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Feeling worried? Answer a simple question - “can I control this outcome I’m worried about?”
If no, then there’s no point in worrying; if yes, then act on it!
#WisdomMatters
“Filling the conscious mind with ideal conceptions is a characteristic of Western theosophy, but not the confrontation with the Shadow and the world of darkness. One does not become enlightened by imagining figures of light, but by making the darkness conscious. The latter procedure, however, is disagreeable and therefore not popular.”
— Carl Gustav Jung in his essay The Philosophical Tree, paragraph 335, (1945). Available in Alchemical Studies, Collected Works Volume 13, translated by R. F. C. Hull.
From a unified psychotherapy perspective, although there are times in which it might be appropriate to focus more on one system relative to the other, each person and each problem is made up of all these systems of adaptation operating in a socio-historical-organic context and practitioners should be able to assess and treat all of these systems.
—Gregg Henriques on cognitive Behavioral Therapy versus Psychodynamic Therapy and the Unified Psychotherapy approach
Earn CME: https://www.naccme.com/program/pcod19-sas1This webcast features presentations describe patient-appropriate stimulant pharmacotherapies and evidence...
This is probably the most informative talk I’ve heard on ADHD in a while.
I know it’s meant for clinicians. But, even as someone who has a background in Psychology, I find it fascinating. I nearly cried at the “omission” part because I know for a FACT that that was me before my diagnosis and medication.
They talk about “multiple contacts with healthcare providers” and I was just nodding the entire way. In my undergraduate education, I saw several doctors… and I even saw the school counselor twice in my time at school. Yet, I was NEVER screened for ADHD.
If you have ADHD, or think you might have it, please… I know it’s long, and can get a bit technical in some areas… but please watch this! It’s not boring to me because I CHOSE to study Clinical Psychology, that’s naturally my area of interest, so to me all of this is interesting and fascinating. I’m nearly certain that I hyper-focused on this video until the very end the first time I ever saw it. But, to others with ADHD, that may not be the case.
Common Core Beliefs
Core belief is a belief created in the subconscious mind between birth to age seven, that a person has internalized as a truth or reality.
Becoming conscious of our core beliefs will allow us to unlearn the ones we do not like and make new decisions to create new responses.
Common core belief #1
• I am not worthy, good enough, something is "wrong" with me.
The adult behaviours displayed by this belief are Self betrayal, negative self talk, procrastination, chronic fear of criticisms, performing or playing a role and denying one's own needs and boundaries.
Common core belief #2
• I must betray myself (or parts of myself) in order to be loved and chosen.
The adult behaviours show up as Codependency patterns, enabling partners who harm you and themselves, fear of stating your own needs, a lack of boundaries, inability to be vulnerable, avoidance of romantic relationships or losing yourself in romantic relationships.
Common core belief #3
• I must compete, smear or tear down others to "win" or get what I want.
The adult behaviours are Fear based decision making, an inability to collaborate, assuming everyone has negative intentions or is "out to get you" , black and white, right and wrong polarized thinking and the inability to see a perspective of another.
Common core belief #4
• People will never stay and always abandon them.
This shows up in adults as insecure attachment in romantic relationships, push and pull behaviors, inability to follow through with tasks, controlling tendencies and impulsive behaviors like shopping, changing jobs or relationships without being intentional or fully thinking them through.
Common core belief #5
• I am unlucky, good things do not happen to me.
The adult behaviours are sarcasm as a coping mechanism, "playing small", fear over revealing dreams or goals and aspirations, chronic complaining and emotional dumping as connection.
Common core belief #6
• I am not safe and the world is not safe.
This shows up as addiction or negative behaviours as an attempt to regulate the nervous system,isolation, high reactivity, defensiveness, over independence and a lack of resilience.
It might be that some, if not all really spoke to you. These may be some phrases that you have ultimately heard in your family dynamic again and again that solidified some of these beliefs for you.
This post made by Dr. Nicole LePera, on Instagram, articulated and demonstrated so much of what we live out unconsciously. If we become Aware of our choices and beliefs, then we can change them for the good.
