Posts tagged science
Articles and news from the latest research reports.
Avatar therapy helps silence voices in schizophrenia
An avatar system that enables people with schizophrenia to control the voice of their hallucinations is being developed by researchers at UCL with support from the Wellcome Trust.
The computer-based system could provide quick and effective therapy that is far more successful than current pharmaceutical treatments, helping to reduce the frequency and severity of episodes of schizophrenia.
In an early pilot of this approach involving 16 patients and up to seven, 30 minute sessions of therapy, almost all of the patients reported an improvement in the frequency and severity of the voices that they hear. Three of the patients stopped hearing voices completely after experiencing 16, 13 and 3.5 years of auditory hallucinations, respectively. The avatar does not address the patients’ delusions directly, but the study found that they do improve as an overall effect of the therapy.
The team has now received a £1.3 million Translation Award from the Wellcome Trust to refine the system and conduct a larger scale, randomised study to evaluate this novel approach to schizophrenia therapy which will be conducted at King’s College London Institute of Psychiatry.
The first stage in the therapy is for the patient to create a computer-based avatar, by choosing the face and voice of the entity they believe is talking to them. The system then synchronises the avatar’s lips with its speech, enabling a therapist to speak to the patient through the avatar in real time. The therapist encourages the patient to oppose the voice and gradually teaches them to take control of their hallucinations.
Julian Leff, Emeritus Professor in UCL Mental Health Sciences, developed the therapy and is leading the project. He said: “Even though patients interact with the avatar as though it was a real person, because they have created it, they know that it cannot harm them, as opposed to the voices, which often threaten to kill or harm them and their family. As a result the therapy helps patients gain the confidence and courage to confront the avatar, and their persecutor.
“We record every therapy session on MP3 so that the patient essentially has a therapist in their pocket which they can listen to at any time when harassed by the voices. We’ve found that this helps them to recognise that the voices originate within their own mind and reinforces their control over the hallucinations.
The larger-scale study will begin enrolling the first patients in early July. The team are currently training the therapists and research staff to deliver the avatar therapy and finalising the study set-up. The first results of this larger study are expected towards the end of 2015.
Professor Thomas Craig of King’s College London Institute of Psychiatry, who will lead the larger trial, said: “Auditory hallucinations are a very distressing experience that can be extremely difficult to treat successfully, blighting patients’ lives for many years. I am delighted to be leading the group that will carry out a rigorous randomised study of this intriguing new therapy with 142 people who have experienced distressing voices for many years.
“The beauty of the therapy is its simplicity and brevity. Most other psychological therapies for these conditions are costly and take many months to deliver. If we show that this treatment is effective, we expect it could be widely available in the UK within just a couple of years as the basic technology is well developed and many mental health professionals already have the basic therapy skills that are needed to deliver it.”
Schizophrenia affects around 1 in 100 people worldwide, the most common symptoms being delusions (false beliefs) and auditory hallucinations (hearing voices). The illness often has a devastating effect, making it impossible to work and to sustain social relationships. Even with the most effective anti-psychotic medication, around one in four people with schizophrenia continue to suffer from persecutory auditory hallucinations, severely impairing their ability to concentrate.
Current guidelines from the National Institute for Health and Care Excellence (NICE) recommend that schizophrenia is treated using a combination of medication and talking therapies, such as cognitive behavioural therapy. However, fewer than one in ten patients with schizophrenia in the UK have access to this kind of psychological therapy.
Ted Bianco, Director of Technology Transfer and Acting Director of the Wellcome Trust, said: “At a time when many companies have become wary about investing in drug discovery for mental health, we are delighted to be able to facilitate the evaluation of an alternative approach to treatment based on the fusion of a talking therapy with computer-assisted ‘training’.
“In addition to the attraction that the intervention is not reliant on development of a new medication, the approach has the benefit of being directly testable in patients. Should the results of the trial prove encouraging, we expect there may be further applications of the basic strategy worth exploring in other areas of mental health.”
Lead Acts to Trigger Schizophrenia
Study in Mice Points to a Synergistic Relationship Between Lead Exposure and Schizophrenia Gene
Mice engineered with a human gene for schizophrenia and exposed to lead during early life exhibited behaviors and structural changes in their brains consistent with schizophrenia. Scientists at Columbia University’s Mailman School of Public Health and the Johns Hopkins University School of Medicine say their findings suggest a synergistic effect between lead exposure and a genetic risk factor, and open an avenue to better understanding the complex gene-environment interactions that put people at risk for schizophrenia and other mental disorders.
