Seeking the Causes of Hyperactivity

The 60 trillion cells that comprise our bodies communicate constantly.  Information travels when chemical compounds released by some cells are received by receptors in the membrane of another cell. In a paper published in the Journal of Neuroscience, the OIST Cell Signal Unit, led by Professor Tadashi Yamamoto, reported that mice lacking an intracellular trafficking protein called LMTK3, are hyperactive.  Hyperactivity is a behavioral disorder that shows symptoms including restlessness, lack of coordination, and aggressive behavior. Identifying the genetic factors that contribute to such behaviors may help to explain the pathological mechanisms underlying autism and Attention Deficit Hyperactivity Disorder, ADHD, in humans.

LMTK3 is abundant in two brain regions: the cerebral cortex, which coordinates perception, movement, and thought, and the hippocampus, which governs memory and learning. In the brain, neurons communicate via connections called synapses. To send a message, a nerve terminus in the pre-synapse releases neurotransmitters to be received by the post-synaptic receptors. Yamamoto’s team discovered that LMTK3 regulates trafficking of neurotransmitter receptors at synapses. In neurons of mice deficient in LMTK3, internalization of receptors are augmented in the post-synapse, suggesting that synaptic communication is impaired. The LMTK3-deficient mice exhibited various hyperactive behaviors such as restlessness and hypersensitivity to sound. Interestingly, their dopamine levels were elevated. Dopamine is a neurotransmitter known to be involved in regulation of movement and hormone levels, motivation, learning, and expression of emotion. Excessive dopamine secretion results in schizophrenia, causing a loss of integrity of neuronal activity, and abnormal thoughts and emotions. The relationships between regulation of neurotransmitter receptor expression by LMTK3, dopamine turnover, and the biochemical pathways that induce hyperactivity, remain unknown.

Functions of many human proteins are still not understood. The Cell Signal Unit continues genetic studies of intracellular proteins that maintain and regulate complex functions such as behaviors, through their activities inside cells. “We hope to advance our research in order to elucidate genetic defects that result in behavioral abnormalities,” Yamamoto said.

Childhood’s end: ADHD, autism and schizophrenia tied to stronger inhibitory interactions in adolescent prefrontal cortex

Key cognitive functions such as working memory (which combines temporary storage and manipulation of information) and executive function (a set of mental processes that helps connect past experience with present action) are associated with the brain’s prefrontal cortex. Unlike other brain regions, the prefrontal cortex does not mature until early adulthood, with the most pronounced changes being seen between its peripubertal (onset of puberty) and postpubertal developmental states. Moreover, this maturation period is correlated with cognitive maturation – but the physical neuronal changes during this transition have remained for the most part unknown. Recently, however, scientists at the Wake Forest School of Medicine in Winston-Salem, NC recorded and compared prefrontal cortical activity peripubertal and adult monkeys.

The researchers found that compared with adults, peripubertal monkeys showed lower connectivity due to stronger inhibitory interactions, suggesting that intrinsic (or resting state) inhibitory connections – that is, inhibitory neural connections that are active in the absence of any particular task – decline with maturation. The scientists then concluded that prefrontal intrinsic connectivity changes are a possible substrate for cognitive maturation.

Prof. Christos Constantinidis discusses the paper that he, Dr. Xin Zhou and their co-authors published in Proceedings of the National Academy of Sciences. When comparing the functional connectivity between pairs of neurons in neuronal activity recorded from the prefrontal cortex of peripubertal and adult monkeys and evaluating the developmental stage of peripubertal rhesus monkeys with a series of morphometric, hormonal, and radiographic measures, Constantinidis tells Medical Xpress that a major challenge was to obtain neural activity from the brain of monkeys around the time of puberty. “We needed to make ourselves experts in the developmental trajectories of monkeys and conduct experiments just at the right time relative to the onset of puberty,” he explains.

Read more

Study ties father’s age at childbearing to higher rates of psychiatric, academic problems in kids

An Indiana University study in collaboration with medical researchers from Karolinska Institute in Stockholm has found that advancing paternal age at childbearing can lead to higher rates of psychiatric and academic problems in offspring than previously estimated.

Examining an immense data set — everyone born in Sweden from 1973 until 2001 — the researchers documented a compelling association between advancing paternal age at childbearing and numerous psychiatric disorders and educational problems in their children, including autism, ADHD, bipolar disorder, schizophrenia, suicide attempts and substance abuse problems. Academic problems included failing grades, low educational attainment and low IQ scores.

