Finding the patterns of white matter growth that support children’s cognitive development

Joëlle Bagautdinova was the lead author on this study. Joëlle is broadly interested in brain development and how this may go awry in psychiatric disorders. For her PhD in Dr. Ted Satterthwaite’s lab, Joëlle is using neuroimaging to study the mechanisms underlying brain development, cognition and psychiatric disorders. She is particularly interested in understanding the potential role of sleep as a risk factor in the emergence of mental illness.

or technically,

Development of white matter fiber covariance networks supports executive function in youth

[See Original Abstract on Pubmed]

Authors of the study: Joëlle Bagautdinova, Josiane Bourque, Valerie J. Sydnor, Matthew Cieslak,Aaron F. Alexander-Bloch, Maxwell A. Bertolero, Philip A. Cook, Raquel E. Gur, Ruben C. Gur, Fengling Hu, Bart Larsen, Tyler M. Moore, Hamsanandini Radhakrishnan, David R. Roalf, Russel T. Shinohara, Tinashe M. Tapera, Chenying Zhao, Aristeidis Sotiras, Christos Davatzikos, and Theodore D. Satterthwaite

Recently, many neuroscientists have been trying to uncover the developmental “blueprint” of the brain’s gray matter, or the specific ways in which brain regions grow and change over the course of adolescence. However, less attention has been paid to the brain’s white matter, which is the insulated, wire-like “tracts” that connect one brain region to another. NGG student Joëlle Bagautdinova and her colleagues in the Satterthwaite lab filled this gap by investigating white matter’s structural development in MRI scans from almost 1000 people ages 8 to 22 years.

While it famously does NOT imply causation, correlation can show parts of the brain have similar structures and, therefore, might be following the same developmental blueprint. So, Joëlle and her colleagues decided to cluster every point along the brain’s white matter tracts (Figure 1) into groups with similar structures (Figure 2). Specifically, they grouped points with similar fiber density, or how many “wires” are packed together to make the tract, and cross-section, or how thick the tract is (Figure 1); they refer to the combination of these measurements as “FDC”. She also tested to see how each group’s FDC values changed across adolescence.

Figure 1. White matter tracts can be measured by their density and cross-section.

Figure 2. Points of white matter can be grouped by how similar their FDC (fiber density and cross-section) values are.

Usually, researchers assume that all points along a tract will develop similarly; however, because Joëlle determined her groups based on how similar the points are, different points along the same tract could be put into different groups, while points from more than one tract could be lumped together. This allowed her to uncover brand new relationships between different white matter tracts and unique subsections that develop differently than the white matter tract. For instance, she found that FDC in the lower part of the corticospinal tract, which connects the brain and spinal cord, was different than the FDC in the upper corticospinal tract, and each portion had its own unique growth trajectory. All in all, the researchers found 14 different groups of similarly-structured white matter regions, 12 of which showed significant structural changes across this period of adolescent development.

The age at which each white matter group developed most also seems to follow a pattern. Specifically, they found that the white matter in the lower back area of the brain matures earlier in adolescence while the white matter in the upper front area of the brain doesn’t mature until a bit later. These early-maturing white matter tracts tend to connect parts of the brain that do what scientists call “lower-order functions” like vision processing, basic movement, and emotions – all things that children can do pretty well. Meanwhile, the later-maturing white matter tracts tend to connect brain regions that do “higher order” functions like complex reasoning. Overall, the fact that white matter maturation seems to progress “basic” to “complex” tracts suggests that white matter may play a big role in the brain’s development across adolescence.

Finally, Joëlle and her colleagues wanted to see if these white matter structures helped kids’ executive function, which is one of these “higher order” cognitive functions that includes planning, organizing, and impulse control. They found that if you remove the effects of age, kids with better executive function tend to have higher FDC in all but one white matter group. This means that white matter tracts that are thicker and/or more tightly packed do a better job of sending signals between brain regions, especially those in the front of the brain that are responsible for cognition, and that this enhanced signaling may allow children to have stronger executive functions.

By using new, cutting-edge analyses, Joëlle and her collaborators were able to: uncover brand-new, biologically-based relationships between white matter areas; chart how these areas develop over adolescence; and show which white matter structures seem to help with cognitive function. All in all, this work fills in important gaps in our understanding how the brains we’re born with mature into the brains of capable, full-grown adults.

About the brief writer: Margaret Gardner

Margaret is a PhD student in the Brain-Gene-Development Lab working with Dr. Aaron Alexander-Bloch. She is interested in studying how different biological and demographic factors influence people’s brain development and their risk for mental illnesses.

Want to learn more about this exciting research? Check out Joëlle’s paper here!

Little kids, big insights: What childhood can teach us about how the brain supports cognition

Ursula Tooley was the lead author on this study. Ursula is a postdoctoral research scholar at Washington University in St. Louis. Her research examines functional brain network development in neonates and toddlers, with a focus on the pace of brain maturation and how neuroplasticity changes across development. She received her Ph.D. in Neuroscience in 2022 from the University of Pennsylvania, under the direction of Dr. Allyson Mackey and Dr. Dani Bassett, where she studied functional brain network development in children and adolescents. She received her B.S. in Neuroscience from the University of Arizona, where she conducted research on sleep disruption in children with Down syndrome.

or technically,

The age of reason: Functional brain network development during childhood

[See Original Abstract on Pubmed]

Authors of the study: Ursula A. Tooley, Anne T. Park, Julia A. Leonard, Austin L. Boroshok, Cassidy L. McDermott, Matthew A. Tisdall, Dani S. Bassett, and Allyson P. Mackey.