Source : Dr. Nicole LePera aka TheHolisticPsychologist (Instagram) and Anna Akana (Youtube)
As a note, Antisocial Personality Disorder is also listed in this chapter of the DSM-5. That is because it is related to Conduct Disorder - you don’t qualify for a diagnosis of Antisocial Personality Disorder unless you met the criteria for Conduct Disorder by age 15!
What chapter would you like to see next?
You can see my previous DSM-5 posts here:
Paraphilic Disorders
Personality Disorders
(Image caption: Mouse Central Amygdala containing Prepronociceptin (green) and PKC delta (magenta) neurons)
The Neurobiology of Noshing: Why is it so easy to overeat calorie-rich tasty foods?
When you eat something super tasty, ever wonder why you really don’t want to stop even though you know you’ve eaten enough? Scientists at the UNC School of Medicine may have found the reason.
In lab experiments, Thomas Kash, PhD, the John R. Andrews Distinguished Professor in the Department of Pharmacology, and colleagues discovered a specific network of cellular communication emanating from the emotion-processing region of the brain, motivating mice to keep eating tasty food even though their basic energy needs had been met.
The existence of this mammalian brain circuit, described in a paper in Neuron, might help explain why humans so often overeat in our modern environment of abundant and delicious fare. The circuit is a byproduct of evolution, when large calorie-rich meals were scarce, and so our brains were wired to devour as many calories as humanly possible because no one knew when the next super meal would come.
“This circuit seems to be the brain’s way of telling you that if something tastes really good, then it’s worth whatever price you’re paying to get to it, so don’t stop,” Kash said.
Scientists in search of anti-obesity remedies have spent decades researching and targeting brain cells and circuits involved in ordinary, “homeostatic” feeding, which is triggered by hunger and keeps our energy level up. But this approach has had limited success. More recently, some scientists have been studying “hedonic” feeding – the pleasure-driven eating of calorie-rich food that tends to go way beyond our strict energy needs.
Hedonic feeding is thought to reflect modern humans’ lingering adaptation for ancient environments where famines were frequent. Perceiving calorie-rich food as particularly tasty and pleasurable, and bingeing on it whenever it was available, would have conferred a crucial survival advantage by storing up extra energy. Following that instinct now, in a time of plenty, can lead to obesity – a condition affecting about 40 percent of adults in the United States – and related conditions such as diabetes, heart disease, and cancers.
“There’s just so much calorically dense food available all the time now, and we haven’t yet lost this wiring that influences us to eat as much food as possible,” Kash said.
Experiments in the past few years have suggested that our wiring for hedonic feeding involves nociceptin, a small protein that works as a signaling molecule in the mammalian nervous system. Kash’s laboratory and other groups have found that compounds blocking nociceptin activity – called nociceptin receptor antagonists – have little or no effect on homeostatic feeding by lab rats and mice, but these compounds do curb hedonic bingeing on tasty, calorie-rich foods. Thus, drug developers have eyed these antagonists as potential anti-obesity, anti-binge-eating drugs, and researchers have been eager to identify the specific brain circuits through which they work. The goal would be to develop a more targeted treatment.
Identifying this circuit is largely what Kash and colleagues accomplished in their new study. They engineered mice to produce a fluorescent molecule along with nociceptin, literally illuminating the cells that drive nociceptin circuits. There are multiple nociceptin circuits in the brain, but Kash and colleagues observed that one in particular became active when the mice got a chance to binge on calorie-rich food. The circuit projects to different parts of the brain, including those known to regulate feeding. It starts in an emotion-processing region of the brain called the central amygdala.
Deleting about half of the nociceptin-making neurons in this circuit reduced the mice’s bingeing and kept their weight down when they had access to rich food, without affecting their intake of ordinary chow.
“Scientists have studied the amygdala for a long time, and they’ve linked it to pain and anxiety and fear, but our findings here highlight that it does other things too, like regulate pathological eating,” Kash said.
He and his team are now studying in more detail how this circuit works, the timing of its activity in relation to feeding and other factors, and how nociceptin antagonists alter its functions.