Among the findings: When compared to a child born to a 24-year-old father, a child born to a 45-year-old father is 3.5 times more likely to have autism, 13 times more likely to have ADHD, two times more likely to have a psychotic disorder, 25 times more likely to have bipolar disorder and 2.5 times more likely to have suicidal behavior or a substance abuse problem. For most of these problems, the likelihood of the disorder increased steadily with advancing paternal age, suggesting there is no particular paternal age at childbearing that suddenly becomes problematic. 

"We were shocked by the findings," said Brian D’Onofrio, lead author and associate professor in the Department of Psychological and Brain Sciences in the College of Arts and Sciences at IU Bloomington. "The specific associations with paternal age were much, much larger than in previous studies. In fact, we found that advancing paternal age was associated with greater risk for several problems, such as ADHD, suicide attempts and substance use problems, whereas traditional research designs suggested advancing paternal age may have diminished the rate at which these problems occur."

The study, “Parental Age at Childbearing and Offspring Psychiatric and Academic Morbidity,” was published today in JAMA Psychiatry.

Notably, the researchers found converging evidence for the associations with advancing paternal age at childbearing from multiple research designs for a broad range of problems in offspring. By comparing siblings, which accounts for all factors that make children living in the same house similar, researchers discovered that the associations with advancing paternal age were much greater than estimates in the general population. By comparing cousins, including first-born cousins, the researchers could examine whether birth order or the influences of one sibling on another could account for the findings.

The authors also statistically controlled for parents’ highest level of education and income, factors often thought to counteract the negative effects of advancing paternal age because older parents are more likely to be more mature and financially stable. The findings were remarkably consistent, however, as the specific associations with advancing paternal age remained.

"The findings in this study are more informative than many previous studies," D’Onofrio said. "First, we had the largest sample size for a study on paternal age. Second, we predicted numerous psychiatric and academic problems that are associated with significant impairment. Finally, we were able to estimate the association between paternal age at childbearing and these problems while comparing differentially exposed siblings, as well as cousins. These approaches allowed us to control for many factors that other studies could not."

In the past 40 years, the average age for childbearing has been increasing steadily for both men and women. Since 1970 for instance, the average age of first-time mothers in the U.S. has gone up four years from 21.5 to 25.4. For men the average is three years older. In the northeast, the ages are higher. Yet the implications of this fact — both socially and in terms of the long-term effects on the health and well-being of the population as a whole — are not yet fully understood.

Moreover, while maternal age has been under scrutiny for a number of years, a more recent body of research has begun to explore the possible effects of advancing paternal age on a variety of physical and mental health issues in offspring. Existing studies have pointed to increasing risks for some psychological disorders with advancing paternal age. Yet the results are often inconsistent with one another, statistically inconclusive or unable to take certain confounding factors into account.

The working hypothesis for D’Onofrio and his colleagues who study this phenomenon is that unlike women, who are born with all their eggs, men continue to produce new sperm throughout their lives. Each time sperm replicate, there is a chance for a mutation in the DNA to occur. As men age, they are also exposed to numerous environmental toxins, which have been shown to cause mutations in the DNA found in sperm. Molecular genetic studies have, in fact, shown that sperm of older men have more genetic mutations.

This study and others like it, however, perhaps signal some of the unforeseen, negative consequences of a relatively new trend in human history. As such, D’Onofrio said, it may have important social and public policy implications. Given the increased risk associated with advancing paternal age at childbearing, policy-makers may want to make it possible for men and women to accommodate children earlier in their lives without having to set aside other goals.

"While the findings do not indicate that every child born to an older father will have these problems," D’Onofrio said, "they add to a growing body of research indicating that advancing paternal age is associated with increased risk for serious problems. As such, the entire body of research can help to inform individuals in their personal and medical decision-making."

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.

Shedding new light on learning disorders

A Michigan State University researcher has discovered the first anatomical evidence that the brains of children with a nonverbal learning disability – long considered a “pseudo” diagnosis – may develop differently than the brains of other children.

The finding, published in Child Neuropsychology, could ultimately help educators and clinicians better distinguish between – and treat – children with a nonverbal learning disability, or NLVD, and those with Asperger’s, or high functioning autism, which is often confused with NLVD.

“Children with nonverbal learning disabilities and Asperger’s can look very similar, but they can have very different reasons for why they behave the way they do,” said Jodene Fine, assistant professor of school psychology in MSU’s College of Education.

Understanding the biological differences in children with learning and behavioral challenges could help lead to more appropriate intervention strategies.

Children with nonverbal learning disability tend to have normal language skills but below average math skills and difficulty solving visual puzzles. Because many of these kids also show difficulty understanding social cues, some experts have argued that NVLD is related to high functioning autism – which this latest study suggests may not be so.

