Posts tagged neuroscience

ScienceDaily (June 25, 2012) — Researchers have discovered how a hormone in the gut slows the rate at which the stomach empties and thus suppresses hunger and food intake. Results of the animal study were presented June 25 at The Endocrine Society’s 94th Annual Meeting in Houston.

"The gut hormone glucagon-like peptide 2, or GLP-2, functions as a neurotransmitter and fine-tunes gastric emptying through — as suspected — its receptor action in the brain," said the lead investigator, Xinfu Guan, PhD, assistant professor of pediatrics and medicine at Baylor College of Medicine in Houston.

The researchers found that this action occurs in the GLP-2 receptor specifically in a key group of nerve cells in the brain, called pro-opiomelanocortin, or POMC, neurons. These neurons are in the hypothalamus, the part of the brain that produces appetite-controlling neuropeptides.

In their study using molecular methods, mice lacking this GLP-2 receptor in the POMC neurons showed late-onset obesity and higher food intake compared with normal wild-type mice. The mutant, or GLP-2 receptor “knockout,” mice also had accelerated gastric emptying after a liquid meal, as found on a noninvasive breath test. The faster the gastric emptying, the higher the food intake, scientists know.

Therefore, obese people may have something wrong with this hormone receptor, which alters their gastric emptying rate, Guan speculated. Many studies have shown that nondiabetic, obese humans have accelerated gastric emptying.

The researchers also found that this receptor quickly activated the PI3K intracellular signaling pathway in the POMC neurons. This, in turn, induces neuronal excitation (transmission of signals) and gene expression, according to Guan.

These findings, Guan said, show that in the central nervous system the GLP-2 receptor plays an important physiological role in the control of food intake and gastric emptying.

"This study has advanced our understanding of the brain-gut neural circuits that mediate eating behavior via modulating gastric emptying, which contributes to the control of body weight," he said.

Source: Science Daily

ScienceDaily (June 25, 2012) — Women with moderate to severe depression had substantial improvement in their symptoms of depression after they received treatment for their vitamin D deficiency, a new study finds.

The case report series was presented June 23 at The Endocrine Society’s 94th Annual Meeting in Houston.

Because the women did not change their antidepressant medications or other environmental factors that relate to depression, the authors concluded that correction of the patients’ underlying shortage of vitamin D might be responsible for the beneficial effect on depression.

"Vitamin D may have an as-yet-unproven effect on mood, and its deficiency may exacerbate depression," said Sonal Pathak, MD, an endocrinologist at Bayhealth Medical Center in Dover, Del. "If this association is confirmed, it may improve how we treat depression."

Pathak presented the research findings in three women, who ranged in age from 42 to 66. All had previously diagnosed major depressive disorder, also called clinical depression, and were receiving antidepressant therapy. The patients also were being treated for either Type 2 diabetes or an underactive thyroid (hypothyroidism).

Because the women had risk factors for vitamin D deficiency, such as low vitamin D intake and poor sun exposure, they each underwent a 25-hydroxyvitamin D blood test. For all three women, the test found low levels of vitamin D, ranging from 8.9 to 14.5 nanograms per milliliter (ng/mL), Pathak reported. Levels below 21 ng/mL are considered vitamin D deficiency, and normal vitamin D levels are above 30 ng/mL, according to The Endocrine Society.

Over eight to 12 weeks, oral vitamin D replacement therapy restored the women’s vitamin D status to normal. Their levels after treatment ranged from 32 to 38 ng/mL according to the study abstract.

After treatment, all three women reported significant improvement in their depression, as found using the Beck Depression Inventory. This 21-item questionnaire scores the severity of sadness and other symptoms of depression. A score of 0 to 9 indicates minimal depression; 10 to 18, mild depression; 19 to 29, moderate depression; and 30 to 63, severe depression.

One woman’s depression score improved from 32 before vitamin D therapy to 12, a change from severe to mild depression. Another woman’s score fell from 26 to 8, indicating she now had minimal symptoms of depression. The third patient’s score of 21 improved after vitamin D treatment to 16, also in the mild range.

