Posts tagged corpus callosum
Articles and news from the latest research reports.
Alternative pathways let right and left communicate in early split brains
During the last century, many patients have undergone a variety of brain surgeries in an attempt to alleviate all sorts of psychiatric maladies, from hysteria and depression (mainly in women) to schizophrenia and epilepsy. Early on, doctors believed that psychiatric patients suffered from aberrant wiring among different brain areas and that cutting the connections between these areas would help patients regain normal brain circuits as well as their mental health. For instance, since the 1940s, several patients with intractable epilepsy have been treated with callosotomy, a surgical procedure that severs part or most of the corpus callosum. Curiously, some individuals are already born without the corpus callosum, a condition known as callosal dysgenesis (CD).
In 1968, the neurobiologist Roger Sperry confirmed that both callosotomized and CD patients have either absent or massively diminished connections between brain hemispheres. However, these two types of patients show a paradoxical difference concerning the transfer of information between the two sides of their brains. While typical callosotomized patients suffer from a disconnection syndrome in which there is minor or no communication between the left and right brain hemispheres, in CD patients, the two hemispheres are in fact able to communicate with each other.
For instance, when an unseen object is held in the right hand and thus recognized by the left hemisphere, both callosotomized and CD individuals can easily name that object verbally, because it is the left hemisphere that most often dominates verbal language. However, when an object is held in the left hand and thus recognized by the right hemisphere, callosotomized patients fail to verbally name the object because the missing corpus callosum prevents the right hemisphere from communicating with the left hemisphere. Conversely, CD patients have no difficulties in naming an unseen object regardless of the hand holding it.
The observation that the corpus callosum is the main connector between brain hemispheres earned Roger Sperry the Nobel Prize in 1981, but his own paradoxical discovery that CD patients do not present the classical disconnection syndrome observed in callosotomized patients remained unexplained until now.
In an article entitled “Structural and functional brain rewiring clarifies preserved inter-hemisphere transfer in humans born without the corpus callosum” and published in the Proceedings of the National Academy of Sciences (PNAS), a group of scientists from Rio de Janeiro and Oxford puts an end to Sperry’s paradox.
Previous work had led to the hypothesis that a defect in callosal formation would cause the brains of CD patients to create alternative pathways early on in life, but little was known about these potential pathways. The group led by Fernanda Tovar-Moll and Roberto Lent at the D’Or Institute for Research and Education and the Institute of Biomedical Sciences in Rio de Janeiro, Brazil, tested the brains of patients with CD using state of the art functional neuroimaging methods. The researchers were able to identify, morphologically describe and establish the function of two alternative pathways that help compensate for the lack of the corpus callosum. These pathways enable the transfer of complex tactile information between hemispheres, an ability missing in surgically callosotomized patients. Furthermore, by comparing six CD patients with 12 normal individuals, the group was able to demonstrate that CD patients present tactile recognition abilities similar to those observed in controls, indicating a functional role for these newly discovered brain pathways.
The authors believe that the development of alternative pathways results from the brain’s ability for long-distance plasticity and occurs in the utero during embryo development, which indicates that connections formed in the human brain early in development can be greatly modified, and most likely by environmental or genetic factors.
These findings will change the way we perceive the mechanisms of brain plasticity and may pave the way for a better understanding of a number of human disorders resulting from abnormal neuronal connections during embryonic development.
(Image caption: MRI images from a neurotypical control (left) and an adult with complete agenesis of the corpus callosum (right). The corpus callosum is indicated in red, fading as the fibers enter the hemispheres in order to suggest that they continue on. The anterior commissure is indicated by light aqua. The image illustrates the dramatic lack of inter hemispheric connections in callosal agenesis. Credit: Lynn Paul/Caltech)
Research Update: An Autism Connection
Building on their prior work, a team of neuroscientists at Caltech now report that rare patients who are missing connections between the left and right sides of their brain—a condition known as agenesis of the corpus callosum (AgCC)—show a strikingly high incidence of autism. The study is the first to show a link between the two disorders.
The findings are reported in a paper published April 22, 2014, in the journal Brain.
