Foetal exposure to excessive stress hormones in the womb linked to adult mood disorders

Exposure of the developing foetus to excessive levels of stress hormones in the womb can cause mood disorders in later life and now, for the first time, researchers have found a mechanism that may underpin this process, according to research presented today (Sunday) at the British Neuroscience Association Festival of Neuroscience (BNA2013) in London.

The concept of foetal programming of adult disease, whereby the environment experienced in the womb can have profound long-lasting consequences on health and risk of disease in later life, is well known; however, the process that drives this is unclear. Professor Megan Holmes, a neuroendocrinologist from the University of Edinburgh/British Heart Foundation Centre for Cardiovascular Science in Scotland (UK), will say: “During our research we have identified the enzyme 11ß-HSD2 which we believe plays a key role in the process of foetal programming.”

Adverse environments experienced while in the womb, such as in cases of stress, bereavement or abuse, will increase levels of glucocorticoids in the mother, which may harm the growing baby. Glucocorticoids are naturally produced hormones and they are also known as stress hormones because of their role in the stress response.

“The stress hormone cortisol may be a key factor in programming the foetus, baby or child to be at risk of disease in later life. Cortisol causes reduced growth and modifies the timing of tissue development as well as having long lasting effects on gene expression,” she will say.

Prof Holmes will describe how her research has identified an enzyme called 11ß-HSD2 (11beta-hydroxysteroid dehydrogenase type 2) that breaks down the stress hormone cortisol to an inactive form, before it can cause any harm to the developing foetus. The enzyme 11ß-HSD2 is present in the placenta and the developing foetal brain where it is thought to act as a shield to protect against the harmful actions of cortisol.

Prof Holmes and her colleagues developed genetically modified mice that lacked 11ß-HSD2 in order to determine the role of the enzyme in the placenta and foetal brain. “In mice lacking the enzyme 11ß-HSD2, foetuses were exposed to high levels of stress hormones and, as a consequence, these mice exhibited reduced foetal growth and went on to show programmed mood disorders in later life. We also found that the placentas from these mice were smaller and did not transport nutrients efficiently across to the developing foetus. This too could contribute to the harmful consequences of increased stress hormone exposure on the foetus and suggests that the placental 11ß-HSD2 shield is the most important barrier.

“However, preliminary new data show that with the loss of the 11ß-HSD2 protective barrier solely in the brain, programming of the developing foetus still occurs, and, therefore, this raises questions about how dominant a role is played by the placental 11ß-HSD2 barrier. This research is currently ongoing and we cannot draw any firm conclusions yet.

“Determining the exact molecular and cellular mechanisms that drive foetal programming will help us identify potential therapeutic targets that can be used to reverse the deleterious consequences on mood disorders. In the future, we hope to explore the potential of these targets in studies in humans,” she will say.

Prof Holmes hopes that her research will make healthcare workers more aware of the fact that children exposed to an adverse environment, be it abuse, malnutrition, or bereavement, are at an increased risk of mood disorders in later life and the children should be carefully monitored and supported to prevent this from happening.

In addition, the potential effects of excessive levels of stress hormones on the developing foetus are also of relevance to individuals involved in antenatal care. Within the past 20 years, the majority of women at risk of premature delivery have been given synthetic glucocorticoids to accelerate foetal lung development to allow the premature babies to survive early birth.

“While this glucocorticoid treatment is essential, the dose, number of treatments and the drug used, have to be carefully monitored to ensure that the minimum effective therapy is used, as it may set the stage for effects later in the child’s life,” Prof Holmes will say.

Puberty is another sensitive time of development and stress experienced at this time can also be involved in programming adult mood disorders. Prof Holmes and her colleagues have found evidence from imaging studies in rats that stress in early teenage years could affect mood and emotional behaviour via changes in the brain’s neural networks associated with emotional processing.

The researchers used fMRI (Functional Magnetic Resonance Imaging) to see which pathways in the brain were affected when stressed, peripubertal rats responded to a specific learned task.

