'Darting' mice may hold clues to ADHD, autism, bipolar disorder

Mice inserted with a rare human genetic variation in the dopamine transporter could lead to improvements in the diagnosis and treatment of brain disorders. Credit: Image courtesy of Vanderbilt University Medical Center

A darting mouse may hold an important clue in the development of Attention Deficit Hyperactivity Disorder (ADHD), autism and bipolar disorder, according to a study by a Vanderbilt University-led research team recently published in the Proceedings of the National Academy of Sciences.

The transgenic mouse, into which was inserted a rare human genetic variation in the dopamine transporter (DAT), could lead to improvements in the diagnosis and treatment of these all-too-common brain disorders, said Randy Blakely, Ph.D., the report's senior author.
The mutation, which has been found in people with ADHD, autism and bipolar disorder, affects the function of DAT, a protein that regulates the brain's supply of the neurotransmitter by removing excess dopamine from the synapse, or the space between nerve cells.

The DAT mutation causes the transporter to become "leaky" and spew out dopamine like "a vacuum cleaner in reverse," said Blakely, Allan D. Bass Professor of Pharmacology.

While mice with leaky DAT proteins have too much dopamine hanging around their synapses, surprisingly they aren't particularly hyperactive, possibly because DAT can still remove some of the dopamine.

But the mice exhibit an unusual "darting behavior." While their wild-type littermates are docile and quite unresponsive when researchers pick them up, those with the mutation "take off."

"Early on," Blakely said, "we could tell which ones carried the mutation by observing this response." Heightened anxiety does not appear to be the cause.

Blakely and his colleagues wonder whether this behavior is a form of "impulsivity." Rather than acting on their memories of being picked up a lot, the mice are opting for an inappropriate escape strategy.

Normal mice also stand up a lot to explore their cage. This "rearing" behavior is exacerbated by stimulant drugs. But not in these mice.

"We wonder whether this may be a sign that their behavior is driven less by searching for clues to appropriate behavior versus acting on innate impulses," Blakely said.

Other, better tests of impulsivity that evaluate premature decision-making can be applied in rodents and humans. "These tests are next on our docket," he said.

The actions of amphetamine and methylphenidate (Ritalin) are also affected by the mutation. In normal animals and people without ADHD, the stimulants flood the synapse with dopamine, eliciting hyperactivity.

But when given to the mutant animals, the drug demonstrates a "blunted" effect on both dopamine release and on locomotor activation compared to normal animals.

Blakely wonders whether stimulants like Adderall and Ritalin quell hyperactive and impulsive behaviors in some children with ADHD by reducing inappropriate dopamine leak. 
"These mice may give us much better clues as to how these drugs are acting," he said.
To that end, Blakely recently received a five-year, $2-million grant from the National Institutes of Health (NIH grant number MH109054) to pursue explorations of these mice.

"Dopamine has classically been implicated in reward and the ability to detect novelty and to respond to pleasure and to engage in effective social interactions," he continued. The darting mice thus might shed light on a much broader spectrum of behaviors.

"We've got a lot to do," he said, "a lot of needy people (to help)."

Source: Vanderbilt University Medical Center

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Slow to mature, quick to distract: ADHD brain study finds slower development of key connections

By examining hundreds of fMRI brain scans of children with ADHD and those without, the researchers identified key connections between brain networks that matured more slowly in ADHD brains.
Credit: Sripada lab, University of Michigan

A peek inside the brains of more than 750 children and teens reveals a key difference in brain architecture between those with attention deficit hyperactivity disorder and those without.

Kids and teens with ADHD, a new study finds, lag behind others of the same age in how quickly their brains form connections within, and between, key brain networks.

The result: less-mature connections between a brain network that controls internally-directed thought (such as daydreaming) and networks that allow a person to focus on externally-directed tasks. That lag in connection development may help explain why people with ADHD get easily distracted or struggle to stay focused.

What's more, the new findings, and the methods used to make them, may one day allow doctors to use brain scans to diagnose ADHD -- and track how well someone responds to treatment. This kind of neuroimaging "biomarker" doesn't yet exist for ADHD, or any psychiatric condition for that matter.