Results appear online in Schizophrenia Bulletin.
Going back to 2004, work by scientists at the Mailman School suggested a connection between prenatal lead exposure in humans and increased risk for schizophrenia later in life. But a big question remained: How could lead trigger the disease? Based on his own research, Tomás R. Guilarte, PhD, senior author of the new study, believed the answer was in the direct inhibitory effect of lead on the N-methyl-D-aspartate receptor (NMDAR), a synaptic connection point important to brain development, learning, and memory. His research in rodents found that exposure to lead blunted the function of the NMDAR. The glutamate hypothesis of schizophrenia postulates that a deficit in glutamate neurotransmission and specifically hypoactivity of the NMDAR can explain a significant portion of the dysfunction in schizophrenia.
In the new study, Dr. Guilarte, professor and chair of the department of Environmental Health Sciences at the Mailman School, and his co-investigators focused on mice engineered to carry the mutant form of Disrupted-in-Schizophrenia-1 (DISC1), a gene that is a risk factor for the disease in humans. Beginning before birth, half of the mutant DISC1 mice were fed a diet with lead, and half were given a normal diet. A second group of normal mice not expressing the mutant DISC1 gene were also split into the two feeding groups. All mice were put through a battery of behavioral tests and their brains were examined using MRI.
Mutant mice exposed to lead and given a psychostimulant exhibited elevated levels of hyperactivity and were less able to suppress a startle in response to a loud noise after being given an acoustic warning. Their brains also had markedly larger lateral ventricles—empty spaces containing cerebrospinal fluid—compared with other mice. These results mirror what is known about schizophrenia in humans.
While the role of genes in schizophrenia and mental disorders is well established, the effect of toxic chemicals in the environment is only just beginning to emerge. The study’s results focus on schizophrenia, but implications could be broader.
“We’re just scratching the surface,” says Dr. Guilarte. “We used lead in this study, but there are other environmental toxins that disrupt the function of the NMDAR.” One of these is a family of chemicals in air pollution called polycyclic aromatic hydrocarbons or PAHs. “Similarly, any number of genes could be in play,” adds Dr. Guilarte, noting that DISC1 is among many implicated in schizophrenia.
Future research may reveal to what extent schizophrenia is determined by environmental versus genetic factors or their interactions, and what other mental problems might be in the mix. One ongoing study by Dr. Guilarte is looking at whether lead exposure alone can contribute to deficits of one specialized type of neuron called parvalbumin-positive GABAergic interneuron that is known to be affected in the brain of schizophrenia patients. Scientists are also interested to establish the critical window for exposure—whether in utero or postnatal, or both.
“The animal model provides a way forward to answer important questions about the physiological processes underlying schizophrenia,” says Dr. Guilarte.
(Image: Flickr)
Gene sequencing project finds new mutations to blame for a majority of brain tumor subtype
The St. Jude Children’s Research Hospital – Washington University Pediatric Cancer Genome Project has identified mutations responsible for more than half of a subtype of childhood brain tumor that takes a high toll on patients. Researchers also found evidence the tumors are susceptible to drugs already in development.
The study focused on a family of brain tumors known as low-grade gliomas (LGGs). These slow-growing cancers are found in about 700 children annually in the U.S., making them the most common childhood tumors of the brain and spinal cord. For patients whose tumors cannot be surgically removed, the long-term outlook remains bleak due to complications from the disease and its ongoing treatment. Nationwide, surgery alone cures only about one-third of patients.
Using whole genome sequencing, researchers identified genetic alterations in two genes that occurred almost exclusively in a subtype of LGG termed diffuse LGG. This subtype cannot be cured surgically because the tumor cells invade the healthy brain. Together, the mutations accounted for 53 percent of the diffuse LGG in this study. Researchers also demonstrated that one of the mutations, which had not previously been linked to brain tumors, caused tumors when introduced into the glial brain cells of mice.
The findings appear in the April 14 advance online edition of the scientific journal Nature Genetics.
“This subtype of low-grade glioma can be a nasty chronic disease, yet prior to this study we knew almost nothing about its genetic alterations,” said David Ellison, M.D., Ph.D., chair of the St. Jude Department of Pathology and the study’s corresponding author. The first author is Jinghui Zhang, Ph.D., an associate member of the St. Jude Department of Computational Biology.
The Pediatric Cancer Genome Project is using next-generation whole genome sequencing to determine the complete normal and cancer genomes of children and adolescents with some of the least understood and most difficult to treat cancers. Scientists believe that studying differences in the 3 billion chemical bases that make up the human genome will provide the scientific foundation for the next generation of cancer care.