Prof Holmes will say: “We showed that in stressed ‘teenage’ rats, the part of the brain region involved in emotion and fear (known as amygdala) was activated in an exaggerated fashion when compared to controls. The results from this study clearly showed that altered emotional processing occurs in the amygdala in response to stress during this crucial period of development.”

(Image: iStockphoto)

Flies Model a Potential Sweet Treatment for Parkinson’s disease

Researchers from Tel Aviv University describe experiments that could lead to a new approach for treating Parkinson’s disease (PD) using a common sweetener, mannitol. This research is presented today at the Genetics Society of America’s 54th Annual Drosophila Research Conference in Washington D.C., April 3-7, 2013.

Mannitol is a sugar alcohol familiar as a component of sugar-free gum and candies. Originally isolated from flowering ash, mannitol is believed to have been the “manna” that rained down from the heavens in biblical times. Fungi, bacteria, algae, and plants make mannitol, but the human body can’t. For most commercial uses it is extracted from seaweed although chemists can synthesize it. And it can be used for more than just a sweetener.

The Food and Drug Administration approved mannitol as an intravenous diuretic to flush out excess fluid. It also enables drugs to cross the blood-brain barrier (BBB), the tightly linked cells that form the walls of capillaries in the brain. The tight junctions holding together the cells of these tiniest blood vessels come slightly apart five minutes after an infusion of mannitol into the carotid artery, and they stay open for about 30 minutes.

Mannitol has another, less-explored talent: preventing a sticky protein called α-synuclein from gumming up the substantia nigra part of the brains of people with PD and Lewy body dementia (LBD), which has similar symptoms to PD. In the disease state, the proteins first misfold, then form sheets that aggregate and then extend, forming gummy fibrils.

Certain biochemicals, called molecular chaperones, normally stabilize proteins and help them fold into their native three-dimensional forms, which are essential to their functions. Mannitol is a chemical chaperone. So like a delivery person who both opens the door and brings in the pizza, mannitol may be used to treat Parkinson’s disease by getting into the brain and then restoring normal folding to α-synuclein.

Daniel Segal, PhD, and colleagues at Tel Aviv University investigated the effects of mannitol on the brain by feeding it to fruit flies with a form of PD that has highly aggregated α-synuclein.

The researchers used a “locomotion climbing assay” to study fly movement. Normal flies scamper right up the wall of a test tube, but flies whose brains are encumbered with α-synuclein aggregates stay at the bottom, presumably because they can’t move normally. The percentage of flies that climb one centimeter in 18 seconds assesses the effect of mannitol.

An experimental run tested flies daily for 27 days. After that time, 72% of normal flies climbed up, in comparison to 38% of the PD flies. Their lack of ascension up the sides of the test tube indicated “severe motor dysfunction.”

In contrast, were flies bred to harbor the human mutant α-synuclein gene, who as larvae feasted on mannitol that sweetened the medium at the bottoms of their vials. These flies fared much better — 70% of them could climb after 27 days. And slices of their brains revealed a 70% decrease in accumulated misfolded protein compared to the brains of mutant flies raised on the regular medium lacking mannitol.

It’s a long way from helping climbing-impaired flies to a new treatment for people, but the research suggests a possible novel therapeutic direction. Dr. Segal, however, cautioned that people with PD or similar movement disorders should not chew a ton of mannitol-sweetened gum or sweets; that will not help their current condition. The next step for researchers is to demonstrate a rescue effect in mice, similar to improved climbing by flies, in which a rolling drum (“rotarod”) activity assesses mobility.

“Until and if mannitol is proven to be efficient for PD on its own, the more conservative and possibly more immediate use can be the conventional one, using it as a BBB disruptor to facilitate entrance of other approved drugs that have problems passing through the BBB,” Dr. Segal said. A preliminary clinical trial of mannitol on a small number of volunteers might follow if results in mice support those seen in the flies, he added, but that is still many research steps away.