Other studies have suggested that vitamin D has an effect on mood and depression, but there is a need for large, good-quality, randomized controlled clinical trials to prove whether there is a real causal relationship, Dr Pathak said.

"Screening at-risk depressed patients for vitamin D deficiency and treating it appropriately may be an easy and cost-effective adjunct to mainstream therapies for depression," she said.

Source: Science Daily

ScienceDaily (June 25, 2012) — Widely available EEG testing can distinguish children with autism from neurotypical children as early as age 2, finds a study from Boston Children’s Hospital. The study is the largest, most rigorous study to date to investigate EEGs as a potential diagnostic tool for autism, and offers hope for an earlier, more definitive test.

Widely available EEG testing can distinguish children with autism from neurotypical children as early as age 2, finds a new study. The study is the largest, most rigorous study to date to investigate EEGs as a potential diagnostic tool for autism, and offers hope for an earlier, more definitive test. (Credit: © dule964 / Fotolia)

Researchers Frank H. Duffy, MD, of the Department of Neurology, and Heidelise Als, PhD, of the Department of Psychiatry at Boston Children’s Hospital, compared raw EEG data from 430 children with autism and 554 control subjects, ages 2 to 12, and found that those with autism had consistent EEG patterns indicating altered connectivity between brain regions — generally, reduced connectivity as compared with controls.

While altered connectivity occurred throughout the brain in the children with autism, the left-hemisphere language areas stood out, showing reduced connectivity as compared with neurotypical children, consistent with neuroimaging research. Findings were published June 26 in the online open-access journal BMC Medicine.

Duffy and Als focused on children with “classic” autism who had been referred for EEGs by neurologists, psychiatrists or developmental pediatricians to rule out seizure disorders. Those with diagnosed seizure disorders were excluded, as were children with Asperger’s syndrome and “high functioning” autism, who tend to dominate (and skew) the existing literature because they are relatively easy to study. The researchers also excluded children with genetic syndromes linked to autism (such as Fragile X or Rett syndrome), children being treated for other major illnesses, those with sensory disorders like blindness and deafness and those taking medications.

"We studied the typical autistic child seeing a behavioral specialist — children who typically don’t cooperate well with EEGs and are very hard to study," says Duffy. "No one has extensively studied large samples of these children with EEGs, in part because of the difficulty of getting reliable EEG recordings from them."

The researchers used techniques developed at Boston Children’s Hospital to get clean waking EEG recordings from children with autism, such as allowing them to take breaks. They used computer algorithms to adjust for the children’s body and eye movements and muscle activity, which can throw off EEG readings.

To measure connectivity in the brain, Duffy and Als compared EEG readings from multiple electrodes placed on the children’s scalps, and quantified the degree to which any two given EEG signals — in the form of waves — are synchronized, known as coherence. If two or more waves rise and fall together over time, it indicates that those brain regions are tightly connected. (Duffy likens coherence to two people singing “Mary Had a Little Lamb” together. If they can see and hear each other, they are more likely to sing in synchrony — so their coherence is high.)

In all, using computational techniques, the researchers generated coherence readings for more than 4,000 unique combinations of electrode signals, and looked for the ones that seemed to vary the most from child to child. From these, they identified 33 coherence “factors” that consistently distinguished the children with autism from the controls, across all age groups (2 to 4, 4 to 6, and 6 to 12 years).

Duffy and Als repeated their analysis 10 times, splitting their study population in half different ways and using half to identify the factors, and the other half to test and validate them. Each time, the classification scheme was validated.

"These factors allowed us to make a discriminatory rule that was highly significant and highly replicable," says Duffy. "It didn’t take anything more than an EEG — the rest was computational. Our choice of variables was completely unbiased — the data told us what to do."

The researchers believe the findings could be the basis for a future objective diagnostic test of autism, particularly at younger ages when behavior-based measures are unreliable. Their most immediate goal is to repeat their study in children with Asperger’s syndrome and see if its EEG patterns are similar to or different from autism. They also plan to evaluate children whose autism is associated with conditions such as tuberous sclerosis, fragile X syndrome and extremely premature birth.