The corpus callosum is the largest connection in the human brain, connecting the left and right brain hemispheres via about 200 million fibers. In very rare cases it is surgically cut to treat epilepsy—causing the famous “split-brain” syndrome, for whose discovery the late Caltech professor Roger Sperry received the Nobel Prize. People with AgCC are like split-brain patients in that they are missing their corpus callosum—except they are born this way. In spite of this significant brain malformation, many of these individuals are relatively high-functioning individuals, with jobs and families, but they tend to have difficulty interacting with other people, among other symptoms such as memory deficits and developmental delays. These difficulties in social behavior bear a strong resemblance to those faced by high-functioning people with autism spectrum disorder.
"We and others had noted this resemblance between AgCC and autism before," explains Lynn Paul, lead author of the study and a lecturer in psychology at Caltech. But no one had directly compared the two groups of patients. This was a challenge that the Caltech team was uniquely positioned to do, she says, since it had studied patients from both groups over the years and had tested them on the same tasks.
"When we made detailed comparisons, we found that about a third of people with AgCC would meet diagnostic criteria for an autism spectrum disorder in terms of their current symptoms," says Paul, who was the founding president of the National Organization for Disorders of the Corpus Callosum.
The research was done in the laboratory of Ralph Adolphs, Bren Professor of Psychology and Neuroscience and professor of biology at Caltech and a coauthor of the study. The team looked at a range of different tasks performed by both sets of patients. Some of the exercises that involved certain social behaviors were videotaped and analyzed by the researchers to assess for autism. The team also gave the individuals questionnaires to fill out that measured factors like intelligence and social functioning.
"Comparing different clinical groups on exactly the same tasks within the same lab is very rare, and it took us about a decade to accrue all of the data," Adolphs notes.
One important difference between the two sets of patients did emerge in the comparison. People with autism spectrum disorder showed autism-like behaviors in infancy and early childhood, but the same type of behaviors did not seem to emerge in individuals with AgCC until later in childhood or the teen years.
"Around ages 9 through 12, a normally formed corpus callosum goes through a developmental ‘growth spurt’ which contributes to rapid advances in social skills and abstract thinking during those years," notes Paul. "Because they don’t have a corpus callosum, teens with AgCC become more socially awkward at the age when social skills are most important."
According to Adolphs, it is important to note that AgCC can now be diagnosed before a baby is born, using high-resolution ultrasound imaging during pregnancy. This latest development also opens the door for some exciting future directions in research.
"If we can identify people with AgCC already before birth, we should be in a much better position to provide interventions like social skills training before problems arise," Paul points out. "And of course from a research perspective it would be tremendously valuable to begin studying such individuals early in life, since we still know so little both about autism and about AgCC."
For example, the team would like to discern at what age subtle difficulties first appear in AgCC individuals, and at what point they start looking similar to autism, as well as what happens in the brain during these changes.
"If we could follow a baby with AgCC as it grows up, and visualize its brain with MRI each year, we would gain such a wealth of knowledge," Adolphs says.
Shedding new light on learning disorders
A Michigan State University researcher has discovered the first anatomical evidence that the brains of children with a nonverbal learning disability – long considered a “pseudo” diagnosis – may develop differently than the brains of other children.
The finding, published in Child Neuropsychology, could ultimately help educators and clinicians better distinguish between – and treat – children with a nonverbal learning disability, or NLVD, and those with Asperger’s, or high functioning autism, which is often confused with NLVD.
“Children with nonverbal learning disabilities and Asperger’s can look very similar, but they can have very different reasons for why they behave the way they do,” said Jodene Fine, assistant professor of school psychology in MSU’s College of Education.
Understanding the biological differences in children with learning and behavioral challenges could help lead to more appropriate intervention strategies.
Children with nonverbal learning disability tend to have normal language skills but below average math skills and difficulty solving visual puzzles. Because many of these kids also show difficulty understanding social cues, some experts have argued that NVLD is related to high functioning autism – which this latest study suggests may not be so.
Fine and Kayla Musielak, an MSU doctoral student in school psychology, studied about 150 children ages 8 to 18. Using MRI scans of the participants’ brains, the researchers found that the children diagnosed with NVLD had smaller spleniums than children with other learning disorders such as Asperger’s and ADHD, and children who had no learning disorders.
The splenium is part of the corpus callosum, a thick band of fibers in the brain that connects the left and right hemispheres and facilitates communication between the two sides. Interestingly, this posterior part of the corpus callosum serves the areas of the brain related to visual and spatial functioning.
