Prenatal Exposure to Alcohol Disrupts Brain Circuitry

Prenatal exposure to alcohol severely disrupts major features of brain development that potentially lead to increased anxiety and poor motor function, conditions typical in humans with Fetal Alcohol Spectrum Disorders (FASD), according to neuroscientists at the University of California, Riverside.

In a groundbreaking study, the UC Riverside team discovered that prenatal exposure to alcohol significantly altered the expression of genes and the development of a network of connections in the neocortex — the part of the brain responsible for high-level thought and cognition, vision, hearing, touch, balance, motor skills, language, and emotion — in a mouse model of FASD. Prenatal exposure caused wrong areas of the brain to be connected with each other, the researchers found.

These findings contradict the recently popular belief that consuming alcohol during pregnancy does no harm.

“If you consume alcohol when you are pregnant you can disrupt the development of your baby’s brain,” said Kelly Huffman, assistant professor of psychology at UC Riverside and lead author of the study that appears in the Nov. 27 issue of The Journal of Neuroscience, the official, peer-reviewed publication of the Society of Neuroscience. Study co-authors are UCR Ph.D. students Hani El Shawa and Charles Abbott.

“This research helps us understand how substances like alcohol impact brain development and change behavior,” Huffman explained. “It also shows how prenatal alcohol exposure generates dramatic change in the brain that leads to changes in behavior. Although this study uses a moderate- to high-dose model, others have shown that even small doses alter development of key receptors in the brain.”

Researchers have long known that ethanol exposure from a mother’s consumption of alcohol impacts brain and cognitive development in the child, but had not previously demonstrated a connection between that exposure and disruption of neural networks that potentially leads to changes in behavior.

Huffman’s team found dramatic changes in intraneocortical connections between the frontal, somatosensory and visual cortex in mice born to mothers who consumed ethanol during pregnancy. The changes were especially severe in the frontal cortex, which regulates motor skill learning, decision-making, planning, judgment, attention, risk-taking, executive function and sociality.

The neocortex region of the mammalian brain is similar in mice and humans, although human processing is more complex. In previous research, Huffman and her team created what amounts to an atlas of the neocortex, identifying the development of regions, gene expression and the cortical circuit over time. That research is foundational to understanding behavioral disorders such as autism and FASD.

Children diagnosed with FASD may have facial deformities and can exhibit cognitive, behavioral and motor deficits from ethanol-related neurobiological damage in early development. Those deficits may include learning disabilities, reduced intelligence, mental retardation and anxiety or depression, Huffman said.

Milder forms of FASD may produce no facial deformities, such as wideset eyes and smooth upper lip, but behavioral issues such as hyperactivity, hyperirritability and attention problems may appear as the child develops, she added.

Based on her earlier research, Huffman said, she expected to find some disruption of intraneocortical circuitry, but thought it would be subtle.

“I was surprised that the result of alcohol exposure was quite dramatic,” she said. “We found elevated levels of anxiety, disengaged behavior, and difficulty with fine motor coordination tasks. These are the kinds of things you see in children with FASD.”

The next phase of her research will examine whether deficits related to prenatal exposure to alcohol continue in subsequent generations.

The bottom line, Huffman said, is that women who are pregnant or who are trying to get pregnant should abstain from drinking alcohol.

“Would you put whiskey in your baby’s bottle? Drinking during pregnancy is not that much different,” she said. “If you ask me if you have three glasses of wine during pregnancy will your child have FASD, I would say probably not. If you ask if there will be changes in the brain, I would say, probably. There is no safe level of drinking during pregnancy.”

Molecular sensor detects early signs of multiple sclerosis

For some, the disease multiple sclerosis (MS) attacks its victims slowly and progressively over a period of many years. For others, it strikes without warning in fits and starts. But all patients share one thing in common: the disease had long been present in their nervous systems, hiding under the radar from even the most sophisticated detection methods. But now, scientists at the Gladstone Institutes have devised a new molecular sensor that can detect MS at its earliest stages—even before the onset of physical signs.