The new findings come from a team in the University of Michigan Medical School's Department of Psychiatry. They used highly advanced computing techniques to analyze a large pool of detailed brain scans that were publicly shared for scientists to study. Their results are published in the Proceedings of the National Academy of Sciences.

Lead author Chandra Sripada, M.D., Ph.D., and colleagues looked at the brain scans of 275 kids and teens with ADHD, and 481others without it, using "connectomic" methods that can map interconnectivity between networks in the brain.

The scans, made using function magnetic resonance imaging (fMRI) scanners, show brain activity during a resting state. This allows researchers to see how a number of different brain networks, each specialized for certain types of functions, were "talking" within and amongst themselves.

The researchers found lags in development of connection within the internally-focused network, called the default mode network or DMN, and in development of connections between DMN and two networks that process externally-focused tasks, often called task-positive networks, or TPNs. They could even see that the lags in connection development with the two task-related networks -- the frontoparietal and ventral attention networks -- were located primarily in two specific areas of the brain.

The new findings mesh well with what other researchers have found by examining the physical structure of the brains of people with and without ADHD in other ways.
Such research has already shown alterations in regions within DMN and TPNs. So, the new findings build on that understanding and add to it.

The findings are also relevant to thinking about the longitudinal course of ADHD from childhood to adulthood. For instance, some children and teens "grow out" of the disorder, while for others the disorder persists throughout adulthood. Future studies of brain network maturation in ADHD could shed light into the neural basis for this difference.

"We and others are interested in understanding the neural mechanisms of ADHD in hopes that we can contribute to better diagnosis and treatment," says Sripada, an assistant professor and psychiatrist who holds a joint appointment in the U-M Philosophy department and is a member of the U-M Center for Computational Medicine and Bioinformatics. "But without the database of fMRI images, and the spirit of collaboration that allowed them to be compiled and shared, we would never have reached this point."

Sripada explains that in the last decade, functional medical imaging has revealed that the human brain is functionally organized into large-scale connectivity networks. These networks, and the connections between them, mature throughout early childhood all the way to young adulthood. "It is particularly noteworthy that the networks we found to have lagging maturation in ADHD are linked to the very behaviors that are the symptoms of ADHD," he says.

Studying the vast array of connections in the brain, a field called connectomics, requires scientists to be able to parse through not just the one-to-one communications between two specific brain regions, but the patterns of communication among thousands of nodes within the brain. This requires major computing power and access to massive amounts of data -- which makes the open sharing of fMRI images so important.

"The results of this study set the stage for the next phase of this research, which is to examine individual components of the networks that have the maturational lag," he says. 

"This study provides a coarse-grained understanding, and now we want to examine this phenomenon in a more fine-grained way that might lead us to a true biological marker, or neuromarker, for ADHD."

Sripada also notes that connectomics could be used to examine other disorders with roots in brain connectivity -- including autism, which some evidence has suggested stems from over-maturation of some brain networks, and schizophrenia, which may arise from abnormal connections. Pooling more fMRI data from people with these conditions, and depression, anxiety, bipolar disorder and more could boost connectomics studies in those fields.
Volunteers needed for research:

To develop such a neuromarker, Sripada has embarked on follow-up research. One study is enrolling children between the ages of 7 and 17 who have ADHD and a comparison group of those without it; information is at http://umhealth.me/adhdchild. Another study is enrolling adults between the ages of 18 and 35 who have ADHD and a comparison group of those without it; information is at http://umhealth.me/adhdadult. Of note, fMRI scans do not expose a person to radiation. Anyone interested in these studies can email Psych-study@med.umich.edu or call (734) 232-0353; for the study of children, parents should make the contact and consent to research on behalf of their children.

