Posts tagged science
Articles and news from the latest research reports.
Role of Calcium in Familial Alzheimer’s Disease Clarified in Penn Study, Pointing to New Therapeutic Options
In 2008, researchers at the Perelman School of Medicine at the University of Pennsylvania showed that mutations in two proteins associated with familial Alzheimer’s disease (FAD) disrupt the flow of calcium ions within neurons. The two proteins interact with a calcium release channel in an intracellular compartment. Mutant forms of these proteins that cause FAD, but not the normal proteins, result in exaggerated calcium signaling in the cell.
Now, the same team, led by J. Kevin Foskett, PhD, chair of Physiology, and a graduate student, Dustin Shilling, has found that suppressing the hyperactivity of the calcium channels alleviated FAD-like symptoms in mice models of the disease. Their findings appear this week in the Journal of Neuroscience.
Current therapies for Alzheimer’s include drugs that treat the symptoms of cognitive loss and dementia, and drugs that address the pathology of Alzheimer’s are experimental. These new observations suggest that approaches based on modulating calcium signaling could be explored, says Foskett.
The two proteins, called PS1 and PS2 (presenilin 1 and 2), interact with a calcium release channel, the inositol trisphosphate receptor (IP3R), in the endoplasmic reticulum. Mutant PS1 and PS2 increase the activity of the IP3R, in turn increasing calcium levels in the cell. “We set out to answer the question: Is increased calcium signaling, as a result of the presenilin-IP3R interaction, involved in the development of familial Alzheimer’s disease symptoms, including dementia and cognitive deficits?” says Foskett. “And looking at the findings of these experiments, the answer is a resounding ‘yes.’”
Robust Phenomenon
Exaggerated intracellular calcium signaling is a robust phenomenon seen in cells expressing FAD-causing mutant presenilins, in both human cells in culture and in mice. The team used two FAD mouse models to look for these connections. Specifically, they found that reducing the expression of IP3R1, the dominant form of this receptor in the brain, by 50 percent, normalized the exaggerated calcium signaling observed in neurons of the cortex and hippocampus in both mouse models.
(Image caption: Amyloid-beta (antibody 12F4) and hyper-phosphorylated tau (antibody AT180) immunostaining of hippocampus from 18-month-old mice. Amyloid plaques (top row) and intracellular tau tangles (bottom row) in the 3xTg mouse were strongly reduced by genetic deletion of 50% of the IP3R1 in the 3xTg/Opt mouse. Wild-type (WT) and Opt mice expressing 50% of InsP3R exhibited no pathology. Credit: J. Kevin Foskett, PhD & Dustin Shilling, Perelman School of Medicine, University of Pennsylvania)
In addition, using 3xTg mice – animals that contain presenilin 1 with an FAD mutation, as well as expressed mutant human tau protein and APP genes — the team observed that the reduced expression of IP3R1 profoundly decreased amyloid plaque accumulation in brain tissue and the hyperphosphorylation of tau protein, a biochemical hallmark of advanced Alzheimer’s disease. Reduced expression of IP3R1 also rescued defective electrical signaling in the hippocampus, as well and memory deficits in the 3xTg mice, as measured by behavioral tests.
“Our results indicate that exaggerated calcium signaling, which is associated with presenilin mutations in familial Alzheimer’s disease, is mediated by the IP3R and contributes to disease symptoms in animals,” says Foskett. “Knowing this now, the IP3 signaling pathway could be considered a potential therapeutic target for patients harboring mutations in presenilins linked to AD.”
The ‘calcium dysregulation’ hypothesis
“The ‘calcium dysregulation’ hypothesis for inherited, early-onset familial Alzheimer’s disease has been suggested by previous research findings in the Foskett lab. Alzheimer’s disease affects as many as 5 million Americans, 5 percent of whom have the familial form. The hallmark of the disease is the accumulation of tangles and plaques of amyloid beta protein in the brain.
“The ‘amyloid hypothesis’ that postulates that the primary defect is an accumulation of toxic amyloid in the brain has long been used to explain the cause of Alzheimer’s”, says Foskett. In his lab’s 2008 Neuron study, cells that carried the disease-causing mutated form of PS1 showed increased processing of amyloid beta that depended on the interaction of the PS proteins with the IP3R. This observation links dysregulation of calcium inside cells with the production of amyloid, a characteristic feature in the brains of people with Alzheimer’s disease.