“We were surprised to find that many of these tumors could be traced to a single genetic alteration,” said co-author Richard K. Wilson, Ph.D., director of The Genome Institute at Washington University School of Medicine in St. Louis. “This is a major pathway through which low-grade gliomas develop and it provides new clues to explore as we search for better treatments.”
The study involved whole genome sequencing of 39 paired tumor and normal tissue samples from 38 children and adolescents with different subtypes of LGG and related tumors called low-grade glioneuronal tumors (LGGNTs). Although many cancers develop following multiple genetic abnormalities, 62 percent of the 39 tumors in this study stemmed from a single genetic alteration.
Previous studies have linked LGGs to abnormal activation of the MAPK/ERK pathway. The pathway is involved in regulating cell division and other processes that are often disrupted in cancer. Until now, however, the genetic alterations involved in driving this pathway were unknown for some types of LGG and LGGNT.
This study linked activation in the pathway to duplication of a key segment of the FGFR1 gene, which investigators discovered in brain tumors for the first time. The segment is called a tyrosine kinase domain. It functions like an on-off switch for several cell signaling pathways, including the MAPK/ERK pathway. Investigators also demonstrated that experimental drugs designed to block activity along two altered pathways worked in cells with theFGFR1 tyrosine kinase domain duplication. “The finding suggests a potential opportunity for using targeted therapies in patients whose tumors cannot be surgically removed,” Ellison said.
Researchers also showed that the FGFR1 abnormality triggered an aggressive brain tumor in glial cells from mice that lacked the tumor suppressor gene Trp53.
Whole-genome sequencing found previously undiscovered rearrangements in the MYB and MYBL1 genes in diffuse LGGs. These newly identified abnormalities were also implicated in switching on the MAPK/ERK pathway.
Researchers checked an additional 100 LGGs and LGGNTs for the same FGFR1, MYB and MYBL1 mutations. Overall, MYB was altered in 25 percent of the diffuse LGGs, and 24 percent had alterations in FGFR1. Researchers also turned up numerous other mutations that occurred in just a few tumors. The affected genes included BRAF, RAF1, H3F3A, ATRX, EP300, WHSC1 and CHD2.
“The Pediatric Cancer Genome Project has provided a remarkable opportunity to look at the genomic landscape of this disease and really put the alterations responsible on the map. We can now account for the genetic errors responsible for more than 90 percent of low-grade gliomas,” Ellison said. “The discovery that FGFR1 and MYB play a central role in childhood diffuse LGG also serves to distinguish the pediatric and adult forms of the disease.”
(Source: stjude.org)
Healthy lifestyle choices mean fewer memory complaints
Research has shown that healthy behaviors are associated with a lower risk of Alzheimer’s disease and dementia, but less is known about the potential link between positive lifestyle choices and milder memory complaints, especially those that occur earlier in life and could be the first indicators of later problems.
To examine the impact of these lifestyle choices on memory throughout adult life, UCLA researchers and the Gallup organization collaborated on a nationwide poll of more than 18,500 individuals between the ages of 18 and 99. Respondents were surveyed about both their memory and their health behaviors, including whether they smoked, how much they exercised and how healthy their diet was.
As the researchers expected, healthy eating, not smoking and exercising regularly were related to better self-perceived memory abilities for most adult groups. Reports of memory problems also increased with age. However, there were a few surprises.
Older adults (age 60–99) were more likely to report engaging in healthy behaviors than middle-aged (40–59) and younger adults (18–39), a finding that runs counter to the stereotype that aging is a time of dependence and decline. In addition, a higher-than-expected percentage of younger adults complained about their memory.
"These findings reinforce the importance of educating young and middle-aged individuals to take greater responsibility for their health — including memory — by practicing positive lifestyle behaviors earlier in life," said the study’s first author, Dr. Gary Small, director of the UCLA Longevity Center and a professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA who holds the Parlow–Solomon Chair on Aging.
Published in the June issue of International Psychogeriatrics, the study may also provide a baseline for the future study of memory complaints in a wide range of adult age groups.
For the survey, Gallup pollsters conducted land-line and cell phone interviews with 18,552 adults in the U.S. The inclusion of cell phone–only households and Spanish-language interviews helped capture a representative 90 percent of the U.S. population, the researchers said.
"We found that the more healthy lifestyle behaviors were practiced, the less likely one was to complain about memory issues," said senior author Fernando Torres-Gil, a professor at UCLA’s Luskin School of Public Affairs and associate director of the UCLA Longevity Center.