Source: University of Michigan Health System

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Link between prenatal antidepressant exposure, autism risk called into question

The authors note that, while genetic factors are known to play a substantial role in autism, exactly how that risk may be exacerbated by environmental factors is not well understood. While animal studies and investigations based on health records have suggested an increased risk associated with prenatal antidepressant exposure, others found no such association. Credit: © milosducati / Fotolia

Previous studies that have suggested an increased risk of autism among children of women who took antidepressants during pregnancy may actually reflect the known increased risk associated with severe maternal depression. In a study receiving advance online publication in Molecular Psychiatry, investigators from Massachusetts General Hospital (MGH) report that -- while a diagnosis of autism spectrum disorder was more common in the children of mothers prescribed antidepressants during pregnancy than in those with no prenatal exposure -- when the severity of the mother's depression was accounted for, that increased risk was no longer statistically significant. An increased risk for attention-deficit hyperactivity disorder (ADHD), however, persisted even after controlling for factors relating to a mother's mental health.

"We know that untreated depression can pose serious health risks to both a mother and child, so it's important that women being treated with antidepressants who become pregnant, or who are thinking about becoming pregnant, know that these medications will not increase their child's risk of autism," says Roy Perlis, MD, MSc, MGH Department of Psychiatry, senior author of the report.

The authors note that, while genetic factors are known to play a substantial role in autism, exactly how that risk may be exacerbated by environmental factors is not well understood. 

While animal studies and investigations based on health records have suggested an increased risk associated with prenatal antidepressant exposure, others found no such association. And since discontinuing antidepressant treatment significantly increases the risk of relapse -- including an increased risk of postpartum depression -- the current study was designed to clarify whether or not any increased autism risk could actually be attributed to the medication.

To investigate this possibility, the research team analyzed electronic health record data for children born at MGH, Brigham and Women's Hospital, or Newton Wellesley Hospital -- hospitals belonging to Partners HealthCare System -- for whom a diagnostic code for pervasive developmental disorder, a category that includes autism, was entered at least once between 1997 and 2010. They matched data for almost 1,400 such children with that of more than 4,000 controls with no autism diagnoses, born the same years and matched for a variety of demographic factors.

The children's information was paired with that of their mothers, noting any factors related to the diagnosis and treatment of major depression or other mental illness, including prescriptions for antidepressants and other psychotropic drugs. A similar analysis was done for almost 2,250 children with an ADHD diagnosis, compared with more than 5,600 matched controls with no ADHD diagnoses.

While prenatal exposure to antidepressants did increase the risk for either condition, in the autism-focused comparison, adjusting for factors indicating more severe maternal depression reduced the strength of that association to an insignificant level. Taking antidepressants with stronger action in the serotonin pathway, which has been suspected of contributing to a possible autism risk, did not increase the incidence of the disorder. In addition, the children of mothers who took a serotonin-targeting non-antidepressant drug for severe morning sickness had no increased autism incidence. Prescriptions for antipsychotic drugs sometimes used to treat severe, treatment-resistant depression, as well as psychotic disorders, did appear to increase the risk for autism. For ADHD, however, the increased risk associated with prenatal antidepressant exposure remained significant, although reduced, even after adjustment for the severity of maternal depression.

"There are a range of options -- medication and non-medication -- for treating depression and anxiety in pregnancy," says Perlis, an associate professor of Psychiatry at Harvard Medical School. "But if antidepressants are needed, I hope parents can feel reassured about their safety."

Source: Massachusetts General Hospital

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Credit score can also describe health status

It appears the same behaviors that ruin credit ruin health too. Credit: © Ivelin Radkov / Fotolia

A credit score doesn't just reduce a person's entire financial history down to a single number and somehow predict their credit-worthiness.

It might also be saying something about a person's health status, too, according to a new analysis from a long-term study of the physical and mental health of more than 1,000 New Zealanders who have been monitored continuously from birth to age 38.

The latest paper from the study, appearing this week in the Proceedings of the National Academy of Sciences, has found a strong relationship between low credit scores and poor cardiovascular health.

This doesn't mean that poor financial management hurts your health, post-doctoral researcher Salomon Israel of Duke University is quick to point out. It's that the sort of personal attributes that can lead to a poor credit score can also contribute to poor health.

This and other studies from the Dunedin Multidisciplinary Health and Development Study in New Zealand have found that self-control, planning ahead and perseverance are attributes that predict both better financial status and better health.