Fine and Kayla Musielak, an MSU doctoral student in school psychology, studied about 150 children ages 8 to 18. Using MRI scans of the participants’ brains, the researchers found that the children diagnosed with NVLD had smaller spleniums than children with other learning disorders such as Asperger’s and ADHD, and children who had no learning disorders.

The splenium is part of the corpus callosum, a thick band of fibers in the brain that connects the left and right hemispheres and facilitates communication between the two sides. Interestingly, this posterior part of the corpus callosum serves the areas of the brain related to visual and spatial functioning.

In a second part of the study, the participants’ brain activity was analyzed after they were shown videos in an MRI that portrayed both positive and negative examples of social interaction. (A typical example of a positive event was a child opening a desired birthday present with friend; a negative event included a child being teased by other children.)

The researchers found that the brains of children with nonverbal learning disability responded differently to the social interactions than the brains of children with high functioning autism, or HFA, suggesting the neural pathways that underlie those behaviors may be different.

“So what we have is evidence of a structural difference in the brains of children with NLVD and HFA, as well as evidence of a functional difference in the way their brains behave when they are presented with stimuli,” Fine said.

While more research is needed to better understand how nonverbal learning disability fits into the family of learning disorders, Fine said her findings present “an interesting piece of the puzzle.”

“I would say at this point we still don’t have enough evidence to say NVLD is a distinct diagnosis, but I do think our research supports the idea that it might be,” she said.

Brain anatomy and language in young children

Language ability is usually located in the left side of the brain. Researchers studying brain development in young children who were acquiring language expected to see increasing levels of myelin, a nerve fiber insulator, on the left side. They didn’t: The larger myelin structure was already there. Their study underscores the importance of environment in language development.

Researchers from Brown University and King’s College London have gained surprising new insights into how brain anatomy influences language acquisition in young children.

Their study, published in the Journal of Neuroscience, found that the explosion of language acquisition that typically occurs in children between 2 and 4 years old is not reflected in substantial changes in brain asymmetry. Structures that support language ability tend to be localized on the left side of the brain. For that reason, the researchers expected to see more myelin — the fatty material that insulates nerve fibers and helps electrical signals zip around the brain — developing on the left side in children entering the critical period of language acquisition. But that is not what the research showed.

“What we actually saw was that the asymmetry of myelin was there right from the beginning, even in the youngest children in the study, around the age of 1,” said the study’s lead author, Jonathan O’Muircheartaigh, the Sir Henry Wellcome Postdoctoral Fellow at King’s College London. “Rather than increasing, those asymmetries remained pretty constant over time.”

That finding, the researchers say, underscores the importance of environment during this critical period for language.

O’Muircheartaigh is currently working in Brown University’s Advanced Baby Imaging Lab. The lab uses a specialized MRI technique to look at the formation of myelin in babies and toddlers. Babies are born with little myelin, but its growth accelerates rapidly in the first few years of life.

The researchers imaged the brains of 108 children between ages 1 and 6, looking for myelin growth in and around areas of the brain known to support language.

While asymmetry in myelin remained constant over time, the relationship between specific asymmetries and language ability did change, the study found. To investigate that relationship, the researchers compared the brain scans to a battery of language tests given to each child in the study. The comparison showed that asymmetries in different parts of the brain appear to predict language ability at different ages.

“Regions of the brain that weren’t important to successful language in toddlers became more important in older children, about the time they start school,” O’Muircheartaigh said. “As language becomes more complex and children become more proficient, it seems as if they use different regions of the brain to support it.”

Interestingly, the association between asymmetry and language was generally weakest during the critical language period.

“We found that between the ages of 2 and 4, myelin asymmetry doesn’t predict language very well,” O’Muircheartaigh said. “So if it’s not a child’s brain anatomy predicting their language skills, it suggests their environment might be more influential.”

The researchers hope this study will provide a helpful baseline for future research aimed at pinpointing brain structures that might predict developmental disorders.

“Disorders like autism, dyslexia, and ADHD all have specific deficits in language ability,” O’Muircheartaigh said. “Before we do studies looking at abnormalities we need to know how typical children develop. That’s what this study is about.”

“This work is important, as it is the first to investigate the relationship between brain structure and language across early childhood and demonstrate how this relationship changes with age,” said Sean Deoni, assistant professor of engineering, who oversees the Advanced Baby Imaging Lab. “The study highlights the advantage of collaborative work, combining expertise in pediatric imaging at Brown and neuropsychology from the King’s College London Institute of Psychiatry, making this work possible.”