(Image: Wikimedia Commons)

Researchers shine light on how stress circuits learn

Researchers at the University of Calgary’s Hotchkiss Brain Institute have discovered that stress circuits in the brain undergo profound learning early in life. Using a number of cutting edge approaches, including optogenetics, Jaideep Bains, PhD, and colleagues have shown stress circuits are capable of self-tuning following a single stress. These findings demonstrate that the brain uses stress experience during early life to prepare and optimize for subsequent challenges.

The team was able to show the existence of unique time windows following brief stress challenges during which learning is either increased or decreased. By manipulating specific cellular pathways, they uncovered the key players responsible for learning in stress circuits in an animal model. These discoveries culminated in the publication of two back-to-back studies in the April 7 online edition of Nature Neuroscience [1, 2], one of the world’s top neuroscience journals.

"These new findings demonstrate that systems thought to be ‘hardwired’ in the brain, are in fact flexible, particularly early in life," says Bains, a professor in the Department of Physiology and Pharmacology. "Using this information, researchers can now ask questions about the precise cellular and molecular links between early life stress and stress vulnerability or resilience later in life."

Stress vulnerability, or increased sensitivity to stress, has been implicated in numerous health conditions including cardiovascular disease, obesity, diabetes and depression. Although these studies used animal models, similar mechanisms mediate disease progression in humans.

"Our observations provide an important foundation for designing more effective preventative and therapeutic strategies that mitigate the effects of stress and meet society’s health challenges," he says.

Brain Games are Bogus

A decade ago, a young Swedish researcher named Torkel Klingberg made a spectacular discovery. He gave a group of children computer games designed to boost their memory, and, after weeks of play, the kids showed improvements not only in memory but in overall intellectual ability. Spending hours memorizing strings of digits and patterns of circles on a four-by-four grid had made the children smarter. The finding countered decades of psychological research that suggested training in one area (e.g., recalling numbers) could not bring benefits in other, unrelated areas (e.g., reasoning). The Klingberg experiment also hinted that intelligence, which psychologists considered essentially fixed, might be more mutable: that it was less like eye color and more like a muscle.

It seemed like a breakthrough, offering new approaches to education and help for people with A.D.H.D., traumatic brain injuries, and other ailments. In the years since, other, similar experiments yielded positive results, and Klingberg helped found a company, Cogmed, to commercialize the software globally. (Pearson, the British publishing juggernaut, purchased it in 2010.) Brain training has become a multi-million-dollar business, with companies like Lumosity, Jungle Memory, and CogniFit offering their own versions of neuroscience-you-can-use, and providing ambitious parents with new assignments for overworked but otherwise healthy children. The brain-training concept has made Klingberg a star, and he now enjoys a seat on an assembly that helps select the winners of the Nobel Prize in Physiology or Medicine. The field has become a staple of popular writing. Last year, the New York Times Magazine published a glowing profile of the young guns of brain training called “CAN YOU MAKE YOURSELF SMARTER?”

The answer, however, now appears to be a pretty firm no—at least, not through brain training. A pair of scientists in Europe recently gathered all of the best research—twenty-three investigations of memory training by teams around the world—and employed a standard statistical technique (called meta-analysis) to settle this controversial issue. The conclusion: the games may yield improvements in the narrow task being trained, but this does not transfer to broader skills like the ability to read or do arithmetic, or to other measures of intelligence. Playing the games makes you better at the games, in other words, but not at anything anyone might care about in real life.

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Flies with personality

Fruit flies may have more individuality and personality than we imagine.

And it might all be down to a bit of genetic shuffling in nerve cells that makes every fly brain unique, suggest Oxford University scientists.

Their new study has found that small genetic elements called ‘transposons’ are active in neurons in the fly brain. Transposons are also known as 'jumping genes', as these short scraps of DNA have the ability to move, cutting themselves out from one position in the genome and inserting themselves somewhere else.

