Neuroscientists studying the link between poor sleep and schizophrenia have found that irregular sleep patterns and desynchronised brain activity during sleep could trigger some of the disease’s symptoms. The findings suggest that these prolonged disturbances might be a cause and not just a consequence of the disorder’s debilitating effects.
The possible link between poor sleep and schizophrenia prompted the research team, led by scientists from the University of Bristol, the Lilly Centre for Cognitive Neuroscience and funded by the Medical Research Council (MRC), to explore the impact of irregular sleep patterns on the brain by recording electrical brain activity in multiple brain regions during sleep.
For many people, sleep deprivation can affect mood, concentration and stress levels. In extreme cases, prolonged sleep deprivation can induce hallucinations, memory loss and confusion all of which are also symptoms associated with schizophrenia.
Dr Ullrich Bartsch, one of the study’s researchers, said: ‘Sleep disturbances are well-documented in the disease, though often regarded as side effects and poorly understood in terms of their potential to actually trigger its symptoms.’
Using a rat model of the disease, the team’s recordings showed de-synchronisation of the waves of activity which normally travel from the front to the back of the brain during deep sleep. In particular the information flow between the hippocampus — involved in memory formation, and the frontal cortex — involved in decision-making, appeared to be disrupted. The team’s findings reported distinct irregular sleep patterns very similar to those observed in schizophrenia patients.
Dr Matt Jones, the lead researcher from the University’s School of Physiology and Pharmacology, added: ‘Decoupling of brain regions involved in memory formation and decision-making during wakefulness are already implicated in schizophrenia, but de-coupling during sleep provides a new mechanistic explanation for the cognitive deficits observed in both the animal model and patients: sleep disturbances might be a cause, not just a consequence of schizophrenia. In fact, abnormal sleep patterns may trigger abnormal brain activity in a range of conditions.’
Cognitive deficits — reduced short term memory and attention span, are typically resistant to medication in patients. The findings from this study provide new angles for neurocognitive therapy in schizophrenia and related psychiatric diseases. Bristol University

Many patients who have genetic testing for Lynch syndrome, a hereditary predisposition to colon cancer, receive the inconclusive result ‘variants of uncertain clinical significance.’ This can be a problem, as people with Lynch syndrome have a much higher probability to develop colon cancer, and often develop colon cancer at an earlier age than is common among the general population; consequently, they need to begin screening at a much younger age.
Now, between two-thirds and three-fourths of these genetic variants can be classified into categories that indicate the most appropriate screening and treatment guidelines, according to two complementary papers recently published. The two papers, both co-authored by Sean Tavtigian, Ph.D., a Huntsman Cancer Institute (HCI) investigator and associate professor in the Department of Oncological Sciences at the University of Utah, provide a model that could help physicians as they assess their patient’s risk to develop cancer.
According to the American Cancer Society, about 143,460 new cases of colon cancer will be diagnosed in the United States this year. The National Cancer Institute estimates that two to four percent of all colon cancer is attributable to Lynch syndrome.
Mutations in mismatch repair genes, which proof-read DNA to correct genetic typos that occur during the replication process, are known to be the cause of the syndrome. ‘Some people in families with Lynch syndrome have already known mutations, and a small number of missense substitutions have also been classified as pathogenic,’ said Tavtigian. ‘But a fair number have other missense substitutions for which the clinical significance could not be determined, creating uncertainty concerning proper screening and treatment for patients and physicians alike.’
The first of the two studies reported on standardising several already available computer programs that grade the severity of missense substitutions (at the genomic level, these mutations affect only a single structural unit of DNA rather than an entire gene; at the protein level, they affect only a single amino acid rather than the entire protein). The second describes how clinical data concerning the tumours, family history, and other factors were combined with that initial information about severity. Taken together, the procedures described in the two papers allow previously unclassified genetic variations to be assessed for the level of risk they pose in colon cancer development.
‘Using these tools, we can evaluate any particular missense substitution and come up with a percentage indicating the probability that it is pathogenic,’ said Tavtigian. ‘I’m very careful to avoid saying pathogenic or neutral as an either-or statement. With missense substitutions, I don’t believe in a binary classification.’ A scale developed by his team in 2008 indicates the appropriate level of clinical action for a given percentage of risk, he adds. Huntsman Cancer Institute