"What it comes down to is that people who don't take care of their money don't take care of their health," said study leader Terrie Moffitt, who is the Nannerl O. Keohane university professor of psychology and neuroscience at Duke. She said this study confirms what the insurance and financial industries may already understand.

Backtracking into the data on these study participants, the researchers found that about 20% of the relationship between credit scores and heart health was accounted for by the attitudes, behaviors and competencies displayed by the study members when they were younger than age 10.

"We're showing that these things take root early in life," Israel said.

Harvard economist David Laibson, who was not involved in the research, said the study "fundamentally transforms our understanding of the psychological factors that connect our health and wealth."

Lamar Pierce, an associate professor of organization & strategy at Washington University in St. Louis, agreed. "This study is important because it identifies common cognitive foundations long before financial and physical health problems emerge," said Pierce, who was not involved in this study. "It provides hope that early life intervention can impede the development of life-long patterns of illness and financial struggle."

Using a standard measure called the Framingham cardiovascular risk score, the Duke researchers estimated the "heart age" of their participants, based on blood pressure, cholesterol levels, blood sugar and smoking habits. At age 38, the participants' Framingham "heart ages" ranged from 22 to 85 years. Participants with higher credit scores had younger "heart ages." The components of the Dunedin study's human capital measure -- educational attainment, cognitive ability and self-control -- each predicted higher credit scores and younger heart age.

The idea of checking credit scores against the detailed personal data in the Dunedin study came from a conversation Moffitt had with her seatmate on a plane about a decade ago. When she told her travelling companion from the life insurance industry that she studied self-control and life outcomes, he said, "We do that too, but we use credit scores."

"The thing that's so compelling about credit scores is that they're both predictive and retrospective," said co-author Avshalom Caspi, the Edward M. Arnett professor of psychology and neuroscience, psychiatry & behavioral sciences at Duke. "They offer a window on the future, but also a window on the past."

In recent years, credit scores have been used for pre-employment screening and many other functions beyond their original intent, Israel said. This study seems to bear out their usefulness as a proxy for a person's reliability and steadfastness, and in turn how healthy they may be.

"Our findings suggest that life insurance companies that acquire an applicant's credit score are also indirectly acquiring information about that applicant's educational attainment, intelligence and personality, right back to childhood," the authors wrote.

The link might work the other way as well. In less developed countries where credit scores aren't available, a Harvard team has been experimenting with using a 40-minute personality quiz to assess candidates' credit-worthiness for microloans.

This research was supported by the New Zealand Health Research Council, US National Institute on Aging (AG032282, T32-AG000029), the UK Medical Research Council (MR/K00381X) the Jacobs Foundation and the Yad Hanadiv Rothschild Foundation.

Source: Duke University

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'Darting' mice may hold clues to ADHD, autism, bipolar disorder

Mice inserted with a rare human genetic variation in the dopamine transporter could lead to improvements in the diagnosis and treatment of brain disorders. Credit: Image courtesy of Vanderbilt University Medical Center

 A darting mouse may hold an important clue in the development of Attention Deficit Hyperactivity Disorder (ADHD), autism and bipolar disorder, according to a study by a Vanderbilt University-led research team recently published in the Proceedings of the National Academy of Sciences.

The transgenic mouse, into which was inserted a rare human genetic variation in the dopamine transporter (DAT), could lead to improvements in the diagnosis and treatment of these all-too-common brain disorders, said Randy Blakely, Ph.D., the report's senior author.

The mutation, which has been found in people with ADHD, autism and bipolar disorder, affects the function of DAT, a protein that regulates the brain's supply of the neurotransmitter by removing excess dopamine from the synapse, or the space between nerve cells.

The DAT mutation causes the transporter to become "leaky" and spew out dopamine like "a vacuum cleaner in reverse," said Blakely, Allan D. Bass Professor of Pharmacology.

While mice with leaky DAT proteins have too much dopamine hanging around their synapses, surprisingly they aren't particularly hyperactive, possibly because DAT can still remove some of the dopamine.

But the mice exhibit an unusual "darting behavior." While their wild-type littermates are docile and quite unresponsive when researchers pick them up, those with the mutation "take off."