The inherent randomness of the process is likely to make every fly brain unique, potentially providing behavioural individuality – or ‘fly personality’. So says Professor Scott Waddell, who led the work at the University of Oxford Centre for Neural Circuits and Behaviour: ‘We have known for some time that individual animals that are supposed to be genetically identical behave differently.

'The extensive variation between fly brains that this mechanism could generate might demystify why some behave while others misbehave,' he suggests.

The Oxford researchers, along with US colleagues at the University of Massachusetts Medical School and Howard Hughes Medical Institute, were able to deep-sequence the DNA from small numbers of nerve cells in the brains of Drosophila fruit flies.

They identified many transposons that were inserted in a number of important memory-related genes. Whether this is detrimental or advantageous to the fly remains an open question, the researchers say.

Scott Waddell notes that neural transposition has been described in rodent and human brains, and transposons have historically been considered to be problematic parasites. New insertions of transposons can on occasion disrupt genes (as was found in this study), and transposons have been associated to some human disorders such as schizophrenia.

However, it is also possible that organisms have harnessed transposition to generate variation within cells, and by extension create variation between individual animals that may turn out to be favourable.

Scott Waddell wants next to determine whether neural transposition provides an explanation for variation in fruit fly behaviour by finding ways of halting the process in flies in his lab.

State science fair winner creates robot

The winner of this year’s State Science and Engineering Fair is from South Florida, and her project can someday make life easier for the physically challenged.

"It captures the brain waves of electrochemical activity. Basically, the nerve impulse produced by the brain, and it sends it over to the robot," said Daniela Rodriguez.

Steve is an award winning robot controlled by brain waves. He was invented by 13-year-old Daniela Rodriguez, who loves math and science. “I’ve always been interested in robotics; it’s my passion,” she said.

This year, Rodriguez won first place in the Annual State Science and Engineering Fair against 900 other finalists.

Rodriguez’ goal is to help people. “If the person is disabled, they can sit in their wheelchair, and they can use their thoughts and brain waves to control its movements, so they don’t have to move,” she said.

Her science project comes from the heart. Her mother was diagnosed with multiple sclerosis in 1996, and she is trying to find a way to keep her mom independent. “I work really hard to try to stay mobile, but the fact that she wants to help patients dealing with this illness is just a Godsend” said Rodriguez’ mom Jeannie.

Rodriguez’ wants to one day use her technology to help paralyzed people. Steve’s technology can even give wounded veterans the ability to use their brains to move the robot. “To help them move around in their wheelchairs or move their prosthetics because usually prosthetics now is just the muscle movement, but now it can be used and be more natural. It’s moving by your brain,” said Rodriguez.

Not only is Rodriguez winning awards, prosthetic companies have expressed interest in her program.

Non-Invasive Brain-to-Brain Interface (BBI): Establishing Functional Links between Two Brains

Transcranial focused ultrasound (FUS) is capable of modulating the neural activity of specific brain regions, with a potential role as a non-invasive computer-to-brain interface (CBI). In conjunction with the use of brain-to-computer interface (BCI) techniques that translate brain function to generate computer commands, we investigated the feasibility of using the FUS-based CBI to non-invasively establish a functional link between the brains of different species (i.e. human and Sprague-Dawley rat), thus creating a brain-to-brain interface (BBI). The implementation was aimed to non-invasively translate the human volunteer’s intention to stimulate a rat’s brain motor area that is responsible for the tail movement. The volunteer initiated the intention by looking at a strobe light flicker on a computer display, and the degree of synchronization in the electroencephalographic steady-state-visual-evoked-potentials (SSVEP) with respect to the strobe frequency was analyzed using a computer. Increased signal amplitude in the SSVEP, indicating the volunteer’s intention, triggered the delivery of a burst-mode FUS (350 kHz ultrasound frequency, tone burst duration of 0.5 ms, pulse repetition frequency of 1 kHz, given for 300 msec duration) to excite the motor area of an anesthetized rat transcranially. The successful excitation subsequently elicited the tail movement, which was detected by a motion sensor. The interface was achieved at 94.0±3.0% accuracy, with a time delay of 1.59±1.07 sec from the thought-initiation to the creation of the tail movement. Our results demonstrate the feasibility of a computer-mediated BBI that links central neural functions between two biological entities, which may confer unexplored opportunities in the study of neuroscience with potential implications for therapeutic applications.