Early and middle childhood (4-10 years old) are full of developmental milestones. How children speak, move, learn, and play is constantly evolving and improving. Kids build social networks, become better able to control their attention, and begin to develop cognitive skills, like reasoning. However, despite the rapid cognitive development happening during this early childhood period, neuroscientists have very little information about how brain function is changing. 

This is because getting a clear picture of brain activity, like getting a clear picture of anything, requires that the subject stays almost perfectly still. If you’ve ever watched a 4-year-old sit at the dinner table, it comes as no surprise that they don’t make the best neuroimaging subjects. Functional magnetic resonance imaging (fMRI) scanners, which take many consecutive snapshots of brain activity, are even more sensitive to motion than cameras. The tiniest movements, even just a few millimeters, can blur the images and make it impossible for neuroscientists to tell what brain activity belongs to which brain region. So, most neuroimaging work to date uses subjects over 7 years old, which means that while researchers work to understand how the brain develops to support cognition, they’re missing many of the first pieces of the puzzle. 

Here’s where recent Neuroscience Graduate Group alumn Ursula Tooley and collaborators from the Robust Methods for Magnetic Resonance group stepped in. The team engineered a way to monitor and correct for head motion inside the scanner, allowing them to collect high-quality neuroimaging data from wiggly subjects during this critical early childhood period. Specifically, this motion-tracking technology gave the researchers a way to record exactly how much and in which direction kids were moving at any given point during the scan. Ursula could then use this information to correct (think: realign) the images of brain activity or exclude the child from the study if they moved too much. The ability to precisely monitor head position in real time also created an opportunity for kids to practice the correct behavior. Before the scanning session, children came to the lab to watch a movie while laying in a mock scanner that made the same whirring noises and beeps as the real deal. Each time they moved their head more than 1 millimeter, the movie paused. Incorporating this period of exploring the scanner and the scanning expectations meant that most of the kids who enrolled in the study stayed still enough for usable images of brain activity to be collected. This is a huge feat for Ursula and the team as well as a huge win for neuroscience, making it possible to take an earlier look at the developing brain.

Over the course of the study, Ursula and her colleagues scanned a diverse group of 92 children ages 4-10 from the Philadelphia community. Each child completed an fMRI scan as well as a series of cognitive tests (which they did outside of the scanner) designed to measure the strength of their cognitive reasoning abilities. What is cognitive reasoning? Reasoning is an umbrella term describing the ability to process information, problem solve, and make predictions based on pattern recognition (Fig. 1). Successful cognitive reasoning involves much of the brain and improves dramatically during early and middle childhood. Research suggests that how kids perform on cognitive reasoning tasks is predictive of their academic achievement — even years down the road! By combining a child's cognitive reasoning ability with information about their brain activity, Ursula was able to ask whether and how changes in brain function might support this shift in cognitive performance.

Figure 1

An example question from the cognitive reasoning test, which was administered at different difficulty levels to children in the study depending on their age. Here, we see the red rectangle switches from the background (left) to the foreground (right). To answer the question correctly, the child has to understand this spatial relationship for the rectangles and extend it to the pentagons.

Ursula used resting-state fMRI data (data collected while the kids laid “at rest” in the scanner) to explore the brain’s functional organization. In other words, she inferred how much different brain regions talk to each other based on how their activity fluctuates together over time. As such, regions with activity that rises and falls together are likely functionally connected. These groups of connected brain regions are called “systems.” The brain has many of these functionally-connected systems, and neuroscience research shows that they can rewire and reconfigure themselves. For example, another neuroimaging study of older kids and young adults (ages 8-22) from Philadelphia showed that the organization of these brain systems changes with age [1]. Specifically, our brain systems become more segregated and more modular as we move towards adulthood, with weaker connections between systems and stronger connections within systems (Fig. 2). Ursula found the same trends in her data with older kids tending to have more segregated brain systems than younger kids, suggesting that our brain’s functional architecture is flexible and continues to refine as we age.

Figure 2

As we age and develop, our brain systems (red, green, and blue ovals) reorganize, moving from more integrated (e.g., many connections between systems) to more modular (e.g., more connections within systems and fewer connections between systems). Ursula’s work shows that this brain system separation supports the development of cognitive skills, like reasoning.

Do some systems remodel more than others? Ursula found that changes in connectivity were largest in brain systems involved in abstract cognition, visual processing, and attention. As it turns out, these are the same systems involved in cognitive reasoning. For instance, reasoning is supported by the brain’s visual areas taking in information from the world while attention systems focus the brain’s resources on what’s important to the task at hand while ignoring distractors. Given what we know about the blossoming of cognitive reasoning during childhood, Ursula wondered if there could be a relationship between these changes in brain connectivity and cognitive ability. To test this, Ursula compared the patterns of brain system connectivity for each child with their scores on the cognitive reasoning test (Fig. 1). She found that the remodeling of cognition, visual processing, and attention systems was associated with increased cognitive ability! In other words, kids who had more mature patterns of brain system connectivity were better equipped to reason about the world and their place in it.