First author J. Andrew Hardaway, PhD, research assistant professor of pharmacology at the UNC School of Medicine, said, “Our study is one of the first to describe how the brain’s emotional center contributes to eating for pleasure. It adds support to the idea that everything mammals eat is being dynamically categorized along a spectrum of good/tasty to bad/disgusting, and this may be physically represented in subsets of neurons in the amygdala. The next major step and challenge is to tap into these subsets to derive new therapeutics for obesity and binge eating.”
Other scientists are studying nociceptin antagonists as possible treatments not only for obesity and binge-eating but also for depression, pain, and substance abuse.
“The behavioral effects of blocking nociceptin activity probably involve multiple mechanisms in the brain,” Kash said. “But on the whole, blocking nociceptin seems to stabilize behavior, bringing it closer to normal.”
Exercise activates memory neural networks in older adults
How quickly do we experience the benefits of exercise? A new University of Maryland study of healthy older adults shows that just one session of exercise increased activation in the brain circuits associated with memory - including the hippocampus - which shrinks with age and is the brain region attacked first in Alzheimer’s disease.
“While it has been shown that regular exercise can increase the volume of the hippocampus, our study provides new information that acute exercise has the ability to impact this important brain region,” said Dr. J. Carson Smith, an associate professor of kinesiology in the University of Maryland School of Public Health and the study’s lead author.
The study is published in the Journal of the International Neuropsychological Society.
Dr. Smith’s research team measured the brain activity (using fMRI) of healthy participants ages 55-85 who were asked to perform a memory task that involves identifying famous names and non famous ones. The action of remembering famous names activates a neural network related to semantic memory, which is known to deteriorate over time with memory loss.
This test was conducted 30 minutes after a session of moderately intense exercise (70% of max effort) on an exercise bike and on a separate day after a period of rest. Participants’ brain activation while correctly remembering names was significantly greater in four brain cortical regions (including the middle frontal gyrus, inferior temporal gryus, middle temporal gyrus, and fusiform gyrus) after exercise compared to after rest. The increased activation of the hippocampus was also seen on both sides of the brain.
“Just like a muscle adapts to repeated use, single sessions of exercise may flex cognitive neural networks in ways that promote adaptations over time and lend to increased network integrity and function and allow more efficient access to memories,” Dr. Smith explained.
Pathology Rethink
Huntington’s disease is a rare and incurable, neurodegenerative disorder characterised by uncontrolled movements, changes in mood, and declines in reasoning and memory. The causative mutation – which creates an abnormally extended version of the huntingtin protein – was discovered decades ago, yet the protein’s normal function and how its mutation leads to pathology remain unclear. Because huntingtin interacts with many cellular proteins, its abnormal extension was widely considered to be a gain-of-function mutation – one that causes excessive recruitment of interacting proteins resulting in toxicity. But recent work reveals that loss of huntingtin function in mouse brain striatal neurons (red) can cause Huntington’s-like pathology and symptoms too, including impaired neuronal survival, infiltration of other brain cells called glial astrocytes (cyan), and movement and coordination deficits. This new view of Huntington’s pathology suggests that current therapies aimed at suppressing the mutant protein may in fact be counterproductive and that a new drug design perspective might be required.
Today is Rare Disease Day
Written by Ruth Williams
Image from work by Caley J. Burrus and colleagues
Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
Image copyright held by the original authors
Research published in Cell Reports, January 2020
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How Do We Make Moral Decisions?
When it comes to making moral decisions, we often think of the golden rule: do unto others as you would have them do unto you. Yet, why we make such decisions has been widely debated. Are we motivated by feelings of guilt, where we don’t want to feel bad for letting the other person down? Or by fairness, where we want to avoid unequal outcomes? Some people may rely on principles of both guilt and fairness and may switch their moral rule depending on the circumstances, according to a Radboud University – Dartmouth College study on moral decision-making and cooperation. The findings challenge prior research in economics, psychology and neuroscience, which is often based on the premise that people are motivated by one moral principle, which remains constant over time. The study was published in Nature Communications.
“Our study demonstrates that with moral behavior, people may not in fact always stick to the golden rule. While most people tend to exhibit some concern for others, others may demonstrate what we have called ‘moral opportunism,’ where they still want to look moral but want to maximize their own benefit,” said lead author Jeroen van Baar, a postdoctoral research associate in the department of cognitive, linguistic and psychological sciences at Brown University, who started this research when he was a scholar at Dartmouth visiting from the Donders Institute for Brain, Cognition and Behavior at Radboud University.