Improved Hearing Anticipated for Implant Recipients

The cochlear implant is widely considered to be the most successful neural prosthetic on the market. The implant, which helps deaf individuals perceive sound, translates auditory information into electrical signals that go directly to the brain, bypassing cells that don’t serve this function as they should because they are damaged.

According to the National Institute on Deafness and Other Communication Disorders, approximately 188,000 people worldwide have received cochlear implants since these devices were introduced in the early 1980s, including roughly 41,500 adults and 25,500 children in the United States.

Despite their prevalence, cochlear implants have a long way to go before their performance is comparable to that of the intact human ear. Led by Pamela Bhatti, Ph.D., a team of researchers at the Georgia Institute of Technology has developed a new type of interface between the device and the brain that could dramatically improve the sound quality of the next generation of implants.

A normal ear processes sound the way a Rube Goldberg machine flips a light switch — via a perfectly-timed chain reaction involving a number of pieces and parts. First, sound travels down the canal of the outer ear, striking the eardrum and causing it to vibrate. The vibration of the eardrum causes small bones in the middle ear to vibrate, which in turn, creates movement in the fluid of the inner ear, or cochlea. This causes movement in tiny structures called hair cells, which translate the movement into electrical signals that travel to the brain via the auditory nerve.

Dysfunctional hair cells are the most common culprit in a type of hearing loss called sensorineural deafness, named for the resulting breakdown in communication between the ear and the brain. Sometimes the hair cells don’t function properly from birth, but severe trauma or a bad infection can cause irreparable damage to these delicate structures as well.

Contemporary cochlear implants

Traditional hearing aids, which work by amplifying sound, rely on the presence of some functioning hair cells. A cochlear implant, on the other hand, bypasses the hair cells completely. Rather than restoring function, it works by translating sound vibrations captured by a microphone outside the ear into electrical signals. These signals are transmitted to the brain by the auditory nerve, which interprets them as sound.

Cochlear implants are only recommended for individuals with severe to profound sensorineural hearing loss, meaning those who aren’t able to hear sounds below 70 decibels. (Conversational speech typically occurs between 20 and 60 decibels.)

The device itself consists of an external component that attaches via a magnetic disk to an internal component, implanted under the skin behind the ear. The external component detects sounds and selectively amplifies speech. The internal component converts this information into electrical impulses, which are sent to a bundle of thin wire electrodes threaded through the cochlea.

Improving the interface

As an electrical engineer, Bhatti sees the current electrode configuration as a significant barrier to clear sound transmission in the current device.

"In an intact ear, the hair cells are plentiful, and are in close contact with the nerves that transmit sound information to the brain," says Bhatti. "The challenge with the implant is getting efficient coupling between the electrodes and the nerves."

Contemporary implants contain between 12 and 22 wire electrodes, each of which conveys a signal for a different pitch. The idea is the more electrodes, the clearer the message.

So why not add more wire electrodes to the current design and call it a day?

Much like house-hunting in New York City, the problem comes down to a serious lack of available real estate. At its widest, the cochlea is 2 millimeters in diameter, or about the thickness of a nickel. As it coils, it tapers down to a mere 200 micrometers, about the width of a human hair.

"While we’d like to be able to increase the number of electrodes, the space issue is a major challenge from an engineering perspective," says Bhatti.

With funding from the National Science Foundation, Bhatti and her team have developed a new, thin-film, electrode array that is up to three times more sensitive than traditional wire electrodes, without adding bulk.

