How sleep deprivation harms memory

August 23, 2016
Science Daily/eLife
Researchers have discovered a piece in the puzzle of how sleep deprivation negatively affects memory.

For the first time, a study in mice, to be published in the journal eLife, shows that five hours of sleep deprivation leads to a loss of connectivity between neurons in the hippocampus, a region of the brain associated with learning and memory.

"It's clear that sleep plays an important role in memory -- we know that taking naps helps us retain important memories. But how sleep deprivation impairs hippocampal function and memory is less obvious," says first author Robbert Havekes, PhD, Assistant Professor at the Groningen Institute for Evolutionary Life Sciences.

It has been proposed that changes in the connectivity between synapses -- structures that allow neurons to pass signals to each other -- can affect memory. To study this further, the researchers examined the impact of brief periods of sleep loss on the structure of dendrites, the branching extensions of nerve cells along which impulses are received from other synaptic cells, in the mouse brain.

They first used the Golgi silver-staining method to visualize the length of dendrites and number of dendritic spines in the mouse hippocampus following five hours of sleep deprivation, a period of sleep loss that is known to impair memory consolidation. Their analyses indicated that sleep deprivation significantly reduces the length and spine density of the dendrites belonging to the neurons in the CA1 region of the hippocampus.

They repeated the sleep-loss experiment, but left the mice to sleep undisturbed for three hours afterwards. This period was chosen based on the scientists' previous work showing that three hours is sufficient to restore deficits caused by lack of sleep. The effects of the five-hour sleep deprivation in the mice were reversed so that their dendritic structures were similar to those observed in the mice that had slept.

The researchers then investigated what was happening during sleep deprivation at the molecular level. "We were curious about whether the structural changes in the hippocampus might be related to increased activity of the protein cofilin, since this can cause shrinkage and loss of dendritic spines," Havekes says.

"Our further studies revealed that the molecular mechanisms underlying the negative effects of sleep loss do in fact target cofilin. Blocking this protein in hippocampal neurons of sleep-deprived mice not only prevented the loss of neuronal connectivity, but also made the memory processes resilient to sleep loss. The sleep-deprived mice learned as well as non-sleep deprived subjects."

Ted Abel, PhD, Brush Family Professor of Biology at the University of Pennsylvania and senior author of the study, explains: "Lack of sleep is a common problem in our 24/7 modern society and it has severe consequences for health, overall wellbeing, and brain function.

"Despite decades of research, the reasons why sleep loss negatively impacts brain function have remained unknown. Our novel description of a pathway through which sleep deprivation impacts memory consolidation highlights the importance of the neuronal cell network's ability to adapt to sleep loss. What is perhaps most striking is that these neuronal connections are restored with several hours of recovery sleep. Thus, when subjects have a chance to catch up on much-needed sleep, they are rapidly remodeling their brain."
Science Daily/SOURCE :https://www.sciencedaily.com/releases/2016/08/160823125219.htm

Study strengthens evidence that cognitive activity can reduce dementia risk

Bias analysis shows any confounding factors not enough to account for benefits found in previous studies

August 24, 2016
Science Daily/Massachusetts General Hospital
A formal bias analysis of previous studies finding that cognitive activities can reduce the risk of Alzheimer's disease and other dementias concluded that any confounding factors in the earlier studies probably do not totally account for any associations between cognitive activity and dementia risk.

Are there any ways of preventing or delaying the development of Alzheimer's disease or other forms of age-associated dementia? While several previously published studies have suggested a protective effect for cognitive activities such as reading, playing games or attending cultural events, questions have been raised about whether these studies reveal a real cause-and-effect relationship or if the associations could result from unmeasured factors. To address this question, a Boston-based research team conducted a formal bias analysis and concluded that, while potentially confounding factors might have affected previous studies' results, it is doubtful that such factors totally account for observed associations between cognitive activities and a reduced risk of dementia.

"Our paper lends support to a potential role for late-in-life cognitive activity in prevention of Alzheimer's disease," says Deborah Blacker MD, ScD, director of the Gerontology Research Unit in the Massachusetts General Hospital Department of Psychiatry and senior author of the report in the September issue of the journal Epidemiology. "While it is possible that socioeconomic factors such as educational level might contribute to the association between cognitive activity and reduced risk, any bias introduced by such factors is probably not strong enough to fully account for the observed association."

