Stanford researchers map brain circuitry affected by Parkinson’s disease

Image by iStock/D3Damon
Image by iStock/D3Damon

In the brain, neurons never work alone. Instead, critical functions of the nervous system are orchestrated by interconnected networks of neurons distributed across the brain — such as the circuit responsible for motor control.

Researchers are trying to map out these neural circuits to understand how disease or injury disrupts healthy brain cell communication. For instance, neuroscientists are investigating how Parkinson’s disease causes malfunctions in the neural pathways that control motion.

Now, Stanford researchers have developed a new brain mapping technique that reveals the circuitry associated with Parkinson’s tremors, a hallmark of the disease. The multi-disciplinary team turned on specific types of neurons and observed how this affected the entire brain, which allowed them to map out the associated neural circuit.

Specifically, they performed rat studies using optogenetics to modify and turn on specific types of neurons in response to light and functional MRI to measure the resulting brain activity based on changes in blood flow. These data were then computationally modeled to map out the neural circuit and determine its function.

The research was led by Jin Hyang Lee, PhD, a Stanford electrical engineer who is an assistant professor of neurology and neurological sciences, of neurosurgery and of bioengineering. A recent Stanford News release explains the results:

“Testing her approach on rats, Lee probed two different types of neurons known to be involved in Parkinson’s disease — although it wasn’t known exactly how. Her team found that one type of neuron activated a pathway that called for greater motion while the other activated a signal for less motion. Lee’s team then designed a computational approach to draw circuit diagrams that underlie these neuron-specific brain circuit functions.”

“This is the first time anyone has shown how different neuron types form distinct whole brain circuits with opposite outcomes,” Lee said in the release.

Lee hopes their research will help improve treatments for Parkinson’s disease by providing a more precise understanding of how neurons work to control motion. In the long run, she also thinks their new brain mapping technique can be used to help design better therapies for other brain diseases.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Dr. B’s brain collection helps local students learn anatomy

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Photo courtesy of Donna Bouley

Most of the time, veterinary pathologist Donna Bouley, DVM, PhD, provides pathology support for Stanford researchers and clinicians who work with animals.

But she also has an unusual hobby: Bouley, known to all as Dr. B, collects animal brains. Since 1997, she and others have taken “Dr. B’s Brain Collection” to local schools for a variety of science programs. Fascinated by this idea, I contacted her to learn more.

What inspired you to create your brain collection? What does it include?

“When I first started as faculty at Stanford, there were some preserved brains in the necropsy [animal autopsy] lab. I decided to start collecting more brains from animals that came to necropsy, when we didn’t need their brains to make our diagnosis. The word somehow got out that such a resource existed on campus. Now, I actually have two collections that are almost identical, because multiple labs were interested in borrowing the collection at the same time.

In each collection, I try to have at least one of the following brains: sheep, pig, dog, macaque, squirrel monkey, rabbit, owl, rat, mouse, cyclid (fish), and Xenopus laevis (an African Clawed frog). The brains are preserved and sealed in ‘seal-a-meal’ style bags or jars.

If any new species come through necropsy, I try to get brains from those animals. I also have to replace damaged ones each year, since the enthusiasm of middle schoolers can often result in the rough handling of my bagged brains. My necropsy tech keeps a close watch over the condition of the collections and replaces brains as needed or when available.”

How do you use the collection at Stanford?

“I teach a freshman seminar called Comparative Anatomy and Physiology of Mammals that tends to have several pre-vet and pre-med students each year. I use these brains to demonstrate various features that are similar or different between them, such as overall size, location of the cerebellum or the extent of brain surface folds and ridges. For instance, in lower mammals such as rodents — that survive mainly on instinct rather than cognitive processing — the brain has a very smooth surface. In mammals such as a pig, dog, or macaque that are higher functioning and quite intelligent, the brain surface is highly folded or convoluted. And dolphins and elephants have even more convolutions in their brains than humans!

I also have colleagues that teach Comparative Neuroanatomy at the graduate level and they borrow the brains.

I can only speak about my own college student reactions to exposure to this field and tell you in general they are amazed and in awe. They never look at animals the same after taking my class.”