Clinical trials for AD have largely been directed at reducing the amyloid burden in the brain. So far, says Foskett, these trials have failed to demonstrate therapeutic benefits. One idea is that the interventions started too late in the disease process. Accordingly, anti-amyloid clinical trials are now underway using asymptomatic FAD patients because it is known that they will eventually develop the disease, whereas predicting who will develop the common form of AD is much less certain.
“There has been an assumption that FAD is simply AD with an earlier, more aggressive onset,” says Foskett. “However, we don’t know if the etiology of FAD pathology is the same as that for common AD. So the relevance of our findings for understanding common AD is not clear. What’s important, in my opinion, is to recognize that AD could be a spectrum of diseases that result in common end-stage pathologies. FAD might therefore be considered an orphan-disease, and it’s important to find effective treatments, specifically for these patients - ones that target the IP3R and calcium signaling.”
(Image caption: These images show the movement of patient-derived neural progenitor cells from a sphere of neurons in a migration assay. How far and quickly the neurons move indicates whether they may behave atypically in the brain. Credit: Courtesy of the Salk Institute for Biological Studies)
New stem cell research points to early indicators of schizophrenia
Using new stem cell technology, scientists at the Salk Institute have shown that neurons generated from the skin cells of people with schizophrenia behave strangely in early developmental stages, providing a hint as to ways to detect and potentially treat the disease early.
The findings of the study, published online in April’s Molecular Psychiatry, support the theory that the neurological dysfunction that eventually causes schizophrenia may begin in the brains of babies still in the womb.
"This study aims to investigate the earliest detectable changes in the brain that lead to schizophrenia," says Fred H. Gage, Salk professor of genetics. "We were surprised at how early in the developmental process that defects in neural function could be detected."
Currently, over 1.1 percent of the world’s population has schizophrenia, with an estimated three million cases in the United States alone. The economic cost is high: in 2002, Americans spent nearly $63 billion on treatment and managing disability. The emotional cost is higher still: 10 percent of those with schizophrenia are driven to commit suicide by the burden of coping with the disease.
Although schizophrenia is a devastating disease, scientists still know very little about its underlying causes, and it is still unknown which cells in the brain are affected and how. Previously, scientists had only been able to study schizophrenia by examining the brains of patients after death, but age, stress, medication or drug abuse had often altered or damaged the brains of these patients, making it difficult to pinpoint the disease’s origins.
The Salk scientists were able to avoid this hurdle by using stem cell technologies. They took skin cells from patients, coaxed the cells to revert back to an earlier stem cell form and then prompted them to grow into very early-stage neurons (dubbed neural progenitor cells or NPCs). These NPCs are similar to the cells in the brain of a developing fetus.
The researchers generated NPCs from the skin cells of four patients with schizophrenia and six people without the disease. They tested the cells in two types of assays: in one test, they looked at how far the cells moved and interacted with particular surfaces; in the other test, they looked at stress in the cells by imaging mitochondria, which are tiny organelles that generate energy for the cells.
On both tests, the Salk team found that NPCs from people with schizophrenia differed in significant ways from those taken from unaffected people.
In particular, cells predisposed to schizophrenia showed unusual activity in two major classes of proteins: those involved in adhesion and connectivity, and those involved in oxidative stress. Neural cells from patients with schizophrenia tended to have aberrant migration (which may result in the poor connectivity seen later in the brain) and increased levels of oxidative stress (which can lead to cell death).
These findings are consistent with a prevailing theory that events occurring during pregnancy can contribute to schizophrenia, even though the disease doesn’t manifest until early adulthood. Past studies suggest that mothers who experience infection, malnutrition or extreme stress during pregnancy are at a higher risk of having children with schizophrenia. The reason for this is unknown, but both genetic and environmental factors likely play a role.
"The study hints that there may be opportunities to create diagnostic tests for schizophrenia at an early stage," says Gage, who holds the Vi and John Adler Chair for Research on Age-Related Neurodegenerative Disease.