In a new study from the laboratory of Gladstone Investigator Katerina Akassoglou, PhD, scientists reveal in animal models that the heightened activity of a protein called thrombin in the brain could serve as an early indicator of MS. By developing a fluorescently labeled probe specifically designed to track thrombin, the team found that active thrombin could be detected at the earliest phases of MS—and that this active thrombin correlates with disease severity. These findings, reported online in Annals of Neurology, could spur the development of a much-needed early-detection method for this devastating disease.

MS, which afflicts millions of people worldwide, develops when the body’s immune system attacks the protective myelin sheath that surrounds nerve cells. This attack damages the nerve cells, leading to a host of symptoms that include numbness, fatigue, difficulty walking, paralysis and loss of vision. While some drugs can delay these symptoms, they do not treat the disease’s underlying causes—causes that researchers are only just beginning to understand.

Last year, Dr. Akassoglou and her team found that a key step in the progression of MS is the disruption of the blood brain barrier (BBB). This barrier physically separates the brain from the blood circulation and if it breaks down, a blood protein called fibrinogen seeps into the brain. When this happens, thrombin responds by converting fibrinogen into fibrin—a protein that should normally not be present in the brain. As fibrin builds up in the brain, it triggers an immune response that leads to the degradation of the nerve cells’ myelin sheath, over time contributing to the progression of MS.

"We already knew that the buildup of fibrin appears early in the development of MS—both in animal models and in human patients, so we wondered whether thrombin activity could in turn serve as an early marker of disease." said Dr. Akassoglou, who directs the Gladstone Center for In Vivo Imaging Research (CIVIR). She is also a professor of neurology at the University of California, San Francisco, with which Gladstone is affiliated. "In fact, we were able to detect thrombin activity even in our animal models—before they exhibited any of the disease’s neurological signs."

New compound for slowing the aging process can lead to novel treatments for brain diseases

Novel Rehabilitation Device Improves Motor Skills after Stroke

Using a novel stroke rehabilitation device that converts an individual’s thoughts to electrical impulses to move upper extremities, stroke patients reported improvements in their motor function and ability to perform activities of daily living. Results of the study were presented today at the annual meeting of the Radiological Society of North America (RSNA).

"Each year, nearly 800,000 people suffer a new or recurrent stroke in the United States, and 50 percent of those have some degree of upper extremity disability," said Vivek Prabhakaran, M.D., Ph.D., director of functional neuroimaging in radiology at the University of Wisconsin-Madison. "Rehabilitation sessions with our device allow patients to achieve an additional level of recovery and a higher quality of life."

Dr. Prabhakaran, along with co-principal investigator Justin Williams, Ph.D., and a multidisciplinary team, built the new rehabilitation device by pairing a functional electrical stimulation (FES) system, which is currently used to help stroke patients recover limb function, and a brain control interface (BCI), which provides a direct communication pathway between the brain and this peripheral stimulation device.

In an FES system, electrical currents are used to activate nerves in paralyzed extremities. Using a computer and an electrode cap placed on the head, the new BCI-FES device (called the Closed-Loop Neural Activity-Triggered Stroke Rehabilitation Device) interprets electrical impulses from the brain and transmits the information to the FES.

"FES is a passive technique in that the electrical impulses move the patients’ extremities for them," Dr. Prabhakaran said. "When a patient using our device is asked to imagine or attempt to move his or her hand, the BCI translates that brain activity to a signal that triggers the FES. Our system adds an active component to the rehabilitation by linking brain activity to the peripheral stimulation device, which gives the patients direct control over their movement."

The Wisconsin team conducted a small clinical trial of their rehabilitation device, enlisting eight patients with one hand affected by stroke. The patients were also able to serve as a control group by using their normal, unaffected hand. Patients in the study represented a wide range of stroke severity and amount of time elapsed since the stroke occurred. Despite having received standard rehabilitative care, the patients had varying degrees of residual motor deficits in their upper extremities. Each underwent nine to 15 rehabilitation sessions of two to three hours with the new device over a period of three to six weeks.