In a second part of the study, the participants’ brain activity was analyzed after they were shown videos in an MRI that portrayed both positive and negative examples of social interaction. (A typical example of a positive event was a child opening a desired birthday present with friend; a negative event included a child being teased by other children.)
The researchers found that the brains of children with nonverbal learning disability responded differently to the social interactions than the brains of children with high functioning autism, or HFA, suggesting the neural pathways that underlie those behaviors may be different.
“So what we have is evidence of a structural difference in the brains of children with NLVD and HFA, as well as evidence of a functional difference in the way their brains behave when they are presented with stimuli,” Fine said.
While more research is needed to better understand how nonverbal learning disability fits into the family of learning disorders, Fine said her findings present “an interesting piece of the puzzle.”
“I would say at this point we still don’t have enough evidence to say NVLD is a distinct diagnosis, but I do think our research supports the idea that it might be,” she said.
Well-connected hemispheres of Einstein’s brain may have sparked brilliance
The left and right hemispheres of Albert Einstein’s brain were unusually well connected to each other and may have contributed to his brilliance, according to a new study conducted in part by Florida State University evolutionary anthropologist Dean Falk.
"This study, more than any other to date, really gets at the ‘inside’ of Einstein’s brain," Falk said. "It provides new information that helps make sense of what is known about the surface of Einstein’s brain."
The study, “The Corpus Callosum of Albert Einstein’s Brain: Another Clue to His High Intelligence,” was published in the journal Brain. Lead author Weiwei Men of East China Normal University’s Department of Physics developed a new technique to conduct the study, which is the first to detail Einstein’s corpus callosum, the brain’s largest bundle of fibers that connects the two cerebral hemispheres and facilitates interhemispheric communication.
"This technique should be of interest to other researchers who study the brain’s all-important internal connectivity," Falk said.
Men’s technique measures and color-codes the varying thicknesses of subdivisions of the corpus callosum along its length, where nerves cross from one side of the brain to the other. These thicknesses indicate the number of nerves that cross and therefore how “connected” the two sides of the brain are in particular regions, which facilitate different functions depending on where the fibers cross along the length. For example, movement of the hands is represented toward the front and mental arithmetic along the back.
In particular, this new technique permitted registration and comparison of Einstein’s measurements with those of two samples — one of 15 elderly men and one of 52 men Einstein’s age in 1905. During his so-called “miracle year” at 26 years old, Einstein published four articles that contributed substantially to the foundation of modern physics and changed the world’s views about space, time, mass and energy.
The research team’s findings show that Einstein had more extensive connections between certain parts of his cerebral hemispheres compared to both younger and older control groups.
The research of Einstein’s corpus callosum was initiated by Men, who requested the high-resolution photographs that Falk and other researchers published in 2012 of the inside surfaces of the two halves of Einstein’s brain. In addition to Men, the current research team included Falk, who served as second author; Tao Sun of the Washington University School of Medicine; and, from East China Normal University’s Department of Physics, Weibo Chen, Jianqi Li, Dazhi Yin, Lili Zang and Mingxia Fan.
(Image: National Museum of Health and Medicine)
Mental Fog with Tamoxifen is Real; Scientists Find Possible Antidote
A team from the University of Rochester Medical Center has shown scientifically what many women report anecdotally: that the breast cancer drug tamoxifen is toxic to cells of the brain and central nervous system, producing mental fogginess similar to “chemo brain.”
However, in the Journal of Neuroscience, researchers also report they’ve discovered an existing drug compound that appears to counteract or rescue brain cells from the adverse effects of the breast cancer drug.
Corresponding author Mark Noble, Ph.D., professor of Biomedical Genetics and director of the UR Stem Cell and Regenerative Medicine Institute, said it’s exciting to potentially be able to prevent a toxic reaction to one of the oldest and most widely used breast cancer medications on the market. Although tamoxifen is more easily tolerated compared to most cancer treatments, it nonetheless produces troubling side effects in a subset of the large number of people who take it.
By studying tamoxifen’s impact on central nervous system cell populations and then screening a library of 1,040 compounds already in clinical use or clinical trials, his team identified a substance known as AZD6244, and showed that it essentially eliminated tamoxifen-induced killing of brain cells in mice.
