Circadian rhythms can be modified for potential treatment of disorders

UC Irvine-led studies have revealed the cellular mechanism by which circadian rhythms – also known as the body clock – modify energy metabolism and also have identified novel compounds that control this action. The findings point to potential treatments for disorders triggered by circadian rhythm dysfunction, ranging from insomnia and obesity to diabetes and cancer.

UC Irvine’s Paolo Sassone-Corsi, one of the world’s leading researchers on the genetics of circadian rhythms, led the studies and worked with international groups of scientists. Their results are detailed in two companion pieces appearing this week in the early online edition of the Proceedings of the National Academy of Science (1 , 2).

“Circadian rhythms of 24 hours govern fundamental physiological functions in almost all organisms,” said Sassone-Corsi, the Donald Bren Professor of Biological Chemistry. “The circadian clocks are intrinsic time-tracking systems in our bodies that anticipate environmental changes and adapt themselves to the appropriate time of day. Disruption of these rhythms can profoundly influence human health.”

He added that up to 15 percent of people’s genes are regulated by the day-night pattern of circadian rhythms.

Researchers map emotional intelligence in the brain

A new study of 152 Vietnam veterans with combat-related brain injuries offers the first detailed map of the brain regions that contribute to emotional intelligence – the ability to process emotional information and navigate the social world.

The study found significant overlap between general intelligence and emotional intelligence, both in terms of behavior and in the brain. Higher scores on general intelligence tests corresponded significantly with higher performance on measures of emotional intelligence, and many of the same brain regions were found to be important to both. (Watch a video about the research.)

The study appears in the journal Social Cognitive & Affective Neuroscience.

“This was a remarkable group of patients to study, mainly because it allowed us to determine the degree to which damage to specific brain areas was related to impairment in specific aspects of general and emotional intelligence,” said study leader Aron K. Barbey, a professor of neuroscience, of psychology and of speech and hearing science at the Beckman Institute for Advanced Science and Technology at the University of Illinois.

A previous study led by Barbey mapped the neural basis of general intelligence by analyzing how specific brain injuries (in a larger sample of Vietnam veterans) impaired performance on tests of fundamental cognitive processes.

In both studies, researchers pooled data from CT scans of participants’ brains to produce a collective, three-dimensional map of the cerebral cortex. They divided this composite brain into 3-D units called voxels. They compared the cognitive abilities of patients with damage to a particular voxel or cluster of voxels with those of patients without injuries in those brain regions. This allowed the researchers to identify brain areas essential to specific cognitive abilities, and those that contribute significantly to general intelligence, emotional intelligence, or both.

They found that specific regions in the frontal cortex (behind the forehead) and parietal cortex (top of the brain near the back of the skull) were important to both general and emotional intelligence. The frontal cortex is known to be involved in regulating behavior. It also processes feelings of reward and plays a role in attention, planning and memory. The parietal cortex helps integrate sensory information, and contributes to bodily coordination and language processing.

“Historically, general intelligence has been thought to be distinct from social and emotional intelligence,” Barbey said. The most widely used measures of human intelligence focus on tasks such as verbal reasoning or the ability to remember and efficiently manipulate information, he said.

“Intelligence, to a large extent, does depend on basic cognitive abilities, like attention and perception and memory and language,” Barbey said. “But it also depends on interacting with other people. We’re fundamentally social beings and our understanding not only involves basic cognitive abilities but also involves productively applying those abilities to social situations so that we can navigate the social world and understand others.”

The new findings will help scientists and clinicians understand and respond to brain injuries in their patients, Barbey said, but the results also are of broader interest because they illustrate the interdependence of general and emotional intelligence in the healthy mind.

Less tau reduces seizures and sudden death in severe epilepsy

Deleting or reducing expression of a gene that carries the code for tau, a protein associated with Alzheimer’s disease, can prevent seizures in a severe type of epilepsy linked to sudden death, said researchers at Baylor College of Medicine and the Mayo Clinic in Jacksonville, Fla., in a report in the current issue of the Journal of Neuroscience.

A growing understanding of the link between epilepsy and some forms of inherited Alzheimer’s disease led to the finding that could point the way toward new drugs for seizure disorders said Dr. Jeffrey Noebels, professor of neurology at BCM, and director of the Blue Bird Circle Developmental Neurogenetics Laboratory.

In her research, Jerrah Holth, a graduate student in molecular and human genetics at BCM who was working with mice with the severe form of epilepsy in Noebel’s laboratory, deleted the gene for tau. She found that reducing or eliminating tau also prevented the seizures in a severe form of epilepsy that has been associated with sudden death and reduced deaths in the animals.

In an earlier experiment, Noebels, in collaboration with Dr. Lennart Mucke at the Gladstone Research Laboratory at the University of California San Francisco, found that mice who carried a human gene that leads to accumulation of the beta amyloid protein and the amyloid plaques that accumulate in the brains of people with Alzheimer’s disease, also had epileptic seizures arising in the hippocampus, the region of the brain associated with memory storage and retrieval.