How do others use the brain collection?

“Graduate students from Stanford psychology or neurobiology labs generally take a brain collection to nearby middle schools, where they work with students during a science class. They most likely also bring some human brains that they compare to the animal brains. Having unique visual teaching tools — real brains, not models or pictures — helps the middle schoolers gain insight into the complexity of the nervous system. Learning about anatomy from a truly comparative aspect is incredibly valuable, because it demonstrates the similarities as well as the unique differences between humans and other mammals.

I’m sure that ‘Dr. B’s Brains’ provide a very lasting impression on students.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Alzheimer’s researchers call on citizen scientists to play an online game

Image by geralt
Image by geralt

Many people, like me, have helplessly watched a loved one suffer and die from dementia. Now there is something you can do to help accelerate Alzheimer’s research — play a game.

The game, called Stall Catchers, is part of the EyesOnALZ project that uses citizen scientists to analyze Alzheimer’s research data. The game was developed by the Human Computation Institute, in collaboration with scientists from Cornell University, MIT and the University of California, Berkeley. The research team is trying to understand the association between reduced blood flow in the brain and Alzheimer’s disease.

The game features movies of real blood vessels in live mouse brains. Players must search for clogged vessels where blood flow is blocked, or stalled. Each movie is seen by many citizen scientists and then checked by a research scientist in order to quickly and accurately identify the stalls.

Past research has shown that Alzheimer’s is associated with the accumulation of beta amyloid proteins that clump together into sticky, neurotoxic aggregates called amyloid plaques. These proteins are normally cleared by the blood stream, but the formation of amyloid plaques slows down this clearance process.

Recent animal studies, performed by the Schaffer-Nishimura Lab at Cornell, suggest that improving blood flow in the brain may help reduce the devastating effects of amyloid accumulation. The researchers discovered that up to two percent of capillaries in the brains of Alzhiemer’s-affected mice were clogged — 10 times more than usual — and this caused up to a 30 percent decrease in overall blood flow in the brain.

“Advanced optical techniques have allowed us to peer into the brain of mice affected by Alzheimer’s disease,” said Chris Schaffer, PhD, the principal investigator in the Schaffer-Nishimura Lab, in a recent news release. “For the first time, we were able to identify the mechanism that is responsible for the significant blood flow reduction in Alzheimer’s, and were even able to reverse some of the cognitive symptoms typical to the disease.”

Now the main challenge for the Cornell researchers is the time-consuming process of manually analyzing all the brain movies to identify the stalled vessels. They need to study up to a thousand vessels for each animal. That’s why they collaborated with the experienced citizen teams at UC Berkeley and MIT to create the Stall Catchers game to get help from the public.

“Today, we have a handful of lab experts putting their eyes on the research data,” said Pietro Michelucci, PhD, the EyesOnALZ principal investigator, in a news story. “If we can enlist thousands of people to do that same analysis by playing an online game, then we have created a huge force multiplier in our fight against this dreadful disease.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

 

Researchers discover “brain signature” for fibromyalgia using brain scans

portrait-1006703_1280Millions of patients suffering from fibromyalgia often experience widespread musculoskeletal pain, sleep disturbances, fatigue, headaches and mood disorders. Many also struggle to even get diagnosed, since there are currently no laboratory tests for fibromyalgia and the main symptoms overlap with many other conditions. However, new research may help.

Scientists from the University of Colorado, Boulder may have found a pattern of brain activity that identifies the disease. They used functional MRI (fMRI) scans to study the brain activity of 37 fibromyalgia patients and 35 matched healthy controls, while the participants were exposed to a series of painful and non-painful sensations.

As reported recently in the journal PAIN, the research team identified three specific neurological patterns correlated with fibromyalgia patients’ hypersensitivity to pain.

Using the combination of all three patterns, they were able to correctly classify the fibromyalgia patients and the controls with 92 percent sensitivity and 94 percent specificity — meaning that their test accurately identified 92 percent of those with and 94 percent of those without the disease.