Blacker and her colleagues from Harvard T.H. Chan School of Public Health maintain a database on the Alzheimer's Research Forum website cataloging evidence from observational studies and some clinical trials about known and proposed risk and protective factors for the devastating neurologic disorder. The current paper was developed from the database's systematic review of studies examining the impact of cognitive activity, conducted by lead author Guatam Sajeev, ScD, as part of his Harvard Chan school dissertation.

The research team analyzed 12 peer-reviewed epidemiologic studies that examined the relationship between late-in-life cognitive activities and the incidence of Alzheimer's disease or other forms of dementia. The studies were selected on the basis of prespecified criteria for the AlzRisk database, included almost 14,000 individual participants and consistently showed a benefit, sometimes substantial, for cognitive activity.

Since any observational studies are likely to be confounded by unmeasured factors -- such as participants' socioeconomic level or the presence of conditions like depression -- the researchers also conducted a bias analysis designed to evaluate how much such factors might influence reported associations between the amount of cognitive activity and dementia risk. This analysis indicated that bias due to unmeasured factors was unlikely to account for all of the association because the impact of such factors is likely to be considerably smaller than the observed effect.

The group also investigated the possible role of reverse causation -- whether a reduction in cognitive activity among those already in the long phase of cognitive decline that precedes Alzheimer's dementia might have led to an apparent rather than a real causal relationship. The findings of that analysis could not rule out the possibility that reverse causation contributed substantially to the observed associations, but analyses restricted to studies with longer term follow-up might be better able to address this question, the authors note.

"Ultimately, clinical trials with long-term follow-up are the surest way to definitively address reverse causation," says co-author and AlzRisk co-director Jennifer Weuve, MPH, ScD, of Boston University School of Public Health. "Trials could also confront the vexing question of whether training to improve specific cognitive skills has benefits that extend into everyday functions. But not every question about cognitive activity is well-suited for a trial. To fill those gaps, innovations in epidemiology, such as the analytic techniques used in this study, should help us get even greater insights from available observational data."

Blacker adds, "Cognitive activity looks like it may offer some modest protection, and based on our bias analysis, I am somewhat less skeptical than I was previously. But remember that any impact will be relative, not absolute. I typically advise people to engage in cognitive activities that they find interesting and enjoyable for their own sake. There is no evidence that one kind of activity is better than another, so I would advise against spending money on programs claiming to protect against dementia."
Science Daily/SOURCE :https://www.sciencedaily.com/releases/2016/08/160824144019.htm

Western diet increases Alzheimer's risk

August 25, 2016
Science Daily/Taylor & Francis
Globally, about 42 million people now have dementia, with Alzheimer’s disease as the most common type of dementia. Rates of Alzheimer’s disease are rising worldwide. The most important risk factors seem to be linked to diet, especially the consumption of meat, sweets, and high-fat dairy products that characterize a Western Diet. The evidence of these risk factors, which come from ecological and observational studies, also shows that fruits, vegetables, grains, low-fat dairy products, legumes, and fish are associated with reduced risk.

In addition to reviewing the journal literature, a new ecological study was conducted using Alzheimer's disease prevalence from 10 countries (Brazil, Chile, Cuba, Egypt, India, Mongolia, Nigeria, Republic of Korea, Sri Lanka, and the United States) along with dietary supply data 5, 10, and 15 years before the prevalence data. Dietary supply of meat or animal products (minus milk) 5 years before Alzheimer's disease prevalence had the highest correlations with Alzheimer's disease prevalence in this study. The study discussed the specific risk each country and region faces for developing Alzheimer's disease based on their associated dietary habits.

Residents of the United States seem to be at particular risk, with each person in the U.S. having about a 4% chance of developing Alzheimer's disease, likely due in part to the Western dietary pattern, which tends to include a large amount of meat consumption. The author, William B. Grant, states, "reducing meat consumption could significantly reduce the risk of Alzheimer's disease as well as of several cancers, diabetes mellitus type 2, stroke, and, likely, chronic kidney disease."