Kristen Brennand, the first author of the paper and assistant professor at Icahn School of Medicine at Mount Sinai, said the researchers were surprised that the skin-derived neurons remained in such an early stage of development. “We realized they weren’t mature neurons but only as old as neurons in the first trimester,” Brennand says. “So we weren’t studying schizophrenia but the things that go wrong a long time before patients actually get sick.”
Interestingly, the study also found that antipsychotic medication such as clozapine and loxapine did not improve migration in NPCs (in particular, loxapine actually worsened migration in these cells).
"That was an experiment that gave the opposite results from what we were expecting," says Brennand. "Though in hindsight, using drugs that treat symptoms might not be helpful in trying to prevent the disease."
The next steps to this work will be to increase the sample size to a broader range of patients and to look at hundreds or thousands of patient samples, says Brennand.
(Figure 1: Correspondence between the activity of the medial prefrontal cortex and study results in the second year versus the first year. Horizontal axis shows the degree of activity in the medial prefrontal cortex of various students; vertical axis shows performance improvement in the second academic year compared with the first.)
How the brain builds on prior knowledge
It is easier to learn something new if you can link it to something you already know. A specific part of the brain appears to be involved in this process: the medial prefrontal cortex. The Journal of Cognitive Neuroscience has published these findings, from research by neuroscientists at Radboud university medical center and Radboud University, as an Early Access paper. The findings further enhance our understanding of the brain mechanisms that underlie effective learning.
Neuroscientist Marlieke van Kesteren tested two groups of students who had just started on their second-year of biology or pedagogy studies. While an MRI scanner was registering their brain activity, the students learned short sentences containing new information that expanded on their own or the other study programme. The following day, the students were tested on the information they had learned. As expected, they had retained the information that was related to their own programme better than the unrelated information.
In practice
During the successful retention of related information, a different part of the brain was active than when unrelated information was memorised. ‘The brain area we found, the medial prefrontal cortex, probably linked new information directly to prior knowledge’, Van Kesteren said. ‘In previous studies this brain area came to the fore as well, but only during simple tests. We have specifically shown that this area also plays a role in the neural basis of learning in educational practice.’
Link to study results
To her amazement, Van Kesteren also discovered that the activity in the medial prefrontal cortex corresponded with how well students performed in their second year, compared with the first. So is it possible to predict a student’s future academic success by placing him or her in a scanner? ‘No, certainly not, the links we found were not strong enough’, Van Kesteren explained. ‘We’re mostly talking here about differences of not more than 10% (Figure 1). What’s more, we can’t tell from a simple correlation like this what the chief reason is, and whether a whole lot of other factors are playing a role. But if we know exactly how our brain uses prior knowledge, we could try to address that knowledge more selectively before we start learning new information. For example, you could consider how the new information is related to what you already know.’
Van Kesteren added a tip for secondary school students taking their final exams: ‘If you don’t immediately know the answer to a question, you could first try recalling what you already know about that topic. This might help you to come up with the right answer after all.’
This publication is part of Marlieke van Kesteren’s PhD research, for which she obtained her doctorate at Radboud University Nijmegen in March 2013. In April 2013 she received a Rubicon grant from the Netherlands Organisation for Scientific Research (NWO), allowing her to work on her research into prior knowledge and memory at Stanford University in California for the next two years.
(Image caption: Dendrite of an amygdala principal neuron with dendritic spines (white). Inhibitory synaptic contacts are shown in red. Credit: © MPI f. Brain Research/ J. Letzkus)
A brain capable of learning is important for survival: only those who learn can endure in the natural world. When it learns, the brain stores new information by changing the strength of the junctions that connect its nerve cells. This process is referred to as synaptic plasticity. Scientists at the Max-Planck Institute for Brain Research in Frankfurt, working with researchers from Basel, have demonstrated for the first time that inhibitory neurons need to be at least partly blocked during learning. This disinhibition is a bit like taking the foot off the brake in a car: if the inhibitory neurons are less active, learning is accelerated.
Learning is often a matter of timing: different stimuli become strongly associated if they occur in close succession. The Max Planck scientists made use of this phenomenon in conditioning experiments in which mice learned to react to a tone. For this learning effect to occur, the synapses of the so-called principal neurons in the amygdala need to become more sensitive. The researchers concentrated on two types of inhibitory neurons which produce the proteins parvalbumin and somatostatin and inhibit the principal neurons of the amygdala.
