Brain Connectivity Study Reveals Striking Differences Between Men and Women

A new brain connectivity study from Penn Medicine published today in the Proceedings of National Academy of Sciences found striking differences in the neural wiring of men and women that’s lending credence to some commonly-held beliefs about their behavior.

In one of the largest studies looking at the “connectomes” of the sexes, Ragini Verma, PhD, an associate professor in the department of Radiology at the Perelman School of Medicine at the University of Pennsylvania, and colleagues found greater neural connectivity from front to back and within one hemisphere in males, suggesting their brains are structured to facilitate connectivity between perception and coordinated action. In contrast, in females, the wiring goes between the left and right hemispheres, suggesting that they facilitate communication between the analytical and intuition.

“These maps show us a stark difference—and complementarity—in the architecture of the human brain that helps provide a potential neural basis as to why men excel at certain tasks, and women at others,” said Verma.

For instance, on average, men are more likely better at learning and performing a single task at hand, like cycling or navigating directions, whereas women have superior memory and social cognition skills, making them more equipped for multitasking and creating solutions that work for a group. They have a mentalistic approach, so to speak.

Past studies have shown sex differences in the brain, but the neural wiring connecting regions across the whole brain that have been tied to such cognitive skills has never been fully shown in a large population.

In the study, Verma and colleagues, including co-authors Ruben C. Gur, PhD, a professor of psychology in the department of Psychiatry, and Raquel E. Gur, MD, PhD, professor of Psychiatry, Neurology and Radiology, investigated the gender-specific differences in brain connectivity during the course of development in 949 individuals (521 females and 428 males) aged 8 to 22 years using diffusion tensor imaging (DTI). DTI is water-based imaging technique that can trace and highlight the fiber  pathways connecting the different regions of the brain, laying the foundation for a structural connectome or network of the whole brain.

This sample of youths was studied as part of the Philadelphia Neurodevelopmental Cohort, a National Institute of Mental Health-funded collaboration between the University of Pennsylvania Brain Behavior Laboratory and the Center for Applied Genomics at the Children’s Hospital of Philadelphia. 

The brain is a roadmap of neural pathways linking many networks that help us process information and react accordingly, with behavior controlled by several of these sub-networks working in conjunction. 

In the study, the researchers found that females displayed greater connectivity in the supratentorial region, which contains the cerebrum, the largest part of the brain, between the left and right hemispheres. Males, on the other hand, displayed greater connectivity within each hemisphere. 

By contrast, the opposite prevailed in the cerebellum, the part of the brain that plays a major role in motor control, where males displayed greater inter-hemispheric connectivity and females displayed greater intra-hemispheric connectivity. 

These connections likely give men an efficient system for coordinated action, where the cerebellum and cortex participate in bridging between perceptual experiences in the back of the brain, and action, in the front of the brain, according to the authors. The female connections likely facilitate integration of the analytic and sequential processing modes of the left hemisphere with the spatial, intuitive information processing modes of the right side.

The authors observed only a few gender differences in the connectivity in children younger than 13 years, but the differences were more pronounced in adolescents aged 14 to 17 years and young adults older than 17.

The findings were also consistent with a Penn behavior study, of which this imaging study was a subset of, that demonstrated pronounced sexual differences.  Females outperformed males on attention, word and face memory, and social cognition tests. Males performed better on spatial processing and sensorimotor speed. Those differences were most pronounced in the 12 to 14 age range.

“It’s quite striking how complementary the brains of women and men really are,” said Dr. Ruben Gur.  “Detailed connectome maps of the brain will not only help us better understand the differences between how men and women think, but it will also give us more insight into the roots of neurological disorders, which are often sex related.”

Next steps are to quantify how an individual’s neural connections are different from the population; identify which neural connections are gender specific and common in both; and to see if findings from functional magnetic resonance imaging (fMRI) studies fall in line with the connectome data.

Do glial connectomes and activity maps make any sense?

