Brain Blogger » Neuroscience & Neurology http://brainblogger.com Health and Science Blog Covering Brain Topics Wed, 13 May 2015 23:28:53 +0000 en-US hourly 1 http://wordpress.org/?v=4.2.2 Debunking the Myths of Marijuana Withdrawal “Syndrome” http://brainblogger.com/2015/05/13/debunking-the-myths-of-marijuana-withdrawal-syndrome/ http://brainblogger.com/2015/05/13/debunking-the-myths-of-marijuana-withdrawal-syndrome/#comments Wed, 13 May 2015 12:00:49 +0000 http://brainblogger.com/?p=19482 “Reefer Madness” ideology has yet to be quashed, where well-to-do, model students take one fateful puff and they are severely hooked, avoiding Trainspotting-esque withdrawal symptoms and instead spiral into a marijuana-laced world of paranoia, aggression, academic failure and mental illness. To the contrary, there are pro-marijuana myths, where marijuana could never be addictive and is a benign, happy little drug that can do absolutely no harm. As such, marijuana withdrawal syndrome is still considered by some to be just about as real as leprechauns, unicorns and the Easter bunny!

Back in reality, becoming addicted to cannabis is a real phenomenon. If you can get addicted to sausages (you can!) why not the green stuff? Putting it simply, addictions are compulsive behaviors that we continue to do despite the negative consequences.

Relatedly, marijuana withdrawal is real and is a diagnostic indicator of marijuana addiction. As with experiencing withdrawal from any addiction, there are physiological and psychological consequences that are unpleasant enough to encourage continued use for some users that are trying to quit.

As stated in a 2015 review in Clinical Pharmacology and Therapeutics:

“Chronic cannabis users typically experience unpleasant withdrawal symptoms when use is discontinued. These symptoms are much less severe than those associated with withdrawal from chronic opioid or depressant use, but aversive enough to encourage continued cannabis use and interfere with cessation attempts in some individuals.”

That being said, there is a load of uneducated nonsense perpetuated about marijuana addiction and withdrawal. Even today, major newspapers — like The Telegraph and The Daily Mail in the UK — have used blatant lies as front-page headlines, such as:

“Cannabis as Addictive as Heroin”

This shameless tabloid hysteria is continuing the misunderstanding of marijuana addiction and withdrawal, keeping us in the fiction and ideology-fueled dark ages. In reality, both of the mythical extremes — pot being super addictive and life destroying, or a totally innocent health giving and withdrawal-free substance — are just that, they are all smoke and mirrors, they are simply polar extreme modern day myths. The reality of marijuana addiction and withdrawal is somewhere in between.

Despite many gung-ho nay and yaysayers wasting their breath with the same old over opinionated claptrap, some real, tangible and clinical evidence is mounting that, if it can be heard over the nonsensical rabble, may be policy, life and society changing. Here are the latest, up-to-the-minute scientific facts on marijuana withdrawal syndrome (which we should note, as always, are susceptible to change and development).

Marijuana Addiction and Withdrawal: The Facts

Literally all scientific means of assessing the risk of taking a drug of abuse, from margin of exposure to expert panel ranking methods, are largely in agreement with one another. They place weed and its infamous active ingredient, THC, at the bottom of a very long list of addictive substances, where alcohol, heroin, crack cocaine and metamfetamine, and the seemingly benign and legal staple cigarettes and its active ingredient, nicotine, generally take the spotlight.

As published in the journal, Drug and Alcohol Dependence:

“The cumulative probability estimate of transition to dependence was 67.5% for nicotine users, 22.7% for alcohol users, 20.9% for cocaine users and 8.9% for cannabis users.”

This means that 9% of people who use marijuana are estimated to become dependent on it. As with all drugs, this value increases to ~16% for those who start smoking pot as teens, which is far less than for other drugs (e.g. 50-75% for cigarettes). Moreover, the chance of getting hooked if you smoke it for the first time after age 25 is practically nil, as described by Professor of Psychiatry, J. Michael Bostwick, M.D. in a paper published in Mayo Clinic Proceedings:

“The risk for new-onset dependence is essentially zero after the age of 25 years, whereas cocaine dependence continues to accrue until the age of 45 years. Likewise, the average age at first alcohol use is the same as for marijuana, but alcohol users will keep on making the transition from social use to dependence for decades after first use.”

With this in mind, the overwhelming majority of adults that smoke a little pot once in a while will not become addicted and thus never be at risk of experiencing withdrawal symptoms that promote relapse and spur addiction. However, as with every psychoactive drug, for more vulnerable users, such as those with chronic stress management problems, mental illness or a genetic predisposition to addiction, the chance of becoming addicted and experiencing withdrawal is undoubtedly greater.

So yes, marijuana withdrawal syndrome is real (it ain’t no Santa Claus, that’s for sure). Chronic and repeated overstimulation of the endocannabinoid system by regularly smoking marijuana can dampen the brain’s natural response to the essential neurotransmitter and cannabinoid receptor activator, dopamine. When abstaining, lower stimulation of cannabinoid receptors can result in the need, be it deemed psychological or physical, to continue use or ride out the negative consequences, i.e. adverse withdrawal symptoms.

Marijuana Withdrawal Syndrome: The Symptoms

So, what will someone addicted to marijuana expect to experience during withdrawal?

We found no research on gradual cannabis abstinence in the literature. However, as the gradual reduction of an agonist substance of dependence is typically associated with less severe and clinically significant withdrawal, The National Cannabis Prevention and Information Centre, NCPIC, surmize that:

“The relatively long plasma half-life of various active cannabis metabolites (typically cited as 1-4 days), suggests that a gradual reduction in cannabis use would be an effective strategy for people with cannabis dependence, where individuals are able to exert some control over their use or where access to their cannabis is regulated by a third party… Advice on gradual cannabis reduction may include smoking smaller bongs or joints, smoking fewer bongs or joints, commencing use later in the day and having goals to cut down by a certain amount by the next review.”

This is an area of research worthy of looking into, although not as profitable or evidently as popular as the many studies already published on a monthly basis investigating the use of pharmaceuticals to aid cannabis cessation.

On the flipside, for those going cold-turkey, 50% of dependent users experience mild to no symptoms, while the other 50% experience DSM-V worthy symptoms of cannabis withdrawal syndrome:

  • Within the first week, insomnia, loss of appetite or increase in appetite (considered equally as common), physical symptoms (stomach pain, shakiness/tremors, sweating, fever, chills or headache) and restlessness tend to approach a peak in their severity. Physical symptoms are generally reported as lower rates than other symptoms.
  • In the later phase of withdrawal,  irritability/anger and vivid, unpleasant dreams, tend to be at their worst more than a week after cessation. There are less reports of depressed moods in comparison with irritability and nervousness (see next point).
  • The symptom of nervousness has shown differing time-courses between studies. One study observed nervousness immediately after cessation, for another, nervousness was at its worst after 9 days.
  • Generally, cannabis withdrawal has been reported to follow a clear time-course with a peak in overall severity of symptoms at ~10 days after last use, followed by a gradual decline over the next 20 days.

That sounds much like the personal reports of marijuana withdrawal symptoms in BrainBlogger’s first ever post on Marijuana Withdrawal Syndrome. For example:

“After using heavily for the past 7 years, and basically all day every day for the last 6 months my side effects are major. i still cant sleep properly although at least now im getting 6 hours which isnt too bad. nausea every day. i have a bad stomach to begin with but i usually dont get sick every day. hot and cold sweats. im freezing right now but about half an hour ago i was boiling. i havent eaten properly since i stopped. the thing i dont like is that i feel spaced out constantly. i feel like im bent even when im not. and not bent in a calm relaxing way either.”

Spice Addiction and Withdrawal

Although deserving of a dedicated article it is important we mention the marijuana-based drug you may never have heard about, spice. Spice is actually a series of synthetic cannabinoids originally developed by pharmaceutical companies that fully activate cannabinoid receptors in the brain, whereas the main active substance in marijuana, THC, is merely a partial agonist in comparison.

While governments around the world are debating the legalization of marijuana, these largely legal synthetic drugs, that compared with marijuana next to nothing is known about, are beginning to ring serious alarm bells.

With natural cannabis, although many of the active chemicals have not been fully investigated, some, like CBD are known to have antipsychotic, anticonvulsive, anti-anxiety and neuroprotective properties that are considered to offset the potential negative side-effects from the main active ingredient THC. With spice products on the otherhand, they don’t contain these protective chemicals and instead only a super-potent version of THC.

Not only is the high itself is totally different and can be highly hallucinogenic and disorientating, it can even cause seizures, overdose and death, with seizures also known to be a symptom of withdrawal. There are a lot of potentially dangerous unknowns with spice. Just because its a legal pharmaceutical doesn’t mean its safe or effective.

Marijuana Withdrawal Syndrome: A Step Too Far?

Have you heard of nicotine withdrawal syndrome? Nope. Why? Because it has never been defined as such in any newspaper I could find online. Even drugs with the worst reputation when it comes to withdrawal symptoms, like heroin, crack and cocaine, have NEVER been defined as a “syndrome” by the mainstream media, although they are referred to as such in science journals. In fact, did you know that caffeine withdrawal has also been given the syndrome title?

Although syndrome simply means a group of signs and symptoms that occur together and characterize a particular abnormality or condition, it seems that journalists have unrightfully ganged up on ganja, portraying it as the only drug deserved of being associated with the more serious sounding term, syndrome.

With promise in being equal to or more effective than some pharmaceutical drugs in treating a number of illnesses (the list is eye-bogglingly phenomenal), shouldn’t we drop the “syndrome” fear mongering in the mainstream media?

It’s simple. It’s not widely addictive. The overwhelming majority of adults can enjoy its effects and not become addicted, and only half of those that become dependent will feel severe withdrawal symptoms. Indeed measures should be taken to understand and protect those at greatest risk from harm, yet we should not blow this out of proportion to prevent hindering the effective and beneficial uses of the cannabis plant.

Let’s not create smoke where there is no fire. Unless we equally apply the term, withdrawal syndrome, to other drugs, let’s drop the currently damaging term, syndrome, from popular media and stick with the bold, the descriptive, the representative, the simple: marijuana withdrawal.

References

Allsop DJ, Norberg MM, Copeland J, Fu S, & Budney AJ (2011). The Cannabis Withdrawal Scale development: patterns and predictors of cannabis withdrawal and distress. Drug and alcohol dependence, 119 (1-2), 123-9 PMID: 21724338

Budney AJ, & Hughes JR (2006). The cannabis withdrawal syndrome. Current opinion in psychiatry, 19 (3), 233-8 PMID: 16612207

Gorelick DA, Levin KH, Copersino ML, Heishman SJ, Liu F, Boggs DL, & Kelly DL (2012). Diagnostic criteria for cannabis withdrawal syndrome. Drug and alcohol dependence, 123 (1-3), 141-7 PMID: 22153944

Hesse M, & Thylstrup B (2013). Time-course of the DSM-5 cannabis withdrawal symptoms in poly-substance abusers. BMC psychiatry, 13 PMID: 24118963

Lopez-Quintero C, Pérez de los Cobos J, Hasin DS, Okuda M, Wang S, Grant BF, & Blanco C (2011). Probability and predictors of transition from first use to dependence on nicotine, alcohol, cannabis, and cocaine: results of the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). Drug and alcohol dependence, 115 (1-2), 120-30 PMID: 21145178

Nutt DJ, King LA, Phillips LD, & Independent Scientific Committee on Drugs (2010). Drug harms in the UK: a multicriteria decision analysis. Lancet, 376 (9752), 1558-65 PMID: 21036393

Sampson CS, Bedy SM, & Carlisle T (2015). Withdrawal Seizures Seen In the Setting of Synthetic Cannabinoid Abuse. The American journal of emergency medicine PMID: 25825034

Image via Yarygin / Shutterstock.

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Best and Worst of Neuroscience and Neurology – April 2015 http://brainblogger.com/2015/05/09/best-and-worst-of-neuroscience-and-neurology-april-2015/ http://brainblogger.com/2015/05/09/best-and-worst-of-neuroscience-and-neurology-april-2015/#comments Sat, 09 May 2015 12:00:33 +0000 http://brainblogger.com/?p=19639 In this article, I will present a selection of research articles published in April. As usual, many new interesting findings were made public this month, and the selection presented in this article reflects mostly my personal opinion of their importance.

27 April was the birthday of Edward Moser, director of the Kavli Institute for Systems Neuroscience and Centre for Neural Computation in Trondheim, Norway, and the receiver of the last year’s Nobel Prize in Physiology and Medicine. Prof. Mozer is heralded for discovering the brain’s positioning system, which helps us navigate in space and works, in a way, similar to GPS.

This month, a number of interesting articles shedding light on how our brain works and how the memories are formed were published.

THE BEST

Being slightly overweight helps the aging brain

People who are slightly overweight tend to have fewer health problems in the older age. In the midst of the current obesity crisis, this fact is rarely mentioned by the popular media.

It turns out that metabolic processes behind this phenomenon are directly linked with the brain. The process involves an enzyme called NAMPT, which is involved in the generation of energy and is produced mostly in the adipose tissue. NAMPT is released from the fat cells and is used elsewhere in the body, including the brain. Low amounts of fat result in low levels of NAMPT and, as a consequence, an insufficient energy supply to the brain. Hypothalamus is particularly affected by the low level of NAMPT. This is important, since the hypothalamus is a key regulator of many physiological functions such as body temperature, blood pressure, sleep cycle and others.

Same metabolic regulator is involved in physical and mental activities

Both physical activities such as running, and mental activities such as memorizing require lots of energy. It turned out that this is not the only similarity between the two. The energy flow in both cases is controlled by the same key metabolic regulator.

Researchers found that the protein ERR-gamma that activates various metabolic pathways turns on fat-burning in muscles and sugar-burning in brain. It is known that activation of ERR-gamma energizes muscles. Mice with missing ERR? were shown to be a very poor learners. Researchers hypothesize that increasing the levels of ERR-gamma may help to enhance learning skills and pave the way to improve the treatment of learning disorders.

Molecular mechanisms behind memory formation further deciphered

Molecular mechanisms underlying the formation of memories remain poorly studied. New paper published this month by neuroscientists from Vanderbilt University makes an important contribution to our understanding of these processes.

Formation of memories involves the formation of dendritic spines, tiny filaments making electrochemical connections between neurons. Researchers have identified a key signalling protein, Asef2, involved in the process of adhering between dendrites and axons. In response to yet unidentified signals, Asef2 triggers the production of actin. Actin is a key component of cytoskeleton that makes possible cell movement and stabilizes the newly formed connections. Formation of dendritic spines is affected in many neurological conditions such as autism and Alzheimer’s disease. It is possible that this process can be restored by targeting the specific proteins involved.

Sleep as a management tool for Alzheimer’s?

Like most of other neurodegenerative conditions, Alzheimer’s disease currently has no effective treatments. But can a simple lifestyle modification, such as getting enough sleep, help in the management of this condition? At least, this appears to be true for the fruit flies with Alzheimer’s-like syndromes.

Scientists have shown that extra sleep helps to restore their ability to form new memories. It remains to be seen if such simple intervention can be helpful for human patients. It was recently shown that a short daytime nap can improve memory as much as 5-fold in healthy humans.

Complex nature of nicotine withdrawal symptoms

Quitting smoking is not an easy task. Nicotine appears to be a very addictive substance, and withdrawal symptoms such as anxiety contribute substantially to the failure of many smokers to get rid of the habit. In a new article published this month, researchers revealed specific neuronal circuits behind the withdrawal symptoms.