The patients also underwent functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI) before, at the mid-point of, at the end of, and one month following the rehabilitation period. fMRI is able to show which areas of the brain are activated while the patient performs a task, and DTI reveals the integrity of fibers within the white matter that connects the brain’s functional areas.

Patients who suffered a stroke of moderate severity realized the greatest improvements to motor function following the rehabilitation sessions. Patients diagnosed with mild and severe strokes reported improved ability to complete activities of daily living following rehabilitation.

Dr. Prabhakaran said the results captured throughout the rehabilitation process—specifically the ratio of hemispheric involvement of motor areas—related well to the behavioral changes observed in patients. A comparison of pre-rehabilitation and post-rehabilitation fMRI results revealed reorganization in the regions of the brain responsible for motor function. DTI results over the course of the rehabilitation period revealed a gradual strengthening of the integrity of the fiber tracts.

"Our hope is that this device not only shortens rehabilitation time for stroke patients, but also that it brings a higher level of recovery than is achievable with the current standard of care," Dr. Prabhakaran said. "We believe brain imaging will be helpful in both planning and tracking a stroke patient’s therapy, as well as learning more about neuroplastic changes during recovery."

MRI Technique Reveals Low Brain Iron in ADHD Patients

Magnetic resonance imaging (MRI) provides a noninvasive way to measure iron levels in the brains of people with attention deficit hyperactivity disorder (ADHD), according to a study being presented today at the annual meeting of the Radiological Society of North America (RSNA). Researchers said the method could help physicians and parents make better informed decisions about medication.

ADHD is a common disorder in children and adolescents that can continue into adulthood. Symptoms include hyperactivity and difficulty staying focused, paying attention and controlling behavior. The American Psychiatric Association reports that ADHD affects 3 to 7 percent of school-age children.

Psychostimulant medications such as Ritalin are among the drugs commonly used to reduce ADHD symptoms. Psychostimulants affect levels of dopamine, a neurotransmitter in the brain associated with addiction.

"Studies show that psychostimulant drugs increase dopamine levels and help the kids that we suspect have lower dopamine levels," said Vitria Adisetiyo, Ph.D., postdoctoral research fellow at the Medical University of South Carolina in Charleston, S.C. "As brain iron is required for dopamine synthesis, assessment of iron levels with MRI may provide a noninvasive, indirect measure of dopamine."

Dr. Adisetiyo and colleagues explored this possibility by measuring brain iron in 22 children and adolescents with ADHD and 27 healthy control children and adolescents using an MRI technique called magnetic field correlation (MFC) imaging. The technique is relatively new, having been introduced in 2006 by study co-authors and faculty members Joseph A. Helpern, Ph.D., and Jens H. Jensen, Ph.D.

"MRI relaxation rates are the more conventional way to measure brain iron, but they are not very specific," Dr. Adisetiyo said. "We added MFC because it offers more refined specificity."

The results showed that the 12 ADHD patients who had never been on medication had significantly lower MFC than the 10 ADHD patients who had been on psychostimulant medication or the 27 typically developing children and adolescents in the control group. In contrast, no significant group differences were detected using relaxation rates or serum measures. The lower brain iron levels in the non-medicated group appeared to normalize with psychostimulant medication.

MFC imaging’s ability to noninvasively detect the low iron levels may help improve ADHD diagnosis and guide optimal treatment. Noninvasive methods are particularly important in a pediatric population, Dr. Adisetiyo noted.

"This method enables us to exploit inherent biomarkers in the body and indirectly measure dopamine levels without needing any contrast agent," she said.

If the results can be replicated in larger studies, then MFC might have a future role in determining which patients would benefit from psychostimulants—an important consideration because the drugs can become addictive in some patients and lead to abuse of other psychostimulant drugs like cocaine.

