Neuroscience

The mental fuzziness induced by cancer treatment could be eased by cognitive exercises performed online, say researchers.

Cancer survivors sometimes suffer from a condition known as “chemo fog”—a cognitive impairment caused by repeated chemotherapy. A study hints at a controversial idea: that brain-training software might help lift this cognitive cloud.

Various studies have concluded that cognitive training can improve brain function in both healthy people and those with medical conditions, but the broader applicability of these results remains controversial in the field.

In a study published in the journal Clinical Breast Cancer, investigators report that those who used a brain-training program for 12 weeks were more cognitively flexible, more verbally fluent, and faster-thinking than survivors who did not train.

Patients treated with chemotherapy show changes in brain structure and function in line with diffuse brain injury, and they often report long-term cognitive effects, says Shelli Kesler, a Stanford University clinical neuropsychologist who led the research. The new study “suggests that cognitive training could be one possible avenue for helping to improve cognitive function in breast cancer survivors treated with chemotherapy,” she says.

The results may not convince everyone. “One of the biggest challenges in the cognitive training world is to show an effect that generalizes to real-world functioning,” says Susan Landau, a neuroscientist at the University of California, Berkeley. Several companies offer commercial cognitive training programs that promise improvements in memory, attention, mental agility, and problem-solving skills. The appeal is clear, says Zach Hambrick, a psychologist at Michigan State University in East Lansing, but whether they have lasting general effects is not.

The fact that companies are marketing these training programs to customers before their value has been rigorously proved has caused some skepticism in the field, say experts. “The field is still growing,” says Suzanne Jaeggi, a neuropsychologist at the University of Maryland. While studies have shown that there are cognitive benefits to the training, it’s very hard to detect an impact on daily life, she says. However, some work, including research by her own group, has shown that working memory exercises can improve reading abilities in schoolchildren.

In the study conducted by Kesler and colleagues, the participants trained at home on Lumosity, a collection of gamelike cognitive exercises developed by Lumos Labs in San Francisco. (Lumos Labs did not fund the study.)

Kesler’s project is one of around two dozen efforts using Lumosity software to study human cognition. With 35 million customers worldwide, Lumosity is collecting what it says is the world’s largest database of human cognition, which could be queried for connections between lifestyle and cognitive ability. “Our technology collects a lot of data and makes it easy to run experiments to learn more generally about human cognitive performance,” says Mike Scanlon, cofounder of Lumos Labs. “We track all of the results from the cognitive testing and training, and we can combine that with demographic information to learn about how people’s cognitive performance changes and develops over the years.”

One such finding, he says, is a correlation between outside weather temperature and cognitive performance: “It turned out that the colder it is, the higher people’s performance is, even though generally they are inside doing this on a computer.”

Most of the scientific projects involving Lumosity’s software are exploring the effectiveness of brain training in different populations, from schoolchildren to stroke patients. For the study on breast cancer survivors, 41 women aged 40 and older, who were at least a year and half past their last chemotherapy treatment, were tested on several cognitive tasks at the beginning of the study. Then half the women used Lumosity training modules for 20 to 30 minutes four times a week for 12 weeks, and all were tested again.

When the investigators tested the participants in verbal memory, processing speed, and cognitive function, they found that the women who had used the brain training program improved in three of five objective measures.

“This is a well-done study—they had not just one transfer test but several,” says Hambrick, who notes that many studies of cognitive training depend on a single test to measure results. “But an issue is the lack of activity within the control group.” Better would be to have the control group do another demanding cognitive task in lieu of Lumosity training—something analogous to a placebo, he says: “The issue is that maybe the improvement in the group that did the cognitive training doesn’t reflect enhancement of basic cognitive processes per se, but could be a motivational phenomenon.”

Even if the effects are due to motivation or some other benefit not related to mental agility, that’s still useful, says Landau. “If [cognitive training] is something that makes people feel good and improves their confidence in their own skills, that’s not trivial at all,” she says. “That could be a big part of the effect that’s observed.”