In particular, the study found that respondents across all age groups who engaged in just one healthy behavior were 21 percent less likely to report memory problems than those who didn’t engage in any healthy behaviors. Those with two positive behaviors were 45 percent less likely to report problems, those with three were 75 percent less likely, and those with more than three were 111 percent less likely.
Interestingly, the poll found that healthy behaviors were more common among older adults than the other two age groups. Seventy percent of older adults engaged in at least one healthy behavior, compared with 61 percent of middle-aged individuals and 58 percent of younger respondents.
In addition, only 12 percent of older adults smoked, compared with 25 percent of young adults and 24 percent of middle-aged adults, and a higher percentage of older adults reported eating healthy the day before being interviewed (80 percent) and eating five or more daily servings of fruits and vegetables during the previous week (64 percent).
According to the researchers, older adults may participate in more healthy behaviors because they feel the consequences of unhealthy living and take the advice of their doctors to adopt healthier lifestyles. Or there simply could be fewer older adults with bad habits, since they may not live as long.
While 26 percent of older adults and 22 percent of middle-aged respondents reported memory issues, it was surprising to find that 14 percent of the younger group complained about their memory too, the researchers said.
"Memory issues were to be expected in the middle-aged and older groups, but not in younger people," Small said. "A better understanding and recognition of mild memory symptoms earlier in life may have the potential to help all ages."
Small said that, generally, memory issues in younger people may be different from those that plague older generations. Stress may play more of a role. He also noted that the ubiquity of technology — including the Internet, texting and wireless devices that can result in constant multi-tasking, especially with younger people — may impact attention span, making it harder to focus and remember.
Small noted that further study and polling may help tease out such memory-complaint differences. Either way, he said, the survey reinforces the importance, for all ages, of adopting a healthy lifestyle to help limit and forestall age-related cognitive decline and neurodegeneration.
The Gallup poll used in the study took place between December 2011 and January 2012 and was part of the Gallup–Healthways Well-Being Index, which includes health- and lifestyle-related polling questions. The five questions asked were: (1) Do you smoke? (2) Did you eat healthy all day yesterday? (3) In the last seven days, on how many days did you have five or more servings of vegetables and fruits? (4) In the last seven days, on how many days did you exercise for 30 minutes or more? (5) Do you have any problems with your memory?
(Source: newsroom.ucla.edu)
Researchers Find Dying Cells Essential to Muscle Development and Repair
Dying cells play an unexpected and vital role in the creation of muscle fibers, researchers at the University of Virginia School of Medicine have determined. The finding could lead to new ways to battle conditions such as muscular dystrophy, facilitate healing after surgery and benefit athletes in their efforts to recover more quickly.
“These dead cells aren’t just a nuisance, which we’ve always considered them to be,” U.Va.’s Kodi S. Ravichandran said. “They have other, important roles before they leave this world.”
Dying cells have long been considered debris that must be removed from the body to avoid causing tissue inflammation. However, the U.Va. research shows that a small number of myoblasts – precursor cells that develop into muscle tissue – must die to allow muscle formation.
The finding suggests that programmed cell death, known as apoptosis, can also influence differentiation of other healthy cells within a tissue. The dying cells express a marker on their surface that signals their death and spurs the body to remove them; that same marker on these dying cells, the U.Va. researchers discovered, cues surrounding cells to develop into muscle fibers. The U.Va. researchers have identified both the membrane marker on the dying cells (a lipid normally hidden on live cells) and a corresponding receptor in the healthy myoblasts that are induced to fuse, said Ravichandran, chairman of the School of Medicine’s Department of Microbiology, Immunology and Cancer Biology.
“It’s been known for a while that there are a few muscle cells that die during exercise, and that building muscle mass depends on a few of those cells dying,” Ravichandran said. “This work puts an interesting spin on that.”
The discovery opens up many intriguing avenues for researchers to explore, including the possibility of producing muscle growth either through the direct application of apoptotic cells or by otherwise stimulating the cellular signaling pathways on the healthy cells. The genes encoding the receptor protein (called BAI1) and some of the components of the signaling pathway are found to be altered in patients with muscular dystrophy and other forms of muscle disorders.
“Because this pathway seems to be involved in muscle repair after injury, this could be relevant for recovery after surgeries, combat injuries in soldiers or any condition that could lead to muscle injury or muscle atrophy,” Ravichandran said. “Take Duchenne muscular dystrophy, for example. One in 3,500 boys that are born have this disease. If we can help alleviate the distress of even a few of these individuals, we would have made significant progress.”