Taken together, Ursula’s work suggests that the massive restructuring of brain systems as kids age might be happening to support the rapid development of cognitive abilities emerging during these early and middle childhood years. Beyond offering a new perspective on healthy brain development, this relationship between brain organization and brain function offers new ways to think about -- and potentially treat -- various neurodevelopmental or neurological disorders.

About the brief writer: Kara McGaughey

Kara is a PhD candidate in Josh Gold’s lab studying how we make decisions in the face of uncertainty and instability. Combining electrophysiology and computational modeling, she’s investigating the neural mechanisms that may underlie this adaptive behavior.

Citations:

1. Baum, G.L., Ciric R., Roalf, D.R., Betzel, R.F., Moore, T.M., Shinohara, R.T., … & Satterthwaite, T.D. (2017). Modular segregation of structural brain networks supports the development of executive function in youth. Current Biology, 27(11). doi: 10.1016/j.cub.2017.04.051.

Want to learn more about how brain function supports the development of cognitive reasoning during childhood? You can find Ursula’s full paper here!

A case of leaky brain barrier: how missing a piece of chromosome 22 can lead to schizophrenia

Alexis Crockett was the lead author on this study. She is interested in understanding how the rest of the body affects the brain to change behavior. One way the body signals to the brain and changes its function is through activation of the immune system. Her research focuses on how the immune system can become activated, and tries to understand how this inflammation is able to bypass all the barriers that are supposed to protect the brain from this inflammation. She is currently continuing this line of study in her postdoctoral fellowship at the Cleveland Clinic in the laboratory of Dr. Dimitrios Davalos.

or technically,

Disruption of the blood-brain barrier in 22q11.2 deletion syndrome

[See Original Abstract on Pubmed]

Authors of the study: Alexis M Crockett, Sean K Ryan, Adriana Hernandez Vásquez, Caroline Canning, Nickole Kanyuch, Hania Kebir, Guadalupe Ceja, James Gesualdi, Elaine Zackai, Donna McDonald-McGinn, Angela Viaene, Richa Kapoor, Naïl Benallegue, Raquel Gur, Stewart A Anderson, Jorge I Alvarez

Our brains are like car radios -- they tune into different stations for various thoughts and experiences. However, sometimes the station might change without a person touching the radio knob, leading them to hear sounds or voices that are not real in a way that they can't control. Imagine you are on a road trip with your friends, listening to a carefully curated Taylor Swift soundtrack, when all of the sudden, you only hear Kanye West rapping -- while your friends insist that Kanye hasn’t been playing at all! The idea of hearing something that no one else does is super confusing and frightening, especially because sometimes these stations that only you are tuned into could be ominous -- rather than Kanye rapping, you might hear someone that sounds like a scary character from a horror movie. Alternatively, what if you suddenly have zero interest in listening to Taylor Swift despite being known as her biggest fan for years? Such sudden disconnect-from-reality circumstances and/or the lack of interest and emotions are experienced by people with schizophrenia, a chronic mental illness that can seriously interfere with daily life functions. Medicine and therapy can help to manage symptoms of schizophrenia, but there is currently no cure. One reason for the lack of a cure is that we have yet to fully pinpoint the causes of this disorder, making it difficult to inform therapeutic strategies directly targeting those causes.

Scientists have identified many different genetic mutations that are linked to schizophrenia diagnoses. However, these mutations are not found in all individuals with schizophrenia. In addition, people with these mutations do not necessarily develop schizophrenia. A complex combination of genetic, environmental and lifestyle factors contributes to the development of this disorder. Generally, diseases with strong genetic drivers often have more well-defined biological mechanisms, which makes them easier to study. One of the strongest genetic risk factors in schizophrenia is the deletion of a segment of chromosome 22, herein referred to as 22q11.2 deletion, which results in the loss of 40-50 genes. Strikingly, approximately 25% of people bearing 22q11.2 deletion are diagnosed with schizophrenia, putting these people at much higher risk than the general population. Hence, deciphering the commonality among individuals with 22q11.2 deletion might help us better understand the disease mechanism(s). Dr. Alexis Crockett, a former Neuroscience Graduate Group student in the Alvarez lab at University of Pennsylvania, set out to explore how 22q11.2 deletion alters the brain in the way(s) that might cause schizophrenia.

Unlike most organs in the body, the brain is extremely delicate, with limited ability to regenerate if it is damaged. Therefore, to protect the brain, access of substances in the bloodstream to the brain is tightly controlled by a special filter, referred to as the blood-brain barrier. This structure forms a barrier that is critical for keeping various harmful particles such as bacteria, viruses, and environmental toxins from the brain. This brain barrier is made possible by densely packed endothelial cells, which are specialized cells that make up the blood vessels, and the many proteins between them like bricks and mortar, respectively. Therefore, only select substances are allowed to pass through the tiny pores of this barrier, if they are small enough or being transported by specific proteins from the blood-facing side of the cell to the brain-facing side of the same cell. This tight barrier is further reinforced by astrocytes which are a type of brain cell. Given that many of the deleted genes in the 22q11.2 region are proteins that make up this brain barrier, Dr. Crockett and colleagues hypothesized that the brain barrier is leaky in patients with 22q11.2 deletion.