Working with lab mice models of multiple sclerosis (MS), UC Davis scientists have detected a novel molecular target for the design of drugs that could be safer and more effective than current FDA-approved medications against MS.

The findings of the research study, published online today in the journal EMBO Molecular Medicine could have therapeutic applications for MS as well as cerebral palsy and leukodystrophies, all disorders associated with loss of white matter, which is the brain tissue that carries information between nerve cells in the brain and the spinal cord.

The target, a protein referred to as mitochondrial translocator protein (TSPO), had been previously identified but not linked to MS, an autoimmune disease that strips the protective fatty coating off nerve fibers of the brain and spinal cord. The mitrochronical TSPO is located on the outer surface of mitochondria, cellular structures that supply energy to the cells. Damage to the fatty coating, or myelin, slows the transmission of the nerve signals that enable body movement as well as sensory and cognitive functioning.

The scientists identified mitochondrial TSPO as a potential therapeutic target when mice that had symptoms of MS improved after being treated with the anti-anxiety drug etifoxine, which interacts with mitochondrial TSPO. When etifoxine, a drug clinically available in Europe, was administered to the MS mice before they had clinical signs of disease, the severity of the disease was reduced when compared to the untreated lab animals. When treated at the peak of disease severity, the animals’ MS symptoms improved.

“Etifoxine has a novel protective effect against the loss of the sheath that insulates the nerve fibers that transmit the signals from brain cells,” said Wenbin Deng, principal investigator of the study and associate professor of biochemistry and molecular medicine at UC Davis.

“Our discovery of etifoxine’s effects on an MS animal model suggests that mitochondrial TSPO represents a potential therapeutic target for MS drug development,” said Deng.

“Drugs designed to more precisely bind to mitochondrial TSPO may help repair the myelin sheath of MS patients and thereby even help restore the transmission of signals in the central nervous system that enable normal motor, sensory and cognitive functions,” he said.

Deng added that better treatments for MS and other demyelinating diseases are needed, especially since current FDA-approved therapies do not repair the damage of immune attacks on the myelin sheath. 

The UC Davis research team hopes to further investigate the therapeutic applications of mitochondrial TSPO in drug development for MS and other autoimmune diseases. To identify more efficacious and safer drug candidates, they plan to pursue research grants that will enable them to test a variety of pharmacological compounds that bind to mitochondrial TSPO and other molecular targets in experimental models of MS and other myelin diseases.

In the first successful experiment with humans using a treatment known as sensory-motor or environmental enrichment, researchers documented marked improvement in young autistic boys when compared to boys treated with traditional behavioral therapies, according to research published by the American Psychological Association.

The rationale for the new treatment is rooted in the fact that autistic children typically have sensory problems, the most common involving smell and touch sensitivity. Building on decades of work in animals documenting the profound effects of environmental enrichment on behavioral and neurological outcomes, the authors of the study predicted that similar enrichment in autistic children would have beneficial effects.

“Because parents can give their child sensory enrichment using items typically available in their home, this therapy provides a low-cost option for enhancing their child’s progress,” said study co-author Cynthia C. Woo, PhD, a project scientist at the University of California Irvine.

The study, which was published online in the APA journal Behavioral Neuroscience, involved 28 autistic boys, ages 3 to 12. Researchers placed the boys in two groups based on their age and autism severity. For six months, both groups participated in standard behavioral therapy but boys in one of the groups also underwent daily environmental enrichment exercises.

Parents of each of the 13 boys in the enrichment group received a kit that contained essential oil fragrances such as apple, lavender, lemon and vanilla to stimulate sense of smell. For touch, the kit contained squares of plastic doormat, smooth foam, a rubber sink mat, aluminum, fine sandpaper, felt and sponges. The kit also included pieces of carpet, hard flooring, pillows, cardboard and bubble wrap that parents laid on the floor to create a multi-textured walking path. Items for the children to manipulate included a piggy bank with plastic coins, miniature plastic fruits and a small fishing pole with a magnetic hook. Many household items were also used, such as bowls for holding water at different temperatures for the child to dip in a hand or foot and metal spoons that parents would warm or cool and touch to the child’s skin.