“In everyday life, we may not notice that our morals are context-dependent since our contexts tend to stay the same daily. However, under new circumstances, we may find that the moral rules we thought we’d always follow are actually quite malleable,” explained co-author Luke J. Chang, an assistant professor of psychological and brain sciences and director of the Computational Social Affective Neuroscience Laboratory (Cosan Lab) at Dartmouth. “This has tremendous ramifications if one considers how our moral behavior could change under new contexts, such as during war,” he added.
To examine moral decision-making within the context of reciprocity, the researchers designed a modified trust game called the Hidden Multiplier Trust Game, which allowed them to classify decisions in reciprocating trust as a function of an individual’s moral strategy. With this method, the team could determine which type of moral strategy a study participant was using: inequity aversion (where people reciprocate because they want to seek fairness in outcomes), guilt aversion (where people reciprocate because they want to avoid feeling guilty), greed, or moral opportunism (a new strategy that the team identified, where people switch between inequity aversion and guilt aversion depending on what will serve their interests best). The researchers also developed a computational, moral strategy model that could be used to explain how people behave in the game and examined the brain activity patterns associated with the moral strategies.
The findings reveal for the first time that unique patterns of brain activity underlie the inequity aversion and guilt aversion strategies, even when the strategies ultimately yield the same behavior. For the participants that were morally opportunistic, the researchers observed that their brain patterns switched between the two moral strategies across different contexts. “Our results demonstrate that people may use different moral principles to make their decisions, and that some people are much more flexible and will apply different principles depending on the situation,” explained Chang. “This may explain why people that we like and respect occasionally do things that we find morally objectionable”.
Research Provides Important Insight on the Brain-Body Connection
A study conducted by University of Arkansas researchers reveals that neurons in the motor cortex of the brain exhibit an unexpected division of labor, a finding that could help scientists understand how the brain controls the body and provide insight on certain neurological disorders.
The researchers studied the neurons in the motor cortex of rats and found that they fall into two groups: “externally focused” neurons that communicate with and control different parts of the body and “internally focused” neurons that only communicate with each other and don’t send signals to other parts of the body. The researchers also found that when they increased inhibition of neurons in the motor cortex, the externally focused neurons switched to internally focused.
“Alterations in inhibitory signaling are implicated in numerous brain disorders,” explained Woodrow Shew, associate professor of physics. “When we increased inhibition in the motor cortex, those neurons responsible for controlling the body become more internally oriented. This means that the signals that are sent to the muscles from the motor cortex might be corrupted by the ‘messy’ internal signals that are normally not present.”
Rett Syndrome, a rare but severe neurological disorder, is one of the brain disorders associated with an increase in inhibition. Shew plans to further research the implications of these findings for Rett Syndrome.
Light, Physical Activity Reduces Brain Aging
Incremental physical activity, even at light intensity, is associated with larger brain volume and healthy brain aging.
Considerable evidence suggests that engaging in regular physical activity may prevent cognitive decline and dementia. Active individuals have lower metabolic and vascular risk factors and these risk factors may explain their propensity for healthy brain aging. However, the specific activity levels optimal for dementia prevention have remained unclear.
The new 2018 Physical Activity-Guidelines for Americans suggest that some physical activity is better than none, but achieving greater than 150 minutes of moderate-to-vigorous (MV) physical activity per week is recommended for substantial health benefits.
Using data from the Framingham Heart Study, the researchers found that for each additional hour spent in light-intensity physical activity was equivalent to approximately 1.1 years less brain aging.
According to the researchers, these results suggest that the threshold of the favorable association for physical activity with brain aging may be at a lower, more achievable level of intensity or volume.
“Every additional hour of light intensity physical activity was associated with higher brain volumes, even among individuals not meeting current Physical Activity-Guidelines. These data are consistent with the notion that potential benefits of physical activity on brain aging may accrue at a lower, more achievable level of intensity or volume,” explained Nicole Spartano, PhD, research assistant professor of medicine.