“As far as I know, no one else has discovered an agent that singles out and protects brain and central nervous system cells while also not protecting cancer cells,” said Noble, who also collaborates with researchers at the UR’s James P. Wilmot Cancer Center. “This creates a whole new paradigm; it’s where we need to go.”
The research is the result of two separate but related projects from Noble’s lab. One investigates the science underlying a condition known as “chemo brain,” and another is looking at how to exploit tamoxifen’s attributes for use in other types of cancer besides early-stage, less-aggressive breast cancer. (The drug is a type of hormonal therapy, which works by stopping the growth of estrogen-sensitive tumors.)
In the Journal of Neuroscience paper, Noble’s team first identified central nervous system (CNS) cells that are most vulnerable to tamoxifen toxicity. Chief among these were oligodendrocyte-type 2 astrocyte progenitor cells (O-2A/OPCs), cells that are essential for making the insulating sheaths (called myelin) required for nerve cells to work properly. Exposure to clinically relevant levels of tamoxifen for 48 hours killed more than 75 percent of these cells.
In earlier work, while studying the biology of the cognitive difficulties that linger in some people being treated for cancer, Noble and colleagues discovered that 5-fluorouracil, (cisplatin, cytarabine, carmustine), and multiple other types of chemotherapy, damages populations of stem cells in the CNS. Published in the Journal of Biology (1, 2) in 2006 and 2008, these studies pioneered analysis of the biological foundations of chemo brain.
“It’s critical to find safe treatments that can rescue the brain from impairment,” Noble said, “because despite increasing awareness and research in this area, some people continue to endure short-term memory loss, mental cloudiness, and trouble concentrating. For some patients the effects wear off over time, but others experience symptoms that can lead to job loss, depression, and other debilitating events.”
Noble’s lab, led by post-doctoral fellow Hsing-Yu Chen, Ph.D., identified 27 drugs that protected O-2A/OPCs from the effects of tamoxifen. Further testing resulted in singling out AZD6244, by other laboratories as a potential cancer therapy.
In mice co-treated with tamoxifen plus AZD6244, cell death in the corpus callosum, the largest white matter (myelinated) structure in the brain, was prevented, the paper reported. Meanwhile, several national clinical trials are testing the safety and effectiveness of AZD6244 in treating multiple cancers, from breast and colon to melanoma and lung.
Researchers were also optimistic about finding that while AZD6244 protected brain cells, it did not also protect cancer cells. New drug compounds have greater value if they do not compromise the effects of existing treatments, and in this case, Noble said, the experiments in his laboratory agreed with studies by other research groups, who found that the combined use of AZD6244 and chemotherapy enhances targeting of cancer cells.
In future work, Noble’s group plans to identify the dosage of AZD6244 that provides maximum protection and minimum disruption to differentiating brain cells. Their research was supported by the U.S. Department of Defense, National Institutes of Health, Susan Komen Race for the Cure, and the Carlson Stem Cell Fund.
This is the second tamoxifen-related study to come from Noble’s lab in 2013. In April they showed in pre-clinical research they could leverage the drug’s various cellular activities so that it might work on more aggressive triple-negative breast cancer. In the journal EMBO Molecular Medicine, Noble and Chen also reported finding an experimental compound that enhances tamoxifen’s ability to work in this new way.
(Source: urmc.rochester.edu)
Reduced brain volume in kids with low birth-weight tied to academic struggles
An analysis of recent data from magnetic resonance imaging (MRI) of 97 adolescents who were part of study begun with very low birth weight babies born in 1982-1986 in a Cleveland neonatal intensive care unit has tied smaller brain volumes to poor academic achievement.
More than half of the babies that weighed less than 1.66 pounds and more than 30 percent of those less than 3.31 pounds at birth later had academic deficits. (Less than 1.66 pounds is considered extremely low birth weight; less than 3.31 pounds is labeled very low birth weight.) Lower birth weight was associated to smaller brain volumes in some of these children, and smaller brain volume, in turn, was tied to academic deficits.
Researchers also found that 65.6 percent of very low birth weight and 41.2 percent of extremely preterm children had experienced academic achievement similar to normal weight peers.