"If all you have is a hammer, everything looks like a nail." This so-called "law of the instrument" has shaped neuroscience to core. It can be rephrased as, if all you have a fancy voltmeter, everything looks like a transient electrical event. No one in the field understands this more Douglass Fields, an NIH researcher who has re-written every neuroscience dogma he has turned his scrupulous eye to. In a paper published yesterday in Nature, Fields questions the conventional wisdom that informs recent efforts to map the brain’s connectivity, and ultimately, its electrical activity. In particular, he questions the value of making detailed maps of neurons, while at the same time neglecting the more abundant, and equally complex “maps” that exist for glia.

When first discovered, the “action potential” generated by a neuron was a rich and multiphysical event. It has since degenerated into a sterile, directionally-rectified electrical blip, whose only interesting parameter is a millisecond-scrutinized timestamp. In the last two years alone, Fields has re-generalized the spike. Having highlighted many of the fine scale physical events that accompany a neuron’s firing, like temperature and volume changes, optical effects, displacement, and myriad nonsynaptic effects, Fields demonstrated the intimate knitting of reverse propagating spikes into the behavior and function of neuronal networks. He also showed how spikes directly control non-neuronal events, in particular, myelination.

The Eyewire project at MIT is a fantastic effort to create detailed neuronal maps—it expands neuroscience to the larger community, and generates much worthwhile scientific spin-off. It is also completely absurd. To have so much talk about brain maps without drawing clear distinction between the glaring contrast in the value of white matter maps and grey matter maps is telling. Maps of the white matter will be indespensible to understanding our own brains. They are highly personal, yet at the same time will be one of the most valuable things we might soon come to share. For the moment here, we can liken them to the subway or transportation map of a complex city.

To try and map the grey matter, at least in our foreseeable era, is to attempt to record the comings and goings of all the people entering and exiting the doors of the trains of our subway system. Not only is the task infinitely harder, pound for pound, it is equally less valuable, and impermanent. Looked at another way, if we imagine some hyper-detailed ecologist mapping the different trees in a forest, one valuable piece of information to have would be the tree species or type. Their age, size, density and distribution would similarly be worthwhile parameters. Also maybe some detail about their finer structure would be predictive of what kind of animals species might live and move about their arbors. Eyewire, on the other hand, is mapping every twig down to the finest termination as a leaf. The problem is that leaves are shed and regenerated anew each year, and while Eyewire might map a few neurons in the same time, synapses morph to a faster drum.

The point of Field’s article is that glial trees have exactly the same level of detail and importance as neural trees, yet they are ignored in the aspirations of the connectomists. In fact, if neurons are like deciduous tress, with long, unpredictable, idiosyncratic and internexed branches, then glial cells, particularly astrocytes, are very much like conifers—they rigidly span nonoverlapping domains in the grey matter, in prototypical, scaffolded form, and with frequently symmetric repeatable structure. If we accept the results of neuroanatomy at face value here, grey matter might be imagined more like an astrocytic christmas tree farm superimposed on a neural rainforest. Stepping back, if given a choice between a grey matter connectome, and a white matter myelome, the latter is undoubtedly where the focus should be for now.

It may be a misstep in our study of glial cells to narrow-mindedly attempt to define for them, only that which has already been defined for neurons. The literature consists largely of a reattribution of transmitter or other chemical mechanisms of neurons to glia. The exceptioned qualifier here is that the speed of these processes—their electricality, directionality and extreme spatial aspect—is not a general feature of glial cells. For glial cells, new mechanisms need to be explored, and the most obvious among them perhaps, is that many of them, particularly the microglial cells, like to move.

It is increasingly appreciated nowadays, that much of the 10 or so watts attributed to the brain for its power budget, is purposed for things other then sending spikes and maintaining static electrical potentials. In the home, we can save on energy by dimming the lights, but to really make a dent, we need to turn off the things that move—things like fans, or the pumps in the HVAC systems. Much of the actual flow and motion inside the cerebral hive is transduced through glial cells. Undoubtedly axons drag diluent down their extent as they transport organelles across improbably expanses, and expel pressurized boluses of irritant (there may in fact be much to be said for an analogy with leaves powering fluid conduction in trees through local evaporation). It is however, the glial cells that seem to be the heavy lifters involved in flow. Transducing hand-picked intracellular flow, and bulk extracellular flow, sourced from the vasculature to neurons, they complete the so-called glymphatic circuit.