Unlike wire electrodes, the new array is also flexible, meaning it can get closer to the inner wall of the cochlea. The researchers believe this will create better coupling between the array and the nervous system, leading to a crisper signal.

According to Bhatti, one of the biggest challenges is actually implanting the device into the spiral-shaped cochlea:

"We could have created the best array in the world, but it wouldn’t have mattered if the surgeon couldn’t get it in the right spot," says Bhatti.

To combat this problem, the team has invented an insertion device that protects the array and serves as a guide for surgeons to ensure proper placement.

Before it’s approved for use in humans, it will need to undergo rigorous testing to ensure that it is both safe and effective; however, Bhatti is already thinking about what’s next. She envisions that one day, the electrodes won’t need to be attached to an array at all. Instead, they will be anchored directly to the cochlea with a biocompatible material that will allow them to more seamlessly integrate with the brain.

The most important thing, according to Bhatti, is not to lose sight of the big picture.

"We are always designing with the end-user in mind," says Bhatti. "The human component is the most important one to consider when we translate science into practice."

New minimally invasive, MRI-guided laser treatment for brain tumor found to be promising in study

The first-in-human study of the NeuroBlate™ Thermal Therapy System finds that it appears to provide a new, safe and minimally invasive procedure for treating recurrent glioblastoma (GBM), a malignant type of brain tumor. The study, which appears April 5 in the Journal of Neurosurgery online, was written by lead author Andrew Sloan, MD, Director of Brain Tumor and Neuro-Oncology Center at University Hospitals (UH) Case Medical Center and Case Comprehensive Cancer Center, who also served as co-Principal Investigator, as well as Principal Investigator Gene Barnett, MD, Director of the Brain Tumor and Neuro-Oncology Center at Cleveland Clinic and Case Comprehensive Cancer Center, and colleagues from UH, Cleveland Clinic, Cleveland Clinic Florida, University of Manitoba and Case Western Reserve University.

NeuroBlate™ is a device that “cooks” brain tumors in a controlled fashion to destroy them. It uses a minimally invasive, MRI-guided laser system to coagulate, or heat and kill, brain tumors. The procedure is conducted in an MRI machine, enabling surgeons to plan, steer and see in real-time the device, the heat map of the area treated by the laser and the tumor tissue that has been coagulated.

"This technology is unique in that it allows the surgeon not only to precisely control where the treatment is delivered, but the ability to visualize the actual effect on the tissue as it is happening," said Dr. Sloan. "This enables the surgeon to adjust the treatment continuously as it is delivered, which increases precision in treating the cancer and avoiding surrounding healthy brain tissue."

The study was a Phase I clinical trial investigating the safety and performance of NeuroBlate™ (formerly known as AutoLITT™), a specially-designed laser probe system. The FDA gave the system’s developer Monteris Medical and the Case Comprehensive Cancer Center, (comprised of the UH Case Medical Center, Cleveland Clinic, and Case Western Reserve University School of Medicine), an investigatory device exemption (IDE) to study the system in patients with GBMs. The device has recently been cleared by the FDA due, in part, to the results of the study.

The paper describes the treatment of the first 10 patients with this technology. These patients, who had a median age of 55, had tumors which were diagnosed to be inoperable or “high risk” for open surgical resection because of their location close to vital areas in the brain, or difficult to access with conventional surgery.

"Overall the NeuroBlate™ procedure was well-tolerated," said Dr. Sloan. "All 10 patients were alert and responsive within one to two hours post-operatively and nine out of the 10 patients were ambulatory within hours. Response and survival was also nearly 10 ½ months, better than expected for patients with such advanced disease."

"Previous attempts using less invasive approaches such as brachytherapy and stereotactic radiosurgery have proven ineffective in recent meta-analysis and randomized trials," said Dr. Barnett. "However, unlike therapies using ionizing radiation, NeuroBlate™ therapy results in tumor death at the time of the procedure. A larger national study will be developed, as a result of this initial success."