Researchers found that signals from two brain regions, the ventral tegmental area (part of the brain associated with pleasure and rewards) and the medial habenula, come together to the interpeduncular nucleus and trigger a number of processes, including the elevation of corticotropin releasing factors (CRF) level. The latter is known to be involved in response to the stress. This increased stimulation of interpeduncular nucleus triggers the feeling of anxiety. The good news is that the drugs blocking CRF receptors already exist, and it might be possible to use them to reduce the stimulation of interpeduncular nucleus and, thus, anxiety.

THE WORST

As usual, this month we have seen a number of publications that have changed our views on some important issues. We may consider them as negative developments, but gaining any knowledge is always a positive thing.

Alcohol consumption in early adulthood: unexpected impact on brain development

It is well known that excessive consumption of alcohol by teenagers affects their memory and learning ability. A new study by researchers at Duke University has now demonstrated that alcohol can also damage the brain of young adults.

The brain continues to mature until the mid-20s, and this is a period when many young people start to drink frequently. Researchers measured the long-term potentiation (LTP) in the hippocampus of rats exposed to the excess of alcohol at the age that corresponds to human early 20s. LTP is involved in the strengthening of synapses and thus the formation of memory, and it was clearly affected in the experimental animals. In addition, the dendritic spines in the hippocampus of rats appeared immature. Scientists think that excess alcohol in early adulthood disrupts the brain’s maturation process.

The impact of air pollution on brain health is seriously underestimated

Long-term exposure to air pollution is known to be damaging for health. Recent data indicate that brain health can also be affected by this environmental factor, as air pollution is statistically linked to increased risk of stroke, anxiety and suicide.

New findings published this month suggest that the damage may be more severe than previously thought. It was found that exposure to the fine particles found in the polluted air increases the risk of covert brain infarcts by as much as 46%. Covert brain infarct is a form of silent stroke which is associated with dementia and worsened cognitive functions.

Intense aggression: unexpected complexity

Extremely aggressive behavior in males is known to be linked to the elevated level of neurotransmitter serotonin. This is the same compound which is central for our feeling of happiness. The level of serotonin, however, is regulated by several other neurotransmitters.

A new study by Japanese researchers focused on the dorsal raphe nucleus – a major hub for serotonin in the brain – located in its most primitive part. Using a novel in vivo technique, researchers found that the intense aggression-linked surge in serotonin in this location is caused by the increased release of neurotransmitter glutamate in the dorsal raphe nucleus. The findings may help in identifying a suitable pharmaceutical target for developing drugs against psychopathy in humans. They also point to the importance of more probing investigations when we want to target specific conditions without affecting other important mechanisms in the brain.

Assumptions on gender-specific brain development proven wrong

The brains of males and females are rather different – certain parts are different in size and have different numbers of neurons, which are also differently connected. It was long assumed that the brain acquires its gender-specific characteristics during a short period of prenatal development, and once this period is over, the window for further changes is closed. But new findings published this month demonstrate that these assumptions are incorrect.

Researchers found that inhibiting of DNA methyltransferases, the enzymes involved in the repressing of genes, in preoptic area of the rats brain, may “un-silence” some genes and lead to masculinization of female brains. Female rats who received the injections of DNA methyltransferase inhibitors went on to develop more masculine brain feature. Moreover, these rats demonstrated typically male characteristics in their reproductive behavior. It would be interesting to investigate if some related processes in the human postnatal development may be linked to homosexuality.

Death of lactate shuttle theory?

The brain consumes one-fifth of all energy generated in the body. It was always believed that this extreme energy consumption is facilitated by the brain support cells, astrocytes, that produce energy from sugar and pass it to neurons. However, a new article published in Nature Communication this month is likely to prove that this lactate shuttle theory is wrong.

Using a new technique called 2-photon microscopy, the scientists observed the lactate consumption by different cells in the brain directly in real time. They found that neurons and not astrocytes take up glucose directly. Moreover, stimulation of cells led to the increased glucose consumption by neuron while no changes in the glucose consumption by astrocytes were observed. The findings are important – it appears that some chapters in the basic neuroscience textbooks will now need to be rewritten.

References

Dissel, S., Angadi, V., Kirszenblat, L., Suzuki, Y., Donlea, J., Klose, M., Koch, Z., English, D., Winsky-Sommerer, R., van Swinderen, B., & Shaw, P. (2015). Sleep Restores Behavioral Plasticity to Drosophila Mutants Current Biology DOI: 10.1016/j.cub.2015.03.027

Evans, J., Robinson, C., Shi, M., & Webb, D. (2015). The Guanine Nucleotide Exchange Factor (GEF) Asef2 Promotes Dendritic Spine Formation via Rac Activation and Spinophilin-dependent Targeting Journal of Biological Chemistry, 290 (16), 10295-10308 DOI: 10.1074/jbc.M114.605543

Lundgaard, I., Li, B., Xie, L., Kang, H., Sanggaard, S., Haswell, J., Sun, W., Goldman, S., Blekot, S., Nielsen, M., Takano, T., Deane, R., & Nedergaard, M. (2015). Direct neuronal glucose uptake heralds activity-dependent increases in cerebral metabolism Nature Communications, 6 DOI: 10.1038/ncomms7807

Nugent, B., Wright, C., Shetty, A., Hodes, G., Lenz, K., Mahurkar, A., Russo, S., Devine, S., & McCarthy, M. (2015). Brain feminization requires active repression of masculinization via DNA methylation Nature Neuroscience, 18 (5), 690-697 DOI: 10.1038/nn.3988

Pei, L., Mu, Y., Leblanc, M., Alaynick, W., Barish, G., Pankratz, M., Tseng, T., Kaufman, S., Liddle, C., Yu, R., Downes, M., Pfaff, S., Auwerx, J., Gage, F., & Evans, R. (2015). Dependence of Hippocampal Function on ERR?-Regulated Mitochondrial Metabolism Cell Metabolism, 21 (4), 628-636 DOI: 10.1016/j.cmet.2015.03.004

Risher, M., Fleming, R., Risher, W., Miller, K., Klein, R., Wills, T., Acheson, S., Moore, S., Wilson, W., Eroglu, C., & Swartzwelder, H. (2015). Adolescent Intermittent Alcohol Exposure: Persistence of Structural and Functional Hippocampal Abnormalities into Adulthood Alcoholism: Clinical and Experimental Research DOI: 10.1111/acer.12725

Takahashi, A., Lee, R., Iwasato, T., Itohara, S., Arima, H., Bettler, B., Miczek, K., & Koide, T. (2015). Glutamate Input in the Dorsal Raphe Nucleus As a Determinant of Escalated Aggression in Male Mice Journal of Neuroscience, 35 (16), 6452-6463 DOI: 10.1523/JNEUROSCI.2450-14.2015

Wilker, E., Preis, S., Beiser, A., Wolf, P., Au, R., Kloog, I., Li, W., Schwartz, J., Koutrakis, P., DeCarli, C., Seshadri, S., & Mittleman, M. (2015). Long-Term Exposure to Fine Particulate Matter, Residential Proximity to Major Roads and Measures of Brain Structure Stroke, 46 (5), 1161-1166 DOI: 10.1161/STROKEAHA.114.008348

Yoon, M., Yoshida, M., Johnson, S., Takikawa, A., Usui, I., Tobe, K., Nakagawa, T., Yoshino, J., & Imai, S. (2015). SIRT1-Mediated eNAMPT Secretion from Adipose Tissue Regulates Hypothalamic NAD+ and Function in Mice Cell Metabolism, 21 (5), 706-717 DOI: 10.1016/j.cmet.2015.04.002

Zhao-Shea, R., DeGroot, S., Liu, L., Vallaster, M., Pang, X., Su, Q., Gao, G., Rando, O., Martin, G., George, O., Gardner, P., & Tapper, A. (2015). Increased CRF signalling in a ventral tegmental area-interpeduncular nucleus-medial habenula circuit induces anxiety during nicotine withdrawal Nature Communications, 6 DOI: 10.1038/ncomms7770

Image via bikeriderlondon / Shutterstock.

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Preventing Alzheimer’s Disease – Interview with Dean Sherzai of Cedars-Sinai http://brainblogger.com/2015/05/06/preventing-alzheimers-disease-interview-with-dean-sherzai-of-cedars-sinai/ http://brainblogger.com/2015/05/06/preventing-alzheimers-disease-interview-with-dean-sherzai-of-cedars-sinai/#comments Wed, 06 May 2015 12:00:51 +0000 http://brainblogger.com/?p=19489 Numerous studies show promise in the prevention of Alzheimer’s disease in animal models, but invariably fail in humans. However, time after time, lifestyle changes have been shown to alter the course of illness in large population studies. My interview with Dean Sherzai, MD, PhD, director of the Alzheimer’s Disease Prevention Program at Cedars-Sinai, aims to shed light on preventing Alzheimer’s Disease with both therapeutics and lifestyle modifications.

Shaheen Lakhan: What does the Alzheimer’s Disease Prevention Program at Cedars-Sinai offer to patients, caregivers, and the biomedical community?

Dean Sherzai: The Alzheimer’s Disease Prevention Program offers a new approach to Alzheimer’s care, emphasizing prevention and focusing on the creation of an all-encompassing support network for patients and their families.

Prevention is a part of the Alzheimer’s spectrum that rarely has been talked about, due somewhat to the fact that we only recently have begun to identify many of the factors that influence risk. The insidious nature of the disease – with onset starting many years before its seemingly irreversible symptoms appear – has reinforced a sense that Alzheimer’s strikes at random, without warning and without recourse. Now, with the growing recognition that its course can be changed if the disease is diagnosed early enough, we are working to make innovative early detection screening technologies available.

Even in cases where disease exists and prevention no longer is possible, we look to slow disease progress and spare patients and families the heaviest burdens for as long as possible.

Caring for a person with Alzheimer’s hits families hard financially, through lost work and wages, and emotionally, with the grief that comes from gradually losing a loved one. The effects are physical, too. According to the Alzheimer’s Association, people caring for patients with Alzheimer’s and dementia had $9.3 billion in additional health care costs of their own in 2013. Too often, patients and families are left on their own after a diagnosis is made, and the tensions and financial burdens tear them apart.

Our center is designed to serve as a coordinating resource, working with other professionals and community agencies to provide education, counseling and support. If we can help families foresee and manage the inevitable challenges they will encounter, we can help them draw closer instead of being driven apart.

We are only at the beginning of our understanding of all the factors that come together to produce Alzheimer’s, and we have a lot to learn about stopping, reversing and curing the disease. But we have strong clues with basic and animal research pointing us in promising directions. Several studies are about to start at Cedars-Sinai, and as these and many other research projects are translated from pre-clinical to clinical trials, we will need patient volunteers.

A program like ours, based at a hospital with a strong research component, will provide doctors and researchers with a large number of well-documented cases, enabling them to provide the latest advances to patients while collecting immense amounts of data in the search for treatments and cures.

SL: Why do potential therapeutics for dementia work in animal models and not humans?

DS: About 50 drugs have worked in animal models, but not in humans. Part of the answer lies in the fact that even the best models do not perfectly represent disease in humans. But a much more significant factor, we believe, is that therapeutics that have worked in animals were initiated in humans too late in the disease process to be beneficial. We have learned that Alzheimer’s causes damage in the brain many years before symptoms appear, by which time more than half of brain cells are irreversibly injured.

It may be that some of the therapies do work – but only if they are initiated early enough. This is one reason our center aims to identify people at risk and provide early detection screening.

SL: What lifestyle changes can alter the development of neurodegenerative diseases? What is the evidence regarding nutrition and risk of dementia?

DS: Nutrition, exercise and certain kinds of mental activity can affect quality and quantity of life. Thirty minutes of moderate exercise most days, adopting a Mediterranean-style diet, and engaging in enjoyable activities that stimulate the brain appear to be helpful in delaying onset and influencing progression of Alzheimer’s. So far, no drug can do that.

The Alzheimer’s Association summarizes some of the nutrition guidelines coming from recent research. Many studies, such as those at the Fisher Center for Alzheimer’s Research Foundation, indicate that a diet that is good for the heart also is beneficial for brain health.

There is evidence that a vegetable-based diet has a positive effect on cognitive health and disease modification. There is also evidence that regular
not only has positive influence on disease progression, but may actually slow down brain atrophy. The data on cognitive exercises is still weak, but the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (the FINGER study) and others have shown that the positive effect one sees in relation to cognitive exercises is usually in the context of support and social activity.

SL: Where should we focus federal research funding for dementia?

DS: For the last few decades we have been focusing on this devastating disease at a later stage of the disease, which appears not to have responded to any therapies. Today we need to focus on early detection and intervention. This means that a significant amount of dollars must be directed to three major areas:

  • identification of early biomarkers of the disease,
  • larger screening programs that catch a greater proportion of the population at risk for the disease, and
  • intervention trials at these earlier stages when we believe there is greater hope for disease modification and abatement.

SL: What are the most promising technologies/therapeutics for dementia prevention, early detection and treatment?

DS: Many different avenues are being explored. Researchers at Cedars-Sinai will be investigating two drugs already on the market for other conditions, and we are studying ways to spur the immune system to help fend off Alzheimer’s.

In the area of early detection, several innovative approaches have been proposed. One noninvasive, relatively inexpensive technology, pioneered at Cedars-Sinai and now in clinical trials in the U.S. and Australia, is believed to detect Alzheimer’s-associated changes in the retina at the back of the eye even before they develop in the brain. If the device receives Food and Drug Administration approval, it could offer an easy, painless, widely available, early detection screening, which in turn could lead to early intervention with lifestyle modifications and eventually medications to stop or slow the disease.

SL: Any closing remarks for the readers of Brain Blogger?

DS: We as a society and as treatment professionals must do more for patients and caregivers affected by Alzheimer’s. A center like ours, with a network of community partners, can make a tremendous difference in the way the disease affects a family. Also, we must all work to move from a sense of helplessness to one of empowerment. Certainly, there is a genetic component of Alzheimer’s, but there are steps we can take to change the course of the disease and reduce its impact in individual lives and globally.

Image via Ocskay Bence / Shutterstock.

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How Does Meditation Make You Smarter? http://brainblogger.com/2015/05/02/how-does-meditation-make-you-smarter/ http://brainblogger.com/2015/05/02/how-does-meditation-make-you-smarter/#comments Sat, 02 May 2015 12:00:38 +0000 http://brainblogger.com/?p=19478 Unless you’ve been living under a rock, you don’t need to be told about the relaxing effects of meditation. The practitioners vouch for it; and those who don’t, do not dispute it either. Those in the Far East have known for centuries that meditating brings mental peace and spiritual bliss. Now scientists claim that meditation can even alter the brain’s chemistry and functionality.

Over the years, neuroscientists have carried out brain imaging tests on long-term practitioners of meditation, including several Tibetan monks. According to the results of these studies, not only sustained meditative practices but also short-term meditation can produce profound physical, biochemical, and functional changes in the brain.

The Dalai Lama, Meditation, and the Neuroplasticity of the Brain

The slew of research studies into the neural effects of meditation is believed to have been influenced by His Holiness the Dalai Lama. Buddhists have a long tradition of intensive meditation. The Dalai Lama sent some of his most accomplished meditation practitioners to the University of Wisconsin to have their meditating brains probed into by neuroscientist Richard Davidson. What followed was a revolutionary experiment that eventually proved the phenomenon of “neuroplasticity” – the ability of the human brain to continuously evolve structurally and functionally.

Davidson conducted his experiment on two groups of subjects. The Dalai Lama’s disciples had undergone extensive meditation training for 5,000-10,000 hours, spanning periods between 15 and 40 years. The other group consisted subjects who had no prior experience with meditation but were made to go through a week-long meditation training session before the experiment.

