Brain Development in Schizophrenia Strays from the Normal Path

Schizophrenia is generally considered to be a disorder of brain development and it shares many risk factors, both genetic and environmental, with other neurodevelopmental disorders such as autism and intellectual disability.

The normal path for brain development is determined by the combined effects of a complex network of genes and a wide range of environmental factors.

However, longitudinal brain imaging studies in both healthy and patient populations are required in order to map the disturbances in brain structures as they emerge, i.e., the disturbed trajectories of brain development.

A new study by an international, collaborative group of researchers has measured neurodevelopment in schizophrenia, by studying brain development during childhood and adolescence in people with and without this disorder. With access to new statistical approaches and long-term follow-up with participants, in some cases over more than a decade, the researchers were able to describe brain development patterns associated with schizophrenia.

"Specifically, this paper shows that parts of the brain’s cortex develop differently in people with schizophrenia," said first author Dr. Aaron F. Alexander-Bloch, from the National Institute of Mental Health.

"The mapping of the path that the brain follows in deviating from normal development provides important clues to the underlying causes of the disorder," said Dr. John Krystal, Editor of Biological Psychiatry.

The findings were derived by investigating the trajectory of cortical thickness growth curves in 106 patients with childhood-onset schizophrenia and a comparison group of 102 healthy volunteers.

Each participant, ranging from 7–32 years of age, had repeated imaging scans over the course of several years. Then, using over 80,000 vertices across the cortex, the researchers modeled the effect of schizophrenia on the growth curve of cortical thickness.

This revealed differences that occur within a specific group of highly-connected brain regions that mature in synchrony during typical development, but follow altered trajectories of growth in schizophrenia.

"These findings show a relationship between the hypothesis that schizophrenia is a neurodevelopmental disorder and the longstanding hypothesis – first articulated by the German anatomist Karl Wernicke in the late 19th century – that it is a disease of altered connectivity between regions of the brain," added Alexander-Bloch.

This theoretical consistency is important, as it allows researchers to better focus future studies of brain connectivity in schizophrenia, by targeting the brain regions known to be affected.

(Image caption: Example axial sections of a three-dimensional MPF map (A) obtained from a 63-year old woman with SPMS disease course and results of brain tissue segmentation (B-D). Segmentation masks corresponding to white matter (WM) (B), gray matter (GM) (C), and lesi)

MRI Shows Gray Matter Myelin Loss Strongly Related to MS Disability

People with multiple sclerosis (MS) lose myelin in the gray matter of their brains and the loss is closely correlated with the severity of the disease, according to a new magnetic resonance imaging (MRI) study. Researchers said the findings could have important applications in clinical trials and treatment monitoring. The study appears online in the journal Radiology.

Loss of myelin, the fatty protective sheath around nerve fibers, is a characteristic of MS, an inflammatory disease of the central nervous system that can lead to a variety of serious neurological symptoms and disability. MS is typically considered a disease of the brain’s signal-conducting white matter, where myelin is most abundant, but myelin is also present in smaller amounts in gray matter, the brain’s information processing center that is made up primarily of nerve cell bodies. Though the myelin content in gray matter is small, it is still extremely important to proper function, as it enables protection of thin nerve fibers connecting neighboring areas of the brain cortex, according to Vasily L. Yarnykh, Ph.D., associate professor in the Department of Radiology at University of Washington in Seattle.

“The fact that MS patients lose myelin not only in white but also in gray matter has been proven by earlier post-mortem pathological studies,” he said. “However, the clinical significance of the myelin loss, or demyelination, in gray matter has not been established because of the absence of appropriate imaging methods.”

To learn more about associations between MS and demyelination in both white and gray matter, Dr. Yarnykh and colleagues used a refined MRI technique that provides information on the content of biological macromolecules – molecules present in tissues and composed of a large number of atoms, such as proteins, lipids and carbohydrates. The new method, known as macromolecular proton fraction (MPF) mapping, has been hampered in the past because of the length of time required for data collection, but improvements now allow much faster generation of whole-brain maps that reflect the macromolecular content in tissues.