Researchers instructed the parents of children in the enrichment group to conduct two sessions a day of four to seven exercises involving different combinations of sensory stimuli for touch, temperature, sight and movement. Each session took 15 to 30 minutes to complete. The children also listened to classical music once a day.

Following six months of therapy, 42 percent of the children in the enrichment group significantly improved in behaviors such as relating to people and responding to sights and sounds, compared to 7 percent of the standard care group, according to the study. The children in the enrichment group also improved on scores for cognitive function, which covers aspects of perception and reasoning, whereas the average scores for the children in the standard care group decreased. In addition, 69 percent of parents in the enrichment group reported improvement in their child’s overall autism symptoms, compared to 31 percent of parents of the standard care group, the authors wrote.

“Sensory enrichment may well be an effective therapy for the treatment of autism, particularly in children much past the toddler stage,” said study co-author Michael Leon, PhD, a professor of neurobiology and behavior with the University of California Irvine.

“This is an exciting study for several reasons,” said Mark Blumberg, PhD, editor of Behavioral Neuroscience. “It is well designed, it builds on established findings from numerous experiments using non-human animals and it addresses the critical need to find effective treatments for autism. The obvious next step has to be replication of these results in a larger-scale study.”

Before the experiment, most of the children in both groups were undergoing the standard treatment for autism, applied behavior analysis, which typically involves 25 to 40 hours a week with a trained professional for a number of years, the study said. Some children in both groups were also undergoing speech therapy, social skills therapy, physical therapy for fine motor skills or occupational therapy with different types of exercises. Most current therapies for autism must be started at a very young age to be effective, whereas environmental enrichment worked for boys at least to age 12, the study said.

The researchers are now conducting a larger randomized clinical trial that includes girls. Another important next step will be to test environmental enrichment therapy when a child is not also receiving other standard treatments, the authors noted.

A study led by researchers from Plymouth University Peninsula Schools of Medicine and Dentistry has for the first time revealed how the loss of a particular tumour suppressing protein leads to the abnormal growth of tumours of the brain and nervous system.

The study is published in Brain: A Journal of Neurology.

Tumour suppressors exist in cells to prevent abnormal cell division in our bodies. The loss of a tumour suppressor called Merlin leads to tumours in many cell types within our nervous systems. There are two copies of a tumour suppressor, one on each chromosome that we inherit from our parents. The loss of Merlin can be caused by random loss of both copies in a single cell, causing sporadic tumours, or by inheriting one abnormal copy and losing the second copy throughout our lifetime as is seen in the inherited condition of neurofibromatosis type 2 (NF2).

With either sporadic loss or inherited NF2, these tumours lacking the Merlin protein develop in the Schwann cells that form the sheaths that surround and electrically insulate neurons. These tumours are called schwannomas, but tumours can also arise in the cells that form the membrane around the brain and spinal cord, and the cells that line the ventricles of the brain.

Although the schwannomas are slow-growing and benign, they are frequent and come in numbers. The sheer number of tumours caused by this gene defect can overwhelm a patient, often leading to hearing loss, disability and eventually death. Patients can suffer from 20 to 30 tumours at any one time, and the condition typically manifests in the teenage years and through into adulthood.

No effective therapy for these tumours exists, other than repeated invasive surgery or radiotherapy aiming at a single tumour at a time and which is unlikely to eradicate the full extent of the tumours.

The Brain study investigated how loss of a protein called Sox10 functions in causing these tumours. Sox10 is known to play a major role in the development of Schwann cells, but this is the first time it has been shown to be involved in the growth of schwannoma tumour cells. By understanding the mechanism, the research team has opened the way for new therapies to be developed that will provide a viable to alternative to surgery or radiotherapy.

The study, undertaken by researchers from Plymouth University Peninsula Schools of Medicine and Dentistry with colleagues from the State University of New York and Universitat Erlangen-Nurmberg, was led by Professor David Parkinson.