The brain scan and EEG results of these two groups showed that the monks had greater gamma wave activity in their brains than the non-meditating subjects. The non-meditating subjects, however, recorded a slight increase in gamma wave activity in their brains after undergoing the meditation training.

The Role of Gamma Waves

Electrical activity in the brain manifests as waves. These waves have different frequencies, and at greater than 40 Hertz, gamma waves have some of the highest frequencies of all brain waves. High-frequency gamma waves have frequencies greater than 80 Hertz. Gamma wave activity is associated with higher mental processes like thinking, cognition, and memory formation and recall.

Sustained meditative practices can result in improved brain functionality by increasing the gamma wave activity. Here’s how:

When nerve cells “fire” synchronously, there is improved communication between the different regions of the brain. This aids higher mental processes. High gamma wave activity in the brain indicates thousands of neural cells are firing in unison and sending out signals to different parts of the brain at great speeds. Synchronized neural activity not only improves cognitive functioning but also keeps the brain active and energized to prevent age-related neural degeneration.

According to one study published this year, the brains of long-term meditation practitioners can produce very high frequency gamma waves, ranging between 100 and 245 Hertz. In particular, the increased gamma wave activity is seen in areas of the brains involved in monitoring (dorso-lateral prefrontal cortex), focused attentiveness (superior frontal sulcus, intraparietal sulcus, and the supplementary motor region), and engaging attention (visual cortex). These areas of the brain are associated with awareness and attention that are crucial to perform higher mental tasks like learning new skills. The studies indicate that long-term meditation practice improves attention in the practitioners that translates into more efficient learning.

Another recent study has reported that long-term meditation practitioners are generally able to process information more efficiently than non-practitioners.

Researchers have found that the ability to attend to a task with full focus is also greater in long-term meditation practitioners than novices because the former show less activity in the amygdala region in response to distracting sounds. This finding suggests that advanced meditation practitioners have greater control over how they react to emotions rising within them. Emotionally reactive behavior hampers steady concentration.

The Long-Term Effects of Meditation

The above-mentioned experiments were conducted on subjects while they were meditating. But those who have just made the foray into meditation or are contemplating embarking on the journey would be pleased to know that the effects of meditation continue well after they get up from their mats and change out of their robes!

It was recently demonstrated that experienced meditation practitioners exhibit higher gamma wave activity in the parietal-occipital region of the brain even when they are asleep. This proves that long-term meditation alters the pattern of spontaneous activity in the brain and the effects are long-lasting. This is one of the seminal studies on the neuroplasticity of the brain.

Implications of the Meditation Studies

Neuroscientists have brought into the limelight the benefits of meditation that Eastern seers, mystics, and monks knew from time immemorial. But the discovery of the phenomenon of neuroplasticity of the brain has turned everything neuroscientists believed about the workings of the brain on its head (pun not intended). Earlier scientists believed the neural connections become fixed when an individual reaches adulthood and remain so throughout his life. The connections that get lost due to any trauma or a disease can never be replaced. Fortunately, they have been proved wrong.

The concept of neuroplasticity of the brain and the effects of meditation give hope to countless victims of traumatic brain injury or those suffering from potentially debilitating psychological conditions like ADHD. These people can now dream of restoring the connections in their brains, rediscovering memories, and re-learning the skills they had forgotten. Educationists, teachers, and parents can consider introducing children to meditative practices at a young age. In fact, child psychologists and school counselors can explore meditation as a way to help children with learning disabilities acquire new skills and apply these successfully.

Meditation is an ancient Eastern practice, and it seems that Tibetan monks living in secluded monasteries high up in the mountains had decoded the secrets of the human brain long before EEGs and MRIs came along.

References

Brefczynski-Lewis, J., Lutz, A., Schaefer, H., Levinson, D., & Davidson, R. (2007). Neural correlates of attentional expertise in long-term meditation practitioners Proceedings of the National Academy of Sciences, 104 (27), 11483-11488 DOI: 10.1073/pnas.0606552104

Davidson RJ, & Lutz A (2008). Buddha’s Brain: Neuroplasticity and Meditation. IEEE signal processing magazine, 25 (1), 176-174 PMID: 20871742

Ferrarelli, F., Smith, R., Dentico, D., Riedner, B., Zennig, C., Benca, R., Lutz, A., Davidson, R., & Tononi, G. (2013). Experienced Mindfulness Meditators Exhibit Higher Parietal-Occipital EEG Gamma Activity during NREM Sleep PLoS ONE, 8 (8) DOI: 10.1371/journal.pone.0073417

Hauswald, A., Übelacker, T., Leske, S., & Weisz, N. (2015). What it means to be Zen: Marked modulations of local and interareal synchronization during open monitoring meditation NeuroImage, 108, 265-273 DOI: 10.1016/j.neuroimage.2014.12.065

Kim, D., Rhee, J., & Kang, S. (2014). Reorganization of the brain and heart rhythm during autogenic meditation Frontiers in Integrative Neuroscience, 7 DOI: 10.3389/fnint.2013.00109

Moran, L., & Hong, L. (2011). High vs Low Frequency Neural Oscillations in Schizophrenia Schizophrenia Bulletin, 37 (4), 659-663 DOI: 10.1093/schbul/sbr056

Tang, Y., Ma, Y., Fan, Y., Feng, H., Wang, J., Feng, S., Lu, Q., Hu, B., Lin, Y., Li, J., Zhang, Y., Wang, Y., Zhou, L., & Fan, M. (2009). Central and autonomic nervous system interaction is altered by short-term meditation Proceedings of the National Academy of Sciences, 106 (22), 8865-8870 DOI: 10.1073/pnas.0904031106

Image via Ditty_about_summer / Shutterstock.

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How Does the Brain Respond to Gossip? http://brainblogger.com/2015/04/25/how-does-the-brain-respond-to-gossip/ http://brainblogger.com/2015/04/25/how-does-the-brain-respond-to-gossip/#comments Sat, 25 Apr 2015 16:31:17 +0000 http://brainblogger.com/?p=19455 Newspapers use up reams of paper to report it. The air around your office cubicle, or in the cafeteria, hangs heavy with it. When best friends meet, they discuss it in hushed whispers. Gossip is an integral part of our communication. And if evolutionary psychologist Robin Dunbar is to be believed, gossip makes up the lion’s share—a whopping two-thirds—of our conversations. We talk about other topics like music, sports, politics, and the weather in the remaining time. That is a lot of time we spend discussing other people’s affairs, some of which are not in good light.

So why do perfectly sensible, reasonably intelligent, and genuinely compassionate people engage in gossiping? What do they gain from it? Do only women do it? And do people who love gossiping get a malicious pleasure out of listening to stories of failed romances and scandals? Neuroscientists have probed into the brains of people when they gossip to unearth the science behind it.

How Does Gossip Affect Us?

Gossip affects us; it either tickles us or makes us shudder. But did you know that different kinds of gossip affect us in different ways?

According to a study published this year and carried out on a random sampling of men and women, the subjects were generally more pleased to hear positive gossip than negative news. However, they were more distressed by negative gossip about themselves than about other people like their friends, acquaintances, and celebrities. Not many surprises there.

These findings were arrived at after the subjects were made to fill out a questionnaire. The scientists also carried out fMRI scans of the subjects’ brains as they listened to positive and negative gossip about themselves, their best friends, and celebrities.

According to the findings from these scan reports, listening to gossip about themselves heightened activity in the superior medial prefrontal cortex of the subjects’ brains. This region also responded to negative gossip about others. The subjects recorded increased activity in the orbital prefrontal cortex region of their brains in response to positive gossip about themselves.

The prefrontal cortex is one of the brain regions involved in social cognition and executive control. Social cognition is the ability to regulate our thoughts, behavior, and actions based on the real, imaginary, or assumed presence of other people. In other words, social cognition is a trait that makes us want to conform to the accepted norms and rules of society. Executive control is the ability to channelize our thought patterns, behavior, and actions based on internal goals. The neurotransmitter dopamine regulates the functionality of this region and activates the reward system.

The activation of prefrontal cortex region of the brain in response to positive gossip about oneself indicates that most human beings want to be seen as conforming to social standards of morality and success. They see more rewards in being “seen” in a positive light by the world at large than staying true to their internal moral compass.

On the other hand, we think that we are repulsed by negative gossip about others. But the fMRI images obtained during the above study bust this myth. The activation of the superior medial prefrontal cortex region in response to negative gossip about others indicates that although we are not elated by the falling-from-grace stories of other people, we are amused. This finding would seem morally unacceptable to many. After all, we don’t like to think of ourselves as fiends who gloat at others’ miseries and misfortunes.

But don’t be so hard on yourself. Gossiping is good for you!

Is Gossip Good or Bad?

Although moral purists might frown upon the practice, scientists say that gossip serves self-preservation purposes. According to them, there are also definite social benefits of gossiping.

Social scientists believe that gossip is an integral tool for observational learning. We exchange information about others when we gossip. Negative gossip makes you realize how society perceives acts of moral transgression, and you indirectly learn a lesson on how to live within a community and adhere to its rules. In this instance, negative gossip serves as a tool for indirect learning; you learn how to act correctly without having to bear the costs and consequences of a negative action.

Gossip acts as a self-improvement tool in another way. Positive gossip about ourselves gives us the motivation to carry on with our good behavior or sustain positive habits. It also provides us with hints about acceptable behavioral traits within the context of a particular society.

Some scientists point out to the benefit of prosocial gossip. They say exchanging negative information about the reputation of another person puts vulnerable people on alert and protects them from future anti-social or exploitative acts of the person who is the subject of the gossip. According to scientists, prosocial gossip promotes cooperation and bonding amongst people and creates a safety net.

At another level, the sharing of negative reputational information also acts as a check on the anti-social behavioral traits of people. According to scientists, when negative reputational information is shared with many people, the group as a whole usually chooses to ostracize the wrongdoer. Ostracism compels the person excluded from his group to resort to better behavior to win approval. Ostracism may also act as a deterrent to anti-social behavior by others.

Researchers also claim that sharing negative gossip promotes social bonds. They say that indulging in negative gossiping with another person usually triggers conversations that involve downward social comparisons. These conversations are powerful ego-boosters. What is more, by sharing negative information about another person, we unknowingly create distinct social identities—the gossiper brings the person he is gossiping with into his ambit and creates an in-group while the person being gossiped about is made out to be an outsider (the creation of an out-group).

It seems that gossiping is not entirely a wasteful pursuit of time and energy. Our brains get a kick from exchanging juicy tidbits of information about someone we know intimatel (our best friends) or can only observe from a distance (celebrities). Gossip about ourselves is like a mirror to our actions and behavior and lets us rectify ourselves, so we can become more responsible members of the society.

References

Baumeister, R., Zhang, L., & Vohs, K. (2004). Gossip as cultural learning. Review of General Psychology, 8 (2), 111-121 DOI: 10.1037/1089-2680.8.2.111

BOSSON, J., JOHNSON, A., NIEDERHOFFER, K., & SWANN, W. (2006). Interpersonal chemistry through negativity: Bonding by sharing negative attitudes about others Personal Relationships, 13 (2), 135-150 DOI: 10.1111/j.1475-6811.2006.00109.x

Dunbar, R. (2004). Gossip in evolutionary perspective. Review of General Psychology, 8 (2), 100-110 DOI: 10.1037/1089-2680.8.2.100

Feinberg, M., Willer, R., & Schultz, M. (2014). Gossip and Ostracism Promote Cooperation in Groups Psychological Science, 25 (3), 656-664 DOI: 10.1177/0956797613510184

Feinberg, M., Willer, R., Stellar, J., & Keltner, D. (2012). The virtues of gossip: Reputational information sharing as prosocial behavior. Journal of Personality and Social Psychology, 102 (5), 1015-1030 DOI: 10.1037/a0026650

Martinescu, E., Janssen, O., & Nijstad, B. (2014). Tell Me the Gossip: The Self-Evaluative Function of Receiving Gossip About Others Personality and Social Psychology Bulletin, 40 (12), 1668-1680 DOI: 10.1177/0146167214554916

Peng X, Li Y, Wang P, Mo L, & Chen Q (2015). The ugly truth: negative gossip about celebrities and positive gossip about self entertain people in different ways. Social neuroscience, 10 (3), 320-36 PMID: 25580932

Image via g-stockstudio / Shutterstock.

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Correlates between the Science of Learning and the Practice of Teaching http://brainblogger.com/2015/04/23/correlates-between-the-science-of-learning-and-the-practice-of-teaching/ http://brainblogger.com/2015/04/23/correlates-between-the-science-of-learning-and-the-practice-of-teaching/#comments Thu, 23 Apr 2015 22:48:57 +0000 http://brainblogger.com/?p=19449 The phenomenon of human learning is not a unitary construct, rather it comprises a gamut of cognitive traits including memory, attention, decision making and social functioning. According to David Ausubel, an eminent educational psychologist: “The single most important factor influencing learning is what the learner already knows. Ascertain this and teach him accordingly”.

What we already know and can retrieve is underpinned by the neural system of memory, and the use of pre-existing neural networks can form the basis of further learning. Retrospective evaluations of events in the “long term” (in behavioural neuroscience, this refers to a period longer than a day) have found memory processing to be a high fidelity system. However, the transient storage of information, i.e., working memory, appears to be less resilient and prone to rapid deterioration.

“Consolidation” is the term attributed to the hypothetical transformation of a memory trace from an unstable, short-term form to a stable, long-term form. Recent research has focused on a rather enigmatic aspect of memory processing, dubbed “reconsolidation” – it is a special state brought about by the retrieval of items in the long-term memory, which makes them prone to alterations.

Learning is not simply based on enhanced neural activity, but also structural modifications that can be determined by changes in synaptic density (synaptogenesis). In a study involving rats, this question was explored by training a test group for a low-intensity but challenging motor skill, compared to the other groups that were exposed to high-intensity physical exercise but with relatively little learning involved. Notably, a higher density of blood vessels was found in the latter (angiogenesis, a compensatory response to increased/repetitive synaptic activity), but a significant increase in synaptic density was only found in the former, thereby demonstrating that learning is underpinned by neuro-structural changes in the brain.

The cortical-hippocampal system – comprising complex, bi-directional flow of information between the neocortex, the parahippocampal region and the hippocampus – underpins the neural coding mechanisms of conscious memory. The latter is particularly important in the organisation of memories in space and time.

Consistent with the recent advances in the neurobiology of learning, a list of potential correlates will be discussed from the literature that either inform the basis of accepted teaching practices or provide ideas for further exploration with the aim of improving the current design of learning environments. It must be acknowledged, however, that cognitive neuroscience has not advanced to a point yet where it could translate into guidelines for effective teaching practices (nor would such a circumscribed approach necessarily provide the desired outcomes), but drawing parallels between the two fields illustrate the neural underpinnings of the pedagogy of education, and highlight some of the pervasive ‘neuromyths’ that have taken root in the education sector and the society at large by courtesy of the so-called ‘brain-based learning’ industry.

Repetition

It has been proposed that repetition of information can improve normal retention and retrieval processes. The neural execution of the reconsolidation phase is energy efficient (using pre-existing neural connections). Moreover, it provides an opportunity to modify the memory trace both in terms of content and structure.

Previous psychophysiological studies in humans have used a range of somatosensory stimuli or verbal suggestions (stressors) during the retrieval phase in order to improve memory performance; immersion of arm in ice-cold water and the use of negatively arousing pictures are amongst the different stressors used in experimental conditions. In the real world, students can exploit reconsolidation by practicing self-testing. This can produce a moderate level of stress – a mnemonic enhancer – by facilitating synaptic potentiation mediated by a moderate release of stress hormones, glucocorticoids. In contrast, high levels of stress/glucocorticoids can have the opposing effect on memory and learning processes. The seeming malleability of memory trace upon retrieval/reactivation has an important clinical implication in the context of consolidated fear memories which could then be blocked by amnesic agents.