Breakthrough Study Reveals Biological Basis for Sensory Processing Disorders in Kids

Sensory processing disorders (SPD) are more prevalent in children than autism and as common as attention deficit hyperactivity disorder, yet it receives far less attention partly because it’s never been recognized as a distinct disease.

In a groundbreaking new study from UC San Francisco, researchers have found that children affected with SPD have quantifiable differences in brain structure, for the first time showing a biological basis for the disease that sets it apart from other neurodevelopmental disorders.

One of the reasons SPD has been overlooked until now is that it often occurs in children who also have ADHD or autism, and the disorders have not been listed in the Diagnostic and Statistical Manual used by psychiatrists and psychologists.

“Until now, SPD hasn’t had a known biological underpinning,” said senior author Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging and bioengineering at UCSF. “Our findings point the way to establishing a biological basis for the disease that can be easily measured and used as a diagnostic tool,” Mukherjee said.

The work is published in the open access online journal NeuroImage:Clinical.

‘Out of Sync’ Kids

Sensory processing disorders affect 5 to 16 percent of school-aged children.

Children with SPD struggle with how to process stimulation, which can cause a wide range of symptoms including hypersensitivity to sound, sight and touch, poor fine motor skills and easy distractibility. Some SPD children cannot tolerate the sound of a vacuum, while others can’t hold a pencil or struggle with social interaction. Furthermore, a sound that one day is an irritant can the next day be sought out.  The disease can be baffling for parents and has been a source of much controversy for clinicians, according to the researchers.

“Most people don’t know how to support these kids because they don’t fall into a traditional clinical group,” said Elysa Marco, MD, who led the study along with postdoctoral fellow Julia Owen, PhD. Marco is a cognitive and behavioral child neurologist at UCSF Benioff Children’s Hospital, ranked among the nation’s best and one of California’s top-ranked centers for neurology and other specialties, according to the 2013-2014 U.S. News & World Report Best Children’s Hospitals survey.

“Sometimes they are called the ‘out of sync’ kids. Their language is good, but they seem to have trouble with just about everything else, especially emotional regulation and distraction. In the real world, they’re just less able to process information efficiently, and they get left out and bullied,” said Marco, who treats affected children in her cognitive and behavioral neurology clinic.

“If we can better understand these kids who are falling through the cracks, we will not only help a whole lot of families, but we will better understand sensory processing in general. This work is laying the foundation for expanding our research and clinical evaluation of children with a wide range of neurodevelopmental challenges – stretching beyond autism and ADHD,” she said.

Imaging the Brain’s White Matter

In the study, researchers used an advanced form of MRI called diffusion tensor imaging (DTI), which measures the microscopic movement of water molecules within the brain in order to give information about the brain’s white matter tracts. DTI shows the direction of the white matter fibers and the integrity of the white matter. The brain’s white matter is essential for perceiving, thinking and learning.

The study examined 16 boys, between the ages of eight and 11, with SPD but without a diagnosis of autism or prematurity, and compared the results with 24 typically developing boys who were matched for age, gender, right- or left-handedness and IQ. The patients’ and control subjects’ behaviors were first characterized using a parent report measure of sensory behavior called the Sensory Profile. 

The imaging detected abnormal white matter tracts in the SPD subjects, primarily involving areas in the back of the brain, that serve as connections for the auditory, visual and somatosensory (tactile) systems involved in sensory processing, including their connections between the left and right halves of the brain. 

“These are tracts that are emblematic of someone with problems with sensory processing,” said Mukherjee. “More frontal anterior white matter tracts are typically involved in children with only ADHD or autistic spectrum disorders. The abnormalities we found are focused in a different region of the brain, indicating SPD may be neuroanatomically distinct.” 

The researchers found a strong correlation between the micro-structural abnormalities in the white matter of the posterior cerebral tracts focused on sensory processing and the auditory, multisensory and inattention scores reported by parents in the Sensory Profile. The strongest correlation was for auditory processing, with other correlations observed for multi-sensory integration, vision, tactile and inattention.

The abnormal microstructure of sensory white matter tracts shown by DTI in kids with SPD likely alters the timing of sensory transmission so that processing of sensory stimuli and integrating information across multiple senses becomes difficult or impossible.

“We are just at the beginning, because people didn’t believe this existed,” said Marco. “This is absolutely the first structural imaging comparison of kids with research diagnosed sensory processing disorder and typically developing kids. It shows it is a brain-based disorder and gives us a way to evaluate them in clinic.”

Future studies need to be done, she said, to research the many children affected by sensory processing differences who have a known genetic disorder or brain injury related to prematurity.