He said: “We have for the first time shown that human schwannoma cells have reduced expression of Sox10 protein and messenger RNA. By identifying this correlation and gaining an understanding of the mechanism of this process, we hope that drug-based therapies may in time be created and introduced that will reduce or negate the need for multiple surgery or radiotherapy.”

Investigation by researchers from the University of Exeter and ETH Zurich has shed new light on a protein which is linked to a common neurological disorder called Charcot-Marie-Tooth disease.

Peroxisomes (green) and mitochondria (red) in a mammalian cell. The nucleus (blue) contains the cellular DNA.

The team has discovered that a protein previously identified on mitochondria - the energy factories of the cell - is also found on the fat-metabolising organelles peroxisomes, suggesting a closer link between the two organelles.

Charcot-Marie-Tooth disease is currently incurable and affects around one in every 2,500 people in the UK, meaning that it is one of the most common inherited neurological disorders, thus understanding the molecular basis of the disease is of great importance. Symptoms can range from tremors and loss of touch sensation in the feet and legs to difficulties with breathing, swallowing, speaking, hearing and vision.

The research published online in EMBO Reports combines work from University of Exeter Biosciences researcher Dr Michael Schrader and PhD student Sofia Guimaraes. The major finding of the study is that the protein GDAP1, originally thought to only be involved in fragmentation of mitochondria, also contributes to the regulation of peroxisome number through their division.

Peroxisomes are small organelles occurring in nearly all cells, from yeast to crop plants to humans, and are essential for cell viability due to their important role in the metabolism of fatty acids and reactive oxygen species. Peroxisomes are also of particular interest as they play a key role in ageing.

This current study shows that the division of both mitochondria and peroxisomes follows a similar mechanism, although many of the disease-causing mutations occur in a region of the gene that is more critical for mitochondrial than peroxisomal division.

Dr Michael Schrader said of this project: “This study supports our hypothesis of a closer connection between mitochondria and peroxisomes. We have identified several membrane proteins, which are shared by both organelles, particularly key components of the division machinery, meaning there must be coordinated biogenesis and cross-talk.”

As numerous diseases have been linked to problems in the mitochondria, Dr Schrader proposes that this connection could have far-reaching medical implications.

This work contributes to the research being addressed through the prestigious Marie Curie Initial Training Network PERFUME programme (PERoxisome, FUnction, and MEtabolism), recently awarded to Michael Schrader along with several other top European research groups which focus on peroxisome biology.

Our researchers have found a previously undiscovered link between epileptic seizures and the signs of autism in adults.

Dr SallyAnn Wakeford from the Department of Psychology revealed that adults with epilepsy were more likely to have higher traits of autism and Asperger syndrome.

Characteristics of autism, which include impairment in social interaction and communication as well as restricted and repetitive interests, can be severe and go unnoticed for many years, having tremendous impact on the lives of those who have them.

The research found that epileptic seizures disrupt the neurological function that affects social functioning in the brain resulting in the same traits seen in autism.

Dr Wakeford said: “The social difficulties in epilepsy have been so far under-diagnosed and research has not uncovered any underlying theory to explain them. This new research links social difficulties to a deficit in somatic markers in the brain, explaining these characteristics in adults with epilepsy.”

Dr Wakeford and her colleagues discovered that having increased autistic traits was common to all epilepsy types, however, this was more pronounced for adults with Temporal Lobe Epilepsy (TLE).

The researchers suggest that one explanation may be because anti-epileptic drugs are often less effective for TLE. The reason why they suspect these drugs are implicated is because they were strongly related to the severity of autistic characteristics.

Dr Wakeford carried out a comprehensive range of studies with volunteers with epilepsy and discovered that all of the adults with epilepsy showed autism traits.

She said: “It is unknown whether these adults had a typical developmental period during childhood or whether they were predisposed to having autistic traits before the onset of their epilepsy. However what is known is that the social components of autistic characteristics in adults with epilepsy may be explained by social cognitive differences, which have largely been unrecognised until now.”

Dr Wakeford said the findings could lead to improved treatment for people with epilepsy and autism. She said: “Epilepsy has a history of cultural stigma, however the more we understand about the psychological consequences of epilepsy the more we can remove the stigma and mystique of this condition.