Repeated testing has been shown to improve the retention of information, a phenomenon termed the “testing effect”, over and above any effect of repeated study. This effect is particularly robust when the tests require effortful recall, e.g. mechanistic questions rather than recognition tests such as multiple choice, and when testing is spaced out over time.

Spacing of learning

In addition to repeated retrieval, the value of spacing in learning is another interesting concept. However, further examination is warranted of the optimal intervals/spacing times for revisiting content for long-term consolidation. These observations support the concept of the spiral curriculum, which advocates revisiting topics in increasing levels of difficulty throughout the course. The latter point of the deepening of content upon successive encounters is equally important. It appears that our brains are better at retaining information when it is structured/mechanistic, context-based and goal-oriented. The use of similes, metaphors, analogies and other short mnemonics can also be helpful in memory retention.

Small learning groups

It could be argued that teaching in small groups is beneficial, not least because of the potential activation of stressor pathways triggered by the need to share the underlying reasoning processes. Breaking down a question into small parts could facilitate incremental/structured learning across the multiple levels of difficulty. Such an approach may also facilitate active engagement of students, including those who otherwise opt out from the learning process often with little engagement in the first place. With interactive, small-group teaching, as compared to the traditional, didactic forms of teaching to large groups of students, the students are more likely to embrace responsibility and ownership of the learning process, in part due to the engagement of the motivational and reward circuitry.

Reward

Reward is an important tenet of the learning process. It appears that our brains engage in “temporal discounting” to measure the relative value of a choice. For example, the seemingly short-term reward of having learnt a new skill as compared to the more long-term, greater reward of having a respected career, income, etc.

It is plausible that the reward system could be incorporated into the learning design by, for example, sharing with the students the scientific rationale underpinning the instructor’s choice for a particular learning model or teaching practice. It is tempting to suggest a more dynamic role of a tutor with the position being swapped with the students following an initial period of formalised tutorship. Indeed, it has been shown that social and cognitive concordance between the teacher and the learner can improve the latter’s perception of their learning experience.

While inclusion of a reward component in the learning design seems important, it may well be equally important to address the fear of failure associated with learning. Could it be a learnt effect? If so, could it be unlearnt then? In a sense, this is what the pain rehabilitation specialists do to reverse those avoidance/compensatory responses that contribute to the therapeutic intractability of chronic pain. Indeed, the phenomenon of fear is complicated, not least because of the myriad social and cultural connotations. However, it is plausible that individuals who find the learning process intrinsically rewarding are less likely to be overwhelmed by the fear of failure.

While emphasising the value of interactive, small-group teaching, it is important to acknowledge that learning preferences can vary greatly across individuals, and hence a combination of different teaching strategies should be adopted. Mental rehearsal of actions or thoughts, regardless of an external or an internal trigger, could facilitate the learning of an advanced skill, e.g. a complex surgical procedure. Likewise, it may help to overcome the fear of failure, for instance, in case of public speaking. The mirror neuron system is believed to subserve the inner imitation of an external event. Where feasible, visualisation technologies could be incorporated into the established learning paradigms. More generally, a multi-media approach of content delivery might also help to minimise cognitive distraction and improve attention, in addition to promoting memory retention by repetition of content.

Emotional state

Consistent with the findings in brain-damaged patients, our apparent rational thinking is in fact underpinned by hidden emotional processes. The role of emotions is vitally important as all the cognitive traits pertinent to education are inextricably linked to emotion. This poses a serious question in terms of the translation of knowledge from a structured educational setting to a real-world situation. According to Immordino-Yang and Damasio (2007):

“Knowledge and reasoning divorced from emotional implications and learning lack meaning and motivation and are of little use in the real world.”

Hence, it is important that a learning environment is not devoid of emotion, and that students are provided ample opportunities to engage in real-life problem solving as an integral part of the learning experience.

Conclusions

A greater integration between the science of learning and the practice of teaching is highly warranted, not least because of the “frequently exaggerated” and “at times misleading” claims of the brain-based learning industry about “improvements in the speed and efficiency of cognitive processing and dramatic gains in “intelligence”” by the use of “brain-training games”. These observations were shared in a consensus report by The Stanford Center on Longevity and the Berlin Max Planck Institute for Human Development.

While there is some evidence of short-term task-specific improvements in working memory, there is no clear evidence that these effects are transferrable to other untrained working memory tasks or broader everyday skills. Not to mention, financial, social and other opportunity costs associated with brain-training games warrant due consideration. Indeed, a range of other strategies are promoted to improve learning: for instance, choosing a learning design based on whether a student is “left-brained” or “right-brained” or the use of “brain buttons” (by applying pressure to an area between the first and second ribs under the collar bone) to reorganise/refocus the brain for reading and writing. Such learning strategies are often based on an exaggerated or flawed interpretation of scientific facts.

Scientific progression is underpinned by incremental and seemingly small discoveries; however, the claims of the brain-based learning industry are anything but that. Although an effort has been made by the scientific community in recent years to raise awareness about these issues, a lot more work needs to be done in particular to raise awareness amongst the educators as well as the broader community. The role of science communicators could be useful in bridging the current gap between the real neuroscience of learning and the pervasive propaganda of the commercial “brain-based” programs.

References

Black, J., Isaacs, K., Anderson, B., Alcantara, A., & Greenough, W. (1990). Learning causes synaptogenesis, whereas motor activity causes angiogenesis, in cerebellar cortex of adult rats. Proceedings of the National Academy of Sciences, 87 (14), 5568-5572 DOI: 10.1073/pnas.87.14.5568

Carr, L., Iacoboni, M., Dubeau, M., Mazziotta, J., & Lenzi, G. (2003). Neural mechanisms of empathy in humans: A relay from neural systems for imitation to limbic areas Proceedings of the National Academy of Sciences, 100 (9), 5497-5502 DOI: 10.1073/pnas.0935845100

Dudai, Y. (2012). The Restless Engram: Consolidations Never End Annual Review of Neuroscience, 35 (1), 227-247 DOI: 10.1146/annurev-neuro-062111-150500

Dudai, Y. (2006). Reconsolidation: the advantage of being refocused Current Opinion in Neurobiology, 16 (2), 174-178 DOI: 10.1016/j.conb.2006.03.010

Dumas TC, Gillette T, Ferguson D, Hamilton K, & Sapolsky RM (2010). Anti-glucocorticoid gene therapy reverses the impairing effects of elevated corticosterone on spatial memory, hippocampal neuronal excitability, and synaptic plasticity. The Journal of neuroscience : the official journal of the Society for Neuroscience, 30 (5), 1712-20 PMID: 20130180

Eichenbaum H (2000). A cortical-hippocampal system for declarative memory. Nature reviews. Neuroscience, 1 (1), 41-50 PMID: 11252767]

Friedlander, M., Andrews, L., Armstrong, E., Aschenbrenner, C., Kass, J., Ogden, P., Schwartzstein, R., & Viggiano, T. (2011). What Can Medical Education Learn From the Neurobiology of Learning? Academic Medicine, 86 (4), 415-420 DOI: 10.1097/ACM.0b013e31820dc197

Goswami, U. (2006). Neuroscience and education: from research to practice? Nature Reviews Neuroscience, 7 (5), 406-413 DOI: 10.1038/nrn1907

Hall, S., Stephens, J., Andrade, T., Davids, J., Powell, M., & Border, S. (2014). Perceptions of junior doctors and undergraduate medical students as anatomy teachers: Investigating distance along the near-peer teaching spectrum Anatomical Sciences Education, 7 (3), 242-247 DOI: 10.1002/ase.1419

HARDEN, R. (1999). What is a spiral curriculum? Medical Teacher, 21 (2), 141-143 DOI: 10.1080/01421599979752

Immordino-Yang, M., & Damasio, A. (2007). We Feel, Therefore We Learn: The Relevance of Affective and Social Neuroscience to Education Mind, Brain, and Education, 1 (1), 3-10 DOI: 10.1111/j.1751-228X.2007.00004.x

Jantsch, H., Gawlitza, M., Geber, C., Baumgärtner, U., Krämer, H., Magerl, W., Treede, R., & Birklein, F. (2009). Explicit episodic memory for sensory-discriminative components of capsaicin-induced pain: Immediate and delayed ratings Pain, 143 (1), 97-105 DOI: 10.1016/j.pain.2009.02.004

Karpicke, J., & Roediger, H. (2008). The Critical Importance of Retrieval for Learning Science, 319 (5865), 966-968 DOI: 10.1126/science.1152408

Larsen, D., Butler, A., & Roediger III, H. (2008). Test-enhanced learning in medical education Medical Education, 42 (10), 959-966 DOI: 10.1111/j.1365-2923.2008.03124.x

Lichtenstein, E., & Brewer, W. (1980). Memory for goal-directed events Cognitive Psychology, 12 (3), 412-445 DOI: 10.1016/0010-0285(80)90015-8

Nader K, Schafe GE, & Le Doux JE (2000). Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval. Nature, 406 (6797), 722-6 PMID: 10963596

Rainville, P., Doucet, J., Fortin, M., & Duncan, G. (2004). Rapid deterioration of pain sensory-discriminative information in short-term memory Pain, 110 (3), 605-615 DOI: 10.1016/j.pain.2004.04.024

Image via Boumen Japet / Shutterstock.

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Deciphering Troubled Teens’ Risk-Taking Behavior http://brainblogger.com/2015/04/17/deciphering-troubled-teens-risk-taking-behavior/ http://brainblogger.com/2015/04/17/deciphering-troubled-teens-risk-taking-behavior/#comments Fri, 17 Apr 2015 12:00:06 +0000 http://brainblogger.com/?p=19409 The rebellious teenager makes everyone edgy. Their parents are an anxious lot. Their teachers are at their wit’s end trying to figure out ways to rein them in. The traffic sergeants roll their eyes in exasperation when they land up drunk behind the wheel. Sociologists are intrigued and want to know what is it that makes them act the way they do — is it genes, hormones, a rite of passage, peer pressure, or an entirely unknown reason?

Risk-taking behavior in adolescents is also a cause for concern. These kids are not only exposing themselves to danger with their penchant for speed, addictive substances, and irresponsible sexual behavior, but also putting the lives of other people at risk.

The risk-loving teenager gets ticked off for being immature. But scientists now know better. They have uncovered the reasons behind risk-taking behavior in adolescents. The teens are not entirely to blame; it is the way their brains develop during these years — a little lopsidedly — that makes them act the way they do.

A Timetable for Sensation-Seeking Behavior and Impulsivity

Adolescents are often chided for their sensation-seeking behavior, an overwhelming urge to seek out novel experiences. Many people equate this tendency to look for “thrills” with impulsive or risk-taking behavior. But according to scientists, sensation-seeking behavior and impulsivity have definite but distinct developmental timetables.

Sensation-seeking behavior is on the rise between 10 and 15 years of age. The tendency usually decreases after this period or stabilizes. But impulsivity starts to decline from around the age of 10 years. So there is a particular stage in their development when they do seek out thrills, but their impulsivity at these times is triggered by their peculiar brain chemistry. Teenagers do not engage in risk-taking behavior because they get a high from it.

The Brain of an Adolescent

Scientists have uncovered what goes on inside the brain of an adolescent that makes him behave impulsively. What happens is an intriguing interplay of neuronal and socio-emotional factors.

During adolescence, the subcortical region of the brain matures rapidly. This region is associated with the motivation system. So the individual becomes increasingly responsive to new sensations and novel situations and experiences. It becomes sensitive to rewards, so individuals are often found to engage in reward-seeking behavior.

Most adolescents want to be accepted by their peers. They want to conform to peer standards. If you remember your own days of adolescence, you know that an act of daredevilry gets you those oh-so-delicious admiring glances and a pat on the back from your peers. Peer acceptance acts on the dopaminergic system of the brain and adolescents begin to associate these acts of daredevilry with reward.

But if their brains have become mature enough to be motivated by rewards, what makes adolescents act impulsively? Shouldn’t they be also mature enough to distinguish between socially acceptable behavior and reckless acts that endanger themselves and those around them?

Scientists have the answers to these questions.

The adolescent brain is mature, but only in certain regions. The rapid development of the limbic and paralimbic structures of the brain makes a young person seek out new experiences while the maturity of the subcortical region influences his reward system. But the ability to differentiate between safe and reckless acts involves the executive functionality of the brain.

The higher-level cognitive functionality of the brain is regulated by the orbital frontal cortex region. According to research findings, adolescent brains do not show much maturity in this region. In fact, the development in this area is more similar to what can be found in the brains of children than in adults. There is less focus on activities, which explains why adolescents are not able to determine the risks in their actions.

The slow development of the cognitive-control system also means that adolescents are less able to control impulsive behavior.

So the developing brains of adolescents are actually maturing in a skewed manner. The motivation and rewards system develops faster than the cognitive-control system. This developmental gap makes adolescents vulnerable to risk-taking behavior. So contrary to popular notion, adolescents are not reckless because they are immature, ignorant, or irrational. They are impulsive not because they don’t care.

Adolescent Brains are Comfortable with Ambiguity

Another study associates risk-taking behavior amongst adolescents to a greater willingness on their part to accept and be comfortable with ambiguity or even not knowing. This study found that compared to adults, adolescents are more likely to rush into and get involved in situations where they don’t know the chances of their success or where there is an equal chance of them winning or failing.

Scientists believe that this trait amongst adolescents is biologically motivated. The chance of young animals surviving and thriving in the wild is dependent on their ability to make the most of learning opportunities.

Can Adolescent Impulsivity be Curbed?

Risk-taking behavior in adolescents costs life and money. Adolescents who are prone to behavior like speeding and driving under the influence of addictive substances endanger the lives of others. Those who indulge in substance abuse harm themselves and shatter families. Again, adolescents with substance abuse are more vulnerable to developing other kinds of risk-taking behavior like delinquency and risky sexual behavior. The result is countless lives are wasted. In this context, there are significant implications of the findings from the above studies.

Trying to change the attitudes of adolescents towards risky behavior seems futile. After all, they don’t have much control over how their brains make them perceive situations and react to these. In such a scenario, providing parental support and guidance and establishing a positive school environment assume critical importance. Parents, family members, teachers, and counselors should make a concerted effort to educate these vulnerable youngsters about the risks and costs (both to themselves and to the society) of impulsive behavior.

Puberty, hormonal changes, and the lopsided developments of their brains. Adolescents have to grapple with a lot. Risk-taking behavior in adolescents is their way of letting you know that they are feeling incapable of handling hall that is happening inside their heads and they need your help.