“We have really only just begun to uncover the relationship between physical activity and brain health.” Dr. Spartano emphasizes the need to explore the impact of physical inactivity on brain aging in different race, ethnic, and socio-economic groups. She is leading a team effort to investigate these patterns at multiple sites all over the country. “We couldn’t do this research without the commitment of the Framingham Heart Study participants who have given so much to the medical community over the years. Our research also hinges on the multi-disciplinary team of investigators at Boston University and external collaborators.” She also acknowledges the importance of funding for research in this area and is grateful for support from the National Institute on Aging, American Heart Association, and Alzheimer’s Association.
These finding appear online in JAMA Network Open.
Study shows promise in repairing damaged myelin
A scientific breakthrough provides new hope for millions of people living with multiple sclerosis. Researchers at OHSU have developed a compound that stimulates repair of the protective sheath that covers nerve cells in the brain and spinal cord.
The discovery, involving mice genetically engineered to mimic multiple sclerosis, published today in the journal JCI Insight.
MS is a chronic condition that affects an estimated 2.3 million people worldwide. In MS, the sheath covering nerve fibers in the brain and spinal cord becomes damaged, slowing or blocking electrical signals from reaching the eyes, muscles and other parts of the body. This sheath is called myelin. Although myelin can regrow through exposure to thyroid hormones, researchers have not pursued thyroid hormone therapies due to unacceptable side effects.
Although several treatments and medications alleviate the symptoms of MS, there is no cure.
“There are no drugs available today that will re-myelinate the de-myelinated axons and nerve fibers, and ours does that,” said senior author Tom Scanlan, Ph.D., professor of physiology and pharmacology in the OHSU School of Medicine.
Co-author Dennis Bourdette, M.D., chair of neurology in the OHSU School of Medicine and director of the OHSU Multiple Sclerosis Center, said he expects it will be a few years before the compound advances to the stage of a clinical trial involving people. Yet the discovery provides fresh hope for patients in Oregon and beyond.
“It could have a significant impact on patients debilitated by MS,” Bourdette said.
The discovery reported, if ultimately proven in clinical trials involving people, appears to accomplish two important goals:
Myelin repair with minimal side effects: The study demonstrated that the compound – known as sobetirome – promotes remylenation without the severe side effects of thyroid hormone therapy. Thyroid hormone therapy has not been tried in people because chronic elevated exposure known as hyperthyroidism harms the heart, bone, and skeletal muscle.
Efficient delivery: Researchers developed a new derivative of sobetirome (Sob-AM2) that penetrates the blood brain barrier, enabling a tenfold increase in infiltration to the central nervous system.
“We’re taking advantage of the endogenous ability of thyroid hormone to repair myelin without the side effects,” said lead author Meredith Hartley, Ph.D., an OHSU postdoctoral researcher in physiology and pharmacology.
Co-authors credited the breakthrough to a collaboration that involved scientists and physicians with expertise ranging across neurology, genetics, advanced imaging, physiology and pharmacology.
Potential as a ‘total game-changer’
One patient said the research could be a “total game-changer” for people with MS.
Laura Wieden, 48, has lived with multiple sclerosis since being diagnosed in 1995. The daughter of Portland advertising executive Dan Wieden, she is the namesake and board member of the Laura Fund for Innovation in Multiple Sclerosis, which funded much of the research involved in the study published today.
“I am really optimistic,” Wieden said. “I hope that this will be literally a missing link that could just change the lives of people with MS.”
Scanlan originally developed sobetirome as a synthetic molecule more than two decades ago, initially with an eye toward using it to lower cholesterol. In recent years, Scanlan’s lab adapted it as a promising treatment for a rare metabolic disease called adrenoleukodystrophy, or ALD.
Six years ago, Bourdette suggested trying the compound to repair myelin in MS.
Supported by funding provided through the Laura Fund and the National Multiple Sclerosis Society, the team turned to Ben Emery, Ph.D., an associate professor of neurology in the OHSU School of Medicine. Emery, an expert who previously established his own lab in Australia focused on the molecular basis of myelination, genetically engineered a mouse model to test the treatment.
