Posts Tagged ‘mental illness’

By Bahar Gholipour

Schizophrenia may have a special fingerprint in the brain, even before its symptoms fully emerge. Now, a new method of analyzing this fingerprint — found within the folds of the brain — could help predict which young adults at high risk for schizophrenia will go on to develop the illness, a new study suggests.

The method, which was based on MRI scans of the brain, looked at the correlation between the amount of folding in different brain areas, which can reflect the strength of underlying connections between those areas. Using this method, the researchers could predict the outcome of 79 high-risk individuals with 80 percent accuracy, they reported yesterday (April 25) in the journal JAMA Psychiatry.

These findings need to be confirmed in larger future studies before the method can be used to in the clinic, the researchers said. And even then, a simple brain scan on its own won’t be enough to predict the future — it has to be used in conjunction with other symptoms for which a person is seeking help. But the goal is to find what clues from the brain’s structure could help clinicians better identify and treat patients before they experience full-blown schizophrenia and drop out of schools or lose their jobs due to a psychotic episode, said study investigator Dr. Lena Palaniyappan, an associate professor of psychiatry at Western University in Ontario, Canada.

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What the Folds of Your Brain Could Tell You About Schizophrenia Risk
A simplified representation of the folds in different brain regions.
Credit: University Psychiatric Clinics Basel
Schizophrenia may have a special fingerprint in the brain, even before its symptoms fully emerge. Now, a new method of analyzing this fingerprint — found within the folds of the brain — could help predict which young adults at high risk for schizophrenia will go on to develop the illness, a new study suggests.

The method, which was based on MRI scans of the brain, looked at the correlation between the amount of folding in different brain areas, which can reflect the strength of underlying connections between those areas. Using this method, the researchers could predict the outcome of 79 high-risk individuals with 80 percent accuracy, they reported yesterday (April 25) in the journal JAMA Psychiatry.

These findings need to be confirmed in larger future studies before the method can be used to in the clinic, the researchers said. And even then, a simple brain scan on its own won’t be enough to predict the future — it has to be used in conjunction with other symptoms for which a person is seeking help. But the goal is to find what clues from the brain’s structure could help clinicians better identify and treat patients before they experience full-blown schizophrenia and drop out of schools or lose their jobs due to a psychotic episode, said study investigator Dr. Lena Palaniyappan, an associate professor of psychiatry at Western University in Ontario, Canada. [10 Things You Didn’t Know About the Brain]

Schizophrenia is a mental disorder characterized by psychotic episodes involving delusional thoughts and distorted perception. It is often preceded by subtle symptoms: A teenager who is withdrawn and suspicious, has anxiety, depression or sleep problems, and who experiences subtle changes in thinking and perception may be deemed by a doctor to be at high risk for developing schizophrenia in the next two or three years. But having these symptoms, which overlap with those of many other mental health conditions, doesn’t mean one will surely go on to develop schizophrenia — in fact, just about a third of individuals with these symptoms do.

“It’s really hard to know who is going to develop schizophrenia and who is not,” Palaniyappan told Live Science.

A wrinkle in the brain

Compared with other animals, the surface of the human brain is especially wrinkly — likely as a solution to fit a large brain inside a small skull. The patterns of folds in the brain’s surface, called the cortex, are determined before birth and change very little after the first or second year of life.

Previous studies of people with conditions such as schizophrenia and autism have detected local differences in folding patterns. For example, they have found a smoother surface in one brain region or a more wrinkled one in another, when comparing people with these conditions to the general population.

Palaniyappan and his colleagues examined all the brain regions and the relationship between their folding patterns. The idea is that the degree of folding would be similar between two brain areas if they are strongly interconnected. So, if an individual doesn’t show the same folding patterns as everyone else, it may suggest a problem in the wiring beneath the brain’s surface.

“Imagine two brain regions have a strong wire between them. If you cut the wire off, both of these regions would not be properly folded,” Palaniyappan said.

Sorting through scans

The team collected MRI brain scans from a group of people in Switzerland, who were on average 24 years old. The participants included 79 people with symptoms suggesting a high risk of schizophrenia and 44 healthy control subjects.

Then, the researchers followed the participants for four years and found 16 people in the high-risk group developed schizophrenia.

Looking back at the brain scans, the researchers found that 80 percent of the time, the relationship between folding patterns could correctly identify who developed schizophrenia and who didn’t. Those who did seemed to have a disorganized brain network — the folds of their cortical regions didn’t go hand in hand as much as the folds in the controls and in the high-risk people who didn’t develop the illness.