"This led to the paradigm-shifting hypothesis that excessive neuronal network activity, rather than too little, may contribute to lower cognitive performance and dementia in some forms of Alzheimer’s disease. When this happens, the progression of memory loss may accelerate," said Noebels.

The finding also demonstrated the two disorders may share defects in signaling within brain memory circuits.

The two labs went on to show that deleting the second gene for tau ameliorated both cognitive losses and seizures in the mice whose inherited disorder mimicked Alzheimer’s disease found in humans.

Holth’s finding demonstrates that tau is involved in a far broader range of epilepsy than previously suspected, said Noebels. The type of epilepsy she studied resulted from an inherited potassium ion channel defect that affects the flow of the potassium in and out of nerve cells. She found that removing the gene encoding Tau not only dramatically reduced seizures, but prevented the mice from dying early, which typically happens in these animals.

"Even a partial reduction of the amount of tau protein by 50 percent was highly effective," said Holth. Her finding suggests developing new drugs that lower the normal interactions of the tau protein may reduce seizures and sudden unexpected death for persons with intractable epilepsies, a problem in nearly one-third of the 5 million Americans with this disorder.

Currently, Noebels and his colleagues in the Blue Bird Laboratory are studying whether the loss of tau can correct a seizure disorder once it is already established. If these studies prove fruitful, “the pharmacological discovery programs under development for treatment of Alzheimer’s disease may one day find their way to the epilepsy clinic,” said Noebels.

(Image: ALAMY)

UCLA study first to image concussion-related abnormal brain proteins in retired NFL players

Now, for the first time, UCLA researchers have used a brain-imaging tool to identify the abnormal tau proteins associated with this type of repetitive injury in five retired National Football League players who are still living. Previously, confirmation of the presence of this protein, which is also associated with Alzheimer’s disease, could only be established by an autopsy.

The preliminary findings of the small study are reported Jan. 22 in the online issue of the American Journal of Geriatric Psychiatry, the official journal of the American Association for Geriatric Psychiatry.

Previous reports and studies have shown that professional athletes in contact sports who are exposed to repetitive mild traumatic brain injuries may develop ongoing impairment such as chronic traumatic encephalopathy (CTE), a degenerative condition caused by a build up of tau protein. CTE has been associated with memory loss, confusion, progressive dementia, depression, suicidal behavior, personality changes, abnormal gait and tremors.

"Early detection of tau proteins may help us to understand what is happening sooner in the brains of these injured athletes," said lead study author Dr. Gary Small, UCLA’s Parlow–Solomon Professor on Aging and a professor of psychiatry and biobehavioral sciences at the Semel Institute for Neuroscience and Human Behavior at UCLA. "Our findings may also guide us in developing strategies and interventions to protect those with early symptoms, rather than try to repair damage once it becomes extensive."

Small notes that larger follow-up studies are needed to determine the impact and usefulness of detecting these tau proteins early, but given the large number of people at risk for mild traumatic brain injury — not only athletes but military personnel, auto accident victims and others — a means of testing what is happening in the brain during the early stages could potentially have a considerable impact on public health.

Stem Cell Research Helps to Identify Origins of Schizophrenia

New University at Buffalo research demonstrates how defects in an important neurological pathway in early development may be responsible for the onset of schizophrenia later in life.

The UB findings, published in Schizophrenia Research, test the hypothesis in a new mouse model of schizophrenia that demonstrates how gestational brain changes cause behavioral problems later in life – just like the human disease.

Partial funding for the research came from New York Stem Cell Science (NYSTEM).

The genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways of as many as 160 different genes believed to be involved in the disorder. 

“We believe this is the first model that explains schizophrenia from genes to development to brain structure and finally to behavior,” says lead author Michal Stachowiak, PhD, professor in the Department of Pathology and Anatomical Sciences in the UB School of Medicine and Biomedical Sciences. He also is director of the Stem Cell Engraftment & In Vivo Analysis Facility at the Western New York Stem Cell Culture and Analysis Center at UB.

A key challenge with the disease is that patients with schizophrenia exhibit mutations in different genes, he says.

“How is it possible to have 100 patients with schizophrenia and each one has a different genetic mutation that causes the disorder?” asks Stachowiak. “It’s possible because INFS integrates diverse neurological signals that control the development of embryonic stem cell and neural progenitor cells, and links pathways involving schizophrenia-linked genes.

“INFS functions like the conductor of an orchestra,” explains Stachowiak. “It doesn’t matter which musician is playing the wrong note, it brings down the conductor and the whole orchestra. With INFS, we propose that when there is an alteration or mutation in a single schizophrenia-linked gene, the INFS system that controls development of the whole brain becomes untuned. That’s how schizophrenia develops.”