A ‘Trojan horse’
With promising early results, researchers wanted to see if they could increase the amount of sobetirome that penetrated into the central nervous system.
They did so through a clever trick of chemistry known as a prodrug strategy.
Scientists added a chemical tag to the original sobetirome molecule, creating an inert compound called Sob-AM2. The tag’s main purpose is to eliminate a negative charge that prevents sobetirome from efficiently penetrating the blood-brain barrier. Once Sob-AM2 slips past the barrier and reaches the brain, it encounters a particular type of brain enzyme that cleaves the tag and converts Sob-AM2 back into sobetirome.
“It’s a Trojan horse type of thing,” Scanlan said.
Researchers found that the treatment in mice not only triggered myelin repair, but they also measured substantial motor improvements in mice treated with the compound.
“The mouse showed close to a full recovery,” Scanlan said.
Scientists say they are confident that the compound will translate from mice to people. To that end, OHSU has licensed the technology to Llama Therapeutics Inc., a biotechnology company in San Carlos, California. Llama is working to advance these molecules toward human clinical trials in MS and other diseases.
Bourdette said even though it may not help his patients today, he’s optimistic the discovery eventually will move from the lab into the clinic.
“Right now, what it means is hope,” he said.
(Image caption: General anesthesia drugs were shown to induce unconsciousness by activating a tiny cluster of cells at the base of the brain called the supraoptic nucleus (shown in red), while the rest of the brain remains in a mostly inactive state (shown in blue))
General Anesthesia Hijacks Sleep Circuitry to Knock You Out
The discovery of general anesthesia 170 years ago was a medical miracle, enabling millions of patients to undergo invasive, life-saving surgeries without pain. Yet despite decades of research, scientists still don’t understand why general anesthesia works.
Now scientists think they have discovered part of the answer. In a study published online in Neuron, a Duke University team found that several different general anesthesia drugs knock you out by hijacking the neural circuitry that makes you fall asleep.
The researchers traced this neural circuitry to a tiny cluster of cells at the base of the brain responsible for churning out hormones to regulate bodily functions, mood, and sleep. The finding is one of the first to suggest a role for hormones in maintaining the state of general anesthesia, and provides valuable insights for generating newer drugs that could put people to sleep with fewer side effects.
Ever since the first patient went under general anesthesia in 1846, scientists have been trying to figure out exactly how it works. The prevailing theory has been that many of these drugs tamp down the brain’s normal activities, resulting in the inability to move or feel pain. Similar theories revolved around sleep, the sister state to general anesthesia. However, research over the last decade has shown that sleep is a more active process than previously recognized, with entire sets of neurons clocking in to work while you catch your Z’s.
Fan Wang, Ph.D., a professor of neurobiology at the Duke University School of Medicine, and Li-Feng Jiang-Xie, a graduate student in her laboratory, wondered whether the predominant view of general anesthesia was also one-sided. “Perhaps rather than simply inhibiting neurons, anesthetics could also activate certain neurons in the brain,” said Jiang-Xie.
To test their new theory, Jiang-Xie and Luping Yin, Ph.D., a postdoctoral fellow in the Wang lab, put mice under general anesthesia with several different but commonly used drugs. Then they used molecular markers to track down the neurons that were commonly activated by the anesthetics. They found a cluster of actively firing neurons buried in a tiny brain region called the supraoptic nucleus, which is known to have leggy projections that release large amounts of hormones like vasopressin directly into the bloodstream.
“Most of the anesthesia-activated cells were a kind of hybrid cell that connects the nervous system and the endocrine system,” said Jiang-Xie. “That took us by surprise and led us into unexplored territory for understanding the neural pathways of general anesthesia.”
Next, the researchers tapped a sophisticated technique developed in the Wang lab to turn on or off this specialized group of cells with chemicals or light. When they switched on the cells in mice, the animals stopped moving and fell into a deep slumber called slow wave sleep, typically associated with unconsciousness.
Then the research team killed off this group of cells. The mice continued to move around, unable to fall asleep.