References

Feldstein, S., & Miller, W. (2006). Substance use and risk-taking among adolescents Journal of Mental Health, 15 (6), 633-643 DOI: 10.1080/09638230600998896

Galvan, A., Hare, T., Parra, C., Penn, J., Voss, H., Glover, G., & Casey, B. (2006). Earlier Development of the Accumbens Relative to Orbitofrontal Cortex Might Underlie Risk-Taking Behavior in Adolescents Journal of Neuroscience, 26 (25), 6885-6892 DOI: 10.1523/JNEUROSCI.1062-06.2006

Geier, C. (2013). Adolescent cognitive control and reward processing: Implications for risk taking and substance use Hormones and Behavior, 64 (2), 333-342 DOI: 10.1016/j.yhbeh.2013.02.008

Kipping, R., Campbell, R., MacArthur, G., Gunnell, D., & Hickman, M. (2012). Multiple risk behaviour in adolescence Journal of Public Health, 34 (suppl 1) DOI: 10.1093/pubmed/fdr122

Romer, D. (2010). Adolescent risk taking, impulsivity, and brain development: Implications for prevention Developmental Psychobiology DOI: 10.1002/dev.20442

Romer, D., Betancourt, L., Brodsky, N., Giannetta, J., Yang, W., & Hurt, H. (2011). Does adolescent risk taking imply weak executive function? A prospective study of relations between working memory performance, impulsivity, and risk taking in early adolescence Developmental Science, 14 (5), 1119-1133 DOI: 10.1111/j.1467-7687.2011.01061.x

Steinberg, L. (2008). A social neuroscience perspective on adolescent risk-taking Developmental Review, 28 (1), 78-106 DOI: 10.1016/j.dr.2007.08.002

Steinberg, L. (2007). Risk Taking in Adolescence: New Perspectives From Brain and Behavioral Science Current Directions in Psychological Science, 16 (2), 55-59 DOI: 10.1111/j.1467-8721.2007.00475.x

Steinberg, L., Albert, D., Cauffman, E., Banich, M., Graham, S., & Woolard, J. (2008). Age differences in sensation seeking and impulsivity as indexed by behavior and self-report: Evidence for a dual systems model. Developmental Psychology, 44 (6), 1764-1778 DOI: 10.1037/a0012955

Tymula, A., Rosenberg Belmaker, L., Roy, A., Ruderman, L., Manson, K., Glimcher, P., & Levy, I. (2012). Adolescents’ risk-taking behavior is driven by tolerance to ambiguity Proceedings of the National Academy of Sciences, 109 (42), 17135-17140 DOI: 10.1073/pnas.1207144109

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Microglia – Part 1, Definitions and Developmental Progression http://brainblogger.com/2015/04/12/microglia-part-1-definitions-and-developmental-progression/ http://brainblogger.com/2015/04/12/microglia-part-1-definitions-and-developmental-progression/#comments Sun, 12 Apr 2015 12:00:45 +0000 http://brainblogger.com/?p=19192 One of the more remarkable advances in neuroscience, perhaps on par with Santiago Ramon y Cajal’s Neuron Doctrine (the theory that distinct neurons are the functional units of the brain), is the discovery of microglia — appropriately by Cajal’s student Pio del Rio Hortega.

Since their discovery, microglia have been the center of controversy in many contexts (i.e. ontogeny, neurodevelopment, synaptic plasticity, disease, etc.). This is not an overstatement. For example, Hortega surmised (correctly), back in the 1920s, that these cells hailed from the mesoderm, rather than the neuroectoderm (like all other brain cells) during an organism’s development.

This prediction, however, was not definitively verified until seven decades later, when it was demonstrated that microglia do not populate the neuroectoderm until embryonic day eight. This insight generated further questions, including: from where do these alien cells specifically originate? This question of microglial ontogeny and other definitions will be the focus of Part I of a five part series on the role of microglia in brain function from development to disease, as potential therapeutic targets and culminating with a fun — possibly unexpected — look at futuristic directions.

First, let us define some important terms. Unfortunately, many contemporary authors continue to use antiquated terminology when discussing microglia and this has become somewhat debilitating to the field (not to mention a pet peeve of mine). In 1908, Elie Metchnikoff won the Nobel Prize for his work on phagocytosis, or “cellular act of eating,” which later lead to his description of the macrophage system. This system is made up of cells collectively called mononuclear phagocytes, resulting in what is now called the mononuclear phagocyte system. It is this classification to which the microglial cell fits. Microglia are, after all, the tissue resident phagocytic cells of the brain.

Now, for the purpose of this article, I would like to define two more classification terms: “circulating” monocytes and “tissue-resident” macrophages. This distinction is important developmentally. It was recently demonstrated that circulating and tissue-resident cells arise from temporally and spatially different stem cell pools. For example, nearly all of our organs contain macrophages specifically designed to function within that organ, mainly performing maintenance duty. These tissue-resident macrophages derive from a developmental organ known as the yolk sac (most anatomists might call it an umbilical vesicle now), which is the sight of primitive hematopoeisis (or blood production). In other words, macrophages designed to function in a specific tissue are made first from a special pool of hematopoeitic stem cells and then leave the yolk sac to colonize their respective organs — such as microglia in the brain, Langerhans cells in the skin, or Kupfer cells in the liver. On the other hand, circulating monocytes are produced in the bone marrow later on in development, have a high turn over rate, and are continually produced over a lifetime. These cells mostly meander through the blood and lymphatic system and usually die after becoming activated — not necessarily so for tissue-resident macrophages.

So, it was shown in 2011 in the journal Science for the first time, that microglial ontogeny begins in the yolk sac. From there, they travel through the newly developed blood stream to reach the brain before the aptly named blood brain barrier closes — forever shunning the entry of any other type of mononuclear phagocyte. Here they spend the rest of their lives actively surveying surrounding brain tissue (among other roles to be discussed in following articles), providing a homeostatic milieu for the brain to function efficiently.

This brings us to our last set of definitions: surveillance, primed, activated and dystrophic microglia. I will not go deeply into each category, but I think it is important to understand that microglia are the most dynamic cells in the brain with their unique ability to transition between these activation states.

I would also like to emphasize that these states are contextual and do not necessarily describe a microglial cell as beneficial or destructive to surrounding brain tissue, but instead are responses to molecular cues necessitating some microglial effector function. For example, a microglial cell can be activated in both developmental synapse pruning (beneficial) and phagocytosis of viable neurons during disease (detrimental). No matter what, microglia are never resting — a term that has also deluded the field — but in constant motion within defined, non-overlapping locales.

You can find a live video I have taken of a retinal microglia in this state here. Instead of “resting” microglia, they are more appropriately termed surveillance microglia, as they extend and retract their processes, feeling around the adjacent tissue, sensing the environment.

Primed microglia describes the state between surveillance and activation. One could think of it as a pre-activation state, where they begin showing signs of morphological changes (i.e. shortening and thickening of their processes) and expression of certain molecules.

From there, microglia become fully activated, taking on a rounded (amoeboid) shape and expressing high levels of molecules associated with inflammation and/or phagocytosis.

Lastly, dystrophic describes a dysfunctional state of microglia, in which their processes begin to fragment or even fuse with other microglia. This is usually associated with chronic activation during disease and not usually part of their functional spectrum. These definitions are currently in a state of flux as the field tries to develop a cohesive theory of microglial function.

When looking at a fluorescent image of a mature, surveying microglia, one will notice how elegantly their processes radiate from the small cell body, forming complex, arborous structures. This is not their perpetual morphologic state. On the contrary, they are born as small, amorphous blobs, reminiscent of peripheral macrophages. In fact, their morphological development is the reverse of their transition through activation states. It is not until they enter the developing brain that they begin to ramify. Once they enter, microglia spread out to evenly tile the entire brain, taking up their positions as noble sentinels.

Research is ongoing to determine what molecular cues developing microglia receive (and from where, but probably the brain) to drive their migration into the brain. A few candidate molecules (e.g. CSF-1, IL-34, TGF-beta; no need to memorize these) have been implicated. It can be imagined that as microglia develop from primitive macrophages in the yolk sac, such molecules would create a signaling gradient that microglia, expressing corresponding receptors, would follow to reach their final desination. Think of leaving a trail of biscuits for your stubborn puppy to follow if you want to get her into the kennel.

Once they enter the brain, what keeps them there and in that complex, ramified morphology? What induces them to clear developmentally apoptotic neurons and prune synapses, both to allow appropriate, efficient wiring of the brain? Again, we think we have some ideas, but the precise molecular mechanisms remain unclear. What is clear, however, is that this area of microglial research is still blossoming and constant strides are being made to understand the development of these frenetic little cells.

This could lead us to some interesting insights that will facilitate therapies for diseases where microglia seem to have a role; a topic we will cover in Part III of this series. Now that we have an idea of microglial ontogeny, we will next discuss what role they play in the healthy developing and adult brain in Part II of Microglia.

References

Alliot F, Godin I, & Pessac B (1999). Microglia derive from progenitors, originating from the yolk sac, and which proliferate in the brain. Brain research. Developmental brain research, 117 (2), 145-52 PMID: 10567732

Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, & Merad M (2010). Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science (New York, N.Y.), 330 (6005), 841-5 PMID: 20966214

Gomez Perdiguero E, Klapproth K, Schulz C, Busch K, Azzoni E, Crozet L, Garner H, Trouillet C, de Bruijn MF, Geissmann F, & Rodewald HR (2015). Tissue-resident macrophages originate from yolk-sac-derived erythro-myeloid progenitors. Nature, 518 (7540), 547-51 PMID: 25470051

Kaufmann SH (2008). Immunology’s foundation: the 100-year anniversary of the Nobel Prize to Paul Ehrlich and Elie Metchnikoff. Nature immunology, 9 (7), 705-12 PMID: 18563076

Rezaie P, & Male D (2002). Mesoglia & microglia–a historical review of the concept of mononuclear phagocytes within the central nervous system. Journal of the history of the neurosciences, 11 (4), 325-74 PMID: 12557654

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The Link Between Breastfeeding and IQ http://brainblogger.com/2015/04/08/the-link-between-breastfeeding-and-iq/ http://brainblogger.com/2015/04/08/the-link-between-breastfeeding-and-iq/#comments Wed, 08 Apr 2015 12:00:03 +0000 http://brainblogger.com/?p=19381 It is indeed a pity that in recent times, breastfeeding has grabbed headlines for a slew of controversial reasons. Remember the ruckus some people made about women breastfeeding in public? Well, they got rightly trounced by the saner and the more considerate members of the public. But the flurry of mud-slinging and Twitter rants brought into the open a disturbing fact — many people are still unaware of the transformative physical and mental health benefits of breastfeeding on children.

Many doctors point out that breastfeeding helps new mommies shed the weight they have gained during pregnancy. But as men of science, they should also point out the positive link between breastfeeding and higher IQ of children. After all, this has been proved conclusively in countless studies.

The Effect of Early-Life Diet on IQ

Studies have already conclusively proved the impact of early-life diet on the brain structure of human beings. One study was conducted on two groups of adolescents who were respectively fed on a standard diet and a highly-nutritious diet in the weeks after they were born. The findings show that those adolescents who were on a high nutrient diet had significantly greater verbal IQ than the group that was on a regular diet. This study encouraged scientists to research more on the long-term cognitive benefits of breastfeeding.

Another, more recent investigation has conclusively proven the link between breastfeeding and white matter development, which is related to IQ. It demonstrated that exclusive breastfeeding is related to increase in the volume of white matter throughout the brain and that of the gray matter in the sub-cortical region. Exclusive breastfeeding is also related to the excess thickness of the parietal lobe cortical region.

Scientists have found that the duration of breastfeeding is also a critical factor that determines the mental development of the child. The longer the duration, the more is the cognitive and motor development in children. This finding was reported from a study on 2- and 3-year-old children who were breastfed for various lengths of time.

The Positive Effects of Breastfeeding Evident Well Into Adulthood

Scientists are excited to note that the positive effects of breastfeeding continue to manifest long after adolescence and well into adulthood. A decades-long study was undertaken in Brazil to determine the long-term benefits of exclusive breastfeeding. Breastfeeding information of close to 6,000 infants from various demographic groups was recorded in 1982. After 30 years, the scientists tracked down more than half of the original participants and recorded their IQ levels, educational qualifications, and incomes. The findings were startling.

Infants who were breastfed for 12 months or more scored more on IQ tests, had greater educational attainment, and earned more than those infants who were breastfed for less than a month. The positive correlation between high IQ and both greater educational attainment and income-earning potential is evident, but the findings of this study prove that it is not just breastfeeding that matters. The duration of breastfeeding plays a critical role in the cognitive development of infants.

This is the first study to examine the long-term effects of breastfeeding. The findings of this study should now encourage physicians to educate their patients on the benefits of exclusive breastfeeding at least for the first six months of the baby’s life and continuing the practice well into the first year of age. Hospitals too should encourage breastfeeding amongst new mothers.

What’s in Breastfeeding: The DHA Link

Although it is known that breast milk is rich in all the nutrients that the baby needs to mature intellectually and physically, scientists are not yet sure about the exact mechanisms at work. But they strongly believe that DHA has a role to play.

Docosahexaenoic (DHA) and arachidonic (AA) acids comprise about 20 percent of the fatty acid content in the human brain. Fatty acids are known to promote healthy neuronal growth and repair and myelination. Myelination or the increase in the volume of myelin (a protective layer of protein and fatty substances) around the neurons improves neuronal coordination and enhances brain functionality especially with regards to higher cognitive tasks. Breast milk contains an abundance of long-chain fatty acids like DHA and AA. So scientists believe that there could be a strong DHA link in the positive relation between breastfeeding and higher IQ.

The above findings have critical lateral considerations. Physicians could prescribe DHA supplements to pregnant women, so there is placental transmission of this fatty acid that would, in turn, aid the neural development in the fetus. Lactating mothers can take these supplements in prescribed doses to boost the concentration of DHA in their milk. Infant formula manufacturers should also invest in research and development to determine the optimal amount of DHA they should include in their products.

Breastfeeding, Oxytocin, and Brain Development

Some scientists also believe that the hormone oxytocin may have a role to play in facilitating brain development in breastfed babies. Oxytocin is present in small amounts in maternal milk. Animal studies suggest that oxytocin is also produced by the body in response to the suckling action of babies feeding on mother’s milk.

Oxytocin has long been associated with increased bonding and trust between the mother and the child. But according to more recent data, oxytocin is also instrumental in shaping and supporting the physical development of the central nervous system. It regulates the functions of the autonomic nervous system to ensure smooth motor functioning. Oxytocin also acts as a neural protective agent and heals scarred tissues. So it is evident that the presence and release of oxytocin in the infant body indirectly enhances his mental capabilities by promoting and supporting healthy brain development.

The findings from the above-mentioned studies leave no room for doubt that infants who have been exclusively breastfed for the first six months of their lives grow up to be more happy, healthy, and intelligent than their formula-fed peers. Mothers, are you taking note?

References

Bernard, J., De Agostini, M., Forhan, A., Alfaiate, T., Bonet, M., Champion, V., Kaminski, M., de Lauzon-Guillain, B., Charles, M., & Heude, B. (2013). Breastfeeding Duration and Cognitive Development at 2 and 3 Years of Age in the EDEN Mother–Child Cohort The Journal of Pediatrics, 163 (1), 36-420 DOI: 10.1016/j.jpeds.2012.11.090

Carter, C. (2014). Oxytocin Pathways and the Evolution of Human Behavior Annual Review of Psychology, 65 (1), 17-39 DOI: 10.1146/annurev-psych-010213-115110

Deoni, S., Dean, D., Piryatinsky, I., O’Muircheartaigh, J., Waskiewicz, N., Lehman, K., Han, M., & Dirks, H. (2013). Breastfeeding and early white matter development: A cross-sectional study NeuroImage, 82, 77-86 DOI: 10.1016/j.neuroimage.2013.05.090

Deoni, S., Mercure, E., Blasi, A., Gasston, D., Thomson, A., Johnson, M., Williams, S., & Murphy, D. (2011). Mapping Infant Brain Myelination with Magnetic Resonance Imaging Journal of Neuroscience, 31 (2), 784-791 DOI: 10.1523/JNEUROSCI.2106-10.2011

Guesnet, P., & Alessandri, J. (2011). Docosahexaenoic acid (DHA) and the developing central nervous system (CNS) – Implications for dietary recommendations Biochimie, 93 (1), 7-12 DOI: 10.1016/j.biochi.2010.05.005

Isaacs, E., Gadian, D., Sabatini, S., Chong, W., Quinn, B., Fischl, B., & Lucas, A. (2008). The Effect of Early Human Diet on Caudate Volumes and IQ Pediatric Research, 63 (3), 308-314 DOI: 10.1203/PDR.0b013e318163a271

Krol, K., Rajhans, P., Missana, M., & Grossmann, T. (2015). Duration of exclusive breastfeeding is associated with differences in infants’ brain responses to emotional body expressions Frontiers in Behavioral Neuroscience, 8 DOI: 10.3389/fnbeh.2014.00459

Victora, C., Horta, B., de Mola, C., Quevedo, L., Pinheiro, R., Gigante, D., Gonçalves, H., & Barros, F. (2015). Association between breastfeeding and intelligence, educational attainment, and income at 30 years of age: a prospective birth cohort study from Brazil The Lancet Global Health, 3 (4) DOI: 10.1016/S2214-109X(15)70002-1

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Best and Worst of Neuroscience and Neurology – March 2015 http://brainblogger.com/2015/04/06/best-and-worst-of-neuroscience-and-neurology-march-2015/ http://brainblogger.com/2015/04/06/best-and-worst-of-neuroscience-and-neurology-march-2015/#comments Mon, 06 Apr 2015 11:00:44 +0000 http://brainblogger.com/?p=19359 In this article, I will present a selection of publications that came out in March. There were many interesting developments, both in fundamental neuroscience and neurology, and in the practical aspects of dealing with brain-related diseases and disorders.