The earlier patients with schizophrenia receive psychotherapy or medication, the better they fare, according to a 2005 review of 30 studies published in the American Journal of Psychiatry. Early intervention may even change the course of the illness. One study published last year in Nature Neuropsychopharmacology, for instance, found a longer period of untreated symptoms was associated with weaker connectivity in the brain, especially in areas associated with responding to antipsychotic medications.

https://www.livescience.com/62414-brain-folds-schizophrenia.html

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By Rafi Letzter

Scientists in Switzerland dosed test subjects with LSD to investigate how patients with severe mental disorders lose track of where they end and other people begin.

Both LSD and certain mental disorders, most notably schizophrenia, can make it difficult for people to distinguish between themselves and others. And that can impair everyday mental tasks and social interactions, said Katrin Preller, one of the lead authors of the study and a psychologist at the University Hospital of Psychiatry in Zurich. By studying how LSD breaks down people’s senses of self, the researchers aimed to find targets for future experimental drugs to treat schizophrenia.

“Healthy people take having this coherent ‘self’ experience for granted,” Preller told Live Science, “which makes it difficult to explain why it’s so important.”

Depression, she said, also relates to the sense of self. Whereas people with schizophrenia can lose track of themselves entirely, people with depression tend to “ruminate” on themselves, unable to break obsessive, self-oriented patterns of thought.

But this kind of phenomenon is challenging to study, Preller said.

“If you want to investigate self-experience, you have to manipulate it,” Preller said. “And there are very few substances that can actually manipulate sense of self while patients are lying in our MRI scanner.”

One of the substances that can, however, is LSD. And that’s why this experiment happened in Zurich, Preller said. Switzerland is one of the few countries where it’s possible to use LSD on human beings for scientific research. (Doing so is still quite difficult, though, requiring lots of oversight.)

The experiment itself didn’t sound like the most exciting use of the drug for the test subjects, all of whom were physically healthy and did not have schizophrenia or other illnesses After taking the drug, the subjects lay inside MRI machines with video goggles strapped to their faces, trying to make eye contact with a computer-generated avatar. Once they accomplished this, the subjects then tried to look off at another point in space that the avatar was also looking at. This is the kind of social task, Preller said, that’s very difficult if your sense of self has broken down.

Every study subject tried the task three times: once sober, once on LSD, and once after taking both LSD and a substance called ketanserin. This substance blocks LSD from interacting with a particular serotonin receptor in the brain, which researchers call “5-HT2.”

Previous studies on animals had suggested that 5-HT2 played a key role in LSD’s ability to mess with sense of self. The researchers suspected that blocking the receptor in humans might somewhat reduce the effect of LSD.

But it turned out to more than “somewhat” block the effect: There was no difference between the performance of subjects who took ketanserin and the placebo group.

“This was surprising to us, because LSD interacts with a lot of receptors [in the brain], not just 5-HT2,” Preller said.

But LSD’s most dramatic measurable effects entirely abated when subjects first took ketanserin.

That tentatively indicates that 5-HT2 plays an important role in regulating sense of self in the brain, Preller said. The next step, she added, is to work on drugs that target that receptor and see if they might alleviate some of the symptoms of severe psychiatric illnesses that affect the sense of self.

The paper detailing the study’s results was published today (March 19) at The Journal of Neuroscience.

https://www.livescience.com/62059-schizophrenia-lsd-sense-self.html#?utm_source=ls-newsletter&utm_medium=email&utm_campaign=03202018-ls


3D reconstruction of a serotonin receptor generated by cryo-electron microscopy

by Rebecca Pool

Claiming a world first and using cryo-electron microscopy, researchers from Case Western Reserve University School of Medicine, US, have observed full-length serotonin receptors. The proteins are common drug targets, and the new images provide details about molecular binding sites that could lead to more precise drug design. Serotonin receptors, which reside in cell membranes throughout the body, are highly dynamic and difficult to image. In the past, the receptors have been sectioned into pieces to study, but by capturing full-length samples, researchers have revealed how different portions interact.

Dr Sandip Basak from Physiology and Biophysics, and colleagues, describe ‘a finely tuned orchestration of three domain movements’ that allows the receptors to elegantly control passageways across cell membranes. “The serotonin receptor acts as a gateway, or channel, from outside the cell to inside,” he says. “When serotonin binds onto the receptor, the channel switches conformation from closed to open. It eventually twists into a ‘desensitized’ state, where the channel closes but serotonin remains attached,” he adds. “This prevents it from being reactivated.”

For this study, the researchers used a FEI Titan Krios microscope, operating at 300 kV, and equipped with a Gatan K2-Summit direct detector camera, at the National Cryo-Electron Microscopy Facility in Frederick, Maryland.

“Successful design of safer therapeutics [for cancer therapies and gastrointestinal diseases] has slowed because there is currently a limited understanding of the structure of the serotonin receptor itself, and what happens after serotonin binds,” says research leader, Professor Sudha Chakrapani. “Our new structure of the serotonin receptor in the resting state has the potential to serve as a structural blueprint to drive targeted drug design and better therapeutic strategies.”