The results obtained by the Max Planck researchers show that both cell types are inhibited during different phases of the learning process. This disinhibition enhances the activation of the principal neurons. Moreover, the scientists were able to control the learning behaviour of the mice through the use of optogenetics. In these experiments, they equipped both types of inhibitory neurons in the amygdala with light-sensitive ion channels, allowing them to use light to switch the neurons on or off as required. “When we prevent disinhibition, the mice learn less well. In contrast, enhancing the disinhibition leads to intensified learning”, says Johannes Letzkus from the Max Planck Institute for Brain Research. Next, the scientists aim to identify the nerve pathways which are involved in disinhibition.
Researchers Show Human Learning Altered by Electrical Stimulation of Dopamine Neurons
Stimulation of a certain population of neurons within the brain can alter the learning process, according to a team of neuroscientists and neurosurgeons at the University of Pennsylvania. A report in the Journal of Neuroscience describes for the first time that human learning can be modified by stimulation of dopamine-containing neurons in a deep brain structure known as the substantia nigra. Researchers suggest that the stimulation may have altered learning by biasing individuals to repeat physical actions that resulted in reward.
"Stimulating the substantia nigra as participants received a reward led them to repeat the action that preceded the reward, suggesting that this brain region plays an important role in modulating action-based associative learning," said co-senior author Michael Kahana, PhD, professor of Psychology in Penn’s School of Arts and Sciences.
Eleven study participants were all undergoing deep brain stimulation (DBS) treatment for Parkinson’s disease. During an awake portion of the procedure, participants played a computer game where they chose between pairs of objects that carried different reward rates (like choosing between rigged slot machines in a casino). The objects were displayed on a computer screen and participants made selections by pressing buttons on hand-held controllers. When they got a reward, they were shown a green screen and heard a sound of a cash register (as they might in a casino). Participants were not told which objects were more likely to yield reward, but that their task was to figure out which ones were “good” options based on trial and error.
When stimulation was provided in the substantia nigra following reward, participants tended to repeat the button press that resulted in a reward. This was the case even when the rewarded object was no longer associated with that button press, resulting in poorer performance on the game when stimulation was given (48 percent accuracy), compared to when stimulation was not given (67 percent).
"While we’ve suspected, based on previous studies in animal models, that these dopaminergic neurons in the substantia nigra - play an important role in reward learning, this is the first study to demonstrate in humans that electrical stimulation near these neurons can modify the learning process," said the study’s co-senior author Gordon Baltuch, MD, PhD, professor of Neurosurgery in the Perelman School of Medicine at the University of Pennsylvania. “This result also has possible clinical implications through modulating pathological reward-based learning, for conditions such as substance abuse or problem gambling, or enhancing the rehabilitation process in patients with neurological deficits.”
(Source: uphs.upenn.edu)
Scientists slow brain tumor growth in mice
Much like using dimmer switches to brighten or darken rooms, biochemists have identified a protein that can be used to slow down or speed up the growth of brain tumors in mice.
Brain and other nervous system cancers are expected to claim 14,320 lives in the United States this year.
The results of the preclinical study led by Eric J. Wagner, Ph.D., and Ann-Bin Shyu, Ph.D., of The University of Texas Health Science Center at Houston (UTHealth) and Wei Li, Ph.D., of Baylor College of Medicine appear in the Advance Online Publication of the journal Nature.
“Our work could lead to the development of a novel therapeutic target that might slow down tumor progression,” said Wagner, assistant professor in the Department of Biochemistry and Molecular Biology at the UTHealth Medical School.
Shyu, professor and holder of the Jesse H. Jones Chair in Molecular Biology at the UTHealth Medical School, added, “This link to brain tumors wasn’t previously known.”
“Its role in brain tumor progression was first found through big data computational analysis, then followed by animal-based testing. This is an unusual model for biomedical research, but is certainly more powerful, and may lead to the discovery of more drug targets,” said Li, an associate professor in the Dan L. Duncan Cancer Center and Department of Molecular and Cellular Biology at Baylor.
