people with a history of suicide attempts showed less connectivity in the CCN and between the CCN and DMN, neural circuitry associated with cognitive control and impulsivity, according to the study’s findings.

These differences could present a target for treatment, according to the researchers.

“If we could figure out how to improve connectivity within this brain circuit, we might be able to reduce suicide risk in the future,” Stange said.

Stange and Langenecker emphasize the research is still in its early stages. This was a small study, with only 18 participants with mood disorders and a history of suicide attempts. It will have to be replicated in a larger number of participants, they said.

In addition, the researchers note it is not yet clear whether individuals with mood disorders and at risk for suicide have a different disease from those without such risk, or whether all individuals with mood disorders are at varying degrees of risk for suicide.

The study was published in Psychological Medicine.

Source: The University of Illinois at Chicago

Large Study Shows PTSD Has Strong Genetic Component

In the largest and most diverse genetic study to date of post-traumatic stress disorder (PTSD), scientists reveal that PTSD has a strong genetic component similar to other psychiatric disorders.

The findings are published in the journal Nature Communications.

Despite much research, it has remained unclear why some people go on to develop PTSD after a traumatic event while others do not. Some researchers suggest that the disorder is only a social construct, but other studies point to the fact that genetics may be involved.

In the new study, researchers from the University of California (UC) San Diego School of Medicine and more than 130 additional institutions participating in the Psychiatric Genomics Consortium suggest that genetics may account for between five and 20 percent of the variability in PTSD risk following exposure to a traumatic event.

“Our long-term goal is to develop tools that might help clinicians predict who is at greatest risk for PTSD and personalize their treatment approaches,” said the study’s first and corresponding author Caroline Nievergelt, Ph.D., associate professor of psychiatry at UC San Diego School of Medicine and associate director of neuroscience in the Center of Excellence for Stress and Mental Health at the Veterans Affairs San Diego Healthcare System.

“We can’t always protect people from trauma. But we can treat them in the best ways possible, at the best time.”

The findings show that, like other psychiatric disorders and many other human traits, PTSD is highly polygenic, meaning it is associated with thousands of genetic variants throughout the genome, each making a small contribution to the disorder.

According to the findings, six genomic regions called “loci” contain variants strongly associated with disease risk, providing some clues about the biological pathways involved in PTSD.

“Based on these findings, we can say with certainty that there is just as much of a genetic component to PTSD risk as major depression and other mental illnesses,” said senior author Dr. Karestan Koenen, associate member of the Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard.

“Our limited ability to study the living human brain and uncover the biological roots of PTSD has contributed to the lack of treatments and the stigma around this debilitating condition. Genetics helps us make new discoveries, find opportunities for new therapies, and counter that stigma,” she said.

Since many behavioral traits and psychiatric disorders have some shared genetic factors, the researchers also looked for genetic correlations between PTSD and 235 other disorders, behaviors and physical traits. They discovered significant overlap with 21, including depression, schizophrenia, neuroticism, insomnia, asthma and coronary artery disease.

“Similar to other mental disorders, the genetic contribution to PTSD correlates with that for many other traits,” said Koenen, who is also professor of psychiatric epidemiology in the Harvard T.H. Chan School of Public Health. “Further research is needed to determine what this means — whether some of the same genes that influence risk for PTSD also influence risk for other diseases like, for example, depression.”

To conduct the study, the team collaborated with the Psychiatric Genomics Consortium’s PTSD working group and Cohen Veterans Bioscience, a non-profit organization dedicated to accelerating PTSD and traumatic brain injury research.

The team built an international network of more than 200 researchers, assembling data and DNA samples from more than 60 groups of people with PTSD and control subjects, including the UK Biobank.

The data included more than 200,000 people, which is 10 times larger than the first Psychiatric Genomics Consortium PTSD study, published in 2017. The study group is also the most ancestrally diverse for any psychiatric genetics study to date, with more than 23,000 people with PTSD of European ancestry and more than 4,000 of African ancestry. It also included both civilians and members of the military.

“Our study is distinguished by the fact that it’s international and is highly diverse,” Nievergelt said. “There’s greater representation here than in most studies to date.”

The team used the data to conduct a genome-wide association study (GWAS), using statistical tests to measure the effect of common genetic variants at millions of points across the genome on someone’s likelihood of developing PTSD.

The study uncovered DNA variants at six loci that were significantly tied to PTSD risk. Three of the six loci were specific to certain ancestral backgrounds — two European and one African — and three were only detected in men.

The six loci hint that inflammatory and immune mechanisms may be at play in the disorder, which is consistent with findings from previous research.

Overall, the researchers conclude that PTSD’s heritability — the level of influence genetics has on the variability of PTSD risk in the population — is between five and 20 percent, with some variability by gender. These findings were similar across different ancestral groups.

The research team also developed a polygenic score that could potentially predict one’s risk of developing PTSD following a traumatic event. Polygenic scores take into account the effects of millions of genetic variations and create a measure that can predict a person’s risk of developing a certain trait or disorder.

The team tested their scores on data from men in the UK Biobank dataset, finding that those with the highest scores had 0.4-fold greater odds of developing than those with the lowest scores.

Similarly, when applied to data from the Million Veterans Program — a study of how genes, lifestyle and military exposures impact health and illness — individuals with the highest scores had a significant increase in re-experiencing traumatic memories — a key PTSD symptom.

The researchers assert that polygenic scores are not ready for clinical use. Even larger studies with more diverse datasets are needed to improve the accuracy of PTSD prediction and confirm the genetic findings.

Source: University of California- San Diego