“These findings could mean that adults with epilepsy get access to better services, as there is a wider range of treatments available for those with autism condition.”

Margaret Rawnsley, research administration officer at Epilepsy Action welcomed the findings.

She said: “We welcome any research that could further our understanding of epilepsy and ultimately improve the lives of those with the condition. This research has the potential to tell us more about the links between epilepsy and other conditions, such as autism spectrum disorders.”

Non-invasive brain stimulation techniques aimed at mental and neurological conditions include transcranial magnetic stimulation (TMS) for depression, and transcranial direct current (electrical) stimulation (tDCS), shown to improve memory. Transcranial ultrasound stimulation (TUS) has also shown promise.

Ultrasound consists of mechanical vibrations, like sound, but with frequencies far greater than the upper limit of human hearing, around 20 thousand to 20 million cycles per second (20 kilohertz to 20 megahertz). Ultrasound vibrations penetrate bodily tissue including bone, and are widely used to image anatomical structures via echo effects, e.g. visualizing unborn babies in mothers’ wombs, and organs, blood vessels, nerves and other structures in medical procedures. Virtually every part of the body, including the brain, has been safely imaged with low to moderate intensity ultrasound.

High intensity, focused ultrasound can damage tissue by heating and cavitation, and has been used to ablate tumors and other lesions. ‘Sub-thermal’ ultrasound can safely stimulate neural tissue. In 2002 a UCLA group led by Alexander Bystritsky noticed beneficial side effects in psychiatric patients whose brains were imaged by TUS. A team led by Virginia Tech’s W. Jamie Tyler has shown TUS-induced behavioral and electrophysiological changes in animals. A Harvard group led by S-S Yoo has used focused ultrasound aimed at mouse motor cortex to wag the mouse’s tail. But clinical trials of TUS aimed at human mental states have been lacking.

Now, in an article in the journal Brain Stimulation, a group from the Departments of Anesthesiology and Radiology at the University of Arizona Medical Center in Tucson, Arizona has investigated TUS for modulating mental states in a pilot study in human volunteers suffering from chronic pain. A clinical ultrasound imaging device (General Electric LOGIQe) was used, with the ultrasound probe applied at the scalp overlying the brain’s temporal and frontal cortex (visible on the imaging screen). In random order, each subject received two 15 second exposures: sham/placebo, and 8 megahertz ultrasound (undetectable to subjects). Following exposure, subjects reported (by visual analog scales) significant improvement in mood both 10 minutes and 40 minutes after TUS, but not after sham/placebo. In a followup study (led by University of Arizona psychologists Jay Sanguineti and John JB Allen) preliminary results suggest 2 megahertz TUS (which traverses skull more readily) may be more effective in mood enhancement than 8 megahertz TUS.

The mechanism by which TUS can affect mental states is unknown (as is the mechanism by which the brain produces mental states). Tyler proposed TUS acts by vibrational stretching of neuronal membranes and/or extracellular matrix, but two recent papers from the group of Anirban Bandyopadhyay at National Institute of Material Sciences (NIMS) in Tsukuba, Japan (Sahu et al. [2013] Appl. Phys. Letts.; Sahu et al [2013] Biosensors and Bioelectronics) have suggested another possibility. The NIMS group used nanotechnology to study conductive properties of individual microtubules, protein polymers of tubulin (the brain’s most prevalent protein). Major components of the neuronal cytoskeleton, microtubules grow and extend neurons, form and regulate synapses, are disrupted in Alzheimer’s disease, and theoretically linked to information processing, memory encoding and mental states. Bandyopadhyay’s NIMS group found that microtubules have remarkable electronic conductive properties when excited at certain specific resonant frequencies, e.g. in the low megahertz, precisely the range of TUS.

Dr. Stuart Hameroff, lead author on the new TUS study, said: “This suggests TUS may stimulate natural megahertz resonances in brain microtubules, enhancing not only mood and conscious mental states, but perhaps also microtubule functions in synaptic plasticity, nerve growth and repair. We plan further studies of TUS on traumatic brain injury, Alzheimer’s disease and post-traumatic stress disorders. ‘Tuning the tubules’ may help a variety of mental states and cognitive disorders.”