This research is published in Nature Communications.

https://microscopy-analysis.com/editorials/editorial-listings/first-images-full-length-receptor-structure


Illustration by Paweł Jońca

by Helen Thomson

In March 2015, Li-Huei Tsai set up a tiny disco for some of the mice in her laboratory. For an hour each day, she placed them in a box lit only by a flickering strobe. The mice — which had been engineered to produce plaques of the peptide amyloid-β in the brain, a hallmark of Alzheimer’s disease — crawled about curiously. When Tsai later dissected them, those that had been to the mini dance parties had significantly lower levels of plaque than mice that had spent the same time in the dark.

Tsai, a neuroscientist at Massachusetts Institute of Technology (MIT) in Cambridge, says she checked the result; then checked it again. “For the longest time, I didn’t believe it,” she says. Her team had managed to clear amyloid from part of the brain with a flickering light. The strobe was tuned to 40 hertz and was designed to manipulate the rodents’ brainwaves, triggering a host of biological effects that eliminated the plaque-forming proteins. Although promising findings in mouse models of Alzheimer’s disease have been notoriously difficult to replicate in humans, the experiment offered some tantalizing possibilities. “The result was so mind-boggling and so robust, it took a while for the idea to sink in, but we knew we needed to work out a way of trying out the same thing in humans,” Tsai says.

Scientists identified the waves of electrical activity that constantly ripple through the brain almost 100 years ago, but they have struggled to assign these oscillations a definitive role in behaviour or brain function. Studies have strongly linked brainwaves to memory consolidation during sleep, and implicated them in processing sensory inputs and even coordinating consciousness. Yet not everyone is convinced that brainwaves are all that meaningful. “Right now we really don’t know what they do,” says Michael Shadlen, a neuroscientist at Columbia University in New York City.

Now, a growing body of evidence, including Tsai’s findings, hint at a meaningful connection to neurological disorders such as Alzheimer’s and Parkinson’s diseases. The work offers the possibility of forestalling or even reversing the damage caused by such conditions without using a drug. More than two dozen clinical trials are aiming to modulate brainwaves in some way — some with flickering lights or rhythmic sounds, but most through the direct application of electrical currents to the brain or scalp. They aim to treat everything from insomnia to schizophrenia and premenstrual dysphoric disorder.

Tsai’s study was the first glimpse of a cellular response to brainwave manipulation. “Her results were a really big surprise,” says Walter Koroshetz, director of the US National Institute of Neurological Disorders and Stroke in Bethesda, Maryland. “It’s a novel observation that would be really interesting to pursue.”


A powerful wave

Brainwaves were first noticed by German psychiatrist Hans Berger. In 1929, he published a paper describing the repeating waves of current he observed when he placed electrodes on people’s scalps. It was the world’s first electroencephalogram (EEG) recording — but nobody took much notice. Berger was a controversial figure who had spent much of his career trying to identify the physiological basis of psychic phenomena. It was only after his colleagues began to confirm the results several years later that Berger’s invention was recognized as a window into brain activity.

Neurons communicate using electrical impulses created by the flow of ions into and out of each cell. Although a single firing neuron cannot be picked up through the electrodes of an EEG, when a group of neurons fires again and again in synchrony, it shows up as oscillating electrical ripples that sweep through the brain.

Those of the highest frequency are gamma waves, which range from 25 to 140 hertz. People often show a lot of this kind of activity when they are at peak concentration. At the other end of the scale are delta waves, which have the lowest frequency — around 0.5 to 4 hertz. These tend to occur in deep sleep (see ‘Rhythms of the mind’).

At any point in time, one type of brainwave tends to dominate, although other bands are always present to some extent. Scientists have long wondered what purpose, if any, this hum of activity serves, and some clues have emerged over the past three decades. For instance, in 1994, discoveries in mice indicated that the distinct patterns of oscillatory activity during sleep mirrored those during a previous learning exercise. Scientists suggested that these waves could be helping to solidify memories.

Brainwaves also seem to influence conscious perception. Randolph Helfrich at the University of California, Berkeley, and his colleagues devised a way to enhance or reduce gamma oscillations of around 40 hertz using a non-invasive technique called transcranial alternating current stimulation (tACS). By tweaking these oscillations, they were able to influence whether a person perceived a video of moving dots as travelling vertically or horizontally.

The oscillations also provide a potential mechanism for how the brain creates a coherent experience from the chaotic symphony of stimuli hitting the senses at any one time, a puzzle known as the ‘binding problem’. By synchronizing the firing rates of neurons responding to the same event, brainwaves might ensure that the all of the relevant information relating to one object arrives at the correct area of the brain at exactly the right time. Coordinating these signals is the key to perception, says Robert Knight, a cognitive neuroscientist at the University of California, Berkeley, “You can’t just pray that they will self-organize.”