The research team — led by Caron A.C. Clark, a scientist in the Department of Psychology and Child and Family Center at the University of Oregon — detected an overall reduced volume of mid-brain structures, the caudate and corpus callosum, which are involved in connectivity, executive attention and motor control.
The findings, based a logistic regression analyses of the MRIs done approximately five years ago, were published in the May issue of the journal Neuropsychology. The longitudinal study originally was launched in the 1980s with a grant from the National Institute of Child Health and Human Development (National Institutes of Health, grant HD 26554) to H. Gerry Taylor of Case Western University, who was the senior author and principal investigator on the new paper.
"Our new study shows that pre-term births do not necessarily mean academic difficulties are ahead," Clark said. "We had this group of children that did have academic difficulties, but there were a lot of kids in this data set who didn’t and, in fact, displayed the same trajectories as their normal birth-weight peers."
Academic progress of the 201 original participants had been assessed early in their school years, again four years later and then annually until they were almost 17 years old. “We had the opportunity to explore this very rich data set,” Clark said. “There are very few studies that follow this population of children over time, where their trajectories of growth at school are tracked. We were interested in seeing how development unfolds over time.”
The findings, Clark added, provide new insights but also raise questions such as why some low-birth-weight babies develop normally and others do not? “It is very difficult to pick up which kids will need the most intensive interventions really early, which we know can be really important.”
The findings also provide a snapshot of children of very low birth weights who were born in NICU 30 years ago. Since then, technologies and care have improved, she said, meaning that underweight babies born prematurely today might have an advantage over those followed in the study. However, she added, improving NICUs also are allowing yet smaller babies to survive.
Clark now is exploring these findings for early warning clues that might help drive informed interventions. “Pre-term birth does mean that you are much more likely to experience brain abnormalities that seem to put you at risk for these outcomes,” she said. “They seem to be a pretty strong predictor of poor cognitive development as children age. We really need to find ways to prevent these brain abnormalities and subsequent academic difficulties in these kids who are born so small.”
Atypical brain circuits may cause slower gaze shifting in infants who later develop autism
Infants at 7 months of age who go on to develop autism are slower to reorient their gaze and attention from one object to another when compared to 7-month-olds who do not develop autism, and this behavioral pattern is in part explained by atypical brain circuits.
Those are the findings of a new study led by University of North Carolina School of Medicine researchers and published online March 20 by the American Journal of Psychiatry.
"These findings suggest that 7-month-olds who go on to develop autism show subtle, yet overt, behavioral differences prior to the emergence of the disorder. They also implicate a specific neural circuit, the splenium of the corpus callosum, which may not be functioning as it does in typically developing infants, who show more rapid orienting to visual stimuli," said Jed T. Elison, PhD, first author of the study.
Elison worked on the study, conducted as part of the Infant Brain Imaging Study (IBIS) Network, for his doctoral dissertation at UNC. He now is a postdoctoral fellow at the California Institute of Technology. The study’s senior author is Joseph Piven, MD, professor of psychiatry, director of the Carolina Institute for Developmental Disabilities at UNC, and the principle investigator of the IBIS Network.
The IBIS Network consists of research sites at UNC, Children’s Hospital of Philadelphia, Washington University in St. Louis, the University of Washington in Seattle, the University of Utah in Salt Lake City, and the Montreal Neurological Institute at McGill University, and the University of Alberta are currently recruiting younger siblings of children with autism and their families for ongoing research.
"Difficulty in shifting gaze and attention that we found in 7-month-olds may be a fundamental problem in autism," Piven said. "Our hope is that this finding may help lead us to early detection and interventions that could improve outcomes for individuals with autism and their families."
The study included 97 infants: 16 high-risk infants later classified with an autism spectrum disorder (ASD), 40 high-risk infants not meeting ASD criteria (i.e., high-risk-negative) and 41 low-risk infants. For this study, infants participated in an eye-tracking test and a brain scan at 7 months of age a clinical assessment at 25 months of age.
The results showed that the high-risk infants later found to have ASD were slower to orient or shift their gaze (by approximately 50 miliseconds) than both high-risk-negative and low-risk infants. In addition, visual orienting ability in low-risk infants was uniquely associated with a specific neural circuit in the brain: the splenium of the corpus callosum. This association was not found in infants later classified with ASD.