To explore this hypothesis, they employed a mouse model with a similar 22q11.2 deletion as found in humans. Two proteins in the bloodstream, which are known to normally be kept out of the brain, were instead found in the brain tissue of these mice. Furthermore, they observed a marked increase in the amount of ICAM-1, a protein that aids immune cells in sticking to and migrating across the endothelial cell layer. An intact brain barrier normally restricts entry of the immune cells into the brain to avoid uncontrollable inflammation. However, in the brains of mice with 22q11.2 deletion, there was an increased level of inflammatory proteins in astrocytes of the brain. These evidence indicated a breach of brain barrier along with brain inflammation in the mouse model of 22q11.2 deletion.

Although mice are a valuable animal model for biomedical research, there are important differences between mice and humans. For instance, laboratory mice are quite genetically similar to each other, which fails to reflect the genetic complexity of schizophrenic patients. In order to study 22q11.2 deletion in human cells, Dr. Crockett and colleagues obtained cells from patients with this deletion. They then used established methods to change these cells to resemble the endothelial cells that make up the brain’s barrier, allowing them to examine the integrity of the human brain barrier in the dish. Compared to endothelial-like cells derived from healthy individuals, endothelial-like cells derived from patients with 22q11.2 deletion showed an increase in leakiness. Similar to their findings in mice, there was also a higher level of the adhesion protein ICAM-1 in the human endothelial-like cells with 22q11.2 deletion. Indeed, human immune cells readily crossed endothelial-like cell layer, consistent with known effect of high ICAM-1 level on immune cell migration.

Together, the work led by Dr. Crockett demonstrated that in the context of 22q11.2 deletion, the brain barrier is dysfunctional, permitting the entry of prohibited particles, and subsequently triggering inflammation in the brain. Interestingly, impaired function of the brain barrier has been reported in other cases of schizophrenia without clear genetic mutations, suggesting that a leaky brain barrier might be one of the underlying mechanisms contributing to the development of schizophrenia. Dr. Crockett's findings not only help us further understand the complex origins of this devastating disease, but also may lead to better treatment strategies for schizophrenia by targeting the brain’s barrier.

About the brief writer: Phuong Nguyen

Phuong is a PhD Candidate in Dr. Katy Wellen’s lab at Penn. Her research journey started in her undergraduate study at Drexel University when she performed a drug screening on a fruit fly model of Alzheimer’s disease. She then decided to pursue her PhD training in Neuroscience at Penn. She set out to characterize the brain function of a novel mouse model lacking Acly, an important enzyme for lipid synthesis and various metabolic processes. Interestingly, the brain demonstrated a remarkable resilience to the loss of this enzyme, while the skin of those mice was severely damaged that was associated with fat loss and premature death. Her research work revealed a crosstalk among the skin, the fat tissue, and the dietary lipids. She hopes to continue her research in understanding the complex metabolic crosstalk between organs, especially focusing on the brain, and how nutrition impacts those crosstalks.

Curious to learn more about what Dr. Crockett and colleagues discovered? Check out the details of this work here.

How different levels of brain development help adolescent cognition - or don’t

Adam Pines was the lead author on this study. Adam is a postdoctoral fellow in the Stanford PanLab for Precision Psychiatry and Translational Neuroscience. He completed his Ph.D. in Neuroscience at UPenn in 2022. His other research interests include developmental neuroscience, brain-environment interactions, and adaptive plasticity in the brain.

or technically,

Dissociable multi-scale patterns of development in personalized brain networks

[See Original Abstract on Pubmed]

Authors of the study: Adam R. Pines, Bart Larsen, Zaixu Cui, Valerie J. Sydnor, Maxwell A. Bertolero, Azeez Adebimpe, Aaron F. Alexander-Bloch, Christos Davatzikos, Damien A. Fair, Ruben C. Gur, Raquel E. Gur, Hongming Li, Michael P. Milham, Tyler M. Moore, Kristin Murtha, Linden Parkes, Sharon L. Thompson-Schill, Sheila Shanmugan, Russell T. Shinohara, Sarah M. Weinstein, Danielle S. Bassett, Yong Fan & Theodore D. Satterthwaite

You don’t need to be a scientist to know that kids get smarter as they grow up - they get better at things like problem-solving, thinking flexibly, and remembering information. But what exactly is changing in the brain to make these cognitive skills, which researchers call “executive function” easier?

Like instruments in a band, different areas of the human brain have different roles and will perform together in different combinations to everything from processing what your eyes see, to controlling your muscles, to solving a crossword, to feeling emotions. A group of brain regions that work together is called a functional brain network. Some functional brain networks perform easier, or “lower-order”  tasks, like sensing pain when you get a cut. Others perform harder, more complex tasks, like solving physics equations or learning a language, which are considered “higher-order”. 