The instability of “white matter” in humans may contribute to greater cognitive decline during the aging of humans compared with chimpanzees, scientists from Yerkes National Primate Research Center, Emory University have found.

Yerkes scientists have discovered that white matter — the wires connecting the computing centers of the brain — begins to deteriorate earlier in the human lifespan than in the lives of aging chimpanzees.

This was the first examination of white matter integrity in aging chimpanzees. The results were published April 24 and are available online before print in the journal Neurobiology of Aging.

"Our study demonstrates that the price we pay for greater longevity than other primates may be the unique vulnerability of humans to neurodegenerative disease," says research associate Xu (Jerry) Chen, first author of the paper. “The breakdown of white matter in later life could be part of that vulnerability.” 

Both humans’ longer life spans and distinctive metabolism could lie behind the differences in the patterns of brain aging, says co-author Todd Preuss, PhD, associate research professor in Yerkes’ Division of Neuropharmacology and Neurologic Diseases.

“White matter integrity actually peaks around the same absolute age in both chimpanzees and humans, but humans may experience more degradation because they live longer. Perhaps the need to retain brain capacity late in life is one reason increased brain size was selected for in human evolution,” Preuss says.  

The senior author is James Rilling, PhD, Yerkes researcher, associate professor of anthropology at Emory and director of the Laboratory for Darwinian Neuroscience. Collaborators at the University of Oslo also contributed to the paper.

In the brain, gray matter represents information processing centers, while white matter represents wires connecting these centers. White matter looks white because it is made up of myelin, a fatty electrical insulator that coats the axons of neurons.

If myelin deteriorates, neurons’ electrical signals are not transmitted as effectively, which contributes to cognitive decline. Myelin breakdown has been linked with cognitive decline both in healthy aging and in the context of Alzheimer’s disease.

The team’s data show that white matter integrity, as measured through a form of magnetic resonance imaging (MRI), peaks at age 31 in chimpanzees and at age 30 in humans. The average lifespan of chimpanzees is between 40 to 45 years, although in zoos or research facilities some have lived until 60. For comparison, human life expectancy in some developed countries is more than 80 years.

"The human equivalent of a 31 year old chimpanzee is about 47 years," Rilling says. "Extrapolating from chimpanzees, we could expect that human white matter integrity would peak at age 47, but instead it peaks and begins to decline at age 30."

The researchers collected MRI scans from 32 female chimpanzees and 20 female rhesus macaques and compared them with a pre-existing set of scans from human females. They used diffusion-weighted imaging (a form of MRI) to examine age-related changes in white matter integrity.

Diffusion-weighted imaging picks up microscopic changes in white matter by detecting directional differences in the ability of water molecules to diffuse. When the myelin coating of axons breaks down, water molecules in the brain can diffuse more freely, especially in directions perpendicular to axon bundles, Chen says.

Scientists at Washington University School of Medicine in St. Louis have helped identify many of the biomarkers for Alzheimer’s disease that could potentially predict which patients will develop the disorder later in life. Now, studying spinal fluid samples and health data from 201 research participants at the Charles F. and Joanne Knight Alzheimer’s Disease Research Center, the researchers have shown the markers are accurate predictors of Alzheimer’s years before symptoms develop.

“We wanted to see if one marker was better than the other in predicting which of our participants would get cognitive impairment and when they would get it,” said Catherine Roe, PhD, research assistant professor of neurology. “We found no differences in the accuracy of the biomarkers.”

The study, supported in part by the National Institute on Aging, appears in Neurology.

The researchers evaluated markers such as the buildup of amyloid plaques in the brain, newly visible thanks to an imaging agent developed in the last decade; levels of various proteins in the cerebrospinal fluid, such as the amyloid fragments that are the principal ingredient of brain plaques; and the ratios of one protein to another in the cerebrospinal fluid, such as different forms of the brain cell structural protein tau.