Healthy oscillations

But these oscillations can become disrupted in certain disorders. In Parkinson’s disease, for example, the brain generally starts to show an increase in beta waves in the motor regions as body movement becomes impaired. In a healthy brain, beta waves are suppressed just before a body movement. But in Parkinson’s disease, neurons seem to get stuck in a synchronized pattern of activity. This leads to rigidity and movement difficulties. Peter Brown, who studies Parkinson’s disease at the University of Oxford, UK, says that current treatments for the symptoms of the disease — deep-brain stimulation and the drug levodopa — might work by reducing beta waves.

People with Alzheimer’s disease show a reduction in gamma oscillations5. So Tsai and others wondered whether gamma-wave activity could be restored, and whether this would have any effect on the disease.

They started by using optogenetics, in which brain cells are engineered to respond directly to a flash of light. In 2009, Tsai’s team, in collaboration with Christopher Moore, also at MIT at the time, demonstrated for the first time that it is possible to use the technique to drive gamma oscillations in a specific part of the mouse brain6.

Tsai and her colleagues subsequently found that tinkering with the oscillations sets in motion a host of biological events. It initiates changes in gene expression that cause microglia — immune cells in the brain — to change shape. The cells essentially go into scavenger mode, enabling them to better dispose of harmful clutter in the brain, such as amyloid-β. Koroshetz says that the link to neuroimmunity is new and striking. “The role of immune cells like microglia in the brain is incredibly important and poorly understood, and is one of the hottest areas for research now,” he says.

If the technique was to have any therapeutic relevance, however, Tsai and her colleagues had to find a less-invasive way of manipulating brainwaves. Flashing lights at specific frequencies has been shown to influence oscillations in some parts of the brain, so the researchers turned to strobe lights. They started by exposing young mice with a propensity for amyloid build-up to flickering LED lights for one hour. This created a drop in free-floating amyloid, but it was temporary, lasting less than 24 hours, and restricted to the visual cortex.

To achieve a longer-lasting effect on animals with amyloid plaques, they repeated the experiment for an hour a day over the course of a week, this time using older mice in which plaques had begun to form. Twenty-four hours after the end of the experiment, these animals showed a 67% reduction in plaque in the visual cortex compared with controls. The team also found that the technique reduced tau protein, another hallmark of Alzheimer’s disease.

Alzheimer’s plaques tend to have their earliest negative impacts on the hippocampus, however, not the visual cortex. To elicit oscillations where they are needed, Tsai and her colleagues are investigating other techniques. Playing rodents a 40-hertz noise, for example, seems to cause a decrease in amyloid in the hippocampus — perhaps because the hippo-campus sits closer to the auditory cortex than to the visual cortex.

Tsai and her colleague Ed Boyden, a neuro-scientist at MIT, have now formed a company, Cognito Therapeutics in Cambridge, to test similar treatments in humans. Last year, they started a safety trial, which involves testing a flickering light device, worn like a pair of glasses, on 12 people with Alzheimer’s.

Caveats abound. The mouse model of Alzheimer’s disease is not a perfect reflection of the disorder, and many therapies that have shown promise in rodents have failed in humans. “I used to tell people — if you’re going to get Alzheimer’s, first become a mouse,” says Thomas Insel, a neuroscientist and psychiatrist who led the US National Institute of Mental Health in Bethesda, Maryland, from 2002 until 2015.

Others are also looking to test how manipulating brainwaves might help people with Alzheimer’s disease. “We thought Tsai’s study was outstanding,” says Emiliano Santarnecchi at Harvard Medical School in Boston, Massachusetts. His team had already been using tACS to stimulate the brain, and he wondered whether it might elicit stronger effects than a flashing strobe. “This kind of stimulation can target areas of the brain more specifically than sensory stimulation can — after seeing Tsai’s results, it was a no-brainer that we should try it in Alzheimer’s patients.”

His team has begun an early clinical trial in which ten people with Alzheimer’s disease receive tACS for one hour daily for two weeks. A second trial, in collaboration with Boyden and Tsai, will look for signals of activated microglia and levels of tau protein. Results are expected from both trials by the end of the year.

Knight says that Tsai’s animal studies clearly show that oscillations have an effect on cellular metabolism — but whether the same effect will be seen in humans is another matter. “In the end, it’s data that will win out,” he says.

The studies may reveal risks, too. Gamma oscillations are the type most likely to induce seizures in people with photosensitive epilepsy, says Dora Hermes, a neuroscientist at Stanford University in California. She recalls a famous episode of a Japanese cartoon that featured flickering red and blue lights, which induced seizures in some viewers. “So many people watched that episode that there were almost 700 extra visits to the emergency department that day.”