Dr. Adam Pines, who recently graduated from the Neuroscience Graduate Group, wanted to know how all these functional networks mature as kids age and how this pattern of development relates to kids’ improving executive function. To study this, Adam had two challenges. First, we don’t know how many functional networks there “really” are in the brain; you can divide the brain up into different numbers of chunks and still do a good job of grouping regions that activate together and separating those that don’t (Figure 1, Columns). Second, the layout of everyone’s functional networks is a tiny bit different: one network may take up a little more space in one person, for instance, or the parts of the brain that do a certain task on one person may be just a little bit more to the left on another (Figure 1, Rows). Therefore, Adam made personalized functional networks (PFNs), which are maps of a person’s unique functional network layout, for every subject in the study. He also tried grouping the brain into different numbers of networks to see whether this would change his results.

Figure 1: Illustration of personalized functional networks mapped for varying numbers of networks.

Adam mapped the unique functional networks of each person in the study (PFNs), as shown in the rows. He also divided the brain’s activity into different numbers of networks, with maps of 4, 7, and 13 networks pictured. Different colors show that the brain regions are part of different functional networks.

To make personalized functional networks (PFNs) for each subject (Figure 1, Rows), Adam and his colleagues mapped the layout of every functional network in the average person and mathematically tweaked the layout to fit each participant’s unique pattern of brain activation. Then, they repeated this step using different numbers of networks in their baseline map (Figure 1, Columns) and labeled whether each network did lower- or higher-order functions. In the end, they had 29 brain maps for each person (each dividing brain activity into 2 to 30 functional networks), that they could compare to each participant’s age and score on a test of executive function.

First, Adam compared PFNs across participants ages 8 through 23 and found that lower- and higher-order networks tended to develop differently. Lower-order networks (each of which does an easier task) became more interconnected over the course of adolescence, while higher-order networks (each of which does a harder task) became less interconnected. Next, he tested how these PFN patterns were related to kids’ executive function. Interestingly, he found executive function tends to be better when very low-order and very high-order networks are distinct, but networks that fall in the middle (ones that do medium-complexity tasks) are more interconnected. Dividing the brain into a greater number of PFNs, Adam saw this effect grow stronger, especially in lower-order networks.

Taken together, Adam’s results are surprising because, while aging makes higher-order networks more distinct (which is better for executive function), lower-order networks actually become more interconnected (which is worse for executive function)! This may mean that while increasingly distinct higher-order networks allow kids’ executive function to improve as they grow up, their brains’ lower-order networks are already starting to decline. These findings will be important for future scientists studying how kids’ executive function develops and may help uncover why some kids struggle with cognitive development.

About the brief writer: Margaret Gardner

Margaret is a PhD student in the Brain-Gene-Development Lab working with Dr. Aaron Alexander-Bloch. She is interested in studying how different biological and demographic factors influence people’s brain development and their risk for mental illnesses.

Want to read Adam’s work for yourself? You can find the full article (complete with equations and pretty brain pictures) here!

How do the brain’s structure and function develop together through adolescence?

or technically,

Development of structure-function coupling in human brain networks during youth

[See Original Abstract on Pubmed]

Authors of the study: Graham L. Baum, Zaixu Cui, David R. Roalf, Rastko Ciric, Richard F. Betzel, Bart Larsen, Matthew Cieslak, Philip A. Cook, Cedric H. Xia, Tyler M. Moore, Kosha Ruparel, Desmond J. Oathes, Aaron F. Alexander-Bloch, Russell T. Shinohara, Armin Raznahani, Raquel E. Gur, Ruben C. Gur, Danielle S. Bassett, and Theodore D. Satterthwaite

An important part of learning about the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. is not just understanding the way one individual brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region works, but also how different brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions connect to each other. For example, our eyes receive visual information, but you only know what objects you are looking at because that visual information is also associated with your other senses and your memories. The connections between brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions are not completely set once a person is born, they develop as that person grows. There are several ways that these connections can develop. One way is structural, which is the physical connections between regions. These are the white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions connections that stretch from region to region and the synapsesthe point of communication between neurons; the tiny gap between two neurons, where nerve impulses are relayed formed between cells in different regions. Another type of connection between regions is functional. This means that when one region is active and doing a task, the other region is active as well. When the structure between brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions also supports the functional connections between those regions, that is called structure-function coupling. Graham Baum, Neuroscience Graduate Group student and member of the Satterthwaite lab, wanted to know how structure-function coupling develops in youth.

BrainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions can be classified in groups based on what they process. If a brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region only focuses on a single simple thing such as light, heat or taste, then it is called unimodal. If a brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region associates multiple types of information that come from different brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions, that brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region can be called transmodal. When children grow up, the senses are among the first parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to develop since they are more concrete; they require less abstract thought. The more evolved transmodal parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are the ones that develop later in life. It is also possible to measure how much a transmodal region is connected to other brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions, which is called the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region’s participation coefficient. Graham’s study focused on the differences in development of unimodal and transmodal types of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions.