"It would be beneficial, when the psychiatrist is less confident of a diagnosis, if you could put a patient in a scanner for 15 minutes and confirm that brain iron is low," she said. "And we could possibly identify kids with normal iron levels who could potentially become addicts."

Along with replicating the results in a larger population of patients, the researchers hope to expand their studies to look at the relationship between cocaine addiction and brain iron.

Messy children make better learners

Attention, parents: The messier your child gets while playing with food in the high chair, the more he or she is learning.

Researchers at the University of Iowa studied how 16-month-old children learn words for nonsolid objects, from oatmeal to glue. Previous research has shown that toddlers learn more readily about solid objects because they can easily identify them due to their unchanging size and shape. But oozy, gooey, runny stuff? Not so much.

New research shows that changes if you put toddlers in a setting they know well. In those instances, word learning increases, because children at that age are “used to seeing nonsolid things in this context, when they’re eating,” says Larissa Samuelson, associate professor in psychology at the UI who has worked for years on how children learn to associate words with objects. “And, if you expose them to these things when they’re in a highchair, they do better. They’re familiar with the setting and that helps them remember and use what they already know about nonsolids.”

In a paper published in the journal Developmental Science, Samuelson and her team at the UI tested their idea by exposing 16-month-olds to 14 nonsolid objects, mostly food and drinks such as applesauce, pudding, juice, and soup. They presented the items and gave them made-up words, such as “dax” or “kiv.” A minute later, they asked the children to identify the same food in different sizes or shapes. The task required the youngsters to go beyond relying simply on shape and size and to explore what the substances were made of to make the correct identification and word choice.

Not surprisingly, many children gleefully dove into this task by poking, prodding, touching, feeling, eating—and yes, throwing—the nonsolids in order to understand what they were and make the correct association with the hypothetical names. The toddlers who interacted the most with the foods—parents, interpret as you want—were more likely to correctly identify them by their texture and name them, the study determined. For example, imagine you were a 16-month-old gazing at a cup of milk and a cup of glue. How would you tell the difference by simply looking?

“It’s the material that makes many nonsolids,” Samuelson notes, “and how children name them.”

The setting matters, too, it seems. Children in a high chair were more apt to identify and name the food than those in other venues, such as seated at a table, the researchers found.

“It turns out that being in a high chair makes it more likely you’ll get messy, because kids know they can get messy there,” says Samuelson, the senior author on the paper.

The authors say the exercise shows how children’s behavior, environment (or setting), and exploration help them acquire an early vocabulary—learning that is linked to better later cognitive development and functioning.

“It may look like your child is playing in the high chair, throwing things on the ground, and they may be doing that, but they are getting information out of (those actions),” Samuelson contends. “And, it turns out, they can use that information later. That’s what the high chair did. Playing with these foods there actually helped these children in the lab, and they learned the names better.”

“It’s not about words you know, but words you’re going to learn,” Samuelson adds.

Kids whose bond with mother was disrupted early in life show changes in brain

Children who experience profound neglect have been found to be more prone to a behavior known as “indiscriminate friendliness,” characterized by an inappropriate willingness to approach adults, including strangers.

UCLA researchers are now reporting some of the first evidence from human studies suggesting that this behavior is rooted in brain adaptations associated with early-life experiences. The findings appear in the Dec. 1 issue of the peer-reviewed journal Biological Psychiatry.

The UCLA group used functional magnetic resonance imaging (fMRI) to demonstrate that youths who experienced early maternal deprivation — specifically, time in an institution such as an orphanage prior to being adopted — show similar responses to their adoptive mother and to strangers in a brain structure called the amygdala; for children never raised in an institutional setting, the amygdala is far more active in response to the adoptive mother.

This reduced amygdala discrimination in the brain correlated with parental reports of indiscriminate friendliness. The longer the child spent in an institution before being adopted, the greater the effects.