The adverse side effects of certain hepatitis C medications can now be replicated and observed in Petri dishes and test tubes, thanks to a research team led by Craig Cameron, the Paul Berg Professor of Biochemistry and Molecular Biology at Penn State University. ‘The new method not only will help us to understand the recent failures of hepatitis C antiviral drugs in some patients in clinical trials,’ said Cameron. ‘It also could help to identify medications that eliminate all adverse effects.’ The team’s findings may help pave the way toward the development of safer and more-effective treatments for hepatitis C, as well as other pathogens such as SARS and West Nile virus.
First author Jamie Arnold, a research associate in Cameron’s lab at Penn State, explained that the hepatitis C virus (HCV), which affects over 170,000,000 people worldwide, is the leading cause of liver disease and, although antiviral treatments are effective in many patients, they cause serious side effects in others. ‘Many antiviral medications for treating HCV are chemical analogs for the building blocks of RNA that are used to assemble new copies of the virus’s genome, enabling it to replicate,’ he said. ‘These medications are close enough to the virus’s natural building blocks that they get incorporated into the virus’s genome. But they also are different in ways that lead to the virus’s incomplete replication. The problem, however, is that the medication not only mimics the virus’s genetic material, but also the genetic material of the patient. So, while the drug causes damage to the virus, it also may affect the patient’s own healthy tissues.’
A method to reveal these adverse side effects in the safety of a laboratory setting, rather than in clinical trials where patients may be placed at risk, has been developed by the research team, which includes Cameron; Arnold; Suresh Sharma, a research associate in Cameron’s lab; other scientists at Penn State; and researchers from other academic, government, and corporate labs. ‘We have taken anti-HCV medications and, in Petri dishes and test tubes, we have shown that these drugs affect functions within a cell’s mitochondria,’ Cameron explained. ‘The cellular mitochondria — a tiny structure known as ‘the powerhouse of the cell’ that is responsible for making energy known as ATP — is affected by these compounds and is likely a major reason why we see adverse effects.’ Cameron noted that scientists have known for some time that certain individuals have ‘sick’ mitochondria. Such individuals are likely more sensitive to the mitochondrial side effects of antiviral drugs.
‘We know that antiviral drugs, including the ones used to treat HCV, affect even normal, healthy mitochondria by slowing ATP output,’ Arnold added. ‘While a person with normal mitochondria will experience some ATP and mitochondrial effects, a person who is already predisposed to mitochondrial dysfunction will be pushed over the ‘not enough cellular energy’ threshold by the antiviral drug. The person’s mitochondria simply won’t be able to keep up.’
One of the problems with clinical trials, Arnold explained, is that a drug may be shown to be quite effective but, if even a miniscule percentage of patients have side effects, the U.S. Food and Drug Administration is obligated to put the trial on hold or stop the trial altogether. This possibility makes drug companies reluctant to invest money in drug trials after an adverse event has been observed, even when the drugs could still help millions of people. The researchers hope that their methods eventually will become a part of the pre-clinical development process for this class of antiviral drugs. ‘If we can show, in the lab, that a drug will cause side effects, then these compounds will not enter lengthy, expensive clinical trials and cause harm to patients ‘ he said. ‘What’s more, a drug company can invest its money more wisely and carefully in drug research that will produce safe and effective products. Better and more-willing investments by drug companies ultimately will help patients, because resources will be spent developing drugs that not only work, but that are safe for all patients.’ Penn State Univeristy

A new study reveals that primitive human stem cells are resistant to human cytomegalovirus (HCMV), one of the leading prenatal causes of intellectual disability, deafness and deformities worldwide. Researchers from the University of Pittsburgh School of Medicine found that as stem cells and other primitive cells mature into neurons, they become more susceptible to HCMV, which could allow them to find effective treatments for the virus and to prevent its potentially devastating consequences.

‘Previous studies have focused on other species and other cell types, but those studies did not evaluate what the cytomegalovirus does to human brain cells,’ said Vishwajit Nimgaonkar, M.D., Ph.D., professor of psychiatry at the University of Pittsburgh School of Medicine, and senior author of the report. ‘This study is the first of its kind, and the first to discover that primitive stem cells are actually resistant to HCMV.’

Access to cultured human neurons, necessary to understand the pathogenic effects of HCMV, has been limited by difficulties in growing the brain cells in the laboratory. Yet through human-induced pluripotent stem (iPS) cells, researchers were able to overcome this hurdle.