A brain boost

Nevertheless, there is clearly a growing excitement around treating neurological diseases using neuromodulation, rather than pharmaceuticals. “There’s pretty good evidence that by changing neural-circuit activity we can get improvements in Parkinson’s, chronic pain, obsessive–compulsive disorder and depression,” says Insel. This is important, he says, because so far, pharmaceutical treatments for neurological disease have suffered from a lack of specificity. Koroshetz adds that funding institutes are eager for treatments that are innovative, non-invasive and quickly translatable to people.

Since publishing their mouse paper, Boyden says, he has had a deluge of requests from researchers wanting to use the same technique to treat other conditions. But there are a lot of details to work out. “We need to figure out what is the most effective, non-invasive way of manipulating oscillations in different parts of the brain,” he says. “Perhaps it is using light, but maybe it’s a smart pillow or a headband that could target these oscillations using electricity or sound.” One of the simplest methods that scientists have found is neurofeedback, which has shown some success in treating a range of conditions, including anxiety, depression and attention-deficit hyperactivity disorder. People who use this technique are taught to control their brainwaves by measuring them with an EEG and getting feedback in the form of visual or audio cues.

Phyllis Zee, a neurologist at Northwestern University in Chicago, Illinois, and her colleagues delivered pulses of ‘pink noise’ — audio frequencies that together sound a bit like a waterfall — to healthy older adults while they slept. They were particularly interested in eliciting the delta oscillations that characterize deep sleep. This aspect of sleep decreases with age, and is associated with a decreased ability to consolidate memories.

So far, her team has found that stimulation increased the amplitude of the slow waves, and was associated with a 25–30% improvement in recall of word pairs learnt the night before, compared with a fake treatment7. Her team is midway through a clinical trial to see whether longer-term acoustic stimulation might help people with mild cognitive impairment.

Although relatively safe, these kinds of technologies do have limitations. Neurofeedback is easy to learn, for instance, but it can take time to have an effect, and the results are often short-lived. In experiments that use magnetic or acoustic stimulation, it is difficult to know precisely what area of the brain is being affected. “The field of external brain stimulation is a little weak at the moment,” says Knight. Many approaches, he says, are open loop, meaning that they don’t track the effect of the modulation using an EEG. Closed loop, he says, would be more practical. Some experiments, such as Zee’s and those involving neuro-feedback, already do this. “I think the field is turning a corner,” Knight says. “It’s attracting some serious research.”

In addition to potentially leading to treatments, these studies could break open the field of neural oscillations in general, helping to link them more firmly to behaviour and how the brain works as a whole.

Shadlen says he is open to the idea that oscillations play a part in human behaviour and consciousness. But for now, he remains unconvinced that they are directly responsible for these phenomena — referring to the many roles people ascribe to them as “magical incantations”. He says he fully accepts that these brain rhythms are signatures of important brain processes, “but to posit the idea that synchronous spikes of activity are meaningful, that by suddenly wiggling inputs at a specific frequency, it suddenly elevates activity onto our conscious awareness? That requires more explanation.”

Whatever their role, Tsai mostly wants to discipline brainwaves and harness them against disease. Cognito Therapeutics has just received approval for a second, larger trial, which will look at whether the therapy has any effect on Alzheimer’s disease symptoms. Meanwhile, Tsai’s team is focusing on understanding more about the downstream biological effects and how to better target the hippocampus with non-invasive technologies.

For Tsai, the work is personal. Her grandmother, who raised her, was affected by dementia. “Her confused face made a deep imprint in my mind,” Tsai says. “This is the biggest challenge of our lifetime, and I will give it all I have.”

https://www.nature.com/articles/d41586-018-02391-6

Longer duration of untreated psychosis was associated with accelerated hippocampal atrophy during initial antipsychotic treatment of first-episode schizophrenia, suggesting that psychosis may have persistent, negative effects on brain structure, according to finding published in JAMA Psychiatry.

“Several factors … have been linked to early psychosis and could mediate an association between [duration of untreated psychosis] and hippocampal volume loss, but evidence from longitudinal studies is lacking,” Donald C. Goff, MD, department of psychiatry, New York University Langone Medical Center, and colleagues wrote. “Whereas the negative association of [duration of untreated psychosis] with clinical course is attenuated by the initiation of antipsychotic treatment, the evidence is mixed as to whether antipsychotics contribute to loss of brain volume or protect against it.”

The extent to which loss of brain volume early in psychosis treatment reflects an illness effect, a drug effect or both remains unknown, according to the researchers. Therefore, Goff and colleagues examined loss of hippocampal volume during the first 8 weeks of treatment for schizophrenia, its link to duration of untreated psychosis and molecular biomarkers related to hippocampal volume loss and duration of untreated psychosis.