Source: Science Daily

June 25, 2012 By Traci Pedersen

Scientists have found improvements on memory tests and an increase in brain volume in Chinese seniors who practice tai chi three times a week, according to an article published in the Journal of Alzheimer’s Disease.

The trial also showed increases in brain volume and smaller cognitive improvements in individuals that participated in lively discussions three times per week over the same time period.

Researchers from the University of South Florida and Fudan University in Shanghai conducted an eight-month randomized controlled trial involving a group of seniors who practiced tai chi as well as a group who participated in lively conversations.  Researchers compared these to a control group who received no intervention.

Previous studies have shown an increase in brain volume in people who participated in aerobic exercise, and in one of these trials, memory was improved as well.

However, this was the first trial to prove that a less aerobic form of exercise, tai chi, as well as stimulating discussion, led to similar increases in brain volume and improvements on psychological tests of memory and thinking.

Volunteers who did not participate in the interventions showed brain shrinkage during this time period, consistent with what generally has been observed for persons in their 60s and 70s.

Several studies have shown that dementia and the gradual cognitive decline that precedes it is linked to increasing shrinkage of the brain as nerve cells and their connections are slowly lost.

“The ability to reverse this trend with physical exercise and increased mental activity implies that it may be possible to delay the onset of dementia in older persons through interventions that have many physical and mental health benefits,” said lead author James Mortimer, Ph.D., professor of epidemiology at the University of South Florida College of Public Health.

Research suggests that aerobic exercise is associated with increased production of brain growth factors. It has been undetermined whether forms of exercise like tai chi that include an important mental exercise component could lead to similar changes in brain development.

“If this is shown, then it would provide strong support to the concept of ‘use it or lose it’ and encourage seniors to stay actively involved both intellectually and physically,” Mortimer said.

One question raised by the research is whether sustained physical and mental exercise can help prevent Alzheimer’s disease.

“Epidemiologic studies have shown repeatedly that individuals who engage in more physical exercise or are more socially active have a lower risk of Alzheimer’s disease,” Mortimer said. “The current findings suggest that this may be a result of growth and preservation of critical regions of the brain affected by this illness.”

Source: PsychCentral

ScienceDaily (June 25, 2012) — A team of researchers led by an epidemiologist at Mount Sinai School of Medicine and University of Iceland has found a correlation between the age at which children with attention-deficit/hyperactivity disorder (ADHD) begin taking medication, and how well they perform on standardized tests, particularly in math.

The study, titled, “A Population-Based Study of Stimulant Drug Treatment of ADHD and Academic Progress in Children,” appears in the July, 2012, edition of Pediatrics, and can be viewed online on June 25. Using data from the Icelandic Medicines Registry and the Database of National Scholastic Examinations, the researchers studied 11,872 Icelandic children born between 1994 and 1996. The children started medication for ADHD at different times between fourth and seventh grades.

The findings showed that children who began drug treatment within 12 months of their fourth-grade test declined 0.3 percent in math by the time they took their seventh-grade test, compared with a decline of 9.4 percent in children who began taking medication 25-to-36 months after their fourth-grade test.

The data also showed that girls benefited only in mathematics, whereas boys had marginal benefits in math and language arts.

"Children who began taking medications immediately after their fourth-grade standardized tests showed the smallest declines in academic performance," said the study’s lead author Helga Zoega, PhD, Post Doctoral Fellow of Epidemiology at Mount Sinai’s Institute for Translational Epidemiology. "The effect was greater in girls than boys and also greater for children who did poorly on their fourth grade test."

Stimulants are widely used in the United States as a therapeutic option for children with inattention, impulsivity, and hyperactivity associated with ADHD. The medications are less frequently used in Europe, although their use in Iceland most closely resembles the U.S. Long-term follow-up studies of stimulant use and academic performance are scarce, according to the researchers.