He concludes, "Mounting evidence from ecological and observational studies, as well as studies of mechanisms, indicates that the Western dietary pattern -- especially the large amount of meat in that diet -- is strongly associated with risk of developing Alzheimer's disease and several other chronic diseases. Although the traditional Mediterranean diet is associated with about half the risk for Alzheimer's disease of the Western diet, the traditional diets of countries such as India, Japan, and Nigeria, with very low meat consumption, are associated with an additional 50% reduction in risk of Alzheimer's disease."
Science Daily/SOURCE :https://www.sciencedaily.com/releases/2016/08/160825102121.htm

Scientists shed new light on the role of calcium in learning, memory

August 26, 2016
Science Daily/The Scripps Research Institute
While calcium's importance for our bones and teeth is well known, its role in neurons -- in particular, its effects on processes such as learning and memory -- has been less well defined. A new study offers insights into how calcium in mitochondria -- the powerhouse of all cells -- can impact the development of the brain and adult cognition.

In particular, the team showed in fruit flies, a widely used model system, that blocking a channel that brings calcium to the mitochondria, called "mitochondrial calcium uniporter," causes memory impairment but does not alter learning capacity.

"When we knocked down the activity of the uniporter, we found that flies have a deficit memory," said Ron Davis, chair of the TSRI's Department of Neuroscience. "Intact uniporter function is necessary for full and complete memory in the adult fly. What surprised us is that they were still able to learn -- albeit with a fleeting memory. But we thought they wouldn't be able to learn at all."

The mitochondrial calcium uniporter protein, first identified in 2011, allows calcium ions to move from the cell's interior into mitochondria -- like coal moving through a shoot into a furnace room. It is regulated by other proteins known as MICU1, MICU2 and EMRE. Davis noted that human patients with mutations in MICU1 can exhibit learning disabilities.

"The new study's conclusion is that mitochondrial calcium entry during development is necessary to establish the neuronal competency for supporting adult memory," said TSRI Research Associate Ilaria Drago, the first author of the study.

Drago noted the team found evidence that inhibiting mitochondrial calcium uniporter function led to a decrease in the content of synaptic vesicles (miniscule sacs within the cell where various neurotransmitters are stored) and an increase in the length of axons (the slender filaments of neurons).

While these structural problems were clearly observed, she added, what they mean in terms of neuronal development remains tantalizingly unclear.

"The discovery of a developmental role for the mitochondrial calcium uniporter complex in regulating memory in adult flies is especially intriguing and deserves more exploration," said Davis.

https://www.sciencedaily.com/releases/2016/08/160826083948.htm

Caffeine and its analogues counteract memory deficits by normalizing stress responses in the brain

August 30, 2016
Science Daily/INSERM (Institut national de la santé et de la recherche médicale)
A new study describes the mechanism by which caffeine counteracts age-related cognitive deficits in animals. The study shows that the abnormal expression of a particular receptor -- adenosine A2A, a target for caffeine -- in the brain of rats induces an aging-like profile: namely, memory impairments linked to the loss of stress controlling mechanisms.

The study coordinated by Portuguese researchers from Instituto de Medicina Molecular (iMM Lisboa) and collaborators from Inserm in Lille, France, along with teams from Germany and United States, showed that the abnormal expression of a particular receptor -- adenosine A2A, a target for caffeine -- in the brain of rats induces an aging-like profile: namely, memory impairments linked to the loss of stress controlling mechanisms.

"This is part of a larger study initiated 4 years ago in which we identified the role of this receptor in stress, but we did not know whether its activation would be sufficient to trigger all the changes. We now found that by altering the amount of this receptor alone in neurons from hippocampus and cortex -- memory related areas -- is sufficient to induce a profile that we designate as 'early-aging' combining the memory loss and an increase in stress hormones in plasma (cortisol)," explains Luisa Lopes, Group Leader at iMM Lisboa and the coordinator of the study.

When the same animals were treated with a caffeine analogue, which blocks the action of adenosine A2A receptors, both memory and stress related deficits were normalized.

David Blum, from Inserm research director, adds: "In elderly people, we know there is an increase of stress hormones that have an impact on memory. Our work supports the view that the procognitive effects of A2AR antagonists, namely caffeine, observed in Alzheimer's and age-related cognitive impairments may rely on this ability to counteract the loss of stress controlling mechanisms that occurs upon aging."