Wagner, Shyu, Li and their colleagues discovered a way to slow tumor growth in a mouse model of brain cancer by altering the process by which genes are converted into proteins.
Appropriately called messenger RNA for short, these molecules take the information inside genes and use it to make body tissues. While it was known that the messenger RNA molecules associated with the cancerous cells were shorter than those with healthy cells, the mechanism by which this occurred was not understood.
The research team discovered that a protein called CFIm25 is critical to keeping messenger RNA long in healthy cells and that its reduction promotes tumor growth. The key research finding in this study was that restoring CFIm25 levels in brain tumors dramatically reduced their growth.
“Understanding how messenger RNA length is regulated will allow researchers to begin to develop new strategies aimed at interfering with the process that causes unusual messenger RNA shortening during the formation of tumors,” Wagner said.
Additional preclinical tests are needed before the strategy can be evaluated in humans.
“The work described in the Nature paper by Drs. Wagner and Shyu stems from a high-risk/high-impact Cancer Prevention & Research Institute of Texas (CPRIT) proposal they submitted together and received several years ago,” said Rod Kellems, Ph.D., professor and chairman of the Department of Biochemistry and Molecular Biology at the UTHealth Medical School.
“Their research is of fundamental biological importance in that it seeks to understand the role of messenger RNA length regulation in gene expression,” Kellems said. “Using a sophisticated combination of biochemistry, genetics and bioinformatics, their research uncovered an important role for a specific protein that is linked to glioblastoma tumor suppression.”
(Source: uth.edu)
Study Examines Association Between Small-Vessel Disease, Alzheimer Pathology
Bottom Line: Cerebral small-vessel disease (SVD) and Alzheimer disease (AD) pathology appear to be associated.
Author: Maartje I. Kester, M.D., Ph.D., of the VU University Medical Center, Amsterdam, the Netherlands, and colleagues.
Background: AD is believed to be caused by the buildup of amyloid protein in the brain and tau tangles. Previous studies have suggested that SVD and vascular risk factors increase the risk of developing AD. In both SVD and vascular dementia (VaD), signs of AD pathology have been seen. But it remains unclear how the interaction between SVD and AD pathology leads to dementia.
How the Study Was Conducted: Authors examined the association between SVD and AD pathology by looking at magnetic resonance imaging (MRI)-based microbleeds (MB), white matter hyperintensities (WMH) and lacunes (which are measures for SVD) along with certain protein levels in cerebrospinal fluid (CSF) which reflect AD pathophysiology in patients with AD, VaD and healthy control patients. The authors also examined the relationship of apolipoprotein E (APOE) Ɛ4 genotype, a well-known risk factor for AD.
Results: The presence of both MBs and WMH was associated with lower CSF levels of Aβ42, suggesting a direct relationship between SVD and AD. Amyloid deposits also appear to be abnormal in patients with SVD, especially in (APOE) Ɛ4 carriers.
Discussion: “Our study supports the hypothesis that the pathways of SVD and AD pathology are interconnected. Small-vessel disease could provoke amyloid pathology while AD-associated cerebral amyloid pathology may lead to auxiliary vascular damage.”
(Source: media.jamanetwork.com)
Researchers Identify Genetic Marker Linked to OCD
A group of researchers led by Johns Hopkins scientists say they have identified a genetic marker that may be associated with the development of obsessive-compulsive disorder (OCD), whose causes and mechanisms are among the least understood among mental illnesses.
The results of the research are published online May 13 by the journal Molecular Psychiatry.
“If this finding is confirmed, it could be useful,” says study leader Gerald Nestadt, M.D., M.P.H., a professor of psychiatry and behavioral sciences at the Johns Hopkins University School of Medicine and director of Johns Hopkins’ Obsessive-Compulsive Disorder Program. “We might ultimately be able to identify new drugs that could help people with this often disabling disorder, one for which current medications work only 60 to 70 percent of the time.”
Nestadt and his team conducted what is known as a genome-wide association study, scanning the genomes of more than 1,400 people with OCD and more than 1,000 close relatives of people with the mental disorder. A significant association was identified in OCD patients near a gene called protein tyrosine phosphokinase (PTPRD).