In March, the scientific community marked the birthday of Sir Bernard Katz, German-born biophysicist who received the 1970 Nobel Price in Physiology and Medicine for his investigations of the properties of synapses. Together with Paul Fatt, Sir Katz discovered that neural transmitters are released into the synapses in defined “quantal” portions. The underlying mechanism of exocytosis relies on the release of neurotransmitters from the vesicles of approximately equal size, thus giving this seemingly quantum property to the process of neural transmission. The works of Bernard Katz laid foundation to the modern understanding of the processes of neural transmission.

THE BEST

Last month, we saw quite a few interesting and encouraging publications on the development of treatments for Alzheimer’s disease. All of these new approaches are still in their infancy, but the important thing is that they demonstrate not only the slowing down of disease development but also the possibility of restoring, at least partially, normal brain functions.

New anti-tau immunotherapy for Alzheimer’s

The oligomers of tau proteins are considered as one of the major culprits in the development and progression of Alzheimer’s disease. Scientists from the University of Texas tested the effect of new anti-tau immunotherapy on experimental animals with Alzheimer’s. It turned out that a single dose of immunotherapy reversed the memory deficit in animals. It also reduced the level of beta amyloid oligomers, the building blocks of notorious amyloid plaques that are always seen in the brains of patients with the disease. Clearly there is a cross-talk between two molecular components, since immunotherapy targeted directly only one of them.

Existing drugs to treat Alzheimer’s?

Two existing drugs have also been found active in reversing the effects of Alzheimer’s disease. An existing drug to treat epilepsy, levetiracetam, was found to be able to restore memory and brain functions in patients with amnestic mild cognitive impairment, which is considered an early stage of Alzheimer’s disease. The drug was tested in the first human trial and was shown to improve memory performance in the patients.

Another drug, AZD05030, was developed to treat cancer but failed clinical trials. Surprisingly, it turned out to be effective for Alzheimer’s disease, restoring the memory and brain cell connections in the experimental animals. The compound will soon be tested in clinical trials on humans.

Ultrasound to activate microglial cells

But the most interesting news, in my opinion, came from Australia. Researchers at the University of Queensland have developed a non-invasive ultrasound method that activates microglial cells making them to digest and remove the amyloid plaques. The treatment temporarily opens the blood-brain barrier thus allowing activation of mechanisms that clear away the toxic protein agglomerates from the brain. In the mice with Alzheimer’s disease, the treatment restored the memory to the healthy levels. If this approach will work in humans at least to some degree, it will most certainly represent a breakthrough in the treatment of Alzheimer’s disease.

The differences in young and old brains according to fMRI

Alzheimer’s disease is often considered as one of the common aspects of aging. But in general, the age-related negative changes in brain functions are traditionally viewed as a reflection of changes in the underlying neuronal activity. This view is challenged by new data obtained by researchers from the University of Cambridge.

The scientists re-examined methodology that is used to measure the brain activity, the functional magnetic resonance imaging (fMRI). The problem with fMRI is that it measures neural activity indirectly through changes in regional blood flow. This means that the differences in age-related vascular reactivity should be taken into account when neuronal differences are measured. Researchers used the resting state fMRI measurements from 355 healthy volunteers over their lifetime to get the baseline measures of vascular functions. Once these new baseline data were taken into account, the differences in neuronal activity between young and old brain turned out to be not so big, thus suggesting that they were overestimated in previous studies. The changes in the aging brain are likely to be caused primarily by the vascular changes.

Opening the blood-brain barrier with radiowaves

One of the reasons we have so few therapeutics to target brain diseases is the lack of reliable brain-specific drug delivery systems. The next article provides a radically different approach to address this problem.

Localized and specific drug delivery to the problem site in the body was always viewed by pharmaceutical scientists as a highly desirable aim which is, unfortunately, very difficult to achieve. With 98% of modern drugs unable to cross the blood-brain barrier, the brain is a particularly difficult part of the body to target selectively. A new approach reported by Canadian scientists this month sounds almost futuristic.

They developed a method of delivering magnetic nanoparticles to the specific areas of the brain using the magnetic fields generated by MRI machine. Once there, the nanoparticles can be made to by vibrate and dissipate heat using a radio-frequency field. This creates a mechanical stress that opens a blood-brain barrier locally and for a limited period of time (around 2 hours), thus allowing the delivery of blood-circulating therapeutics into the brain. The method has only been proven on the animals so far, but it appears to be a highly promising strategy for treating multiple brain disorders.

Free will for all?

Fundamental mechanisms of brain functioning continue to attract the attention of neuroscientists. In particular, we are interested in the characteristics of human brain that are unique to us. Free will is among those things that we see as making us who we are.

Well, the newly published study casts certain doubts on this self-glorifying view. It appears that even the animals as simple as worms have free will. Once tempted by the smell of tasty food, they may chose to go and investigate, but may also ignore it altogether and move in another direction. The brain of the microscopic roundworm Caenorhabditis elegans has only 302 neurons and 7,000 synapses. This is a nice simple model for investigating the function of neural systems.

Researchers found that the particular response of the individual worm to the stimulus depends on the current state of a simple three-cell neuronal system in its brain. This system can be influenced by competing motivations, and the final behavioral response is formed on the basis of input provided from all neurons. In general, this is not so different from the responses observed in much more complex brains. And probably this finding should not be so surprising. After all, free will is not just a philosophical concept – it also has lots to do with the decision-making processes in the brain.

THE WORST

As usual, this month we have seen a number of publications that have changed our views on some important issues. We may consider them as negative developments, but gaining any knowledge is always a positive thing.

Potential uses for brain stem cells may be limited

Stem cell therapy is one of the buzz words in the scientific community these days. The possibilities promised by this therapeutic approach are exciting. The discovery of stem cells in the brain brings hope that they can be used to treat a broad range of brain conditions, from neurodegenerative diseases to injuries. However, the new findings of German scientists will probably be seen as a certain setback for such high hopes. The researchers found that the diversity of neurons formed from them is limited. Also, the number of brain stem cells decreases with age. Further research will need to be focused on finding the ways to extend the ability of these cells to renew themselves.

We know less than we thought about inflammation in the brain

It is not uncommon to see scientific research yielding unexpected results. One of these such occasions was reported recently by the scientists from the University of Manchester studying stroke. It is well known that stroke is associated with inflammatory response which, instead of aiding recovery, cause further damage. Researchers were studying stroke-associated inflammasomes, large protein complexes mediating the inflammation and contributing to the cell death. One of such complexes called NLRP3 is known to be associated with injuries. Currently, the inflammasome NLRP3 is a target for developing the drugs against neurodegenerative diseases such as Alzheimer’s that is accompanied by inflammation.

To the researchers’ surprise, it turned out that NLRP3 has nothing to do with the inflammation processes in brain. Instead, two other protein complexes, NLRC4 and AIM2, are involved in the stroke and brain injury. The finding provides new targets for developing the stroke treatments, but also demonstrates once more how little we know about the inflammatory and immune processes in the brain.

Common treatments don’t always produce the results we want

Three publications below shed some light on why certain well established and commonly used treatments do not exactly produce the results we want.

Only in my previous monthly review I was mentioning that our knowledge of the mechanisms of anti-depressant drugs is limited at best. A new article published this month once again confirms this statement. It is generally believed that depression is caused by the imbalance in serotonin signalling. In response to the neuronal firing, serotonin is released from the vesicles in the presynaptic terminals into the synapse. Serotonin is then taken back into the terminals in the process which is targeted by the serotonin re-uptake inhibitors. The action of these drugs increases the level of serotonin in the synapses and thus normalize its balance affected during the depression.

It turned out, however, that exocytosis is not the only process for the serotonin release. The neuromediator can also simply diffuse through the cell membrane. The excessive level of serotonin may affect the firing of serotonergic neurons by autoinhibition, thus leading to the initial slowing down of the antidepressants’ therapeutic action.

HIV remains the largest pandemic in human history. Despite the decades of research and impressive success of anti-retroviral therapy, the complete cure for the disease remains elusive. The largest obstacle on the way to such cure is the presence of reservoirs in the body where the virus can safely hide from the circulating drugs. The brain is one of these reservoirs.

New data published this month show that the virus may infiltrate in the brain as early as four months after the initial infection. Once in the brain, virus may establish a relatively isolated sub-population which is mostly shielded from the drugs by the blood-brain barrier. Unfortunately, very little is currently known about the HIV replication inside the brain. Medical professionals commonly advise the HIV patients not to start the therapy immediately to avoid the long-term side effects of the drugs. Delaying the therapy, however, clearly helps the virus to establish itself in “safe havens” like brain, as current research demonstrates.

Obesity is one of the major risk factors in the development of type II diabetes. But the remarkable thing about the drugs for type II diabetes, such as thiazolidinediones, is that they make people to gain even more fat! Common sense would tell anyone that something is clearly wrong with these drugs. Now we know exactly what this is.

The drugs act directly on the so-called agouti-related protein (AgRP) cells, the hunger-stimulating cells located in the hypothalamus. Activation of these cells in experimental animals makes them immediately hungry. No wonder people treated by anti-diabetics feel much stronger food cravings. And obviously, something should be done with this whole approach to treat diabetes.

References

Bakker, A., Albert, M., Krauss, G., Speck, C., & Gallagher, M. (2015). Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance NeuroImage: Clinical, 7, 688-698 DOI: 10.1016/j.nicl.2015.02.009

Calzolari, F., Michel, J., Baumgart, E., Theis, F., Götz, M., & Ninkovic, J. (2015). Fast clonal expansion and limited neural stem cell self-renewal in the adult subependymal zone Nature Neuroscience, 18 (4), 490-492 DOI: 10.1038/nn.3963

Castillo-Carranza, D., Guerrero-Munoz, M., Sengupta, U., Hernandez, C., Barrett, A., Dineley, K., & Kayed, R. (2015). Tau Immunotherapy Modulates Both Pathological Tau and Upstream Amyloid Pathology in an Alzheimer’s Disease Mouse Model Journal of Neuroscience, 35 (12), 4857-4868 DOI: 10.1523/JNEUROSCI.4989-14.2015

Denes, A., Coutts, G., Lénárt, N., Cruickshank, S., Pelegrin, P., Skinner, J., Rothwell, N., Allan, S., & Brough, D. (2015). AIM2 and NLRC4 inflammasomes contribute with ASC to acute brain injury independently of NLRP3 Proceedings of the National Academy of Sciences, 112 (13), 4050-4055 DOI: 10.1073/pnas.1419090112

Garretson, J., Teubner, B., Grove, K., Vazdarjanova, A., Ryu, V., & Bartness, T. (2015). Peroxisome Proliferator-Activated Receptor   Controls Ingestive Behavior, Agouti-Related Protein, and Neuropeptide Y mRNA in the Arcuate Hypothalamus Journal of Neuroscience, 35 (11), 4571-4581 DOI: 10.1523/JNEUROSCI.2129-14.2015

Gordus, A., Pokala, N., Levy, S., Flavell, S., & Bargmann, C. (2015). Feedback from Network States Generates Variability in a Probabilistic Olfactory Circuit Cell DOI: 10.1016/j.cell.2015.02.018

Kaufman, A., Salazar, S., Haas, L., Yang, J., Kostylev, M., Jeng, A., Robinson, S., Gunther, E., van Dyck, C., Nygaard, H., & Strittmatter, S. (2015). Fyn inhibition rescues established memory and synapse loss in Alzheimer mice Annals of Neurology DOI: 10.1002/ana.24394

Leinenga, G., & Gotz, J. (2015). Scanning ultrasound removes amyloid-  and restores memory in an Alzheimer’s disease mouse model Science Translational Medicine, 7 (278), 278-278 DOI: 10.1126/scitranslmed.aaa2512

Mlinar, B., Montalbano, A., Baccini, G., Tatini, F., Palmini, R., & Corradetti, R. (2015). Nonexocytotic serotonin release tonically suppresses serotonergic neuron activity The Journal of General Physiology, 145 (3), 225-251 DOI: 10.1085/jgp.201411330

Sturdevant, C., Joseph, S., Schnell, G., Price, R., Swanstrom, R., & Spudich, S. (2015). Compartmentalized Replication of R5 T Cell-Tropic HIV-1 in the Central Nervous System Early in the Course of Infection PLOS Pathogens, 11 (3) DOI: 10.1371/journal.ppat.1004720

Tabatabaei, S., Girouard, H., Carret, A., & Martel, S. (2015). Remote control of the permeability of the blood–brain barrier by magnetic heating of nanoparticles: A proof of concept for brain drug delivery Journal of Controlled Release, 206, 49-57 DOI: 10.1016/j.jconrel.2015.02.027

Tsvetanov, K., Henson, R., Tyler, L., Davis, S., Shafto, M., Taylor, J., Williams, N., Cam-CAN, ., & Rowe, J. (2015). The effect of ageing on fMRI: Correction for the confounding effects of vascular reactivity evaluated by joint fMRI and MEG in 335 adults Human Brain Mapping DOI: 10.1002/hbm.22768

Image via anyaivanova / Shutterstock.

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The Dream Of Your Dreams http://brainblogger.com/2015/03/30/the-dream-of-your-dreams/ http://brainblogger.com/2015/03/30/the-dream-of-your-dreams/#comments Mon, 30 Mar 2015 11:00:45 +0000 http://brainblogger.com/?p=19205 Lucid dreaming is one of those things few people think in depth about, even if they’ve had one or two. Still it’s a skill which some people become absolutely fascinated with honing, and having had a fair few of them myself I’m beginning to see why.

Lucidity, as some argue, can be an endless opportunity which is only limited to your imaginative capacity. You can explore any area of your own mind, from base hedonistic fantasy to sublime self-discovery. Discourse with dream characters plucked from your own psyche, learn to play a Beethoven sonata accompanied by the Philharmonic, or simply step into your favourite novel.

Of course while enthralling, the practice itself isn’t quite so easy. Often when lucidity dawns a first-timer will be so excited by the experience they promptly wake up! Once this first obstacle is overcome, there’s still a long road between knowing one is asleep, and being able to choose the direction of the dream.

The technique that’s worked best for me in recent months has been a very simple variety of what is known as a WILD – a Wilfully Induced Lucid Dream. These are attempted when awakening from a fairly long period of sleep and then returning to sleep. The particular method I’ve found success with is simply to await the moment you feel yourself about to fall asleep again, and then alternately press the tips of two fingers against the duvet or pillow for a minute or two while repeating an intention in my mind to become lucid.