The findings have been published online by the journal Nature and will appear in a forthcoming print edition (along with a News and Views highlighting the impact of the work).
(Source: news.virginia.edu)
Immune system to fight brain tumours
Research at Lund University in Sweden gives hope that one of the most serious types of brain tumour, glioblastoma multiforme, could be fought by the patients’ own immune system. The tumours are difficult to remove with surgery because the tumour cells grow into the surrounding healthy brain tissue. A patient with the disease therefore does not usually survive much longer than a year after the discovery of the tumour.
The team has tested different ways of stimulating the immune system, suppressed by the tumour, with a ‘vaccine’. The vaccine is based on tumour cells that have been genetically modified to start producing substances that activate the immune system. The modified tumour cells (irradiated so that they cannot divide and spread the disease) have been combined with other substances that form part of the body’s immune system.
The treatment has produced good results in animal experiments: 75 per cent of the rats that received the treatment were completely cured of their brain tumours.
“Human biology is more complicated, so we perhaps cannot expect such good results in patients. However, bearing in mind the poor prognosis patients receive today, all progress is important”, said doctoral student Sara Fritzell, part of the research group led by consultant Peter Siesjö.
She has previously tested combining the activation of the immune system with chemotherapy. When the chemotherapy was applied directly to the tumour site, the positive effects reinforced each other, and a huge 83 per cent of the mice survived.
“Our idea is in the future to give patients chemotherapy locally in conjunction with the operation to remove as much of the tumour as possible”, said Sara Fritzell.
Peter Siesjö is currently applying for permission to carry out a clinical study on stimulation of the immune system – with or without local chemotherapy – as a treatment for patients with glioblastoma multiforme.
(Source: lunduniversity.lu.se)
Averting the Devastating Effects of Stroke
Researchers at the University of Connecticut Health Center are studying ways to prevent the devastating injuries to the body caused by stroke, a leading cause of serious long-term disability.
One American dies from stroke, sometimes called a “brain attack,” every four minutes. More than five times that many people survive a stroke, and for them, the physical damage it causes can be enormous.
“Stroke often doesn’t kill you, but some patients say they would have rather died than be left with severe disability and not be able to care for themselves,” says Dr. Louise D. McCullough, professor of neurology and neuroscience and director of stroke research. “People can often be disabled from their stroke. They need assistance with feeding and sometimes can’t get out of bed. Many can’t speak or communicate, and this is very isolating. And now we’re seeing an increasing number of stroke survivors as our population ages.”
There are two types of stroke. Ischemic strokes, which account for the vast majority, happen when clots block the blood vessels to the brain and cut off blood flow. Hemorrhagic strokes happen when the wall of a blood vessel breaks and blood leaks into the surrounding brain. Signs of either type of stroke include sudden numbness or weakness of the face or arm or leg, especially on one side of the body, as well as sudden confusion, difficulty speaking or understanding, trouble seeing or walking, dizziness or loss of balance, and/or a sudden severe headache.
McCullough’s research focuses on ischemic stroke. This type of stroke can be treated in an emergency room with “clot-busting” medication called tissue plasminogen activator (tPA), which helps reduce damage to the brain. But tPA can be effective only if given within a few hours of a stroke, and many people don’t immediately realize they are having a stroke and don’t seek help right away. In addition, some people can’t receive tPA because of other health issues.
“Nationwide, only 5 to 8 percent of people who have a stroke get tPA effectively,” she says. “So we’ve been limited in treatment. We’ve never been able to find a drug to protect the brain after stroke. Reperfusion (restoring the blood flow using tPA) is less useful because the brain is already damaged.”
So McCullough’s research involves studying factors such as what contributes to brain injury after a stroke and how it might be reversed. Because women tend to do worse than men in terms of survival and disability, she also is studying the role that hormones play in stroke risk and recovery.
Much of the understanding about stroke and its treatment has stemmed from research in men, but not all of those findings can benefit women, she points out. “Stroke is different in women – how we present, how we respond to drugs, how we recover. Women have a higher risk of stroke, a slower recovery and more cognitive problems. We need to understand the sex differences on a cellular level. For example, cell death occurs by different pathways in the two sexes. We’re trying to figure out why the biology is different and whether that’s important to therapy.”
In addition, women and men respond differently to different types of drugs. McCullough points to basic aspirin as an example of this. In women, a daily dose of aspirin can help prevent stroke but seems to have no impact in preventing heart disease. In men, the opposite is true.
Interestingly, McCullough also has found a correlation between social factors and stroke. In a study funded by the National Institutes of Health (NIH), McCullough is using mouse models to understand the role that social isolation might play in ischemic stroke.