Source: Science Daily

June 25, 2012

The Allen Institute for Brain Science convened the first ever Allen Brain Atlas Hackathon last week, opening its doors to a diverse group of programmers and informatics experts for a non-stop week of collaboration, learning and coding based on its public online platform of data, tools and source code. The event brought together more than 30 participants from top universities and institutes ranging from the Baylor College of Medicine in Houston to the Nencki Institute of Experimental Biology in Poland, as well as from start-ups and established technology companies, to develop data analysis strategies and tools based on the newly enhanced Allen Brain Atlas application programming interface (API).

"This hackathon stems from our longstanding, open approach to science and our belief that putting our data-rich resources in the hands of the many and varied experts around the globe is the most effective way to drive progress in brain research,” said Chinh Dang, Chief Technology Officer of the Allen Institute for Brain Science. “The hackathon projects delivered innovative ways of handling data, offering direct contributions to the informatics and programming communities as well as to neuroscience. We hope that this event serves as a springboard for others out in the community to use our API, and we look forward to seeing what can be done with it.”

The Allen Institute for Brain Science is one of the biggest data producers in neuroscience, with rapidly growing data stores in the petabyte range that it makes publicly available through its Web-based Allen Brain Atlas resources. These resources include, among others, anatomically and genomically comprehensive maps of genes at work in the mouse and human brains and receive approximately 50,000 visits each month from researchers around the globe.

The public API was created as an additional form of data sharing to spur community technology development and further empower scientists to make groundbreaking discoveries about the brain in health and disease—including insights into learning, cognition, development, Alzheimer’s, obesity, schizophrenia, autism, and more—that will deliver better treatment options sooner. The hackathon coincided with the public release of the full Allen Brain Atlas API earlier this month, and a key goal of the event was to ignite community momentum and interest in using it.

Using the Allen Brain Atlas API, developers can create entirely new software applications, mashups and novel data mining tools for making sense of the large and ever-growing volumes of neuroscience data. The API offers data access across species, ages, disease and control states, providing a powerful means to compare many types of data (e.g., histology images, gene expression, and MRI) among many types of samples (e.g., ages, species or diseases).

"The Allen Institute is a leader in large-scale open science, known for providing high-quality data and online tools that advance brain research," said Sean Hill, Executive Director of the International Neuroinformatics Coordinating Facility (INCF). "With the Allen Brain Atlas Hackathon and their public API, they are bringing the same collaborative, community-focused approach to technology development and innovation that is at the core of INCF’s mission."

The hackathon program was designed to provide scientists and programmers a solid foundation in using the Allen Brain Atlas API for data mining, data analysis and tools development. The event featured a handful of speakers from the Allen Institute, as well as external experts who had leveraged earlier versions of the API in their work. As a hands-on workshop, participants spent most of the time working on projects of their choice. The Allen Institute development team actively participated throughout the week to provide specific examples of API usage, as well as to team up with community participants to develop collaborative projects. Participants’ presentations throughout the week showcased their projects and progress, stimulating new ideas and benefiting from the collective feedback and troubleshooting power of the entire group.

Projects ranged from practical applications, such as using a list of glioblastoma-related genes to discover biological patterns that could shed new light on the biology of the disease and developing strategies to use gene expression data with functional brain scanning technologies, to purely creative applications, including translating genomic data into music.

The Allen Brain Atlas Hackathon was hosted by the Allen Institute for Brain Science and funded jointly with the International Neuroinformatics Coordinating Facility (INCF).

Provided by Allen Institute for Brain Science

Source: medicalxpress.com

June 24, 2012 by SETH BORENSTEIN

(AP) — The more we study animals, the less special we seem.