OCD is a condition marked by thoughts and images that chronically intrude in the mind and by repetitive behaviors aimed at reducing the associated anxiety. Some of the least disabling forms of the disorder can add an extra hour to the day’s routine, causing distress and interfering with daily life. Some people are so disabled that they can’t leave their homes.
Experts say OCD affects an estimated 1 to 2 percent of the U.S. population, and the World Health Organization has called it one of the more disabling medical conditions worldwide. Antidepressants known as SSRIs work for some people, but not everyone; the same is true of behavioral therapy.
Nestadt says the genome-wide association study findings of a PTRPD-OCD link add to evidence that the genetic region they identified is important. The gene has already been shown in animals to be possibly involved in learning and memory, traits influenced by OCD in humans. Moreover, some cases of attention-deficit hyperactivity disorder (ADHD) have been associated with the gene, and OCD and ADHD have some symptoms in common. He says the gene also works with another gene family, SLITRK, which has also been associated with OCD in animals.
“OCD research has lagged behind other psychiatric disorders in terms of genetics,” Nestadt says. “We hope this interesting finding brings us closer to making better sense of it — and helps us find ways to treat it.”
(Image credit: Jennifer Soo)
Brain May Never Fully Recover from Exposure to Paint, Glue, Degreasers
People who are exposed to paint, glue or degreaser fumes at work may experience memory and thinking problems in retirement, decades after their exposure, according to a study published in the May 13, 2014, print issue of Neurology®, the medical journal of the American Academy of Neurology.
“Our findings are particularly important because exposure to solvents is very common, even in industrialized countries like the United States.” said study author Erika L. Sabbath, ScD, of Harvard School of Public Health in Boston. “Solvents pose a real risk to the present and future cognitive health of workers, and as retirement ages go up, the length of time that people are exposed is going up, too.”
The study involved 2,143 retirees from the French national utility company. Researchers assessed the workers’ lifetime exposure to chlorinated solvents, petroleum solvents, and benzene, including the timing of last exposure and lifetime dosage. Benzene is used to make plastics, rubber, dye, detergents and other synthetic materials. Chlorinated solvents can be found in dry cleaning solutions, engine cleaners, paint removers and degreasers. Petroleum solvents are used in carpet glue, furniture polishes, paint, paint thinner and varnish. Of the participants, 26 percent were exposed to benzene, 33 percent to chlorinated solvents and 25 percent to petroleum solvents.
Participants took eight tests of their memory and thinking skills an average of 10 years after they had retired, when they were an average age of 66. A total of 59 percent of the participants had impairment on one to three of the eight tests; 23 percent had impairment on four or more tests; 18 percent had no impaired scores.
The average lifetime solvent exposure was determined based on historical company records, and the participants were categorized as having no exposure, moderate exposure if they had less than the average and high exposure if they had higher than the average. They were also divided by when the last exposure occurred, with those last exposed from 12 to 30 years prior to the testing considered as recent exposure and those last exposed 31 to 50 years prior considered as more distant exposure.
The research found that people with high, recent exposure to solvents were at greatest risk for memory and thinking deficits. For example, those with high, recent exposure to chlorinated solvents were 65 percent more likely to have impaired scores on tests of memory and visual attention and task switching than those who were not exposed to solvents. The results remained the same after accounting for factors such as education level, age, smoking and alcohol consumption.
“The people with high exposure within the last 12 to 30 years showed impairment in almost all areas of memory and thinking, including those not usually associated with solvent exposure,” Sabbath said. “But what was really striking was that we also saw some cognitive problems in those who had been highly exposed much longer ago, up to 50 years before testing. This suggests that time may not fully lessen the effect of solvent exposure on some memory and cognitive skills when lifetime exposure is high.”
Sabbath said the results may have implications for policies on workplace solvent exposure limits. “Of course, the first goal is protecting the cognitive health of individual workers. But protecting workers from exposure could also benefit organizations, payers, and society by reducing workers’ post-retirement health care costs and enabling them to work longer,” said Sabbath. “That said, retired workers who have had prolonged exposure to solvents during their career may benefit from regular cognitive screening to catch problems early, screening and treatment for heart problems that can affect cognitive health, or mentally stimulating activities like learning new skills.”
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.