“We’ve found that isolation is as big a risk factor for having a stroke as hypertension (high blood pressure),” she explains. “We also found that if we induce a stroke in a mouse that is isolated from others, the stroke is 40 percent bigger. And three days after a stroke, a mouse that is placed with others does better than a mouse that is alone. So now we’re saying that with hospitalized patients, maybe we should put someone who has had a stroke in a room with, say, someone who has had a hip replacement.”
McCullough earned her medical degree and Ph.D. from UConn’s School of Medicine. She completed an internship, residency and fellowship at Johns Hopkins University in Baltimore before returning to Connecticut after her father, a physicist, suffered a disabling stroke. She hopes her research will help people like her father as well as future generations, including her four children ranging in age from 7 to 13, whose framed artwork covers larger portions of the walls in her office than do the smaller certificates honoring her with Best Doctor awards and Outstanding Teacher recognition.
In a nearby office, Dr. Lauren Hachmann Sansing, assistant professor of neurology, is looking at stroke in another way. Her research focuses on hemorrhagic stroke, the type that results from a ruptured blood vessel in the brain. “This type of stroke is devastating,” she explains. “It affects two million patients a year, and only 50 percent survive it. People may become paralyzed, unable to speak and unconscious due to the mass of blood within the brain.”
This intracerebral bleeding induces an immune reaction in the body in which white blood cells (leukocytes) travel to the brain in response to the injury. Unfortunately, this does further harm by causing brain swelling and actually worsens the cell death caused by the stroke. Sansing has obtained an NIH K08 grant – funds awarded to support the research of new physician-scientists – to study how this immune reaction can be prevented.
“Using a mouse model, we are measuring and quantifying how many leukocytes travel to the brain and how we could block them using certain anti-inflammatory drugs, such as arthritis drugs that target this cell population,” Sansing says. “We are working to determine which pathways are active in patients after a stroke, and we think we are onto something. We’re using drugs already tested in humans, with good safety data, and so we already know the dosing. If we find efficacy in animal models, we can go right to safety in human studies.”
Working to understand and treat this secondary wave of injury after a stroke is an interesting mix of the neurology and immunology courses that Sansing enjoyed as a student. She completed undergraduate studies at Cornell University, her medical degree at SUNY Stony Brook School of Medicine, and a master’s in translational research (which involves converting scientific discovery into health improvement) at the University of Pennsylvania, where she also completed an internship, residency and fellowships in vascular neurology and translational medicine.
“We’re hopeful about our work,” Sansing says. “But there have been many, many treatments for stroke that have worked in animal models but failed to improve outcomes in patients. With the evolution of biomarkers studies and the ability to study proteins and activation in patients, we have a lot of insights into what we should go after as potential targets. Dr. McCullough and I have a large biobank of samples from stroke patients who have donated blood samples to help us study the disease. These samples help ensure that what we study in our animal models is important in our patients.”
Both McCullough and Sansing are involved in active research while also seeing patients, and they say their studies are greatly benefitted by doing both. “It’s like a big puzzle,” Sansing explains. “We create a model, study it, go back to patients, then go back to research. Our overall goal is to someday say we have a new treatment that can make a difference in people’s lives.”
Ketamine Cousin Rapidly Lifts Depression Without Side Effects
GLYX-13, a molecular cousin to ketamine, induces similar antidepressant results without the street drug side effects, reported a study funded by the National Institute of Mental Health (NIMH) that was published last month in Neuropsychopharmacology.
Caption: Neurons in a subsection of the adult rat hippocampus are stained with a monoclonal antibody (yellow) that enhances learning and memory. A portion of this antibody is where GLYX-13 came from. (Source: Dr. Joseph Moskal, Ph.D., Northwestern University)
Background
Major depression affects about 10 percent of the adult population and is the second leading cause of disability in U.S. adults, according to the World Health Organization. Despite the availability of several different classes of antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs), 30 to 40 percent of adults are unresponsive to these medications. Moreover, SSRIs typically take weeks to work, which increases the risk for suicide.
Enter NMDA (N-methyl-D-aspartate) receptor modulators. In the 1970s, researchers linked the receptors to learning and memory. Biotech and pharmaceutical companies in the 1980s attempted to apply chemical blockers to these receptors as a means to prevent stroke. But blocking these receptors led to the opposite effect——the rise of cardiovascular disease. Research in the field dampened until a glutamate receptor antagonist already approved for anesthesia, and known on the streets as “Special K”, ketamine, made headlines in the early 2000s. Human clinical studies demonstrated that ketamine can ward off major and bipolar depressive symptoms within 2 hours of administration and last for several days. Ketamine is fraught with serious side effects including excessive sleepiness, hallucinations, and substance abuse behavior.