In this Dec. 13, 2006 photo provided by the Primate Research Institute of Kyoto University, a 5 1/2-year-old chimpanzee named Ayumu performs a memory test with randomly-placed consecutive Arabic numerals, which are later masked, accurately duplicating the lineup on a touch screen computer in Kyoto, Japan. The young chimpanzees in the study titled “Working memory of numerals in chimpanzees” by Sana Inoue and Tetsuro Matsuzawa could memorize the nine numerals much faster and more accurately than human adults. The evidence that animals are more intelligent and more social than we thought seems to grow each year, especially when it comes to primates. It’s an increasingly hot scientific field with the number of ape and monkey cognition studies doubling in recent years, often with better technology and neuroscience paving the way to unusual discoveries. (AP Photo/Primate Research Institute of Kyoto University) PART OF A SEVEN-PICTURE PACKAGE WITH “ANIMAL SCIENCES”

Baboons can distinguish between written words and gibberish. Monkeys seem to be able to do multiplication. Apes can delay instant gratification longer than a human child can. They plan ahead. They make war and peace. They show empathy. They share.

"It’s not a question of whether they think — it’s how they think," says Duke University scientist Brian Hare. Now scientists wonder if apes are capable of thinking about what other apes are thinking.

The evidence that animals are more intelligent and more social than we thought seems to grow each year, especially when it comes to primates. It’s an increasingly hot scientific field with the number of ape and monkey cognition studies doubling in recent years, often with better technology and neuroscience paving the way to unusual discoveries.

Read more …

ScienceDaily (June 24, 2012) — The blood-brain barrier — the filter that governs what can and cannot come into contact with the mammalian brain — is a marvel of nature. It effectively separates circulating blood from the fluid that bathes the brain, and it keeps out bacteria, viruses and other agents that could damage it.

But the barrier can be disrupted by disease, stroke and multiple sclerosis, for example, and also is a big challenge for medicine, as it can be difficult or impossible to get therapeutic molecules through the barrier to treat neurological disorders.

Now, however, the blood-brain barrier may be poised to give up some of its secrets as researchers at the University of Wisconsin-Madison have created in the laboratory dish the cells that make up the brain’s protective barrier. Writing in the June 24, 2012 edition of the journal Nature Biotechnology, the Wisconsin researchers describe transforming stem cells into endothelial cells with blood-brain barrier qualities.

Access to the specialized cells “has the potential to streamline drug discovery for neurological disease,” says Eric Shusta, a UW-Madison professor of chemical and biological engineering and one of the senior authors of the new study. “You can look at tens of thousands of drug candidates and just ask the question if they have a chance to get into the brain. There is broad interest from the pharmaceutical industry.”

The blood-brain barrier depends on the unique qualities of endothelial cells, the cells that make up the lining of blood vessels. In many parts of the body, the endothelial cells that line capillaries are spaced so that substances can pass through. But in the capillaries that lead to the brain, the endothelial cells nestle in tight formation, creating a semi-permeable barrier that allows some substances — essential nutrients and metabolites — access to the brain while keeping others — pathogens and harmful chemicals — locked out.

The cells described in the new Wisconsin study, which was led by Ethan S. Lippmann, now a postdoctoral fellow at the Wisconsin Institute for Discovery, and Samira M. Azarin, now a postdoctoral fellow at Northwestern University, exhibit both the active and passive regulatory qualities of those cells that make up the capillaries of the intact brain.

The research team coaxed both embryonic and induced pluripotent stem cells to form the endothelial cells of the blood-brain barrier. The use of induced cells, which can come from patients with specific neurological conditions, may be especially important for modeling disorders that compromise the blood-brain barrier. What’s more, because the cells can be mass produced, they could be used to devise high-throughput screens for molecules that may have therapeutic value for neurological conditions or to identify existing drugs that may have neurotoxic qualities.

"The nice thing about deriving endothelial cells from induced pluripotent stem cells is that you can make disease-specific models of brain tissue that incorporate the blood-brain barrier," explains Sean Palecek, a UW-Madison professor of chemical and biological engineering and a senior author of the new report. "The cells you create will carry the genetic information of the condition you want to study."

The generation of the specialized blood-brain barrier endothelial cells, the Wisconsin researchers note, has never been done with stem cells. In addition to the potential applications to screen drugs and model pathologies of the blood-brain barrier, they may also provide a novel window for developmental biologists who are interested in how the barrier comes together and co-develops with the brain.