The markers were studied in volunteers whose ages ranged from 45 to 88. On average, the data available on study participants spanned four years, with the longest recorded over 7.5 years.

The researchers found that all of the markers were equally good at identifying subjects who were likely to develop cognitive problems and at predicting how soon they would become noticeably impaired.

Next, the scientists paired the biomarkers data with demographic information, testing to see if sex, age, race, education and other factors could improve their predictions.

“Sex, age and race all helped to predict who would develop cognitive impairment,” Roe said. “Older participants, men and African Americans were more likely to become cognitively impaired than those who were younger, female and Caucasian.”

Roe described the findings as providing more evidence that scientists can detect Alzheimer’s disease years before memory loss and cognitive decline become apparent.

“We can better predict future cognitive impairment when we combine biomarkers with patient characteristics,” she said. “Knowing how accurate biomarkers are is important if we are going to some day be able to treat Alzheimer’s before symptoms and slow or prevent the disease.”

Clinical trials are already underway at Washington University and elsewhere to determine if treatments prior to symptoms can prevent or delay inherited forms of Alzheimer’s disease. Reliable biomarkers for Alzheimer’s should one day make it possible to test the most successful treatments in the much more common sporadic forms of Alzheimer’s.

Human intelligence cannot be explained by the size of the brain’s frontal lobes, say researchers.

Research into the comparative size of the frontal lobes in humans and other species has determined that they are not - as previously thought - disproportionately enlarged relative to other areas of the brain, according to the most accurate and conclusive study of this area of the brain.

It concludes that the size of our frontal lobes cannot solely account for humans’ superior cognitive abilities.

The study by Durham and Reading universities suggests that supposedly more ‘primitive’ areas, such as the cerebellum, were equally important in the expansion of the human brain. These areas may therefore play unexpectedly important roles in human cognition and its disorders, such as autism and dyslexia, say the researchers.

The study is published in the Proceedings of the National Academy of Sciences (PNAS) today.

The frontal lobes are an area in the brain of mammals located at the front of each cerebral hemisphere, and are thought to be critical for advanced intelligence.

Lead author Professor Robert Barton from the Department of Anthropology at Durham University, said: “Probably the most widespread assumption about how the human brain evolved is that size increase was concentrated in the frontal lobes.

"It has been thought that frontal lobe expansion was particularly crucial to the development of modern human behaviour, thought and language, and that it is our bulging frontal lobes that truly make us human. We show that this is untrue: human frontal lobes are exactly the size expected for a non-human brain scaled up to human size.

"This means that areas traditionally considered to be more primitive were just as important during our evolution. These other areas should now get more attention. In fact there is already some evidence that damage to the cerebellum, for example, is a factor in disorders such as autism and dyslexia."

The scientists argue that many of our high-level abilities are carried out by more extensive brain networks linking many different areas of the brain. They suggest it may be the structure of these extended networks more than the size of any isolated brain region that is critical for cognitive functioning.

Previously, various studies have been conducted to try and establish whether humans’ frontal lobes are disproportionately enlarged compared to their size in other primates such as apes and monkeys. They have resulted in a confused picture with use of different methods and measurements leading to inconsistent findings.

The Durham and Reading researchers, funded by The Leverhulme Trust, analysed data sets from previous animal and human studies using phylogenetic, or ‘evolutionary family tree’, methods, and found consistent results across all their data. They used a new method to look at the speed with which evolutionary change occurred, concluding that the frontal lobes did not evolve especially fast along the human lineage after it split from the chimpanzee lineage.

Finding of disrupted brain gene orchestration gives first direct evidence of circadian rhythm changes in depressed brains, opens door to better treatment

Every cell in our bodies runs on a 24-hour clock, tuned to the night-day, light-dark cycles that have ruled us since the dawn of humanity. The brain acts as timekeeper, keeping the cellular clock in sync with the outside world so that it can govern our appetites, sleep, moods and much more.

But new research shows that the clock may be broken in the brains of people with depression — even at the level of the gene activity inside their brain cells.