The study authors derived live iPS cells by reprogramming cells called fibroblasts obtained from human skin biopsies. The iPS cells were then induced to mature through several stages into neurons, the primary cells in the brain. The researchers were able to evaluate the patterns of damage caused by HCMV on all these cells.

The research findings suggest:
• Human iPS cells do not permit a full viral replication cycle, suggesting for the first time that these cells can resist CMV infection
• CMV infection distorts iPS cell differentiation into neurons, and that may be a mechanism by which infected babies develop impairments of brain maturation and intellectual ability
• iPS-derived mature neurons are more susceptible to CMV infection and once infected show effects including defective function that have been shown in other animal studies and in other human tissues, and the neurons die a few days after infection lab studies, possibly reflecting the impact of CMV on the human brain

‘The findings were quite surprising, but this is only the first in a series of studies on HCMV,’ added Nimgaonkar. ‘There is a lot of interest in what we can do to treat the infection, and current work is already underway to screen for new drugs that could be used to fight these viruses.’

Between 50 and 80 percent of people in the U.S. have been infected by HCMV by the time they reach 40. Infections are rarely serious, but the virus does not leave the body. CMV is also the most common congenital infection in the U.S., and occurs when a mother contracts CMV during pregnancy and passes the virus to her unborn child. According to the U.S. Centers for Disease Control and Prevention, one of every 150 children are born with CMV infection and one in five of them develop permanent problems, such as intellectual disability, vision and hearing loss, and seizures.

Pitt researchers are collaborating with the Drug Discovery Institute to further understand the cellular system and determine which agents are most effective against HCMV and similar viruses, and which treatments would be safe for human use. University of Pittsburgh

Reduced production of myelin, a type of protective nerve fibre that is lost in diseases like multiple sclerosis, may also play a role in the development of mental illness, according to researchers at the Graduate School of Biomedical Sciences at Mount Sinai School of Medicine.
Myelin is an insulating material that wraps around the axon, the threadlike part of a nerve cell through which the cell sends impulses to other nerve cells. New myelin is produced by nerve cells called oligodendrocytes both during development and in adulthood to repair damage in the brain of people with diseases such as multiple sclerosis (MS).
A new study led by Patrizia Casaccia, MD, PhD, Professor of Neuroscience, Genetics and Genomics; and Neurology at Mount Sinai, determined that depriving mice of social contact reduced myelin production, demonstrating that the formation of new oligodendrocytes is affected by environmental changes. This research provides further support to earlier evidence of abnormal myelin in a wide range of psychiatric disorders, including autism, anxiety, schizophrenia and depression.
‘We knew that a lack of social interaction early in life impacted myelination in young animals but were unsure if these changes would persist in adulthood,’ said Dr. Casaccia, who is also Chief of the Center of Excellence for Myelin Repair at the Friedman Brain Institute at Mount Sinai School of Medicine. ‘Social isolation of adult mice causes behavioural and structural changes in neurons, but this is the first study to show that it causes myelin dysfunction as well.’
Dr. Casaccia’s team isolated adult mice to determine whether new myelin formation was compromised. After eight weeks, they found that the isolated mice showed signs of social withdrawal. Subsequent brain tissue analyses indicated that the socially isolated mice had lower-than-normal levels of myelin-forming oligodendrocytes in the prefrontal cortex, but not in other areas of the brain. The prefrontal cortex controls complex emotional and cognitive behaviour.
The researchers also found changes in chromatin, the packing material for DNA. As a result, the DNA from the new oligodendrocytes was unavailable for gene expression.
After observing the reduction in myelin production in socially-isolated mice, Dr. Casaccia’s team then re-introduced these mice into a social group. After four weeks, the social withdrawal symptoms and the gene expression changes were reversed.
‘Our study demonstrates that oligodendrocytes generate new myelin as a way to respond to environmental stimuli, and that myelin production is significantly reduced in social isolation,’ said Dr. Casaccia. ‘Abnormalities occur in people with psychiatric conditions characterised by social withdrawal. Other disorders characterised by myelin loss, such as MS, often are associated with depression. Our research emphasises the importance of maintaining a socially stimulating environment in these instances.’
At Mount Sinai, Dr. Casaccia’s laboratory is studying oligodendrocyte formation to identify therapeutic targets for myelin repair. They are screening newly-developed pharmacological compounds in brain cells from rodents and humans for their ability to form new myelin. EurekAlert