"Neurons develop at the same time as the endothelial cells," Shusta says, noting that, in development, the cells secrete chemical cues that help determine organ specificity.

"We don’t know what all those factors are," Lippmann says. "But with this model, we can go back and look." Identifying all of the molecular factors at play as blank slate stem cells differentiate to become specialized endothelial cells could one day have clinical significance to treat stroke or tamp down the ability of brain tumors to recruit blood vessels needed to sustain cancer.

Source: Science Daily

ScienceDaily (June 24, 2012) — Every day the human brain is presented with tasks ranging from the trivial to the complex. How much mental effort and attention are devoted to each task is usually determined in a split second and without conscious awareness. Now a study from Massachusetts General Hospital (MGH) researchers finds that a structure deep within the brain, believed to play an important role in regulating conscious control of goal-directed behavior, helps to optimize behavioral responses by predicting how difficult upcoming tasks will be. The report is receiving advance online publication in Nature.

"The dorsal anterior cingulate cortex (dACC), which lies deep beneath the outer layer of the frontal lobes, is part of an ancient and enigmatic part of the brain," says Emad Eskandar, MD, of the MGH Department of Neurosurgery, senior author of the Nature paper. “Some have speculated that it plays a role in detecting errors or monitoring for conflicting demands, but exactly how it contributes to regulating behavioral responses is unclear, so we used a variety of scientific techniques to get a better picture of its function.”

The study enrolled six participants who were scheduled to undergo cingulotomy — a procedure in which a small, precisely placed lesion is created within the ACC — to treat severe obsessive compulsive disorder (OCD) that has not responded to other types of treatment. A standard part of the cingulotomy procedure involves microelectrode recordings of the activity of single neurons in the area where the lesion is to be placed. To evaluate dACC function, the investigators recorded brain activity from several neurons within the structure while participants performed a behavioral task testing their reactions to visual images.

The task presented participants with a random series of images of three numerals, which could be 0, 1, 2, or 3. In each image, two of the numerals were identical. Participants responded by pressing one of three buttons, the position of which would indicate the identity of the number that was different, with the left button indicating 1, the middle 2 and the right button 3. Each image was ranked in difficulty depending on how much the position of the target numeral or the identity of the duplicate numerals might distract participants from the correct response. For example, when presented with 3-3-2, the correct response would be to press the middle button for number 2; and that image would be ranked more difficult than 3-2-3, in which both the target number and the correct button were in the same position.

Functional magnetic resonance imaging (fMRI) of four participants performing the behavioral task prior to the cingulotomy procedure revealed that the task increased metabolic activity within the dACC, a result seen in previous fMRI studies. The fMRI images also revealed that responding to more difficult images produced greater activity levels within the dACC and in other structures known to be involved in decision making. Intraoperative microelectrode recordings of all participants demonstrated that this apparent increase in metabolic activity corresponded with an increase in neuronal activity, linking for the first time the increased activation revealed by fMRI with increased neuronal firing.

Analysis of individual neuron activity indicated that dACC neuronal activity remained elevated immediately after difficult trials. Moreover, participant reaction time revealed that the difficulty of the prior trial had an impact on the next trial: if the preceding trial was of the same level of difficulty, reaction time was shorter; if the two tests were of different difficulty levels — even if the second test was easier — reaction time was longer. By anticipating the difficulty of upcoming tasks, the authors note, it appears that the dACC speeds up responses when difficulty levels are constant but slows response time down when faced with changing demands in order to promote accuracy.

While behavioral tests conducted after the cingulotomy procedure — which destroys tissue within the dACC — did not indicate a change in participants’ ability to perform the test accurately, the impact of preceding trials on reaction time appeared to vanish. “Participants could still perform the task, but the dACC’s role of priming the system based on immediate prior experience was gone,” Eskandar explains. “We believe this result indicates an important role for the dACC in rapidly adjusting to different cognitive demands, possibly by recruiting other areas of the brain to solve particular problems.”