To study structure-function coupling, Graham scanned people from ages 8 to 23 using MRI imaging. He made two maps for each person. The first map was a structural map, made with diffusion weighted imagingA method for imaging and measuring properties of white matter using magnetic resonance imaging.. This map showed the physical connections between regions of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. The next map was a functional map. To make this map, each participant was scanned with a MRI machine while they were doing a task where they needed to remember a number of things and then repeat them back to the experimenter. That allowed Graham to make a map of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to see how each region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. communicated with every other region of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. during this task. The last step was to correlate the structural connections with the functional connections. Each region in the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. then had a number to represent its structure-function coupling. This final value is what Graham measured and compared between participants.

The first thing Graham found was that regions that were unimodal had stronger structure-function coupling compared to transmodal areas. The more regions that one brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region was communicating with, the weaker structure-function coupling it had. This was true across all ages. He next wanted to know how structure-function associations would change with age. To do this, he compared the structure-function coupling between younger participants and older participants. BrainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions that were unimodal did not change much with age. The regions that changed the most with age were the transmodal areas that support complex thought.

These age differences in structure-function coupling were exciting, but they were done across different people of different ages. Graham added to this by scanning a group of participants and then scanning those same participants about 2 years later. For most adolescents, 2 years can be a significant amount of time to change in terms of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development. When Graham scanned the same people twice, he confirmed that transmodal brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. regions within the same individuals developed stronger structure-function coupling over time.

The last thing Graham wanted to know is whether these structure-function connections would actually be related to behavior. He looked at how people actually did on the behavioral task that he used to make the functional maps. He found that higher structure-function coupling in a region called the rostrolateral prefrontal cortex (rlPFC) was associated with better performance on the task. The structure-function coupling of the rlPFC could also predict how two people of the same age would do on the task.

Graham’s work shows us something we didn’t know before, how the development of white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions helps to support the way that the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. develops its cognitive abilities. This work gives us the ability to predict brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. function as humans age and develop. Additionally, this work can help us try to understand disorders that are defined by the disconnect between structural and functional development such as certain neuropsychiatric disorders.

About the brief writer: Rebecca Somach

Rebecca is a PhD Candidate in Akiva Cohen’s lab. She is interested in using electrophysiology to answer interesting and novel questions in neuroscience. Her current research focuses on how mild traumatic brain injury alters the neuronal circuitry of sleep.

Want to learn more about structure-function coupling, and how it changes as we develop? Check out Graham’s paper here.

Does connecting with other people get harder as you get older?

or technically,

Social Coordination in Older Adulthood: A Dual-Process Model.

[See Original Abstract on Pubmed]

Authors of the study: Meghan L. Healey and Murray Grossman

Being able to relate to and connect with other people is an important part of staying happy and healthy at any age. Connecting with other people is especially important for your mental health. Having close friendships makes a stressful day not feel as bad and can even make it less likely that you experience anxiety or depression¹. But for older adults, it can become more difficult to stay connected. NGG student Meghan Healey and her mentor Dr. Murray Grossman wanted to ask why that might be- are there any skills that take a hit as you get older and contribute to this increased risk of social isolation?

Social coordination is the process of making sure that you and another person understand a situation or problem that you are working on together. One example of social coordination is giving directions on a road trip. You need to use the information you have available (road signs, landmarks, and the map/GPS) and what you know about what the driver is seeing to get to where you need to go.

Social coordination requires two main skills: working memory and perspective-taking. Working memory is the ability to mentally keep information on-hand for 10 to 60 seconds at a time to easily use when needed. When giving directions, you use your working memory to remember the upcoming turns and whether they are lefts or rights, while also keeping in mind where you currently are. Perspective-taking involves picturing what another person might be seeing as well as considering what they might know or need to know in a particular situation. For example, figuring out which landmarks/road signs the driver can easily see is an example of perspective-taking.

While we don’t know what happens to your social coordination abilities as you get older, working memory and perspective-taking are more studied. Several studies found that working memory gets worse with age. However, the case is still open on whether perspective-taking ability gets better or worse over time. So, Meghan set out to measure how working memory, perspective-taking, and social coordination change as we age.

Meghan came up with a clever way to test each of these skills in the same task. She designed a game where the person playing sees a board with a bunch of objects on it. Next to the board is a cartoon avatar that sometimes can also see the board and sometimes can’t see it as well. It is the player’s job to ‘help’ the avatar by describing which object moves on the board. The amount of information the player gives (too little, too much, or just enough) tests perspective-taking and the number of objects that need to be considered tests working memory. For example, if the avatar is facing the board, then it doesn’t need as much information as when it is facing away from the board. Players that give the too much information when the avatar is facing the board, likely lack perspective taking skills (in this case, the ability to imagine what the avatar can see based on which way it is facing). How well people perform on the game measures social coordination. To test the effect of age on these skills, she asked young adults (20-30 years old) and older adults (56-60 years old) to play this game.

She found that older adults had more difficulty with the parts of the game that tested both working memory and perspective-taking. These results suggest that older adults had worse overall social coordination abilities. Based on what we know from other studies, worse social coordination abilities can lead to difficulties in forming and maintaining relationships. This provides a clue as to why older adults might be more likely to spend time alone than with friends. Based on these findings, we could benefit from future research that tackles how we can improve perspective-taking abilities of older adults to help them build towards healthier social lives.