"Early on," Blakely said, "we could tell which ones carried the mutation by observing this response." Heightened anxiety does not appear to be the cause.

Blakely and his colleagues wonder whether this behavior is a form of "impulsivity." Rather than acting on their memories of being picked up a lot, the mice are opting for an inappropriate escape strategy.

Normal mice also stand up a lot to explore their cage. This "rearing" behavior is exacerbated by stimulant drugs. But not in these mice.

"We wonder whether this may be a sign that their behavior is driven less by searching for clues to appropriate behavior versus acting on innate impulses," Blakely said.

Other, better tests of impulsivity that evaluate premature decision-making can be applied in rodents and humans. "These tests are next on our docket," he said.

The actions of amphetamine and methylphenidate (Ritalin) are also affected by the mutation. In normal animals and people without ADHD, the stimulants flood the synapse with dopamine, eliciting hyperactivity.

But when given to the mutant animals, the drug demonstrates a "blunted" effect on both dopamine release and on locomotor activation compared to normal animals.

Blakely wonders whether stimulants like Adderall and Ritalin quell hyperactive and impulsive behaviors in some children with ADHD by reducing inappropriate dopamine leak.

"These mice may give us much better clues as to how these drugs are acting," he said.

To that end, Blakely recently received a five-year, $2-million grant from the National Institutes of Health (NIH grant number MH109054) to pursue explorations of these mice.

"Dopamine has classically been implicated in reward and the ability to detect novelty and to respond to pleasure and to engage in effective social interactions," he continued. The darting mice thus might shed light on a much broader spectrum of behaviors.

"We've got a lot to do," he said, "a lot of needy people (to help)."

Source: Vanderbilt University Medical Center

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Japanese Town: Half the survivors of mega-earthquake, tsunami, have PTSD symptoms

Though just two of Hirono's 5,418 residents lost their lives in Japan's mega-earthquake and tsunami, a new study shows that the survivors are struggling to keep their sanity.

One year after the quake, Brigham Young University professor Niwako Yamawaki and scholars from Saga University evaluated the mental health of 241 Hirono citizens. More than half of the people evaluated experienced "clinically concerning" symptoms of post-traumatic stress disorder. Two-thirds of the sample reported symptoms of depression.

Those rates exceed levels seen in the aftermath of other natural disasters, but what happened in Japan wasn't just a natural disaster. Leaked radiation from nuclear power plants forced residents of Hirono to relocate to temporary housing far from home.

"This was the world's fourth-biggest recorded earthquake, and also the tsunami and nuclear plant and losing their homes -- boom boom boom boom within such a short time," said Yamawaki, a psychology professor at BYU. "The prevalence one year after is still much higher than other studies of disasters that we found even though some time had passed."

Yamawaki got the idea for this study while shoveling mud from a damaged Japanese home one month after the tsunami flooded coastal towns. She had just arrived for a previously scheduled fellowship at Saga University. During her off-time, she traveled to the affected area and volunteered in the clean-up effort. One seemingly stoic homeowner broke down in tears when Yamawaki and her husband thanked her for the chance to help.

"She said 'This is the first time I have cried since the disaster happened,'" Yamawaki said. "She just said 'Thank you. Thank you for letting me cry.'"

Back at Saga University, Yamawaki collaborated with Hiroko Kukihara to conduct a study on the mental health and resilience of survivors. Their report appears in the journal Psychiatry and Clinical Neurosciences.

Participants in the study lived in temporary housing provided by the Japanese government when Hirono was evacuated. With an average age of 58, the people are noticeably older than the populations of normal Japanese towns. Yamawaki suspects that young people were more likely to permanently relocate elsewhere in Japan following the disaster.

The researchers didn't just measure the rates of mental illness; they also performed a statistical analysis to learn what fostered resilience among the survivors. Eating right, exercising regularly and going to work all promoted resilience and served as a buffer against mental illness.

"Having something to do after a disaster really gives a sense of normalcy, even volunteer work," Yamawaki said.

As the researchers got to know survivors, they heard from so many that they missed seeing their former neighbors. The mass relocation outside the radiation zone broke up many neighborhood ties.
"Japanese are very collectivistic people and their identity is so intertwined with neighbors," Yamawaki said. "Breaking up the community has so much impact on them."