"This is important not only to understand the fundamental changes that occur upon aging, but it also identifies the dysfunctions of the adenosine A2A receptor as a key player in triggering these changes. And a very appealing therapeutic target," concludes Luisa Lopes.
Science Daily/SOURCE :https://www.sciencedaily.com/releases/2016/08/160830113749.htm

Sleeping brain's complex activity mimicked by simple model

New mathematical model could improve understanding of memory consolidation during deep sleep

September 1, 2016
Science Daily/PLOS
Researchers have built and tested a new mathematical model that successfully reproduces complex brain activity during deep sleep, according to a new study.

Recent research has shown that certain patterns of neuronal activity during deep sleep may play an important role in memory consolidation. Michael Schellenberger Costa and Arne Weigenand of the University of Lübeck, Germany, and colleagues set out to build a computational model that could accurately mimic these patterns.

The researchers had previously modeled the activity of the sleeping cortex, the brain's outer layer. However, sleep patterns thought to aid memory arise from interactions between the cortex and the thalamus, a central brain structure. The new model incorporates this thalamocortical coupling, enabling it to successfully mimic memory-related sleep patterns.

Using data from a human sleep study, the researchers confirmed that their new model accurately reproduces brain activity measured by electroencephalography (EEG) during the second and third stages of non-rapid eye movement (NREM) sleep. It also successfully predicts the EEG effects of stimulation techniques known to enhance memory consolidation during sleep.

The new model is a neural mass model, meaning that it approximates and scales up the behavior of a small group of neurons in order to describe a large number of neurons. Compared with other sleep models, many of which are based on the activity of individual neurons, this new model is relatively simple and could aid in future studies of memory consolidation.

"It is fascinating to see that a model incorporating only a few key mechanisms is sufficient to reproduce the complex brain rhythms observed during sleep," say senior authors Thomas Martinetz
 

How 'super aging' older adults retain youthful memory abilities

September 13, 2016
Science Daily/Massachusetts General Hospital
Some loss of memory is often considered an inevitable part of aging, but new research reveals how some people appear to escape that fate.

The study published in The Journal of Neuroscience is the first step in a research program aimed at understanding how some older adults retain youthful thinking abilities and the brain circuits that support those abilities. The program is led by Bradford Dickerson, MD, director of the Frontotemporal Disorders Unit in the MGH Department of Neurology and Lisa Feldman Barrett, PhD, MGH Department of Psychiatry, who are co-senior authors of the new study.

While most older adults experience a gradual decline in memory ability, some researchers have described older adults -- sometimes called "super agers" -- with unusually resilient memories. For the current study, the MGH team enrolled adults ages 60 to 80 -- 17 of whom performed as well as adults four to five decades younger on memory tests, and 23 with normal results for their age group -- and 41 young adults ages 18 to 35.

"Previous research on super aging has compared people over age 85 to those who are middle aged," says Alexandra Touroutoglou, PhD, MGH Neurology, co-senior author with Dickerson and Barrett. "Our study is exciting because we focused on people around or just after typical retirement age -- mostly in their 60s and 70s -- and investigated those who could remember as well as people in their 20s.

Imaging studies revealed that these super agers had brains with youthful characteristics. While the cortex -- the outermost sheet of brain cells that is critical for many thinking abilities -- and other parts of the brain typically shrink with aging, in the brains of super-agers a number of those regions were comparable in size to those of young adults. "We looked at a set of brain areas known as the default mode network, which has been associated with the ability to learn and remember new information, and found that those areas, particularly the hippocampus and medial prefrontal cortex, were thicker in super agers than in other older adults. In some cases, there was no difference in thickness between super agers and young adults," Touroutoglou says.

Barrett, who is also University Distinguished Professor at Northeastern University, adds, "We also examined a group of regions known as the salience network, which is involved in identifying information that is important and needs attention for specific situations, and also found preserved thickness among super-agers in several regions, including the anterior insula and orbitofrontal cortex."