To be strict, perhaps we need to refigure this estimate of 10 watts, expanding it to include non-chemical sources, like the input of hydraulic power into the brain via the heart. If, for example, the brain consumes 20% of the flow from the heart, it also dissipates around 20% of the 100 or more watts of power generated by the heart. That should in fact be a significant contribution. By some estimates, we may have around 100,000 miles of myelinated axons in our brains, all surrounded by glial cells. Similarly, we may have the same amount, 100,000 miles, of capillary in the brain, all surrounded by astrocytic endfeet. Considering the scale of these numbers, it may be useful to start to look at the brain as more of a fluid-transporting machine, as opposed to mainly an electrical device.

The evidence is fairly clear that at the sensory and motor levels, spikes conduct much of the information about a stimulus or movement, particularly the short time scale components of that information. In moving more centrally from both sensory and motor ends, spikes tend to unhinge from real world metrics. If we are not careful to consider what neurons might actually be doing at a more global, physiologic level when they generate and propagate spikes, we may find that while we believe we are recording signals, we are actually just recording the noise of the pumps.

Nanotools for neuroscience and brain activity mapping

The ambitious and controversial Brain Activity Map (BAM), initiative instituted by a small group of researchers last year, has been steadily gaining momentum. Earlier this week, a proof-of-principle Zebrafish BAM was demonstrated with astounding clarity by a pair of researchers at the Howard Hughes Medical Institute.

Following on the heels of that work, an exhaustive 17-page compendium of current and soon-to-be brain mapping tools was published yesterday in ACS Nano by a rapidly snowballing list of disciples.

The BAM roster has been a carefully manicured player list from the beginning, and the role it has as ship wheel to this diffuse effort should not be underestimated. With the ranks now swelling to 27, each contributor to the paper has, in word or in spirit, contributed notably to the 185 referenced technologies on the paper. What we have here is not a research release, this is a textbook for the new neuroscience, and the journal choice, though not publicly accessible, hints at the desire to draw even more nanoscale researchers into the effort.

Media attention has channeled formative criticism to the effort in a way we have not seen before. Those sentiments on the cautionary take at least, might be summarized by likening the BAM scientists to cavemen having just discovered fire. Now sitting in the sand, they appear to be chartering a course to the internal combustion engine as they scribe on the ground with blunt bone instruments. The problem is that having just fleshed out how the brain’s wiring, the connectome, might be extracted, the community elites just leapfrogged to the full activity map, or at least one for some of the lesser animals.

The most extravagant technology proposed is undoubtedly the DNA tickertape. It appears to have been developed initially, at least in part, by Northwestern University’s Konrad Kording. Some of the earlier BAM papers show however that George Church, of human genome project fame, actually holds a patent that might cover some aspects of Kording’s idea. In particular, Church seems responsible for the wickedly unique concept of engineering DNA polymerases to produce predictable errors that would in effect record conditions within the cell or device onto DNA tapes. Fortunately Church, having entered neuroscience some time ago, is also a BAM founding father. His “nucleic acid memory device” could be the means by which the spike activity of each neuron would be recorded.

Among the other wild exotica hinted at in the ACS Nano paper is the DNA barcode proposed by Anthony Zador, from the Cold Spring Harbor Lab. This device would use a genetically modified rabies virus to infiltrate the nervous system, and record every connection in the process, web-crawl style. While Zador is not an author on this or the previous BAM papers, his techniques would not only provide a way to deliver a connectome of a complex brain, they potentially could do it non-destructively. Furthermore, the barcode mechanism would perhaps be the ideal way to propagate the Kording-Church tickertape machinery from cell to cell, bundling topology and activity together.

Many of the neurotools mentioned in the ACSNano paper are logical extensions of current technologies, just slightly smaller and a little higher in resolution. Recording cell activity with voltage-sensitive or calcium-imaging dyes, as was done in the Zebrafish map, may or may not be the process used ten years from now. Other ideas, like accessing neurons through fiber optic probes threaded through the vasculature to the capillaries, were re-invigorated, as were new sensors altogether like nanodiamond and nanogold devices.