While it's hard to fathom the scope of the devastation in the coastal region of Fukushima, most survivors believe something like this will happen again. If so, this new study provides a blueprint for how to help them put their lives back together again.

Source: Brigham Young University
Summary: A new study shows that more than half the survivors in one Japanese town exhibited 'clinically concerning' symptoms of PTSD following the country's mega-earthquake and tsunami. Two-thirds of survivors also reported symptoms of depression. Having work to do has proven important in increasing resilience.

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More than 40 percent of minors in Lorca suffer post-traumatic stress a year after earthquake

A mask, painted by a U.S. Marine who attended art therapy to relieve posttraumatic stress disorder symptoms

Spanish researchers have analysed the impact of the Lorca catastrophe by the percentage of minors suffering post-traumatic stress. Results reveal that 55% of young people displayed this disorder a month on from the earthquake and 40% were still suffering a year later.

On 11 May 2011, Lorca suffered an earthquake measuring 5.1, preceded by another of 4.5, which killed nine people and caused significant material damage.

Two experts from the University of Murcia compared the prevalence of post-traumatic stress disorder (PTSD) on the population of minors in the region in its acute phase (one month after the quake) and as a chronic condition (one year later).

"The analysis indicates that 55% of the minors suffered from post-traumatic stress one month after the earthquake, while after one year this had decreased to 40%," as Concepción López Soler, researcher from the University of Murcia and co-author of the study with Juan José López García, explained.
The results, published in the journal Gaceta Sanitaria, reveal that 75% of the minors presented re-experiencing symptoms (recurrent thoughts, nightmares and physiological manifestations) after one month and 60% after one year.

In addition, a month later, 42% suffered from avoidance of anything related to the tragedy (memory disturbances, emotional blockage) and 24% after one year. 51% also displayed hyperarousal (sleeping difficulties, irritability and concentration problems) after a month and 38% a year later.

The authors argue that post-traumatic reactions generally tend to disappear over time. "After the earthquake new mental health resources were implemented to assist people with severe post-traumatic stress," stresses López Soler.

Primary school pupils in their 3rd and 6th year in educational centres from the municipal area were asked for their voluntary participation in this study. One month after the earthquake the level of PTSD was assessed in 495 minors and in 374 after one year.

"It is important to highlight that the younger age groups and girls are more sensitive to developing these symptoms, which coincides with the results of other studies," the Murcian researcher points out. "Young girls in particular are a special risk group."

Among the younger students, 54% of girls showed symptoms of post-traumatic stress compared to 39% of boys.

The evaluation was carried out using the Diagnostic and Statistical Manual of Mental Disorders criteria (DSM-IV-TR), using the Child PTSD Symptom Scale (CPSS) questionnaire which was developed to evaluate the post-traumatic stress in minors after an earthquake in Northridge (Los Angeles, USA) in 1994.

Stress after trauma
"Natural disasters create a sense of loss of personal safety and endangered survival among the population," adds López Soler. Earthquakes are one of the disasters which cause the greatest psychological disturbances in the population and PTSD is the reaction most associated with adverse conditions.

"With previous earthquakes, the affected population has been quite variable," she states. Three years after the Turkey earthquake in 1999, the prevalence of PTSD was 59%; 18 months after the earthquake in Kashmir (between India and Pakistan), it was 64.8% and ten months after the disaster in L'Aquila (Italy) in 2009, it was greater than 60%.

In comparison with other studies, the prevalence of PTSD is somewhat lower, which according to the authors can be understood to be due both to the lesser intensity of the earthquake and its consequences, and swift normalisation of the environment.

About Posttraumatic stress disorder >>

Source: Plataforma SINC

Summary: Spanish researchers have analyzed the impact of the Lorca catastrophe by the percentage of minors suffering post-traumatic stress. Results reveal that 55% of young people displayed this disorder a month on from the earthquake and 40% were still suffering a year later. On 11 May 2011, Lorca suffered an earthquake measuring 5.1, preceded by another of 4.5, which killed nine people and caused significant material damage.

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