At Shanghai Mental Health Center in China, researchers conducted a longitudinal study with age- and sex-matched healthy controls between Mar. 5, 2013, and Oct. 8, 2014. They assessed 71 patients with nonaffective first-episode psychosis treated with second-generation antipsychotics and 73 controls. They reassessed 31 participants with psychosis and 32 controls 8 weeks later, measuring hippocampal volumetric integrity (HVI), duration of untreated psychosis, 13 molecular biomarkers and 14 single-nucleotide polymorphisms from 12 candidate genes.

Participants in the first-episode psychosis group had lower baseline median left HVI (n = 57) compared with those in the control group (n = 54; P = .001). Left HVI decreased in 24 participants with psychosis at a median annualized rate of –.03791 throughout the 8 weeks of treatment, whereas left HVI increased in 31 controls at a rate of 0.00115 (P = .001). Furthermore, researchers observed an inverse association between the change in left hippocampal volume and duration of untreated psychosis (P = .002).

Although they observed similar results in the right HVI, the relationship between change in right HVI and duration of psychosis was not significant. According to the results of analyses that looked at left-side hippocampal volume only, left HVI was associated with molecular biomarkers of inflammation, oxidative stress, brain-derived neurotrophic factor, glial injury and those reflecting dopaminergic and glutamatergic transmission.

“We found significantly lower HVI at baseline in participants with [first episode psychosis] compared with healthy controls and additional HVI reduction during antipsychotic treatment that correlated with [duration of untreated psychosis], consistent with a persistent, possibly deleterious, effect of untreated psychosis on brain structure,” Goff and colleagues wrote. “Larger longitudinal studies of longer duration are needed to examine the association between [duration of untreated psychosis], hippocampal volume and clinical outcomes.” – by Savannah Demko

https://www.healio.com/psychiatry/schizophrenia/news/online/%7Bf6c3c940-fe57-41d1-9eb7-7c835e3c48ea%7D/longer-duration-of-untreated-psychosis-linked-to-loss-of-brain-volume?utm_source=selligent&utm_medium=email&utm_campaign=psychiatry%20news&m_bt=1162769038120

Bipolar Disorder (BD) is a multifactorial brain disorder in which patients experience radical shifts in mood and undergo periods of depression followed by periods of mania. It has been known for some time that both environmental and genetic factors play important roles in the disease. For instance, being exposed to high levels of stress for long periods, and especially during childhood, has been associated with the development of BD.

Immediate early genes (IEGs) are a class of genes that respond very rapidly to environmental stimuli, and that includes stress. IEGs respond to a stressor by activating other genes that lead to neuronal plasticity, the ability of brain cells to change in form and function in response to changes in the environment. Ultimately, it is the process of neuronal plasticity that gives the brain the ability to learn from and adapt to new experiences.

One type of protein produced by IEGs is the so-called Early Growth Response (EGR) proteins, which translate environmental influence into long-term changes in the brain. These proteins are found throughout the brain and are highly produced in response to environmental changes such as stressful stimuli and sleep deprivation. Without the action played out by these proteins, brain cells and the brain itself cannot appropriately respond to the many stimuli that are constantly received from the environment.

Effective neuronal plasticity also depends on neurotrophins, which are regulatory factors that promote development and survival of brain cells. Brain-derived neurotrophic factor (BDNF) is the neurotrophin mostly found in the brain. It has been extensively investigated in BD patients and has been suggested as a hallmark of BD. Indeed, some studies have shown that the levels of BDNF in the serum of BD patients are reduced whenever patients undergo a period of depression, hypomania, or mania. Other studies have shown that regardless of mood state, BD patients present reduced levels of BDNF. Overall, changes in BDNF levels seem to be a characteristic found in BD patients that may contribute to the pathophysiology of the disease.

Now an international team of researchers from Universidade Federal do Rio Grande do Sul in Brazil, University of Arizona College of Medicine in the United States and McMaster University in Canada have published an article connecting the dots between these two players to explain the impaired cellular resilience observed in BD that in the grand scheme of things may relate to the impaired resilience presented by BD patients to respond to events, including stress.

In a previous study done by the group in 2016, one type of IEG gene known as EGR3, that normally responds to environmental events and stressful stimuli, was found repressed in the brain of BD patients, suggesting that when facing a stressor, the EGR3 in BD patients does not respond to the stimulus appropriately. Indeed, BD patients are highly prone to stress and have more difficulties dealing with stress or adapting to it if compared to healthy individuals. What the research group is now suggesting is that both EGR3 and BDNF may each play a critical role in the impaired cellular resilience seen in BD, and that each of these two genes may affect each other’s expression in the cell. “We believe that the reduced level of BDNF that has been extensively observed in BD patients is caused by the fact that EGR3 is repressed in the brain of BD patients. The two molecules are interconnected in a regulatory pathway that is disrupted in BD patients,” says Fabio Klamt, leading author of the article entitled “EGR3 immediate early gene and the brain-derived neurotrophic factor in bipolar disorder” and published on February 5th in the journal Frontiers in Behavioral Neuroscience.