Using embryonic stem cells, Stachowiak and colleagues at UB and other institutions found that some of the genes implicated in schizophrenia bind the FGFR1 (fibroblast growth factor receptor) protein, which in turn, has a cascading effect on the entire INFS.

The Science Behind ‘Beatboxing’

Acoustical analysis reveals the anatomy behind the fascinating array of sounds people can make.

Using the mouth, lips, tongue and voice to generate sounds that one might never expect to come from the human body is the specialty of the artists known as beatboxers. Now scientists have used scanners to peer into a beatboxer as he performed his craft to reveal the secrets of this mysterious art.

The human voice has long been used to generate percussion effects in many cultures, including North American scat singing, Celtic lilting and diddling, and Chinese kouji performances. In southern Indian classical music, konnakol is the percussive speech of the solkattu rhythmic form. In contemporary pop music, the relatively young vocal art form of beatboxing is an element of hip-hop culture.

Until now, the phonetics of these percussion effects were not examined in detail. For instance, it was unknown to what extent beatboxers produced sounds already used within human language.

To learn more about beatboxing, scientists analyzed a 27-year-old male performing in real-time using MRI. This gave researchers “an opportunity to study the sounds people produce in much greater detail than has previously been possible,” said Shrikanth Narayanan, a speech and audio engineer at the University of Southern California in Los Angeles. “The overarching goals of our work drive at larger questions related to the nature of sound production and mental processing in human communication, and a study like this is a small part of the larger puzzle.”

The investigators made 40 recordings each lasting 20-40 seconds long as the beatboxer produced all the effects in his repertoire, as individual sounds, composite beats, rapped lyrics, sung lyrics and freestyle combinations of these elements. He categorized 17 distinct percussion sounds into five instrumental classes — kick drums, rim shots, snare drums, hi-hats, and cymbals. The artist demonstrated his repertoire at several different tempos, ranging from slower at roughly 88 beats per minute, to faster at 104.

"We were astonished by the complex elegance of the vocal movements and the sounds being created in beatboxing, which in itself is an amazing artistic display," Narayanan said. "This incredible vocal instrument and its many capabilities continue to amaze us, from the intricate choreography of the ‘dance of the tongue’ to the complex aerodynamics that work together to create a rich tapestry of sounds that encode not only meaning but also a wide range of emotions."

"It is absolutely amazing that a person can make these sounds — that a person has such control over the timing of various parts of the speech apparatus," said phonetician Donna Erickson at the Showa University of Music and Sophia University, both in Japan, who did not participate in this study. "It is very exciting to see how far technology has come — that we can see these movements in real time. It gives us a much better understanding of how the various parts of our speech anatomy work."

Brain region associated with selfishness

People with damage to a specific part of the brain entrusted unexpectedly large amounts of money to complete strangers. In an investment game played in the lab, three women with damage to a small part of the brain called the basolateral amygdala handed over nearly twice as much money as healthy people.

These women didn’t expect to make a bunch of money back, an international team of researchers reports online the week of January 21 in the Proceedings of the National Academy of Sciences. Nor did they think the person they invested with was particularly trustworthy. When asked why they would invest so generously, the volunteers couldn’t provide an answer.

The results suggest that normally, the basolateral amygdala enables selfishness — putting the squeeze on generosity.

(Image credit)

New findings on mortality of individuals with schizophrenia

A new study from Lund University in Sweden shows that the average life expectancy of men and women with schizophrenia is 15 years and 12 years shorter respectively than for those who do not suffer from the disease. The study has been carried out in collaboration with Stanford University in the US.

The reasons why people with schizophrenia have a shorter life expectancy have previously been unknown, but have been much discussed in recent years. The research report that has now been published shows that individuals with schizophrenia are more likely to die of two major diseases.

The study followed over six million individuals from 2003 to 2009, of whom 8,277 had schizophrenia, by analysing the Swedish population and health registers.

The results show that people with schizophrenia had contact with the health service over twice as often as people without the condition, but they were no more likely to be diagnosed with cardiovascular disease or cancer.

“Yet we saw an opposing pattern of death from these diseases. It is clear that the health service is failing to diagnose cardiovascular disease and cancer in these patients”, says Jan Sundquist, general practitioner and professor at the Centre for Primary Health Care Research at Lund University.

Women with schizophrenia were 3.3 times more likely to die of cardiovascular disease and men 2.2 times more likely. Women with schizophrenia were 1.7 times more likely to die of cancer while men were 1.4 times more likely, compared with those without schizophrenia. Only 26.3% of the men with schizophrenia who died of cardiovascular disease had been diagnosed before their deaths, compared with 43.7% of the men who did not have schizophrenia.

“It is unacceptable that such a vulnerable group of people, who also have extensive documented contact with the health service, should die prematurely of conditions such as cardiovascular disease and cancer – diseases that should be preventable”, says Professor Sundquist. “A much greater degree of diagnostic and preventive measures could be put in place for this vulnerable group in our society.”