“The method utilizes a standard MRI scanner and doesn’t require any special hardware—only some software modifications,” Dr. Yarnykh said. “MPF mapping allows quantitative assessment of microscopic demyelination in brain tissues that look normal on clinical images, and is the only existing method able to evaluate the myelin content in gray matter.”

The researchers looked at 30 MS patients, including 18 with relapsing-remitting MS (RRMS), the most common type of MS initially diagnosed, and 12 with the more advanced type of disease known as secondary progressive MS (SPMS). Fourteen healthy control participants were also included in the study. Each participant underwent MRI on a 3-Tesla imager, and the researchers reconstructed 3-D whole-brain MPF maps to look at normal-appearing white matter, gray matter and MS lesions. The researchers further compared the results of their imaging technique with clinical tests characterizing neurological dysfunction in MS patients.

The results showed that MPF was significantly lower in both white and gray matter in RRMS patients compared with healthy controls, and was also significantly reduced in both normal-appearing brain tissues and lesions of SPMS patients compared to RRMS patients with the largest relative decrease in gray matter. MPF in brain tissues of MS patients significantly correlated with clinical disability and the strongest associations were found for gray matter.

“The major finding of the study is that the loss of myelin in gray matter caused by MS in its relative amount is comparable to or even larger than that in white matter,” said Dr. Yarnykh. “Furthermore, gray matter demyelination is much more advanced in patients with secondary-progressive MS, and it is very strongly related to patients’ disability. As such, we believe that information about gray matter myelin damage in MS is of primary clinical relevance.”

The improved technique has potentially important applications for MS treatments targeted to protect and restore myelin.

“First, this method may provide an objective measure of the disease progression and treatment success in clinical trials,” Dr. Yarnykh said. “And second, assessment of both gray and white matter damage with this method may become an individual patient management tool in the future.”

Dr. Yarnykh and colleagues are currently conducting additional research on the new method with the support of the National Multiple Sclerosis Society and the National Institutes of Health.

“This study was done on the participants at a single point in time,” he said. “Now we want to compare MS patients with control participants to see how myelin content will evolve over time. We further plan to extend our method to the spinal cord imaging and test whether the combined assessment of demyelination in the brain and spinal cord could better explain disability progression as compared to brain demyelination alone.”

Brain structure could predict risky behavior

Some people avoid risks at all costs, while others will put their wealth, health, and safety at risk without a thought. Researchers at Yale School of Medicine have found that the volume of the parietal cortex in the brain could predict where people fall on the risk-taking spectrum.

Led by Ifat Levy, assistant professor in comparative medicine and neurobiology at Yale School of Medicine, the team found that those with larger volume in a particular part of the parietal cortex were willing to take more risks than those with less volume in this part of the brain. The findings are published in the Sept. 10 issue of the Journal of Neuroscience.

Although several cognitive and personality traits are reflected in brain structure, there has been little research linking brain structure to economic preferences. Levy and her colleagues sought to examine this question in their study.

Study participants included young adult men and women from the northeastern United States. Participants made a series of choices between monetary lotteries that varied in their degree of risk, and the research team conducted standard anatomical MRI brain scans. The results were first obtained in a group of 28 participants, and then confirmed in a second, independent, group of 33 participants.

“Based on our findings, we could, in principle, use millions of existing medical brains scans to assess risk attitudes in populations,” said Levy. “It could also help us explain differences in risk attitudes based in part on structural brain differences.”

Levy cautions that the results do not speak to causality. “We don’t know if structural changes lead to behavioral changes or vice-versa,” she said.

Levy and her team had previously shown that risk aversion increases as people age, and we scientists also know that the cortex thins substantially with age. “It could be that this thinning explains the behavioral changes; we are now testing that possibility,” said Levy, who also notes that more studies in wider populations are needed.

Status and the Brain

Social hierarchy is a fact of life for many animals. Navigating social hierarchy requires understanding one’s own status relative to others and behaving accordingly, while achieving higher status may call upon cunning and strategic thinking. The neural mechanisms mediating social status have become increasingly well understood in invertebrates and model organisms like fish and mice but until recently have remained more opaque in humans and other primates. In a new study in this issue, Noonan and colleagues explore the neural correlates of social rank in macaques. Using both structural and functional brain imaging, they found neural changes associated with individual monkeys’ social status, including alterations in the amygdala, hypothalamus, and brainstem—areas previously implicated in dominance-related behavior in other vertebrates. A separate but related network in the temporal and prefrontal cortex appears to mediate more cognitive aspects of strategic social behavior. These findings begin to delineate the neural circuits that enable us to navigate our own social worlds. A major remaining challenge is identifying how these networks contribute functionally to our social lives, which may open new avenues for developing innovative treatments for social disorders.