Finally, the researchers performed similar experiments on mice under general anesthesia. They found that artificially pre-activating the neuroendocrine cells made the mice stay under general anesthesia for longer periods of time. Conversely, when they silenced these cells, the mice woke up from anesthesia more easily.
This study also revealed a previously unexpected role of the brain’s hormone-secreting cells in promoting deep sleep.
“Many people, particularly those with Alzheimer’s disease, have difficulty falling to sleep, yet current medications have troublesome side effects,” said Yin. “If we can find ways to manipulate this neural circuitry, perhaps by targeting hormones or small peptides, then it could lead to the development of better sleeping pills.”
(Image caption: In the neuron, a protective covering called myelin (grey) insulates the axon and increases the speed of electrical communication along the length of the neuron. Credit: Opus Design)
Neuroscientists reverse some behavioral symptoms of Williams Syndrome
Williams Syndrome, a rare neurodevelopmental disorder that affects about 1 in 10,000 babies born in the United States, produces a range of symptoms including cognitive impairments, cardiovascular problems, and extreme friendliness, or hypersociability.
In a study of mice, MIT neuroscientists have garnered new insight into the molecular mechanisms that underlie this hypersociability. They found that loss of one of the genes linked to Williams Syndrome leads to a thinning of the fatty layer that insulates neurons and helps them conduct electrical signals in the brain.
The researchers also showed that they could reverse the symptoms by boosting production of this coating, known as myelin. This is significant, because while Williams Syndrome is rare, many other neurodevelopmental disorders and neurological conditions have been linked to myelination deficits, says Guoping Feng, the James W. and Patricia Poitras Professor of Neuroscience and a member of MIT’s McGovern Institute for Brain Research.
“The importance is not only for Williams Syndrome,” says Feng, who is one of the senior authors of the study. “In other neurodevelopmental disorders, especially in some of the autism spectrum disorders, this could be potentially a new direction to look into, not only the pathology but also potential treatments.”
Zhigang He, a professor of neurology and ophthalmology at Harvard Medical School, is also a senior author of the paper, which appeared in Nature Neuroscience. Former MIT postdoc Boaz Barak, currently a principal investigator at Tel Aviv University in Israel, is the lead author and a senior author of the paper.
Impaired myelination
Williams Syndrome, which is caused by the loss of one of the two copies of a segment of chromosome 7, can produce learning impairments, especially for tasks that require visual and motor skills, such as solving a jigsaw puzzle. Some people with the disorder also exhibit poor concentration and hyperactivity, and they are more likely to experience phobias.
In this study, the researchers decided to focus on one of the 25 genes in that segment, known as Gtf2i. Based on studies of patients with a smaller subset of the genes deleted, scientists have linked the Gtf2i gene to the hypersociability seen in Williams Syndrome.
Working with a mouse model, the researchers devised a way to knock out the gene specifically from excitatory neurons in the forebrain, which includes the cortex, the hippocampus, and the amygdala (a region important for processing emotions). They found that these mice did show increased levels of social behavior, measured by how much time they spent interacting with other mice. The mice also showed deficits in fine motor skills and increased nonsocial related anxiety, which are also symptoms of Williams Syndrome.
Next, the researchers sequenced the messenger RNA from the cortex of the mice to see which genes were affected by loss of Gtf2i. Gtf2i encodes a transcription factor, so it controls the expression of many other genes. The researchers found that about 70 percent of the genes with significantly reduced expression levels were involved in the process of myelination.
“Myelin is the insulation layer that wraps the axons that extend from the cell bodies of neurons,” Barak says. “When they don’t have the right properties, it will lead to faster or slower electrical signal transduction, which affects the synchronicity of brain activity.”
Further studies revealed that the mice had only about half the normal number of mature oligodendrocytes — the brain cells that produce myelin. However, the number of oligodendrocyte precursor cells was normal, so the researchers suspect that the maturation and differentiation processes of these cells are somehow impaired when Gtf2i is missing in the neurons.
This was surprising because Gtf2i was not knocked out in oligodendrocytes or their precursors. Thus, knocking out the gene in neurons may somehow influence the maturation process of oligodendrocytes, the researchers suggest. It is still unknown how this interaction might work.
“That’s a question we are interested in, but we don’t know whether it’s a secreted factor, or another kind of signal or activity,” Feng says.