About the brief writer: Sara Taylor

Sara is a third year graduate student interested in the genetic basis for social behaviors in autism.

Citations:

1. Ganster, D. C., & Victor, B. (1988). The impact of social support on mental and physical health. British Journal of Medical Psychology, 61(1), 17-36.

If you are interested in learning more about how aging changes the way we interact with one another, check out Meghan’s paper here.

A gene linked to schizophrenia? New insights and new models for the devastating disorder.

or technically,

Loss of the neurodevelopmental gene Zswim6 alters striatal morphology and motor regulation.

[See Original Abstract on Pubmed]

Authors of the study: David J. Tischfield, Dave K. Saraswat, Andrew Furash, Stephen C. Fowler, Marc V. Fuccillo, Stewart A. Anderson

Hallucinations, delusions, and paranoia. Agitation, depression, and trouble sleeping. The symptoms of schizophrenia vary from person to person, but one fact remains the same: there is currently no known cure for the disorder that affects over 77 million people worldwide. Due in large part to its incredibly diverse set of symptoms, schizophrenia is an extremely challenging disorder to study. David Tischfield, a neuroscience graduate student working in the laboratory of Dr. Stewart Anderson at the University of Pennsylvania, tackled this problem by studying the relationship between a recently identified neurodevelopmental geneA unit of DNA that encodes a protein and tells a cell how to function and its contribution to normal and abnormal brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. function.

Thanks to recent advancements in technology, scientists have been able to identify genesA unit of DNA that encodes a protein and tells a cell how to function that are associated with all sorts of diseases and disorders. Two such studies^1,2 have linked ZSWIM6, a geneA unit of DNA that encodes a protein and tells a cell how to function of unknown function, to schizophrenia and other severe neurodevelopmental disordersA disorder in which the development of the central nervous system is disturbed, which often leads to neuropsychiatric problems or impaired function. Building off of these previous studies, David sought to characterize this geneA unit of DNA that encodes a protein and tells a cell how to function in mice and determine its role in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development and disease.

Based on studies performed in humans, we know that patients with schizophrenia often have abnormalities in a part of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. called the striatumA region in the front of the brain that is critical for motor and reward system - a region that plays a role in regulating voluntary movements. This makes sense as many symptoms of schizophrenia are movement-based: agitation, repetitive movements, lack of restraint, impaired coordination, etc. Interestingly, Zswim6 (the proteinAn essential molecule found in all cells. DNA contains the recipes the cell uses to make proteins. Examples of proteins include receptors, enzymes, and antibodies. encoded by the Zswim6 geneA unit of DNA that encodes a protein and tells a cell how to function in mice) is present in very high levels in this region. David therefore wondered if Zswim6 dysfunction in the striatumA region in the front of the brain that is critical for motor and reward system, specifically, could cause developmental brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. abnormalities that could explain some of the symptoms of schizophrenia. To test this, he deleted this geneA unit of DNA that encodes a protein and tells a cell how to function in a group of mice, and then compared the behaviors and brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development of mice with and without Zswim6.

In terms of neurodevelopment, David found that mice lacking Zswim6 had smaller striata than the mice who had normal levels of Zswim6. In line with this, the mice lacking Zswim6 also had a reduced number of medium spiny neuronsA special type of cell located in the human striatum, especially important in the transmission of dopamine. (the main type of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. cell that makes up the striatumA region in the front of the brain that is critical for motor and reward system), as well as significant abnormalities in the structure of these cells. David then performed behavioral experiments on the mice lacking Zswim6 to determine if there were any changes in motor learning and overall behavioral control (remember: the striatumA region in the front of the brain that is critical for motor and reward system is important for regulating movements). Indeed, David found that the mice lacking Zswim6 did show differences in movement-related behavior. Not only did they have a harder time balancing on a rotating "treadmill" of sorts, but the mice without the Zswim6 geneA unit of DNA that encodes a protein and tells a cell how to function also tended to be a lot more hyperactive (think: sprinting around their cage). This hyperactivity was further increased when the mice were given a low dose of amphetamine (a stimulant drug similar to Adderall that speeds up your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. and your movements). However, this increase in hyperactivity with amphetamine was only seen in the mice lacking Zswim6 - low doses of the drug had no effect on regular mice. This finding is important as extreme sensitivity to amphetamines is a common symptom in humans suffering from schizophrenia, and these drugs can actually induce psychosisA symptom of mental illness in which the person loses touch with reality and thinks or behaves in bizarre ways in those who take them. Therefore, this result further links Zswim6 to specific aspects of schizophrenia.

David’s work not only gives us more information about an important geneA unit of DNA that encodes a protein and tells a cell how to function that we previously knew nothing about, but it also provides the field with a new mouse model, the Zswim6 “deleted” mice, that could be extremely useful in future studies of schizophrenia and its related disorders. In particular, this model reproduces the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. region abnormalities, movement problems, and hypersensitivity to amphetamines that are seen in humans with schizophrenia. As schizophrenia is chronic, debilitating, and currently without cure, finding effective ways to study it are of the utmost importance. David’s work leads the way towards understanding the science behind such misunderstood and devastating disorders.