“Ketamine lit the field back up,“ said Joseph Moskal, Ph.D., a molecular neurobiologist at Northwestern University and senior study author. “Our drug, GLYX-13, is very different. It does not block the receptor ion channel, which may account for why it doesn’t have the same side effects.”
Moskal’s journey with GLYX-13 came about from his earlier days as a Senior Staff Fellow in NIMH’s Intramural Research Program. While at NIMH, he created specific molecules, monoclonal antibodies, to use as new probes to understand pathways of learning and memory. Some of the antibodies he created were for NMDA receptors. When he moved to Northwestern University, Moskal converted the antibodies to small protein molecules. Comprised of only four amino acids, GLYX-13 is one of these molecules.
Previous electrophysiological and conditioning studies had suggested that GLYX-13, unlike ketamine, enhanced memory and learning in rats, particularly in the brain’s memory hub or hippocampus. GLYX-13 also produced analgesic effects. Using several rat behavioral and molecular experiments, Moskal’s research team tested four compounds: GLYX-13, an inactive, “scrambled” version of GLYX-13 that had its amino acids rearranged, ketamine, and the SSRI fluoxetine.
Results of the Study
GLYX-13 and ketamine produced rapid acting (1 hour) and long-lasting (24 hour) antidepressant-like effects in the rats. Fluoxetine, an SSRI that typically takes from 2–4 weeks to show efficacy in humans, did not produce a rapid antidepressant effect in this study. As expected, the scrambled GLYX-13 showed no antidepressant-like effects at all. The researchers observed none of the aforementioned side effects of ketamine in the GLYX-13–treated rats.
Protein studies indicated an increase in the hippocampus of the NMDA receptor NR2B and a receptor for the chemical messenger glutamate called AMPA. Electrophysiology studies in this brain region showed that GLYX-13 and ketamine promoted long-lasting signal transmission in neurons, known as long-term potentiation/synaptic plasticity. This phenomenon is essential in learning and memory. The researchers propose how GLYX-13 works: GLYX-13 triggers NR2B receptor activation that leads to intracellular calcium influx and the expression of AMPA, which then is responsible for increased communication between neurons.
These results are consistent with data from a recent Phase 2 clinical trial, in which a single administration of GLYX-13 produced statistically significant reductions in depression scores in patients who had failed treatment with current antidepressants. The reductions were evident within 24 hours and persisted for an average of 7 days. After a single dose of GLYX-13, the drug’s antidepressant efficacy nearly doubled that seen with most conventional antidepressants after 4–6 weeks of dosing. GLYX-13 was well tolerated and it did not produce any of the schizophrenia-like effects associated with other NMDA receptor modulating agents.
Significance
NMDA receptors need a molecule each of the amino acid chemical messengers glutamate and glycine to become activated. Moskal speculates that GLYX-13 either directly binds to the glycine site on the NMDA receptor or indirectly modulates how glycine works with the receptor. Resulting activation of more NMDA and AMPA receptors leads to an increase in memory, learning—and antidepressant effects. By contrast, ketamine only blocks the NMDA receptor, but also increases the activity of the AMPA receptor. Knowledge of these mechanisms could lead to the development of more effective antidepressants.
What’s next
GLYX-13 is now being tested in a Phase 2 repeated dose antidepressant trial, where Moskal and his colleagues at Naurex, Inc., a biotechnology company he founded, hope to find in humans the optimal dosing for the drug. They also want to see if this molecule, and others like it, regulate other NMDA receptor subtypes—there are over 20 of them—and whether it will work on other disorders, such as schizophrenia, attention-deficit hyperactivity disorder, and autism.
“One could call NMDA modulators such as GLYX-13 ‘comeback kids,’” said Moskal. “A toolkit that I developed in 1983 is now setting the stage in 2013 for the development of possible new therapeutics that may provide individuals suffering from depression with a valuable new treatment option.”
Low Doses of THC Can Halt Brain Damage
Extremely low doses of marijuana’s psychoactive component protect brain before and after injury, says TAU researcher
Though marijuana is a well-known recreational drug, extensive scientific research has been conducted on the therapeutic properties of marijuana in the last decade. Medical cannabis is often used by sufferers of chronic ailments, including cancer and post-traumatic stress disorder, to combat pain, insomnia, lack of appetite, and other symptoms.