There are a host of other methods available, and the academic who really established the field of oneirology, Stephen LaBerge, also pioneered the creation of a device which, while no longer available, purported to aid in lucid dream induction, the NovaDreamer. Several similar bits of kit have followed in its wake, and there are rumours of a NovaDreamer II in development from the original team.

The best of these devices, such as the REM Dreamer, play flashing lights and sounds from a sleep mask worn at night which detects rapid eye movement. A new project in the crowdfunding works is Aurora from iWinks, which promises a technologically up-to-the-minute version of the same and is said to be coming out this summer.

These devices’ use is debated within this somewhat specialist yet very passionate field, not in terms of whether they genuinely assist in inducing lucidity (the better designed devices at least appear to do so), but in terms of whether their use will have a built in time-limit for success.

Our minds have a great ability to become used to external stimuli and to “build them into” a dream, such that we don’t notice their intrusion. This is why becoming lucid at the onset of dreaming, or via a trained habit of thought are considered by many oneironauts to be superior techniques. They are internalised methods, and therefore sustainable over the long-term.

One radical step (some may say too far!) is the recent research published in Nature by Ursula Voss and colleagues into weak electrical field bombardment of the brain to induce lucidity. These researchers found that frequencies of 40 Hz created gamma wave brain states which aided the likelihood of lucidity occurring in sleepers. I for one won’t be trying this anytime soon. I think there are pretty strong arguments against risking sending electric signals directly to the frontal lobes to improve my odds at achieving something I can simply accomplish using my own mental faculties.

References

Voss, U., Holzmann, R., Hobson, A., Paulus, W., Koppehele-Gossel, J., Klimke, A., & Nitsche, M. (2014). Induction of self awareness in dreams through frontal low current stimulation of gamma activity Nature Neuroscience, 17 (6), 810-812 DOI: 10.1038/nn.3719

Image via KI Petro / Shutterstock.

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Human Head Transplants – Fantasy to Fact? http://brainblogger.com/2015/03/26/human-head-transplants-fantasy-to-fact/ http://brainblogger.com/2015/03/26/human-head-transplants-fantasy-to-fact/#comments Thu, 26 Mar 2015 11:00:03 +0000 http://brainblogger.com/?p=19203 When English author Mary Shelley penned Frankenstein in 1818, little did she know that her vision might come true, albeit in a slightly different way and as a boon to mankind. Shelley’s Victor Frankenstein created the Monster by sewing together body parts from human corpses. In a way, Frankenstein created Life. Doctors and surgeons today do nothing different; they save lives by transplanting organs, bones, skin, and nerves and veins. To date, they can transplant almost every major organ of the body, like the heart, liver, lungs, kidneys, pancreas, and intestine, but not the head. This may be about to change!

Italian neurosurgeon Dr. Sergio Canavero recently created quite a stir by his announcement that he will attempt the head transplant surgery within three years. He believes that modern medicine already has the means to do this procedure successfully.

Unsurprisingly, Cavanero’s announcement was met with harsh criticism. Mainstream media dutifully covered the potential moral and ethical problems associated with head transplantation. In this article, I’d like to analyse how much science is really behind the Dr. Cavanero’s thinking and whether such surgery can really be done at present time. This is an aspect of the problem which was mostly ignored by the reporters concerned with the ethics.

The Precursor

Although heads have not been transplanted in human beings, this procedure has been attempted in monkeys. In 1970, Robert White and his team transplanted the head of a monkey on to the body of another monkey. The removal of the head and the transplantation was carried out simultaneously. The monkey lived for 8 days, and there were no surgical complications. However, this experiment did not address the challenge of reconnecting the severed spinal cords to prevent paralysis. So no head transplantation experiment in monkeys or humans has been attempted since.

But Dr. Canavero says he has come up with a way to reconnect spinal cords in human beings during a head transplant.

Head Transplant in Humans: The Way Forward

Dr. Canavero has named his human head transplant project HEAVEN. A person who is possibly suffering from an incurable and debilitating medical condition but has a healthy and functioning head and brain will be the recipient. A person who has been declared brain-dead but still has a healthy body will be the donor. So after the procedure, the donor will receive a new head.

Dr. Canavero believes that inducing hypothermia during the transplantation procedure and using sharp severing instruments and specialized healing agents will help him overcome many of the challenges inherent in the procedure.

Human Head Transplant Challenge #1: Sustaining Life After the Head is Severed

The biggest challenge during the human head transplant procedure is to stabilize and keep alive the individual after his head is severed and blood flow stops. Research data show that human beings can be sustained without blood flow if the body is cooled to a temperature range of 12oC and 15oC. At these temperatures, the metabolic activity in the cerebral region drops to about 10 percent of what is normal. The data from cardiac surgery has revealed that producing profound hypothermia causes total cessation of circulation. These conditions can be safely sustained for about 45 minutes without causing any neurological damage to the individual.

Canavero believes 45 minutes is adequate time for the surgeons to reconnect the severed spinal cords.

Human Head Transplant Challenge #2: Preventing Cell Damage in the Spinal Cord Stumps

Dr. Canavero realizes that reattaching the severed spinal cords is not enough to merit a complex and costly head transplant procedure. The individual who has received the new head should be able to regain some of his earlier motor abilities. This implies that the heads should be severed with as little damage to the neuronal cells, so it is easy to restore the connections, and consequently, motor functionality.

According to clinical findings, there have been several instances where patients with sharp wounds to their spinal cords not only survived but also recovered from their initial stages of paralyses and regained their earlier range of motor functionality. On the other hand, one clinical study on the victim of a self-inflicted 0.38 caliber gunshot (with greater scar area) reveals that the patient did not recover from his state of paralysis.

Another study has found that axons have to be regenerated to restore neurological functionality in cases where the damaged nerve is separated by a gap. Axon generation is most effective when this gap is less than two centimeters in length.

So the challenge in human head transplantation is to minimize the scar area when severing the spinal cords. Dr. Canavero proposes using a specialized severance tool that will minimize the scar area and keep cell damage to a minimum. He has in mind the tools that will create the force of less than 10 N during transections. Incidentally, a typical spinal cord injury involves the force of around 26,000 N.

Dr. Canavero believes that an ultra-sharp nanoknife made from a layer of silicon nitride could be used to inflict a sharp cut.

Human Head Transplant Challenge #3: Healing, Regenerating Neurons, and Restoring Connections and Motor Functionality

The chances of restoring the donor’s earlier level of motor abilities increases greatly the faster the severed cords join and the damaged membranes are repaired. And the faster the healing process, the quicker the neural connections will be restored. Usually in healthy individuals, the body’s natural healing mechanisms swing into action when there is a cut or a wound. But to heal the spinal cord tissues in a case of head transplant, Dr. Canavero proposes using a compound called polyethylene glycol (PEG).

According to several research studies, PEG has the ability to heal wounds or reseal at the molecular level. In fact, scientists are already exploring avenues to establish PEG as an effective means of managing and/or treating spinal cord injury and restore or improve motor functionality in patients.

Dr. Canavero also intends to apply electrical stimulation at the point where the two severed ends of the cords fuse to accelerate healing. It has been established that electrical stimulation not only speeds up the axons and dendrons regeneration but can also trigger voluntary movements in individuals with chronic complete paralysis.

Human Head Transplant Challenge #4: Post-Transplant Complications

Organ rejection and poor or impaired blood flow to the transplanted organ are some common post-transplant complications. However, medicine has the means to diagnose these conditions and intervene effectively. For instance, the presence of a couple of serum protein biomarkers confirms acute rejection in renal transplant patients.

Color Flow Doppler (CFD) ultrasonography has been found to be an effective way to monitor blood flow after surgery. These monitoring and diagnostic methods may be implemented to detect post-transplant complications in people who have received a new head.

Every great scientific breakthrough sounds incredulous at first. The idea of a head transplant in humans may sound fantastic, dreadful or ridiculous, depending on your personal position, but I have no doubt that eventually it could be done.

Potential benefits for certain patients are obvious. If human head transplant is successful, paraplegics who have substantial amounts of spinal cord intact and people suffering from muscular dystrophy can dream of an independent and self-sufficient future where they are back to doing the things they love and are able to live more productive lives. Yet, there is also no doubt that the possibility of successful human head transplantation will create serious concerns in many quarters.

References

Angeli, C., Edgerton, V., Gerasimenko, Y., & Harkema, S. (2014). Altering spinal cord excitability enables voluntary movements after chronic complete paralysis in humans Brain, 137 (5), 1394-1409 DOI: 10.1093/brain/awu038

Canavero, S. (2013). HEAVEN: The head anastomosis venture Project outline for the first human head transplantation with spinal linkage (GEMINI) Surgical Neurology International, 4 (2) DOI: 10.4103/2152-7806.113444

Canavero, S. (2015). The “Gemini” spinal cord fusion protocol: Reloaded Surgical Neurology International, 6 (1) DOI: 10.4103/2152-7806.150674

Chen, R., Sigdel, T., Li, L., Kambham, N., Dudley, J., Hsieh, S., Klassen, R., Chen, A., Caohuu, T., Morgan, A., Valantine, H., Khush, K., Sarwal, M., & Butte, A. (2010). Differentially Expressed RNA from Public Microarray Data Identifies Serum Protein Biomarkers for Cross-Organ Transplant Rejection and Other Conditions PLoS Computational Biology, 6 (9) DOI: 10.1371/journal.pcbi.1000940

KHALID, A., QURAISHI, S., ZANG, W., CHADWICK, J., & STACKJR, B. (2006). Color doppler ultrasonography is a reliable predictor of free tissue transfer outcomes in head and neck reconstruction Otolaryngology – Head and Neck Surgery, 134 (4), 635-638 DOI: 10.1016/j.otohns.2005.11.031

Kuffler, D. (2014). An assessment of current techniques for inducing axon regeneration and neurological recovery following peripheral nerve trauma Progress in Neurobiology, 116, 1-12 DOI: 10.1016/j.pneurobio.2013.12.004

Malhotra, S., Dhama, S., Kumar, M., & Jain, G. (2013). Improving neurological outcome after cardiac arrest: Therapeutic hypothermia the best treatment Anesthesia: Essays and Researches, 7 (1) DOI: 10.4103/0259-1162.113981

Rad, I., Khodayari, K., Hadi Alijanvand, S., & Mobasheri, H. (2015). Interaction of polyethylene glycol (PEG) with the membrane-binding domains following spinal cord injury (SCI): introduction of a mechanism for SCI repair Journal of Drug Targeting, 23 (1), 79-88 DOI: 10.3109/1061186X.2014.956668

Image via Family Business / Shutterstock.

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The Physiology and Psychology of Pain http://brainblogger.com/2015/03/19/the-physiology-and-psychology-of-pain/ http://brainblogger.com/2015/03/19/the-physiology-and-psychology-of-pain/#comments Thu, 19 Mar 2015 11:00:38 +0000 http://brainblogger.com/?p=19002 Pick up any newspaper and pore over it. Not only are nations at war but communities in the same country are fighting amongst themselves. People are killing each other for a piece of land, money, or just because they hate a person who looks different from them or worships another God. In the midst of these gory tales of hatred are the stories of triumph — men and women who give up their lives to save others and doctors who put their lives in the line of fire to treat people in far-flung places and war-torn regions.

Why do some people hurt others while others live just to bring a smile on other people’s faces?

Why do some people cause so much pain to others while some dedicate their lives to heal the wounds of strangers?

According to scientists, the perception of pain in oneself and recognizing it in others (empathy) is influenced by the complex interplay of neural circuitry in the individual, biochemical reactions in his brain, societal conventions, and evolutionary mechanisms.

The Perception of Pain in Self

Physical pain has a distinct brain signature. Functional magnetic resonance imaging (fMRI) can evaluate the amount of pain. However, another study has built on these findings to suggest that people “feel” physical pain differently. This difference stems from the way their brains are wired.

According to one recent study, the experience of pain has two distinct neural stages or pathways. The first stage kicks off, say, when you accidentally burn your fingers or cut your hand. The nerves in your hand send signals to the brain. The pain stimuli reach parts of the brain, like the anterior cingulate cortex, that are associated with the perception of pain. The chain of events that make up this stage is similar in all healthy individuals.

But people “react” differently to pain; not everyone utters an “ouch” or reaches out for a painkiller when they are physically hurt. The researchers who took part in the above study now know why. They have discovered a second neural pathway instrumental in the perception of pain. The “feeling” of pain — mild, intense, or unbearable — is determined by the activity in the medial prefrontal cortex and nucleus accumbens. These two regions of the brain are conventionally associated with motivation and emotion.

Scientists now know there are definite emotional and cognitive underpinnings to the perception of pain. This indicates that individuals can regulate and/or alter their perception of pain through mental conditioning techniques like meditation, distraction, and visualization. People who suffer from debilitating pain, triggered by a disease or an injury, can now hope to find relief in coping mechanisms other than popping painkillers.

The Societal Context of Feeling Pain

The perception of pain has a societal basis as well. Several studies have found that individuals tend to report different levels of pain in presence or absence of a highly-empathic person, like a romantic partner, and a complete stranger. Women tend to report less pain in the presence of an “attachment figure” or someone who makes them feel safe. In an experiment, women subjects in a threatening situation showed greater activity in the region of their brains that triggers safety signals (that is, they felt less pain) when they were shown images of their romantic partners.

One study, however, clarifies that the perception of pain in such cases is actually determined by the attachment style of the subject.

Individuals with anxious attachment styles crave close and intimate relationships but tend to sacrifice their needs to keep their partners happy. They are not confident about their partner’s affections and fear the relationship will not last. According to the findings from the above study, women with this attachment style tend to feel more pain in the presence of a person who does not empathize with their conditions. They feel lower pain in the presence of their romantic partners who are perceived to be highly empathic.

Individuals with avoidant attachment styles tend to value independence and self-sufficiency more than intimacy. These people are not comfortable sharing their feelings with strangers and partners alike. So it is not surprising that studies indicate that women with such attachment styles report lesser pain when alone than when in the presence of another individual, who may be a stranger or a romantic partner.

With these findings, doctors may now need to think twice before they ask individuals to be present when their partners are giving birth. It seems that there is no rule of thumb.

The Perception of Pain in Others

Human beings are social animals. The ability to live harmoniously in a society, care for others, and form enduring relationships depends on the quality of empathy. So it is natural that scientists should be curious to know why some people are more empathetic than others or if some situations naturally bring out more empathy.

Scientists believe that empathy is triggered by various cognitive and affective processes. Few years ago a study was carried out on subjects with congenital insensitivity to pain (CIP) to understand if painful experiences from the past influenced the ability to empathize with the pain of others. People with CIP cannot feel anything when subjected to painful stimuli. So they have no “experience” or memory of pain. But curiously, as was found in the study, they can empathize with the pain of others by seeing and hearing pain-related behavior in video clips.

But do you think that emotional cues of pain like seeing groaning and writhing are so powerful that they can move one and all? Unfortunately, no. Empathy is more complex than that.

A new article published this year reports that human beings tend to be more empathetic towards friends than strangers. The study also noted that stress tends to affect the ability to empathize. Individuals who are under stress tend to be less empathic to the pain of strangers than when they are relaxed and peaceful.

The latter finding may explain mob violence or why violence tends to increase during social uprisings. Stress is a powerful trigger that can make people act in a way they would not think about in other situations.

The mechanisms underlying empathy are complex. But it is crucial that scientists delve more into them because it seems that understanding empathy is akin to decoding violent behavior. And the world could certainly do with a lot less violence!