The authors also add that the fact that EGR3 responds very quickly to environmental stimuli renders the molecule a potential drug target. “It is possible to imagine that EGR3 may be modulated in order to increase its expression and that of BDNF, which may have a positive impact on BD patients,” says Bianca Pfaffenseller, a scientist working at Hospital de Clínicas de Porto Alegre, in Brazil, and the first author of the study.

The idea that mental disorders should be seen as any other chronic disease in which the underlying biology plays an important role has replaced the old descriptions of mental illnesses as the result of bad psychological influences. As Nobel prize laureate Eric Kandel has said, “all mental processes are brain processes and therefore all disorders of mental functioning are biological diseases.” The perspective article authored by Fabio Klamt and colleagues supports this view by offering new insights into the underlying biology of this lifelong and devastating mental disorder affecting millions of people worldwide.

This article has been republished from materials provided by Universidade Federal do Rio Grande do Sul. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference
Pfaffenseller, B., Kapczinski, F., Gallitano, A., & Klamt, F. (2018). EGR3 immediate early gene and the brain-derived neurotrophic factor in bipolar disorder. Frontiers in Behavioral Neuroscience, 12, 15.

https://www.technologynetworks.com/genomics/news/potential-drug-target-for-bipolar-identified-297204?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=60440362&_hsenc=p2ANqtz-89oHJTQFUqboYjSURU_IOr9bzx6r5zFJCMV1mEAzlZHgi02vXuuEgb5JNs196HT9b7QaknWb1xraugbZ8U_bITr6Kw-A&_hsmi=60440362

By the time Logan Paul arrived at Aokigahara forest, colloquially known as Japan’s “suicide forest,” the YouTube star had already confused Mount Fuji with the country Fiji. His over 15 million (mostly underage) subscribers like this sort of comedic aloofness—it serves to make Paul more relatable.

After hiking only a couple hundred yards into Aokigahara—where over 247 people attempted to take their own lives in 2010 alone, according to police statistics cited in The Japan Times—Paul encountered a suicide victim’s body hanging from a tree. Instead of turning the camera off, he continued filming, and later uploaded close-up shots of the corpse, with the person’s face blurred out.

“Did we just find a dead person in the suicide forest?” Paul said to the camera. “This was supposed to be a fun vlog.” He went on to make several jokes about the victim, while wearing a large, fluffy green hat.

Within a day, over 6.5 million people had viewed the footage, and Twitter flooded with outrage. Even though the video violated YouTube’s community standards, it was Paul in the end who deleted it.

“I should have never posted the video, I should have put the cameras down,” Paul said in a video posted Tuesday, which followed an earlier written apology. “I’ve made a huge mistake, I don’t expect to be forgiven.” He didn’t respond to two follow-up requests for comment.

YouTube, which failed to do anything about Paul’s video, has now found itself wrapped in another controversy over how and when it should police offensive and disturbing content on its platform—and as importantly, the culture it foments that led to it. YouTube encourages stars like Paul to garner views by any means necessary, while largely deciding how and when to censor their videos behind closed doors.

‘Absolutely Complicit’

Before uploading the video, which was titled “We found a dead body in the Japanese Suicide Forest…” Paul halfheartedly attempted to censor himself for his mostly tween viewers. He issued a warning at the beginning of the video, blurred the victim’s face, and included the number of several suicide hotlines, including one in Japan. He also chose to demonetize the video, meaning he wouldn’t make money from it. His efforts weren’t enough.

“The mechanisms that Logan Paul came up with fell flat,” says Jessa Lingel, an assistant professor at the University of Pennsylvania’s Annenberg School for Communication, where she studies digital culture. “Despite them, you see a video that nonetheless is very disturbing. You have to ask yourself: Are those efforts really enough to frame this content in a way that’s not just hollowly or superficially aware of damage, but that is meaningfully aware of damage?”

The video still included shots of a corpse, including the victim’s blue-turned hands. At one point, Paul referred to the victim as “it.” One of the first things he said to the camera after the encounter was, “This is a first for me,” turning the conversation back to himself.

There’s no excuse for what Paul did. His video was disturbing and offensive to the victim, their family, and to those who have struggled with mental illness. But blaming the YouTube star alone seems insufficient. Both he, and his equally famous brother Jake Paul, earn their living from YouTube, a platform that rewards creators for being outrageous, and often fails to adequately police its own content.