Now Prof. Yosef Sarne of Tel Aviv University’s Adelson Center for the Biology of Addictive Diseases at the Sackler Faculty of Medicine says that the drug has neuroprotective qualities as well. He has found that extremely low doses of THC — the psychoactive component of marijuana — protects the brain from long-term cognitive damage in the wake of injury from hypoxia (lack of oxygen), seizures, or toxic drugs. Brain damage can have consequences ranging from mild cognitive deficits to severe neurological damage.
Previous studies focused on injecting high doses of THC within a very short time frame — approximately 30 minutes — before or after injury. Prof. Sarne’s current research, published in the journals Behavioural Brain Research and Experimental Brain Research, demonstrates that even extremely low doses of THC — around 1,000 to 10,000 times less than that in a conventional marijuana cigarette — administered over a wide window of 1 to 7 days before or 1 to 3 days after injury can jumpstart biochemical processes which protect brain cells and preserve cognitive function over time.
This treatment, especially in light of the long time frame for administration and the low dosage, could be applicable to many cases of brain injury and be safer over time, Prof. Sarne says.
Conditioning the brain
While performing experiments on the biology of cannabis, Prof. Sarne and his fellow researchers discovered that low doses of the drug had a big impact on cell signalling, preventing cell death and promoting growth factors. This finding led to a series of experiments designed to test the neuroprotective ability of THC in response to various brain injuries.
In the lab, the researchers injected mice with a single low dose of THC either before or after exposing them to brain trauma. A control group of mice sustained brain injury but did not receive the THC treatment. When the mice were examined 3 to 7 weeks after initial injury, recipients of the THC treatment performed better in behavioral tests measuring learning and memory. Additionally, biochemical studies showed heightened amounts of neuroprotective chemicals in the treatment group compared to the control group.
The use of THC can prevent long-term cognitive damage that results from brain injury, the researchers conclude. One explanation for this effect is pre- and post-conditioning, whereby the drug causes minute damage to the brain to build resistance and trigger protective measures in the face of much more severe injury, explains Prof. Sarne. The low dosage of THC is crucial to initiating this process without causing too much initial damage.
Preventative and long-term use
According to Prof. Sarne, there are several practical benefits to this treatment plan. Due to the long therapeutic time window, this treatment can be used not only to treat injury after the fact, but also to prevent injury that might occur in the future. For example, cardiopulmonary heart-lung machines used in open heart surgery carry the risk of interrupting the blood supply to the brain, and the drug can be delivered beforehand as a preventive measure. In addition, the low dosage makes it safe for regular use in patients at constant risk of brain injury, such as epileptics or people at a high risk of heart attack.
Prof. Sarne is now working in collaboration with Prof. Edith Hochhauser of the Rabin Medical Center to test the ability of low doses of THC to prevent damage to the heart. Preliminary results indicate that they will find the same protective phenomenon in relation to cardiac ischemia, in which the heart muscle receives insufficient blood flow.
(Source: aftau.org)
Neuroscientists get yes-no answers via brain activity
Western researchers have used neuroimaging to read human thought via brain activity when they are conveying specific ‘yes’ or ‘no’ answers.
Their findings were published today in The Journal of Neuroscience in a study titled, The Brain’s Silent Messenger: Using Selective Attention to Decode Human Thought for Brain-Based Communication.
According to lead researcher Lorina Naci, the interpretation of human thought from brain activity – without depending on speech or action – is one of the most provoking and challenging frontiers of modern neuroscience. Specifically, patients who are fully conscious and awake, yet, due to brain damage, are unable to show any behavioral responsivity, expose the limits of the neuromuscular system and the necessity for alternate forms of communication.
Participants were asked to concentrate on a ‘yes’ or ‘no’ response to questions like “Are you married?” or “Do you have brothers and sisters?” and only think their response, not speak it.
“This novel method allowed healthy individuals to answers questions asked in the scanner, simply by paying attention to the word they wanted to convey. By looking at their brain activity we were able to correctly decode the correct answers for each individual,” said Naci, a postdoctoral fellow at Western’s Brain and Mind Institute. “The majority of volunteers conveyed their answers within three minutes of scanning, a time window that is well-suited for communication with brain-computer interfaces.”
Naci and her Western colleagues Rhodri Cusack, Vivian Z. Jia and Adrian Owen are now utilizing this method to communicate with behaviorally non-responsive patients, who may be misdiagnosed as being in a vegetative state.
“The strengths of this technique, especially its ease of use, robustness, and rapid detection, may maximize the chances that any such patient will be able to achieve brain-based communication,” Naci said.