Tor Wager, PhD, senior author and director of the school’s Cognitive and Affective Control Laboratory, explained the significance of the work in a recent news release:

“Though many pain specialists have established clinical procedures for diagnosing fibromyalgia, the clinical label does not explain what is happening neurologically and it does not reflect the full individuality of patients’ suffering. The potential for brain measures like the ones we developed here is that they can tell us something about the particular brain abnormalities that drive an individual’s suffering. That can help us both recognize fibromyalgia for what it is – a disorder of the central nervous system – and treat it more effectively.”

More research is needed, but this study sheds a bit of light on this “invisible” disease.

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Curious about concussions? A Stanford researcher reflects on current research, outstanding questions

Photo by Steve - Body Slam
Photo by Steve – Body Slam

Football season has begun, reviving concern and discussion over sports-related concussions.

The American Academy of Pediatrics defines a concussion as a direct hit to the head or jarring blow to the body that gets transmitted to the head, resulting in a rapid onset of short lived impairment of neurological function. However, some controversy surrounds even this definition. So I reached out to Jessica Little, PhD, director of clinical research and operations at the Stanford Concussion and Brain Performance Center, to learn more about concussion research and Stanford’s clinical study of teenage athletes.

What should we know about concussions?

“I think it is important to note that concussions are still not well understood. There are hundreds of different definitions of ‘what is a concussion’ and there is currently no single evidence-based consensus on how to identify and treat concussions.

Research has shown that one of the biggest risk factors for sustaining a concussion is a history of having a prior concussion. There is a ‘window of vulnerability’ — the concept that a person experiencing symptoms of concussion is more vulnerable to incurring a second concussion during this time, as the brain has not yet fully recovered. If a truly concussed athlete has problems paying attention or is not coordinated, they can then be vulnerable to another injury. Protocols are often used to track signs and symptoms of concussion, and athletes are not allowed to return to play until these have resolved. However, it would be helpful to have more precise ways to measure attention and coordination on the sidelines to keep impaired athletes out of contact sports until those skills recover.

The vast majority of people with a concussion recover fully after the injury, though not all symptoms may improve at the same rate and everyone recovers a little differently.”

Describe your clinical study for athletes between 12-17 years of age.

“Our study just closed recruitment and we’re prepping all the data for analysis, so it is an exciting time. The study was called EYE-TRAC Advance, short for Eye-Tracking Rapid Attention Computation. Our lab used a specific type of eye-tracking called ‘circular smooth pursuit’ where an athlete follows a dot that moves at predictable speed around a circle. The eye-tracking was in the form of custom-designed portable “goggles,” using built-in cameras and infrared pupil detection.

Our hypothesis is that people without a concussion can ‘sync-up’ with the way the dot is moving pretty easily, while a person with a concussion has a disruption in their ability to focus and pay attention. You often hear people saying that they feel “off” or “out of sync” following a concussion, and we’re trying to quantify that experience. For the study, we baseline tested athletes (before sports participation) with the eye-tracking, as well as other neurocognitive tests that measured things like attention and reaction time. If the athlete later got a concussion, we tested them again as soon as possible and again at 1, 3 and 12 months after the injury. In this way, we’re able to get a clear picture of how their brain recovered over time.

Overall, we reached out to over 60 different organizations and recruited over 1,400 people. We had a specially outfitted ‘mobile testing center’ RV. This allowed us to literally drive up to the side of an athletic field and perform the testing on-site at the school or organization, which really reduced common barriers to participating in a research study, such as the costs and time associated with transportation to and from appointments.”

Can technology play a significant role in preventing concussions?

“A lot of current technologies focus on diagnosing a concussion, but there are far fewer that actually focus on preventing concussions. There are some technologies that measure an athlete’s gait and vestibular-balance ability. If there are impairments, the athletes can be provided skill training to improve any deficits, thus reducing the risk of injury. Other technologies, such as helmet technologies, may be helpful in reducing the instance of skull fractures and other serious injuries, but they haven’t yet proved effective at preventing a concussion — that is caused more by brain rotation, which a helmet can’t fully protect against. One possible preventative solution could come from a neck device that stabilizes the rotational forces while still allowing neck movement at low accelerations, so athletes can move about freely until it senses a potentially dangerous level of force.”