“I think that any analysis that continues to focus on these incidents at the level of the content creator is only really covering part of the structural issues at play,” says Sarah T. Roberts, an assistant professor of information studies at UCLA and an expert in internet culture and content moderation. “Of course YouTube is absolutely complicit in these kinds of things, in the sense that their entire economic model, their entire model for revenue creation is created fundamentally on people like Logan Paul.”

YouTube takes 45 percent of the advertising money generated via Paul and every other creator’s videos. According to SocialBlade, an analytics company that tracks the estimated revenue of YouTube channels, Paul could make as much as 14 million dollars per year. While YouTube might not explicitly encourage Paul to pull ever-more insane stunts, it stands to benefit financially when he and creators like him gain millions of views off of outlandish episodes.

“[YouTube] knows for these people to maintain their following and gain new followers they have to keep pushing the boundaries of what is bearable,” says Roberts.

YouTube presents its platform as democratic; anyone can upload and contribute to it. But it simultaneously treats enormously popular creators like Paul differently, because they command such massive audiences. (Last year, the company even chose Paul to star in The Thinning, the first full-length thriller distributed via its streaming subscription service YouTube Red, as well as Foursome, a romantic comedy series also offered via the service.)

“There’s a fantasy that he’s just a dude with a GoPro on a stick,” says Roberts. “You have to actually examine the motivations of the platform.”

For example, major YouTube creators I have spoken to in the past said they often work with a representative from the company who helps them navigate the platform, a luxury not afforded to the average person posting cat videos. YouTube didn’t respond to a follow-up request about whether Paul had a rep assigned to his channel.

All Things in Moderation

It’s unclear why exactly YouTube let the video stay up so long; it may have be the result of the platform’s murky community guidelines. YouTube’s comment on it doesn’t shed much light either.

“Our hearts go out to the family of the person featured in the video. YouTube prohibits violent or gory content posted in a shocking, sensational or disrespectful manner. If a video is graphic, it can only remain on the site when supported by appropriate educational or documentary information and in some cases it will be age-gated,” a Google spokesperson said in an emailed statement. “We partner with safety groups such as the National Suicide Prevention Lifeline to provide educational resources that are incorporated in our YouTube Safety Center.”

YouTube may have initially decided that Paul’s video didn’t violate its policy on violent and graphic content. But those guidelines only consists of a few short sentences, making it impossible to know.

“The policy is vague, and requires a bunch of value judgements on the part of the censor,” says Kyle Langvardt, an associate law professor at the University of Detroit Mercy Law School and an expert on First Amendment and internet law. “Basically, this policy reads well as an editorial guideline… But it reads terribly as a law, or even a pseudo-law. Part of the problem is the vagueness.”

What might constitute a meaningful step toward transparency would be for YouTube to implement a moderation or edit log, says Lingel. On it, YouTube could theoretically disclose what team screened a video and when. If the moderators choose to remove or age-restrict a video, the log could disclose what community standard violation resulted in that decision. It could be modeled on something like Wikipedia’s edit logs, which show all of the changes made to a specific page.

“When you flag content, you have no idea what happens in that process,” Lingel says. “There’s no reason we can’t have that sort of visibility, to see that content has a history. The metadata exists, it’s just not made visible to the average user.”

Fundamentally, Lingel says, we need to rethink how we envision content moderation. Right now, when a YouTube user flags a video as inappropriate, it’s often left to a low-wage worker to tick a series of boxes, making sure it doesn’t violate any community guidelines (YouTube pledged to expand its content moderation workforce to 10,000 people this year). The task is sometimes even left to an AI, that quietly combs through videos looking for inappropriate content or ISIS recruiting videos. Either way, YouTube’s moderation process is mostly anonymous, and conducted behind closed doors.

It’s helpful that the platform has baseline standards for what is considered appropriate; we can all agree that certain types of graphic content depicting violence and hate should be prohibited. But a positive step forward would be to develop a more transparent process, one centered around open discussion about what should and shouldn’t be allowed, on something like a public moderation forum.

Paul’s video represents a potential turning point for YouTube, an opportunity to become more transparent about how it manages its own content. If it doesn’t take the chance, scandals like this one will only continue to happen.

As for the Paul brothers, they’re likely going to keep making similarly outrageous and offensive videos to entertain their massive audience. On Monday afternoon, just hours after his brother Logan issued an apology for the suicide forest incident, Jake Paul uploaded a new video entitled “I Lost My Virginity…”. At the time this story went live, it already had nearly two million views.

If you or someone you know is considering suicide, help is available. You can call 1-800-273-8255 to speak with someone at the National Suicide Prevention Lifeline 24 hours a day in the United States. You can also text WARM to 741741 to message with the Crisis Text Line.

https://www.wired.com/story/logan-paul-video-youtube-reckoning/?mbid=nl_010317_daily_list1_p1