Critically, the researchers showed not only that super-agers had no shrinkage in these brain networks but also that the size of these regions was correlated with memory ability. One of the strongest correlations between brain size and memory was found in an area at the intersection of the salience and default mode networks. Previous research has shown that this region -- the para-midcingulate cortex -- is an important hub that allows different brain networks to communicate efficiently. "We believe that effective communication between these networks is very important for healthy cognitive aging," Touroutoglou says.

Understanding which factors protect against memory decline could lead to important advances in preventing and treating age-related memory loss and possibly even various forms of dementia, says Dickerson, who is an associate professor of Neurology at Harvard Medical School. "We desperately need to understand how some older adults are able to function very well into their seventh, eight, and ninth decades. This could provide important clues about how to prevent the decline in memory and thinking that accompanies aging in most of us."
Science Daily/SOURCE : https://www.sciencedaily.com/releases/2016/09/160913173303.htm

Brain benefits of aerobic exercise lost to mercury exposure

September 16, 2016
Science Daily/NIH/National Institute of Environmental Health Sciences
Cognitive function improves with aerobic exercise, but not for people exposed to high levels of mercury before birth, according to new research.

Adults with high prenatal exposure to methylmercury, which mainly comes from maternal consumption of fish with high mercury levels, did not experience the faster cognitive processing and better short term memory benefits of exercise that were seen in those with low prenatal methylmercury exposures.

This is one of the first studies to examine how methylmercury exposure in the womb may affect cognitive function in adults. Mercury comes from industrial pollution in the air that falls into the water, where it turns into methylmercury and accumulates in fish. The scientists, based at the Harvard T.H. Chan School of Public Health, suspect that prenatal exposure to methylmercury, known to have toxic effects on the developing brain and nervous system, may limit the ability of nervous system tissues to grow and develop in response to increased aerobic fitness.

"We know that neurodevelopment is a delicate process that is especially sensitive to methylmercury and other environmental toxins, but we are still discovering the lifelong ripple effects of these exposures," said Gwen Collman, Ph.D., director of the NIEHS Division of Extramural Research and Training. "This research points to adult cognitive function as a new area of concern.."

The 197 study participants are from the Faroe Islands, 200 miles north of England, where fish is a major component of the diet. Their health has been followed since they were in the womb in the late 1980s. At age 22, this subset of the original 1,022 participants took part in a follow-up exam that included estimating the participants' VO2 max, or the rate at which they can use oxygen, which increases with aerobic fitness. Also, a range of cognitive tests were performed related to short-term memory, verbal comprehension and knowledge, psychomotor speed, visual processing, long-term storage and retrieval, and cognitive processing speed.

Overall, the researchers found that higher VO2 max values were associated with better neurocognitive function, as expected based on prior research. Cognitive efficiency, which included cognitive processing speed and short term memory, benefitted the most from increased VO2 max.

But when the researchers divided the participants into two groups based on the methylmercury levels in their mothers while they were pregnant, they found that these benefits were confined to the group with the lowest exposure. Participants with prenatal methylmercury levels in the bottom 67 percent, or levels of less than 35 micrograms per liter in umbilical cord blood, still demonstrated better cognitive efficiency with higher VO2 max. However, for participants with higher methylmercury levels, cognitive function did not improve as VO2 max increased.

"We know that aerobic exercise is an important part of a healthy lifestyle, but these findings suggest that early-life exposure to pollutants may reduce the potential benefits," added Collman. "We need to pay special attention to the environment we create for pregnant moms and babies."

The U.S. Food and Drug Administration recommends that children and women of childbearing age eat two to three weekly servings of fish low in mercury as part of a healthy diet. Low mercury fish include salmon, shrimp, pollock, canned light tuna, tilapia, catfish, and cod. Four types of fish should be avoided because of typically high mercury levels -- tilefish from the Gulf of Mexico, shark, swordfish, and king mackerel.