The study concluded that atypical visual orienting is an early feature of later emerging ASD and is associated with a deficit in a specific neural circuit in the brain.
Right-Handed Males, Left-Handed Females?
This is true for sugar gliders (Petaurus breviceps) and grey short-tailed opossums (Monodelphis domestica), say biologists from Saint Petersburg State University, Russia.
Their study, published in the open access journal BMC Evolutionary Biology, shows that handedness in marsupials is dependent on gender.
This preference of one hand over another has developed despite the absence of a corpus callosum, the part of the brain, which in placental mammals allows one half of the brain to communicate with the other.
Many animals show a distinct preference for using one hand (paw, hoof) over another. This is often related to posture – an animal is more likely to show manual laterality if it is upright, related to the difficulty of the task, more complex tasks show a handed preference, or even with age. As an example of all three: crawling human babies show less hand preference than toddlers.
Some species also show a distinct sex effect in handedness but among non-marsupial mammals this tendency is for left-handed males and right-handed females.
In contrast, the team from Russia shows that male quadruped marsupials, such as who walk on all fours, tend to be right-handed while the females are left-handed, especially as tasks became more difficult.
“Marsupials do not have a corpus callosum – which connects the two halves of the mammalian brain together. Reversed sex related handedness is an indication of how the marsupial brain has developed different ways of the two halves of the brain communicating in the absence of the corpus callosum,” explains senior author Dr Yegor Malashichev.
‘Rain Man’-like Brains Mapped with Network Analysis
Innovative Technique Sheds Light on Abnormal Brain Connectivity Responsible for Common Genetic Cause of Autism
A group of researchers at UC San Francisco and UC Berkeley have mapped the three-dimensional global connections within the brains of seven adults who have genetic malformations that leave them without the corpus callosum, which connects the left and right sides of the brain.
These “structural connectome” maps, which combine hospital MRIs with the mathematical tool known as network analysis, are described in the upcoming April 15 issue of the journal Neuroimage. They reveal new details about the condition known as agenesis of the corpus callosum, which is one of the top genetic causes of autism. The condition was part of the mysterious brain physiology of Laurence Kim Peek, the remarkable savant portrayed by Dustin Hoffman in the 1987 movie “Rain Man.”
While some people born with agenesis of the corpus callosum are of normal intelligence and do not have any obvious signs of neurologic disease, approximately 40 percent of people with the condition are at high risk for autism. Given this, the work is a step toward finding better ways to image the brains of people with the condition, said Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging at UCSF who was the co-senior author of the research.
Understanding how brain connectivity varies from person to person may help researchers identify imaging biomarkers for autism to help diagnose it and manage care for individuals. Currently autism is diagnosed and assessed based on cognitive tests, such as those involving stacking blocks and looking at pictures on flip cards.
While the new work falls short of a quantitative measure doctors could use instead of cognitive testing, it does offer a proof-of-principle that this novel technique may shed light on neurodevelopment disorders.
“Because you are looking at the whole brain at the network level, you can do new types of analysis to find what’s abnormal,” Mukherjee said.
The Connection between the Brain Hemispheres and Autism
Agenesis of the corpus callosum can arise if individuals are born missing DNA from chromosome 16 and often leads to autism.
Scientists have long puzzled over what the link is between this disorder and the autistic brain, said co-senior author of the paper Elliott Sherr, MD, PhD, professor of neurology and genetics especially since not all people with this malformation develop autism.
Doctors believe this is because the brain has a rich capacity for rewiring in alternative ways.
Pursuing this question, Mukherjee and Sherr turned to MRI and the mathematical technique of network analysis, which has long supported fields like civil engineering, helping urban planners optimize the timing of traffic lights to speed traffic. This is the first time network analysis has been applied to brain mapping for a genetic cause of autism.
The brain offers a significantly complicated challenge for analysis because, unlike the streets of a given city, the brain has hundreds of billions of neurons, many of which make tens of thousands of connections to each other, making its level of connectivity highly complex.
By comparing the seven rain man-like brains to those of 11 people without this malformation, the scientists determined how particular structures called the cingulate bundles were smaller and the neurons within these bundles were less connected to others in the brain. They also found that the network topology of the brain was more variable in people with agenesis of the corpus callosum than in people without the malformation.