About the brief writer: Kelsey Nemec

As a 2nd year NGG student, Kelsey is interested in using neural stem cells to study neurodevelopment and neurodegeneration in various diseases and disorders.

Citations:

1. Ripke, S., et al., 2013. Genome-wide association analysis identifies 13 new risk loci for schizophrenia. Nat. Genet. 45:1150–1159. Read it here. 

2. Schizophrenia Working Group of the Psychiatric Genomics, C, 2014,. Biological insights from 108 schizophrenia-associated genetic loci. Nature 511:421–427. Read it here.

Want to learn more about how researchers study neurodevelopmental disorders like schizophrenia? You can find David’s full paper here!

Brains get denser during adolescence--and that might not be a bad thing!

Efstathios (Stathis) Gennatas was the lead author on this study.

or technically,

Age-Related Effects and Sex Differences in Gray Matter Density, Volume, Mass, and Cortical Thickness from Childhood to Young Adulthood

[See Original Abstract on Pubmed]

Authors of the study: Gennatas ED, Avants BB, Wolf DH, Satterthwaite TD, Ruparel K, Ciric R, Hakonarson H, Gur RE, Gur RC.

Have you ever wondered what happens to your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. during the tumultuous ride of adolescence? Along with dramatic changes of the body, there are considerable changes of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. We all know that the ability to think, learn, and make decisions improves as children grow up, so it is quite surprising to learn that parts of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. are actually getting smaller during this time.

BrainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. tissue can be divided into two types: gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain and white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions. Gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is a thick layer of cells, much of which tiles the surface of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. Depending on the location, gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is thought to process emotion, speech, decision-making, movement, self-control, and more. White matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions is made of the connections that act as highways among regions of gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain. Because of the fatty biological materials making up these highways, white matterA class of brain tissue made up of long and wire-like axons and tracts, acting as a highway of connections among the brain's cortical surface regions looks white!

As you grow and learn, new connections form. So, it would make sense for the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. to grow in size. Yet, this is not the case! Stathis Gennatas, a former neuroscience graduate student under the direction of Dr. Ruben Gur at the University of Pennsylvania, wondered if we were missing the full story.

There are two common ways to measure how much gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain someone has, using a technique called magnetic resonance imagingA common brain imaging method that exploits different magnetic reactions of brain tissue to take pictures of the brain (MRI), which uses large magnets to make a 3D image of the brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals.. One way to measure gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is to calculate its volume from the MRI image. The second way is to measure the thickness of the gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain. Over and over, teams of scientists have found that both of these measures show a dramatic decline during adolescence, despite rapid improvements in tests of memory and learning.¹

Stathis and his team used MRI to scan the brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of 1189 children and adolescents from the Philadelphia area. As in prior studies, he found that both cortical thickness and gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume did indeed decline during adolescence. However, he also looked at another measure called gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density, which measures how tightly packed gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is in the cortex. Gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density has not historically been examined in studies of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development, which have focused on measures of volume and thickness. Stathis actually found increases in gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density with increasing age; in fact, gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density actually showed the strongest age-related effects, meaning that it changed the most with age. This suggests that perhaps gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain is not being lost during adolescence, but rather, simply being reorganized in a more tightly packed manner.

Stathis found another interesting twist in his study of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure during adolescence. The brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. of boys and girls appeared to be growing differently. Males at this age tend to be bigger and taller, and therefore have larger brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. and more gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain compared to girls. During adolescence, when gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume decreases, female brainsThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. start out with less gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume. Stathis found, though, that females have higher gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density on average than males, possibly compensating for their smaller average gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume.

Increasing gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density provides an important piece of the puzzle as to why gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain volume or cortical thickness decreases in adolescence. This is important because currently, gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density is not routinely considered in studies of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. development in childhood and adolescence, when many psychiatric disorders emerge. Gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density is highly sensitive to changes with age, and thus may help us glean new insight into what changes in brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure accompany the development of mental disorders. These findings might also help us understand why the effects of brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. disorders on females and males differ during the rapid changes of adolescence. Examining gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain density could also be really important for understanding the relationship between brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. structure and cognitive performance. More densely packed gray matterA class of brain tissue made up of layers of cells typically covering the cortical surface of the brain may allow more processing for less space, thus improving learning and memory abilities. In summary, your brainThe brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. shrinking during adolescence might not be such a bad thing.

About the brief writer: Ursula Tooley

Ursula is a PhD Candidate in Allyson Mackey’s and Danielle Bassett’s labs. How does our brain change as we develop from young children to adults, and what functional networks support our ability to learn and reason about the world? How does our early environment shape this? Ursula is a fourth year student interested in the answers to these questions.

Citations:

1. Akshoomoff, N., Newman, E., Thompson, W. K., McCabe, C., Bloss, C. S., Chang, L., ... & Gruen, J. R. (2014). The NIH Toolbox Cognition Battery: Results from a large normative developmental sample (PING). Neuropsychology, 28(1), 1.