In addition, the researchers found that the myelin surrounding axons of the forebrain was significantly thinner than in normal mice. Furthermore, electrical signals were smaller, and took more time to cross the brain in mice with Gtf2i missing.
The study is an example of pioneering research into the contribution of glial cells, which include oligodendrocytes, to neuropsychiatric disorders, says Doug Fields, chief of the nervous system development and plasticity section of the Eunice Kennedy Shriver National Institute of Child Health and Human Development.
“Traditionally myelin was only considered in the context of diseases that destroy myelin, such as multiple sclerosis, which prevents transmission of neural impulses. More recently it has become apparent that more subtle defects in myelin can impair neural circuit function, by causing delays in communication between neurons,” says Fields, who was not involved in the research.
Symptom reversal
It remains to be discovered precisely how this reduction in myelination leads to hypersociability. The researchers suspect that the lack of myelin affects brain circuits that normally inhibit social behaviors, making the mice more eager to interact with others.
“That’s probably the explanation, but exactly which circuits and how does it work, we still don’t know,” Feng says.
The researchers also found that they could reverse the symptoms by treating the mice with drugs that improve myelination. One of these drugs, an FDA-approved antihistamine called clemastine fumarate, is now in clinical trials to treat multiple sclerosis, which affects myelination of neurons in the brain and spinal cord. The researchers believe it would be worthwhile to test these drugs in Williams Syndrome patients because they found thinner myelin and reduced numbers of mature oligodendrocytes in brain samples from human subjects who had Williams Syndrome, compared to typical human brain samples.
“Mice are not humans, but the pathology is similar in this case, which means this could be translatable,” Feng says. “It could be that in these patients, if you improve their myelination early on, it could at least improve some of the conditions. That’s our hope.”
Such drugs would likely help mainly the social and fine-motor issues caused by Williams Syndrome, not the symptoms that are produced by deletion of other genes, the researchers say. They may also help treat other disorders, such as autism spectrum disorders, in which myelination is impaired in some cases, Feng says.
“We think this can be expanded into autism and other neurodevelopmental disorders. For these conditions, improved myelination may be a major factor in treatment,” he says. “We are now checking other animal models of neurodevelopmental disorders to see whether they have myelination defects, and whether improved myelination can improve some of the pathology of the defects.”
This gene could play a major role in reducing brain swelling after stroke
Could a medication someday help the brain heal itself after a stroke, or even prevent damage following a blow to the head? A new USC study lends support to the idea.
When a person has a stroke, the brain responds with inflammation, which expands the area of injury and leads to more disability. In the April 9 issue of Cell Reports, USC researchers describe a key gene involved with tamping down inflammation in the brain, as well as what happens when the injured brain gets an added boost of that gene.
The gene — called TRIM9 — is abundant in the youthful brain but grows scarce with age, just as people become more at risk from stroke. In a lab model of stroke, researchers found that older brains with low TRIM9 levels — or engineered brains missing the TRIM9 gene entirely — were prone to extensive swelling following stroke.
How a gene can decrease brain swelling
But when the scientists used a harmless virus to carry a dose of the gene directly into TRIM9-deficient brains, the swelling decreased dramatically and recovery improved.
Jae Jung, lead author and chair of the Department of Molecular Microbiology and Immunology at the Keck School of Medicine of USC, says it’s unlikely that gene therapy delivered by viruses will become the go-to treatment for strokes, head injuries or encephalitis. It’s too slow, he said, and the best shot at treating stroke is within the first 30 minutes to one hour. Jung says the next step will be identifying what, exactly, flips on the switch for TRIM9 gene expression.
“Maybe there will be a way to chemically activate TRIM9 right after a stroke,” Jung said. “Or maybe a football player can take a medication that turns on TRIM9 gene expression right after they get a blow to the head.”
Brain inflammation: not all bad
Not all inflammation in the brain is bad, Jung added. Inflammation plays a role in fighting infection and helps clear away dead tissue. But when it goes on too long, neurons die; inflammation causes the brain’s blood vessels to become permeable, allowing white blood cells to enter tissue where they don’t belong.