An associate professor of Surgery at Harvard Medical School, Eskandar adds that, while significant cognitive changes have not been reported in patients undergoing cingulotomy, the apparent role of the dACC in adapting to changing situations implies a possible role for the structure in several psychiataric disorders. “A lack of behavior flexibility and adjustment is characteristic of OCD, for example. Whether or not our findings directly relate to these disorders remains to be determined, but we hope that continued study using complex tasks, such as the behavioral test used here, will be helpful in diagnosing or monitoring psychiatric disorders.”

Source: Science Daily

ScienceDaily (June 24, 2012) — Hemimegalencephaly is a rare but dramatic condition in which the brain grows asymmetrically, with one hemisphere becoming massively enlarged. Though frequently diagnosed in children with severe epilepsy, the cause of hemimegalencephaly is unknown and current treatment is radical: surgical removal of some or all of the diseased half of the brain.

This image depicts hemimegalencephaly. (Credit: UC San Diego School of Medicine)

In a paper published in the June 24, 2012 online issue of Nature Genetics, a team of doctors and scientists, led by researchers at the University of California, San Diego School of Medicine and the Howard Hughes Medical Institute, say de novo somatic mutations in a trio of genes that help regulate cell size and proliferation are likely culprits for causing hemimegalencephaly, though perhaps not the only ones.

De novo somatic mutations are genetic changes in non-sex cells that are neither possessed nor transmitted by either parent. The scientists’ findings — a collaboration between Joseph G. Gleeson, MD, professor of neurosciences and pediatrics at UC San Diego School of Medicine and Rady Children’s Hospital-San Diego; Gary W. Mathern, MD, a neurosurgeon at UC Los Angeles’ Mattel Children’s Hospital; and colleagues — suggest it may be possible to design drugs that inhibit or turn down signals from these mutated genes, reducing or even preventing the need for surgery.

Gleeson’s lab studied a group of 20 patients with hemimegalencephaly upon whom Mathern had operated, analyzing and comparing DNA sequences from removed brain tissue with DNA from the patients’ blood and saliva.

"Mathern had reported a family with identical twins, in which one had hemimegalencephaly and one did not. Since such twins share all inherited DNA, we got to thinking that there may be a new mutation that arose in the diseased brain that causes the condition," said Gleeson. Realizing they shared the same ideas about potential causes, the physicians set out to tackle this question using new exome sequencing technology, which allows sequencing of all of the protein-coding exons of the genome at the same time.

The researchers ultimately identified three gene mutations found only in the diseased brain samples. All three mutated genes had previously been linked to cancers.

"We found mutations in a high percentage of the cells in genes regulating the cellular growth pathways in hemimegalencephaly," said Gleeson. "These same mutations have been found in various solid malignancies, including breast and pancreatic cancer. For reasons we do not yet understand, our patients do not develop cancer, but rather this unusual brain condition. Either there are other mutations required for cancer propagation that are missing in these patients, or neurons are not capable of forming these types of cancers."

The mutations were found in 30 percent of the patients studied, indicating other factors are involved. Nonetheless, the researchers have begun investigating potential treatments that address the known gene mutations, with the clear goal of finding a way to avoid the need for surgery.

"Although counterintuitive, hemimegalencephaly patients are far better off following the functional removal or disconnection of the enlarged hemisphere," said Mathern. "Prior to the surgery, most patients have devastating epilepsy, with hundreds of seizures per day, completely resistant to even our most powerful anti-seizure medications. The surgery disconnects the affected hemisphere from the rest of the brain, causing the seizures to stop. If performed at a young age and with appropriate rehabilitation, most children suffer less language or cognitive delay due to neural plasticity of the remaining hemisphere."

But a less-invasive drug therapy would still be more appealing.

"We know that certain already-approved medications can turn down the signaling pathway used by the mutated genes in hemimegalencephaly," said lead author and former UC San Diego post-doctoral researcher Jeong Ho Lee, now at the Korea Advanced Institute of Science and Technology. "We would like to know if future patients might benefit from such a treatment. Wouldn’t it be wonderful if our results could prevent the need for such radical procedures in these children?"

Source: Science Daily