References

Danziger, N. (2006). Is pain the price of empathy? The perception of others’ pain in patients with congenital insensitivity to pain Brain, 129 (9), 2494-2507 DOI: 10.1093/brain/awl155

Decety, J. (2011). The neuroevolution of empathy Annals of the New York Academy of Sciences, 1231 (1), 35-45 DOI: 10.1111/j.1749-6632.2011.06027.x

Eisenberger, N., Master, S., Inagaki, T., Taylor, S., Shirinyan, D., Lieberman, M., & Naliboff, B. (2011). Attachment figures activate a safety signal-related neural region and reduce pain experience Proceedings of the National Academy of Sciences, 108 (28), 11721-11726 DOI: 10.1073/pnas.1108239108

Krahe, C., Paloyelis, Y., Condon, H., Jenkinson, P., Williams, S., & Fotopoulou, A. (2015). Attachment style moderates partner presence effects on pain: a laser-evoked potentials study Social Cognitive and Affective Neuroscience DOI: 10.1093/scan/nsu156

Martin LJ, Hathaway G, Isbester K, Mirali S, Acland EL, Niederstrasser N, Slepian PM, Trost Z, Bartz JA, Sapolsky RM, Sternberg WF, Levitin DJ, & Mogil JS (2015). Reducing social stress elicits emotional contagion of pain in mouse and human strangers. Current biology : CB, 25 (3), 326-32 PMID: 25601547

Sambo, C., Howard, M., Kopelman, M., Williams, S., & Fotopoulou, A. (2010). Knowing you care: Effects of perceived empathy and attachment style on pain perception Pain, 151 (3), 687-693 DOI: 10.1016/j.pain.2010.08.035

Wager, T., Atlas, L., Lindquist, M., Roy, M., Woo, C., & Kross, E. (2013). An fMRI-Based Neurologic Signature of Physical Pain New England Journal of Medicine, 368 (15), 1388-1397 DOI: 10.1056/NEJMoa1204471

Woo, C., Roy, M., Buhle, J., & Wager, T. (2015). Distinct Brain Systems Mediate the Effects of Nociceptive Input and Self-Regulation on Pain PLoS Biology, 13 (1) DOI: 10.1371/journal.pbio.1002036

Image via Tyler Olsen / Shutterstock.

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What Have Your Glia Done For You Today? http://brainblogger.com/2015/03/16/what-have-your-glia-done-for-you-today/ http://brainblogger.com/2015/03/16/what-have-your-glia-done-for-you-today/#comments Mon, 16 Mar 2015 11:00:43 +0000 http://brainblogger.com/?p=19006 How should we approach solving the most fundamental questions in neuroscience? Some would say that our current endeavors into mapping the complement of neuronal connections (the connectome) within the human brain will bring us the most fruitful gains; and they could be right. This is the main focus of several (expensive) big data initiatives such as the BRAIN Initiative, the Human Connectome Project and the Human Brain Project.

However, a major shortcoming of these projects is the lack of goals slated to mapping the other half of the brain; a complement of cells known as glia, of which there are three predominant populations. These cells make up fifty percent of the total brain volume and are integral to normal brain function. A complete understanding of the brain’s “support cells”, as they are also called, along with mapping the neuronal wiring, will be paramount for a global theory of how the brain works to bring about consciousness and our plethora of behaviors.

Microglia

Neuroglia consist mainly of astrocytes, oligodendrocytes and microglia, the last of which do not actually originate in the brain. Instead, microglia (my current field of research), originate in the fetal yolk sac (a structure involved in primitive hematopoesis, or blood formation) where many other primitive and tissue resident macrophages are born. Contrary to original theories, microglia migrate into the brain early in embryonic life and reside there as a stable, self-sustaining population of cells, which are never replaced by bone marrow-derived cells from the periphery.

In essence, unlike other glia, our microglia grow old with us. As a pool of tissue-specific macrophages, microglia constitute the immune cells of the central nervous system. They are capable of mounting an immune response against foreign invaders (e.g. blood cells or proteins and bacteria) as well as clear neuronal debris after injury. As such, they have, somewhat insultingly, been dubbed the “garbage men of the brain.”

It has become clear that this is short-sighted. For example, microglia mediate the elimination of supernumerary synapses from the developing brain through a mechanism known as phagocytosis. Essentially, they gobble up the unnecessary synapses that the brain generates during development, a process without which many developmental and behavioral abnormalities can occur. Understanding this process is thus essential for determining how the brain’s connections are wired.

Extending their services into postnatal life, microglia also maintain the status quo within the brain. For example, when microglia are completely depleted from the central nervous system, adult mice show deficits in learning. In other words, your microglia can make you smarter through learning-induced synaptic remodeling; they act to balance removal of unused or inappropriate synapses allowing neuronal energy expenditure to be allocated to forming efficient synapses.

What important programs do these little “electricians” employ to bring about an appropriately wired brain? How can we manipulate them to prevent or curb neurological and mental illnesses? These are important questions that the neuroscientific community is currently asking, but must be put into the wider framework of mapping the human brain.

Astrocytes

Astrocytes (or astroglia) perform the most diverse set of functions of the glial cells, including sharing with microglia the role of synaptic maintenance. How could they not? A single astrocyte can contact up to one million synapses. At the microstructure level this is known as the “tri-partate synapse”.

It is at this juncture of the pre- and post-synaptic clefts (where the electrical signal of one neuron is coupled via a chemical signal – a neurotransmitter – to the next neuron) and the astroglial process, that astrocytes do most of their work. Here, they can regulate the rate and strength of synaptic transmission across neurons by releasing or sequestering neurotransmitters and modifying extracellular ion concentrations. Not only do they “listen” and “talk” to neurons, but they also provide metabolic support of endothelial cells, which line the brain vasculature, making up the blood brain barrier. At this site, they are also well positioned to regulate the amount of blood flow to a local brain region.

Recently, astrocytes have made public headlines with the discovery of their involvement in bulk clearance of brain metabolic waste during sleep, the importance of which is not lost on us after staying up too late the night before an exam.

Oligodendrocytes

Oligodendrocytes (oligos for short), the central nervous system equivalent of the Schwann cell in the peripheral nervous system, wraps a fatty sheath around the axons of neurons. This sheath known as myelin provides insulation to the axon and allows for much faster propagation of the electrical signal and thus faster communication and transmission of information. Think of it as the insulation around electrical wires on your favorite appliance.

Oligos seem to only function in this capacity, but we do not actually know that – a rough search on PubMed shows about 25 times more papers are published on neurons than oligodendrocytes. For example, a study published this week in the journal Science found that oligos are much more diverse than previously known. The study authors found that this cell type alone could be sub-divided into six classes based on their molecular signatures. We do not yet know the function of each or how each type may play a role in brain cytoarchitecture to facilitate faster, more efficient neuronal signaling, but it should become a priority.

Each of the glial functions listed above (and we have left out other types of glia, such as Bergmann glia, NG2 glia and ependymal cells, but we know even less about them) are essential to global brain plasticity and learning. Because of their intimate relationship with neurons, glial cells hold a central position in influencing cognitive processes. Author of The Other Brain, R. Douglas Fields suggested in a Nature Comment:

“[That] these include processes requiring the integration of information from spatially distinct parts of the brain, such as learning or the experiencing of emotions, which take place over hours, days and weeks, not in milliseconds or seconds.”

In other words, because glia work on the slower chemical level, not via electrical signals, they may facilitate paradigms such as learning, which do not happen instantaneously like say, visual perception. I could not agree more. But at this time, we can only speculate as to how glia might impart their “magical elixir” on neurons, facilitating the workings of the most complex biological entity in the known universe.

Over a century after the start of glial research, we still lack fundamental knowledge of glial numbers, diversity, distribution throughout the brain and function in the context of neurons and between themselves. The “neurotechnologies” that arise from the neurocentric initiatives should additionally be allocated to studying these questions.

If our minds, which emerge from the tangled wet mass of neurons, make us who we are, then paraphrasing my mentor’s mantra sums it up best: What have your glia done for you today?

References

Araque A, Parpura V, Sanzgiri RP, & Haydon PG (1999). Tripartite synapses: glia, the unacknowledged partner. Trends in neurosciences, 22 (5), 208-15 PMID: 10322493

Kettenmann, H. & Ransom, B. R. (eds) Neuroglia 3rd edn (Oxford Univ. Press, 2013).

Paolicelli RC, Bisht K, & Tremblay MÈ (2014). Fractalkine regulation of microglial physiology and consequences on the brain and behavior. Frontiers in cellular neuroscience, 8 PMID: 24860431

Parkhurst CN, Yang G, Ninan I, Savas JN, Yates JR 3rd, Lafaille JJ, Hempstead BL, Littman DR, & Gan WB (2013). Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell, 155 (7), 1596-609 PMID: 24360280

Xie L, Kang H, Xu Q, Chen MJ, Liao Y, Thiyagarajan M, O’Donnell J, Christensen DJ, Nicholson C, Iliff JJ, Takano T, Deane R, & Nedergaard M (2013). Sleep drives metabolite clearance from the adult brain. Science (New York, N.Y.), 342 (6156), 373-7 PMID: 24136970

Zeisel A, Muñoz-Manchado AB, Codeluppi S, Lönnerberg P, La Manno G, Juréus A, Marques S, Munguba H, He L, Betsholtz C, Rolny C, Castelo-Branco G, Hjerling-Leffler J, & Linnarsson S (2015). Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq. Science (New York, N.Y.), 347 (6226), 1138-42 PMID: 25700174

Image via Jose Luis Calvo / Shutterstock.

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Klotho and the Thread of Life – Can We Delay Aging? http://brainblogger.com/2015/03/14/klotho-and-the-thread-of-life/ http://brainblogger.com/2015/03/14/klotho-and-the-thread-of-life/#comments Sat, 14 Mar 2015 11:00:24 +0000 http://brainblogger.com/?p=18992 In Greek mythology, the Fates, or Moirae, were the goddesses who controlled humans’ destiny, from the time they were born to the time they died. The three sisters, Clotho, Lachesis and Atropos, daughters of Zeus and Themis, controlled the thread of human life.

Each Fate had a task: Lachesis was the apportioner, she measured the thread and decided how much lifetime was to be allowed; Atropos, the inevitable, cut the thread choosing when mortals would die; Clotho was the spinner, she spun the thread of a person’s life.

Clotho was the inspiration for naming klotho – a gene that somehow also seems to spin the thread of life. Klotho was another of so many serendipitous discoveries in science: while studying the phenotype of transgenic mice overexpressing another gene, there was an accidental insertion of ectopic DNA in a region of the klotho gene, inhibiting its expression. Makoto Kuro-o and colleagues, from the National Institute of Neuroscience, in Tokyo, Japan, thus found, in 1997, that disruption of the klotho gene caused accelerated aging. Later, it was found that the opposite also happened: by overexpressing klotho in mice, aging was significantly delayed and a longer lifespan was acquired.

The Journal of Neuroscience’s February article, showing that klotho can decrease premature mortality and enhance spatial learning and memory in a mouse model of Alzheimer’s disease piqued my curiosity about this protein. Obviously, the discovery of klotho generated massive research interest – a protein that may stop aging is the Holy Grail of life sciences, I reckon.

But how much is known about klotho? Can it really delay aging in humans?

Although the discovery of klotho has boosted the understanding of the aging process, its function is still not fully understood. In humans, serum levels of klotho decrease with age after 40 years old. This decrease is also observed in patients with several aging-related diseases. But most of what is known so far comes from animal research studies.

Although klotho is mainly produced in the kidneys and in the brain choroid plexus, mutations to its gene cause widespread aging phenotypes, probably due to circulating klotho. Deficiency has been associated with hypertension, renal failure, decreased insulin production and increased insulin sensitivity, early diabetic nephropathy, ectopic calcification in various soft tissues, arteriosclerosis, among others. Increased klotho expression, on the other hand, has been linked to reduced tumor proliferation and anti-inflammatory effects. In the brain, klotho deficiency in mice induced memory deficits, hippocampus degeneration, a reduction in synapses, and impaired axonal transport and myelin production.

Most of these phenotypes seem to be associated with defective calcium metabolism. Klotho seems to be essential in the maintenance of the levels of calcium and phosphorus by negatively regulating the synthesis of active vitamin D; abnormal activation of vitamin D due to klotho insufficiency has actually been shown to lead to degeneration of the dopaminergic system associated with Parkinson’s disease. Klotho also seems to act by increasing the expression of antioxidant enzymes and conferring resistance to oxidative stress, known to cause significant DNA damage.

Klotho and neurodegeneration

Myelin is an insulating material that envelops neurons, being essential for the correct functioning of the nervous system. Altered myelin production is a characteristic of the normal aging process of the brain. In fact, age-related cognitive decline seems to be mostly associated with loss of myelin rather than loss of neurons. There are experimental evidences suggesting that klotho is a key regulator in myelin biology by promoting and maintaining myelination. Therefore, it is possible that the loss of klotho expression may account for the age-related cognitive decline through decreased myelin production.

This link between cognitive decline, myelin abnormalities and klotho downregulation places it as a potential therapeutic target for neuroprotection against myelin-associated age-dependent changes. Compounds that increase klotho expression may therefore become important therapeutic tools for the treatment of neurodegenerative diseases, such as multiple sclerosis and Alzheimer’s disease. Increasing klotho levels may protect myelin integrity and prevent myelin degeneration in the aged brain and promote repair in multiple sclerosis.

This may be quite a wondrous molecule.

Maybe one day we will use klotho to prevent neurodegeneration and keep our brains young. Could we carry out a body transplant when our bodies get old, and use our cloned, younger body? Too much science fiction? Probably. But we once thought we couldn’t go to the Moon.

References

Abraham CR, Chen C, Cuny GD, Glicksman MA, & Zeldich E (2012). Small-molecule Klotho enhancers as novel treatment of neurodegeneration. Future medicinal chemistry, 4 (13), 1671-9 PMID: 22924505

Chen CD, Sloane JA, Li H, Aytan N, Giannaris EL, Zeldich E, Hinman JD, Dedeoglu A, Rosene DL, Bansal R, Luebke JI, Kuro-o M, & Abraham CR (2013). The antiaging protein Klotho enhances oligodendrocyte maturation and myelination of the CNS. The Journal of neuroscience : the official journal of the Society for Neuroscience, 33 (5), 1927-39 PMID: 23365232

Dubal DB, Zhu L, Sanchez PE, Worden K, Broestl L, Johnson E, Ho K, Yu GQ, Kim D, Betourne A, Kuro-O M, Masliah E, Abraham CR, & Mucke L (2015). Life Extension Factor Klotho Prevents Mortality and Enhances Cognition in hAPP Transgenic Mice. The Journal of neuroscience : the official journal of the Society for Neuroscience, 35 (6), 2358-71 PMID: 25673831

Kosakai A, Ito D, Nihei Y, Yamashita S, Okada Y, Takahashi K, & Suzuki N (2011). Degeneration of mesencephalic dopaminergic neurons in klotho mouse related to vitamin D exposure. Brain research, 1382, 109-17 PMID: 21276773

Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, & Nabeshima YI (1997). Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature, 390 (6655), 45-51 PMID: 9363890

Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, Rosenblatt KP, & Kuro-o M (2005). Suppression of aging in mice by the hormone Klotho. Science (New York, N.Y.), 309 (5742), 1829-33 PMID: 16123266

Nabeshima Y (2002). Klotho: a fundamental regulator of aging. Ageing research reviews, 1 (4), 627-38 PMID: 12362891

Xu Y, & Sun Z (2015). Molecular Basis of Klotho: From Gene to Function in Aging. Endocrine reviews PMID: 25695404

Image via Twin Design / Shutterstock.

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