'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

ADHD: Brains not recognizing angry expressions

These two faces were presented to children. Credit: © National Institutes of Natural Sciences

Inattention, hyperactivity, and impulsive behavior in children with ADHD can result in social problems and they tend to be excluded from peer activities. They have been found to have impaired recognition of emotional expression from other faces.

The research group of Professor Ryusuke Kakigi of the National Institute for Physiological Sciences, National Institutes of Natural Sciences, in collaboration with Professor Masami K. 

Yamaguchi and Assistant Professor Hiroko Ichikawa of Chuo University first identified the characteristics of facial expression recognition of children with ADHD by measuring hemodynamic response in the brain and showed the possibility that the neural basis for the recognition of facial expression is different from that of typically developing children.

The findings are discussed in Neuropsychologia.

The research group showed images of a happy expression or an angry expression to 13 children with ADHD and 13 typically developing children and identified the location of the brain activated at that time. They used non-invasive near-infrared spectroscopy to measure brain activity. Near-infrared light, which is likely to go through the body, was projected through the skull and the absorbed or scattered light was measured. The strength of the light depends on the concentration in "oxyhemoglobin" which gives the oxygen to the nerve cells working actively. The result was that typically developing children showed significant hemodynamic response to both the happy expression and angry expression in the right hemisphere of the brain.

On the other hand, children with ADHD showed significant hemodynamic response only to the happy expression but brain activity specific for the angry expression was not observed. 

This difference in the neural basis for the recognition of facial expression might be responsible for impairment in social recognition and the establishment of peer-relationships.

Source: National Institutes of Natural Sciences

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

'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