It’s the first direct evidence of altered circadian rhythms in the brain of people with depression, and shows that they operate out of sync with the usual ingrained daily cycle. The findings, in the Proceedings of the National Academy of Sciences, come from scientists from the University of Michigan Medical School and other institutions.

The discovery was made by sifting through massive amounts of data gleaned from donated brains of depressed and non-depressed people. With further research, the findings could lead to more precise diagnosis and treatment for a condition that affects more than 350 million people worldwide.

What’s more, the research also reveals a previously unknown daily rhythm to the activity of many genes across many areas of the brain – expanding the sense of how crucial our master clock is.

In a normal brain, the pattern of gene activity at a given time of the day is so distinctive that the authors could use it to accurately estimate the hour of death of the brain donor, suggesting that studying this “stopped clock” could conceivably be useful in forensics. By contrast, in severely depressed patients, the circadian clock was so disrupted that a patient’s “day” pattern of gene activity could look like a “night” pattern — and vice versa.

The work was funded in large part by the Pritzker Neuropsychiatric Disorders Research Fund, and involved researchers from the University of Michigan, University of California’s Irvine and Davis campuses, Weill Cornell Medical College, the Hudson Alpha Institute for Biotechnology, and Stanford University.

The team uses material from donated brains obtained shortly after death, along with extensive clinical information about the individual. Numerous regions of each brain are dissected by hand or even with lasers that can capture more specialized cell types, then analyzed to measure gene activity. The resulting flood of information is picked apart with advanced data-mining tools.

Lead author Jun Li, Ph.D., an assistant professor in the U-M Department of Human Genetics, describes how this approach allowed the team to accurately back-predict the hour of the day when each non-depressed individual died – literally plotting them out on a 24-hour clock by noting which genes were active at the time they died. They looked at 12,000 gene transcripts isolated from six regions of 55 brains from people who did not have depression.

This provided a detailed understanding of how gene activity varied throughout the day in the brain regions studied. But when the team tried to do the same in the brains of 34 depressed individuals, the gene activity was off by hours. The cells looked as if it were an entirely different time of day.

“There really was a moment of discovery,” says Li, who led the analysis of the massive amount of data generated by the rest of the team and is a research assistant professor in U-M’s Department of Computational Medicine at Bioinformatics. “It was when we realized that many of the genes that show 24-hour cycles  in the normal individuals were well-known circadian rhythm genes – and when we saw that the people with depression were not synchronized to the usual solar day in terms of this gene activity. It’s as if they were living in a different time zone than the one they died in.”

Huda Akil, Ph.D., the co-director of the U-M Molecular & Behavioral Neuroscience Institute and co-director of the U-M site of the Pritzker Neuropsychiatric Disorders Research Consortium, notes that the findings go beyond previous research on circadian rhythms, using animals or human skin cells, which were more easily accessible than human brain tissues.

“Hundreds of new genes that are very sensitive to circadian rhythms emerged from this research — not just the primary clock genes that have been studied in animals or cell cultures, but other genes whose activity rises and falls throughout the day,” she says. “We were truly able to watch the daily rhythm play out in a symphony of biological activity, by studying where the clock had stopped at the time of death. And then, in depressed people, we could see how this was disrupted.”

Now, she adds, scientists must use this information to help find new ways to predict depression, fine-tune treatment for each depressed patient, and even find new medications or other types of treatment to develop and test. One possibility, she notes, could be to identify biomarkers for depression – telltale molecules that can be detected in blood, skin or hair.

And, the challenge of determining why the circadian clock is altered in depression still remains. “We can only glimpse the possibility that the disruption seen in depression may have more than one cause. We need to learn more about whether something in the nature of the clock itself is affected, because if you could fix the clock you might be able to help people get better,” Akil notes.

The team continues to mine their data for new findings, and to probe additional brains as they are donated and dissected. The high quality of the brains, and the data gathered about how their donors lived and died, is essential to the project, Akil says. Even the pH level of the tissue, which can be affected by the dying process and the time between death and freezing tissue for research, can affect the results. The team also will have access to blood and hair samples from new donors.