Glaringly absent from this paper however, is a clear consensus of what exactly is to be done with these tools. The Zebrafish calcium map, for example, does not discriminate between neuron bodies, axons, dendrites, or synapses. The question of what level of detail is to be the goal of new studies still needs to be asked. This is a tough question because an activity map, like the connectome that would couch it, is rewritten on scales beneath our direct perception—not only is it a moving target, its trajectory is largely unknown. A long-term project such as this based in a set of technologies, as opposed to hypothesis-driven scientific inquiry, needs to balance fluidity with credibility.

Imagining what you would want to do if you were making a BAM of your own brain may emerge as the best way to set the project’s goals. In that case, the researchers may not be going for the whole BAM right away—just the things they would want to know in enough detail to get some answers in the least destructive way possible. If they plow through a bunch of animal studies generating terabytes of data, but cannot then use those methods used to learn about our brains, they will not have been successful. Priority then is to be the nondestructive BAM, focused on those high-interest, highly accessible areas with the highest density of observables wherein the observation risks are low. How to do this is the question of the next BAM installment.

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Alzheimer’s risk gene discovered using imaging method that screens brain’s connections

Scientists at UCLA have discovered a new genetic risk factor for Alzheimer’s disease by screening people’s DNA and then using an advanced type of scan to visualize their brains’ connections.

Alzheimer’s disease, the most common cause of dementia in the elderly, erodes these connections, which we rely on to support thinking, emotion and memory. With no known cure for the disease, the 20 million Alzheimer’s sufferers worldwide lack an effective treatment. And we are all at risk: Our chance of developing Alzheimer’s doubles every five years after age 65.

The UCLA researchers discovered a common abnormality in our genetic code that increases the risk of Alzheimer’s. To find the gene, they used a new imaging method that screens the brain’s connections — the wiring, or circuitry, that communicates information. Switching off such Alzheimer’s risk genes (nine of them have been implicated over the last 20 years) could stop the disorder in its tracks or delay its onset by many years.

The research is published in the March 4 online edition of the journal Proceedings of the National Academy of Sciences.

"We found a change in our genetic code that boosts our risk for Alzheimer’s disease," said the study’s senior author, Paul Thompson, a UCLA professor of neurology and a member of the UCLA Laboratory of Neuro Imaging. "If you have this variant in your DNA, your brain connections are weaker. As you get older, faulty brain connections increase your risk of dementia."

The researchers, Thompson said, screened more than a thousand people’s DNA to find the common “spelling errors” in the genetic code that might heighten their risk for the disease later in life. The new study was the first of its kind to also give each person a “connectome scan,” a special type of scan that measures water diffusion in the brain, allowing scientists to map the strength of the brain’s connections.

The new scan reveals the brain’s circuitry and how information is routed around the brain, in order to discover risk factors for disease. The researchers then combined these connectivity scans with the extensive genomic screening to pinpoint what causes faulty wiring in the brain.

Hundreds of computers, calculating for months, sifted through more than 4,000 brain connections and the entire genetic code, comparing connection patterns in people with different genetic variations. In people whose genetic code differed in one specific gene called SPON1, weaker connections were found between brain centers controlling reasoning and emotion. The rogue gene also affects how senile plaques build up in the brain — one of the hallmarks of Alzheimer’s disease.

"Much of your risk for disease is written in your DNA, so the genome is a good place to look for new drug targets," said Thompson, who in 2009 founded a research network known as Project ENIGMA to pool brain scans and DNA from 26,000 people worldwide. "If we scan your brain and DNA today, we can discover dangerous genes that will undermine your ability to think and plan and will make you ill in the future. If we find these genes now, there is a better chance of new drugs that can switch them off before you or your family get ill."

Developing new therapeutics for Alzheimer’s is a hot area for pharmaceutical research, Thompson said.

It has also been found that the SPON1 gene can be manipulated to develop new treatments for the devastating disease, Thompson noted. When the rogue gene was altered in mice, it led to cognitive improvements and fewer plaques building up in the brain. Alzheimer’s patients show an accumulation of these senile plaques, which are made of a sticky substance called amyloid and are thought to kill brain cells, causing irreversible memory loss and personality changes.