The findings were published Sept. 9 in the journal Environmental Health Perspectives. In addition to NIH funding, the research was supported by the Danish Council for Strategic Research, Programme Commission on Health, Food, and Welfare.
Science Daily/SOURCE :https://www.sciencedaily.com/releases/2016/09/160916120631.htm

How the brain consolidates memories during sleep

October 5, 2016
Science Daily/Ruhr-Universitaet-Bochum
Researchers have studied which brain processes consolidate memories during sleep. They found clear parallels to findings from experimental animal studies.
https://images.sciencedaily.com/2016/10/161005083700_1_540x360.jpg
Hui Zhang analysed the EEG data.
Credit: © RUB, Damian Gorczany

Study with epilepsy patients

Axmacher recorded the brain activity of epilepsy patients who had had electrodes implanted in their brains for medical reasons. The researcher had analyzed EEG data from 13 patients that he had recorded at his former workplace, the Bonn University Hospital.

While the researchers recorded the EEG, the patients first viewed a series of landscape images; then they slept. Later the scientists tested which of the images the test subjects had memorized and which not.
 

Making nerve cells receptive

Postdoctoral researcher Hui Zhang analyzed the data. The preliminary result: During sleep, the same brain activation patterns occurred as when viewing the landscape photos. This reactivation was particularly related to so-called ripple oscillations in the brain.

Ripples are a specific kind of brain activity. A group of interconnected nerve cells sends out signals at high frequency for a short period of time. In the EEG they appear as a characteristic wave form. One theory is: After a ripple event, a brain area is more receptive for long-term storage of reactivated information.

This was also shown by the current analysis of the patient data. After a ripple there was stronger reactivation than during a comparable time period before a ripple.

Mechanism for learning in sleep

"Individual stimuli, in our case landscape images, are reactivated during sleep, and the ripples seem to actively maintain this reactivation," explains Nikolai Axmacher. However, the researchers found this enhancement mechanism only for the reactivation of those images that were recalled during the final test.

In other words: "When a ripple enhances the reactivation, the image is recalled later," says Axmacher. "We are thus apparently dealing with a mechanism for learning in sleep."

Science Daily/SOURCE :https://www.sciencedaily.com/releases/2016/10/161005083700.htm

Exercise may help ward off memory decline

October 19, 2016
Science Daily/American Academy of Neurology
Exercise may be associated with a small benefit for elderly people who already have memory and thinking problems, according to new research. The research involved people with vascular cognitive impairment, which is the second most common cause of dementia after Alzheimer's disease. In vascular cognitive impairment, problems with memory and thinking skills result from damage to large and small blood vessels in the brain.

The research involved people with vascular cognitive impairment, which is the second most common cause of dementia after Alzheimer's disease. In vascular cognitive impairment, problems with memory and thinking skills result from damage to large and small blood vessels in the brain.

"Studies have shown that exercise can help reduce the risk of developing memory problems, but few studies have looked at whether it can help people who already have these problems get better or keep from getting worse," said study author Teresa Liu-Ambrose, PT, PhD, of the University of British Columbia in Vancouver, Canada.

The study involved 70 people with an average age of about 74 who had mild vascular cognitive impairment. Half of the participants took part in one-hour exercise classes three times a week for six months. The other half received information each month about vascular cognitive impairment and a healthy diet, but no information on physical activity.

All of the participants were tested before the study started, at the end of the study and again six months later on their overall thinking skills, executive function skills such as planning and organizing and how well they could complete their daily activities.

Those who exercised had a small improvement on the test of overall thinking skills compared to those who did not exercise. The scores of those who exercised improved by 1.7 points compared to those who did not exercise.

"This result, while modest, was similar to that seen in previous studies testing the use of drugs for people with vascular cognitive impairment," Liu-Ambrose said. "However, the difference was less than what is considered to be a the minimal clinically important difference of three points."

Six months after the participants stopped the exercise program, their scores were no different than those who did not exercise. Also, there was no difference between the two groups at any point on the tests of executive function skills or daily activities.

Those who exercised also improved compared to the other group in their blood pressure and on a test of how far they could walk in six minutes, which measured overall cardiovascular capacity. These findings are also important to note given that high blood pressure is a risk factor for developing vascular cognitive impairment.

Liu-Ambrose said more studies are needed to determine whether exercise can improve thinking abilities in people with mild vascular cognitive impairment. Because the study sample size was based on detecting a difference on the overall thinking skills test, large samples might be needed to detect differences in specific thinking abilities, such as planning, and everyday skills, such as managing one's finances.
Science Daily/SOURCE : https://www.sciencedaily.com/releases/2016/10/161019162748.htm