"The early relationship between children and their parents or primary caregivers has implications for their social interaction later in life, and we believe the amygdala is involved in this process," said Aviva Olsavsky, a resident physician in psychiatry at the Semel Institute for Neuroscience and Human Behavior at UCLA and the study’s first author. "Our findings suggest that even for children who have formed attachments to their adoptive parents, this early period of deprivation has led to changes in the brain that were likely adaptations and that may persist over time."

Indiscriminate friendliness is in some sense a misnomer. The behavior is not characterized by a deep friendliness but simply by a lack of reticence that most young children show toward strangers.

"This can be a very frightening behavior for parents," said Nim Tottenham, an associate professor of psychology at UCLA and the study’s senior author. "The stranger anxiety or wariness that young children typically show is a sign that they understand their parents are very special people who are their source of security. That early emotional attachment serves as a bedrock for many of the developmental processes that follow."

Located in the limbic system of the brain, the amygdala is involved in a variety of functions, including detecting the salience of stimuli, and is believed to play an important role in intense relationships and attachments. Studies in rodents have found that the process of forming a maternal bond early in life has powerful effects on amygdala development and attachment-related behaviors. Research has also shown that youths whose early childhood did not include the typical caregiving experience may exhibit a variety of behaviors, including indiscriminate friendliness, but such behavior had not been well characterized at the brain level.

For the study, 67 youths between the ages of 4 and 17 underwent fMRI while they were shown pictures of their adoptive mother and of an unfamiliar female. Approximately half the children had spent time in institutions, ranging from five months to about five-and-a-half years, before being adopted. As part of the study, the parents of the participating children were given a questionnaire designed to gauge the likelihood of their child wandering away with a stranger, as well as how trusting the child was with new adults.

The UCLA researchers found that while the typically raised children exhibited higher amygdala signals for their mothers relative to strangers, the previously institutionalized youths showed amygdala responses to strangers that were similar to those they showed toward their adoptive mothers. Additionally, the children with a history of institutional rearing showed greater amygdala reactivity to strangers than did the typically raised children. Reduced amygdala differentiation was correlated with greater reports of indiscriminate friendliness by the parents.

In order to understand the heterogeneity of the sample, the researchers examined the role of age at adoption. They found that children who had been adopted later displayed the least discrimination on the scans and the greatest degree of indiscriminate behavior.

The study raised several questions: What, if any, effects does early maternal deprivation has on children as they move into adulthood? And do these findings also apply to less severe forms of deprivation, such as neglectful home environments? The researchers are continuing to use fMRI to examine the role of parents in brain development and the contribution of early experiences to mental health outcomes later in life.

A single spray of oxytocin improves brain function in children with autism

A single dose of the hormone oxytocin, delivered via nasal spray, has been shown to enhance brain activity while processing social information in children with autism spectrum disorders, Yale School of Medicine researchers report in a new study published in the Dec. 2 issue of Proceedings of the National Academy of Sciences.

“This is the first study to evaluate the impact of oxytocin on brain function in children with autism spectrum disorders,” said first author Ilanit Gordon, a Yale Child Study Center adjunct assistant professor, whose colleagues on the study included senior author Kevin Pelphrey, the Harris Professor in the Child Study Center, and director of the Center for Translational Developmental Neuroscience at Yale.

Gordon, Pelphrey, and their colleagues conducted a double-blind, placebo-controlled study of 17 children and adolescents with autism spectrum disorders. The participants, between the ages of 8 and 16.5, were randomly given either oxytocin spray or a placebo nasal spray during a task involving social judgments. Oxytocin is naturally occurring hormone produced in the brain and throughout the body.

“We found that brain centers associated with reward and emotion recognition responded more during social tasks when children received oxytocin instead of the placebo,” said Gordon. “Oxytocin temporarily normalized brain regions responsible for the social deficits seen in children with autism.”

Gordon said oxytocin facilitated social attunement, a process that makes the brain regions involved in social behavior and social cognition activate more for social stimuli (such as faces) and activate less for non-social stimuli (such as cars).

“Our results are particularly important considering the urgent need for treatments to target social dysfunction in autism spectrum disorders,” Gordon added.