Screening genomes has led to many new drug targets in the treatment of cancer, heart disease, arthritis and brain disorders such as epilepsy. But the UCLA team’s approach — screening genomes and performing brain scans of the same people — promises a faster and more efficient search.

"With a brain scan that takes half an hour and a DNA scan from a saliva sample, we can search your genes for factors that help or harm your brain’s connections," Thompson said. "This opens up a new landscape of discovery in medical science."

Human Connectome Project releases major data set on brain connectivity

The Human Connectome Project, a five-year endeavor to link brain connectivity to human behavior, has released a set of high-quality imaging and behavioral data to the scientific community. The project has two major goals: to collect vast amounts of data using advanced brain imaging methods on a large population of healthy adults, and to make the data freely available so that scientists worldwide can make further discoveries about brain circuitry.

The initial data release includes brain imaging scans plus behavioral information — individual differences in personality, cognitive capabilities, emotional characteristics and perceptual function — obtained from 68 healthy adult volunteers. Over the next several years, the number of subjects studied will increase steadily to a final target of 1,200. The initial release is an important milestone because the new data have much higher resolution in space and time than data obtained by conventional brain scans.

The Human Connectome Project (HCP) consortium is led by David C. Van Essen, PhD, Alumni Endowed Professor at Washington University School of Medicine in St. Louis, and Kamil Ugurbil, PhD, Director of the Center for Magnetic Resonance Research and the McKnight Presidential Endowed Chair Professor at the University of Minnesota.

“By making this unique data set available now, and continuing with regular data releases every quarter, the Human Connectome Project is enabling the scientific community to immediately begin exploring relationships between brain circuits and individual behavior,” says Van Essen. “The HCP will have a major impact on our understanding of the healthy adult human brain, and it will set the stage for future projects that examine changes in brain circuits underlying the wide variety of brain disorders afflicting humankind.”

The consortium includes more than 100 investigators and technical staff at 10 institutions in the United States and Europe (www.humanconnectome.org). It is funded by 16 components of the National Institutes of Health via the Blueprint for Neuroscience Research (www.neuroscienceblueprint.nih.gov).

“The high quality of the data being made available in this release reflects an intensive, multiyear effort to improve the data acquisition and analysis methods by this dedicated international team of investigators,” says Ugurbil.

The data set includes information about brain connectivity in each individual, using two distinct magnetic resonance imaging (MRI) approaches. One, called resting-state functional connectivity, is based on spontaneous fluctuations in functional MRI signals that occur in a complex pattern in space and time throughout the gray matter of the brain. Another, called diffusion imaging, provides information about the long-distance “wiring” – the anatomical pathways traversing the brain’s white matter. Each method has its own limitations, and analyses of both functional connectivity and structural connectivity in each subject should allow deeper insight than by either method alone.

Each subject is also scanned while performing a variety of tasks within the scanner, thereby providing extensive information about “Task-fMRI” brain activation patterns. Behavioral data using a variety of tests performed outside the scanner are being released along with the scan data for each subject. The subjects are drawn from families that include siblings, some of whom are twins. This will enable studies of the heritability of brain circuits.

The imaging data set released by the HCP takes up about two terabytes (2 trillion bytes) of computer memory — the equivalent of more than 400 DVDs — and is stored in a customized database called “ConnectomeDB.”

“ConnectomeDB is the next-generation neuroinformatics software for data sharing and data mining. It’s a convenient and user-friendly way for scientists to explore the available HCP data and to download data of interest for their research,” says Daniel S. Marcus, PhD, assistant professor of radiology and director of the Neuroinformatics Research Group at Washington University School of Medicine. “The Human Connectome Project represents a major advance in sharing brain imaging data in ways that will accelerate the pace of discovery about the human brain in health and disease.”

London neuroscience centre to map ‘connectome’ of foetal brain

A state-of-the-art imaging facility at St Thomas’ Hospital in London has been awarded a 15m euro grant to map the development of nerve connections in the brain before and just after birth.