Are there issues with under-reporting concussions?

“Historically, there have been some issues with individuals under-reporting symptoms that would lead to a diagnosis of a concussion. This is often motivated by the idea that they should ‘suck it up,’ ‘don’t want to let the team down’ or the fact that their ability to perform athletically is tied to keeping an athletic scholarship. There is research happening in the field right now trying to figure out the best way to dismantle these types of beliefs and make it more likely that athletes can be properly identified, given the treatment they need, and hopefully continue to safely engage in their sport.”

This is a reposting of my Scope blog story, courtesy of Stanford School of Medicine.

Infections During Pregnancy May Increase Autism Risk

B&W photograph of pregnant woman sitting on couch
Photograph courtesy of Stuart Handy via a Creative Commons license.

Every day our brains help us make sense of the world around us, interpreting the things we see, hear, taste, touch, smell and experience. But if someone’s brain has trouble processing this incoming information, it can be hard to communicate, understand or learn.

Autism spectrum disorders (ASD) are characterized by difficulties in social interaction, verbal and nonverbal communication, and repetitive behaviors. These disorders include autism, Asperger syndrome and Pervasive Developmental Disorder-Not Otherwise Specified.

About 1 in 88 children have been identified with an autism spectrum disorder and over 2 million people are affected in the United States, according to the Centers for Disease Control and Prevention. Government statistics also suggest that the proportion of people with autism spectrum disorders have increased 10 to 17 percent annually in recent years. This is in part due to wider awareness and better screening, but the continued increase is not fully understood.

The cause of ASD is also not fully known, but current research indicates that it is likely due to a complex combination of genetic predisposition and environmental risk factors that influence early brain development. Significant environmental risk factors include the advance age of either parent at the time of conception, maternal illness during pregnancy, extreme prematurity, and very low birth weight.

Over 40 years ago, epidemiological studies determined that the risk of having a child with ASD is increased when the mother has an infection early in the pregnancy. Since a wide range of bacterial and viral infections can increase the risk, studies suggest that activation of the mother’s general immune system is responsible. However, scientists do not completely understand how the activated immune system can disrupt normal brain development to cause ASD.

Research at the University of California Davis Center for Neuroscience provides new insight. Recently published in the Journal of Neuroscience, their studies identify a new biological mechanism that links maternal immune activation to neurodevelopmental disorders.

Kimberley McAllister, a senior author of the study, explained in a press release, “This is the first evidence that neurons in the developing brain of newborn offspring are altered by maternal immune activation. Until now, very little has been known about how maternal immune activation leads to autism spectrum disorder and schizophrenia-like pathophysiology and behaviors in the offspring.”

The researchers studied pregnant mice with immune systems that were activated halfway through gestation compared to pregnant control mice without activated immune systems. They found that the mice exposed to a viral infection had offspring with dramatically elevated levels of immune molecules called major histocompatibility complex 1 (MHC1) on their brain surface.

In the affected newborn mice, these high levels of MCH1 disrupted the development of neural cells in the brain. Specifically, the increase in MCH1 interfered with the neurons’ ability to form the synapses that allow neurons to pass electrical or chemical signals to other cells; consequently these offspring had less than half as many synapses than the control offspring. When MCH1 were returned to normal levels in the neurons of maternal immune-activated offspring, the synapses density returned to normal.

However, MCH1 doesn’t work alone. In a series of additional experiments, the researchers identified the new biological signaling pathway that regulates synapses development caused by maternal immune activation. This signaling pathway requires calcineurin, myocyte enhancer factor-2 and MCH1 to limit synapses density.

A better understanding of the underlying biological mechanisms will hopefully lead to the development of improved prenatal health screening, diagnostic tests and eventually therapies for neurodevelopmental disorders.

Of course, not every child of a bacterially or virally infected mother develops a neurodevelopmental disorder like autism. The effect of maternal immune activation depends on a complex interaction involving the strength of the infection and genetic predisposition.

This is a repost of my KQED Science blog.