The Centre for the Developing Brain — which is partly funded by King’s College London (KCL) — has built a unique neonatal Magnetic Resonance Imaging Clinical Research Facility based in the intensive care unit of the Evelina Children’s Hospital at St Thomas’. It is one of two centres in the world — the other being at Imperial College — to have such a clinical research facility and associated scanner within a neonatal intensive care unit.

Over the next few years a team headed up by David Edwards, a consultant neonatologist and KCL Professor of Paediatrics and Neonatal Medicine, will build up a diagram of connections in the brain of babies as they develop in the womb and then after they are born. The aim is to understand how the human brain assembles itself from a functional and structural perspective. The resulting map is called a connectome and is the brain equivalent of the human genome. It will be made available to the research community to help improve understanding of neurological disorders.

Does Einstein’s brain hold the secret to his genius?

Albert Einstein’s brain fascinates scientists and the general public alike, because it may provide clues to the neurological basis of his extraordinary intellectual abilities. The latest study of the great physicist’s grey matter was published last month. The researchers analyzed previously unpublished photographs of the great physicist’s cerebral cortex, and claim to have identified unusual, and hitherto unknown, features. But some are sceptical about how the findings have been interpreted.

Shortly after Einstein’s death on 18th April, 1955, pathologist Thomas Harvey removed his brain and dissected it into 240 blocks, taking dozens of photographs while he did so. He then sent some of the tissue samples and photographs to a handful of researchers, and eventually, a small number of studies emerged. The early ones showed that Einstein’s brain was, in fact, slightly smaller, and weighed about 200 grams less, than average, but subsequent investigations revealed several unusual features, which were, it was claimed, somehow related to his visuo-spatial skills.

For the new study, anthropologist Dean Falk of Florida State University and her colleagues analyzed 14 of the’s photographs from the museum collection, which together reveal the entire surface of Einstein’s cerebral cortex for the first time, enabling the researchers to examine the pattern of grooves and ridges and in detail and compare them to those seen in other brains.

"The new photographs reveal parts of Einstein’s brain that have not previously been seen in published images," says Falk. "We have identified most of the external details of his cerebral cortex, [and] the complexity and pattern of convolutions on certain parts of Einstein’s cerebral cortex is striking and unusual in comparison to brains from normal individuals."

"This is especially noticeable in the prefrontal cortex, which is important for advanced cognition, the parietal lobes, which are important for spatial and arithmetic reasoning, and the visual cortex. The primary sensory and motor cortices are also extraordinarily expanded in certain parts."

Some argue that any conclusions drawn from such findings could be meaningless. “Studying Einstein’s brain is like studying the writings of Nostradamus,” says Chris Chambers, a cognitive neuroscientist at Cardiff University. “You can read them backwards, forward, or even sideways, and draw whatever conclusions you like.”

"We inevitably end up committing logical fallacies of reverse inference and faulty generalisation: that certain parts of Einstein’s brain may look a bit different to other brains, and that this explains his abilities. But the differences might have no functional importance whatsoever, and this makes any kind of conclusion extremely weak."

Chambers adds that there is enormous variability in human brain structure, and that this poses another problem when trying to interpret such findings. “We’re dealing with just one brain and this makes it impossible to draw any firm conclusions about the population at large. Human brains come in all shapes and sizes and there is no known relationship to cognition. Very few people have the ‘normal’ brain we see in textbooks, and neither did Einstein.”

Clinical neurologist Frederick Lepore, a co-author of the new study, made similar arguments in 2001, and in an interview published online earlier this month, he is quoted as saying that the new study confirms Einstein’s brain “was very different,” but that “we face an insurmountable explanatory gap if we attempt to use our neuroanatomical findings to account for the mind that envisioned the curvature of the universe.”

He goes on to say that the next logical step would be to try to generate Einstein’s connectome, a comprehensive map of the connections in his brain, and that a comparison of the brain to those of other geniuses is another possible avenue of research.

Falk believes that the photographs could help researchers to map Einstein’s connectome. “[We have published]… the ‘roadmap’ that provides a key between these areas and recently emerged histological slides of Einstein’s brain, which may allow scientists to study its internal connectivity. These photographs should become more meaningful in the future, as more is learned about the functions of various regions.”