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Training Your Brain to Prefer Healthy Foods

It may be possible to train the brain to prefer healthy low-calorie foods over unhealthy higher-calorie foods, according to new research by scientists at the Jean Mayer USDA Human Nutrition Research Center on Aging (USDA HNRCA) at Tufts University and at Massachusetts General Hospital. Published online today in the journal Nutrition & Diabetes, a brain scan study in adult men and women suggests that it is possible to reverse the addictive power of unhealthy food while also increasing preference for healthy foods.

“We don’t start out in life loving French fries and hating, for example, whole wheat pasta,” said senior and co-corresponding author Susan B. Roberts, Ph.D., director of the Energy Metabolism Laboratory at the USDA HNRCA, who is also a professor at the Friedman School of Nutrition Science and Policy at Tufts University and an adjunct professor of psychiatry at Tufts University School of Medicine. “This conditioning happens over time in response to eating – repeatedly! - what is out there in the toxic food environment.”

Scientists have suspected that, once unhealthy food addiction circuits are established, they may be hard or impossible to reverse, subjecting people who have gained weight to a lifetime of unhealthy food cravings and temptation. To find out whether the brain can be re-trained to support healthy food choices, Roberts and colleagues studied the reward system in thirteen overweight and obese men and women, eight of whom were participants in a new weight loss program designed by Tufts University researchers and five who were in a control group and were not enrolled in the program.

Both groups underwent magnetic resonance imaging (MRI) brain scans at the beginning and end of a six-month period. Among those who participated in the weight loss program, the brain scans revealed changes in areas of the brain reward center associated with learning and addiction. After six months, this area had increased sensitivity to healthy, lower-calorie foods, indicating an increased reward and enjoyment of healthier food cues. The area also showed decreased sensitivity to the unhealthy higher-calorie foods.

“The weight loss program is specifically designed to change how people react to different foods, and our study shows those who participated in it had an increased desire for healthier foods along with a decreased preference for unhealthy foods, the combined effects of which are probably critical for sustainable weight control,” said co-author Sai Krupa Das, Ph.D., a scientist in the Energy Metabolism Laboratory at the USDA HNRCA and an assistant professor at the Friedman School. “To the best of our knowledge this is the first demonstration of this important switch.” The authors hypothesize that several features of the weight loss program were important, including behavior change education and high-fiber, low glycemic menu plans.

“Although other studies have shown that surgical procedures like gastric bypass surgery can decrease how much people enjoy food generally, this is not very satisfactory because it takes away food enjoyment generally rather than making healthier foods more appealing,” said first author and co-corresponding author Thilo Deckersbach, Ph.D., a psychologist at Massachusetts General Hospital. “We show here that it is possible to shift preferences from unhealthy food to healthy food without surgery, and that MRI is an important technique for exploring the brain’s role in food cues.”

“There is much more research to be done here, involving many more participants, long-term follow-up and investigating more areas of the brain,” Roberts added. “But we are very encouraged that, the weight loss program appears to change what foods are tempting to people.”

How studying damage to the prefrontal lobe has helped unlock the brain’s mysteries

Until the last few decades, the frontal lobes of the brain were shrouded in mystery and erroneously thought of as nonessential for normal function—hence the frequent use of lobotomies in the early 20th century to treat psychiatric disorders. Now a review publishing August 28 in the Cell Press journal Neuron highlights groundbreaking studies of patients with brain damage that reveal how distinct areas of the frontal lobes are critical for a person’s ability to learn, multitask, control their emotions, socialize, and make real-life decisions. The findings have helped experts rehabilitate patients experiencing damage to this region of the brain.

Although fairly common, damage to the prefrontal lobes (also called the prefrontal cortex) is often overlooked and undiagnosed because patients do not manifest obvious deficits. For example, patients with prefrontal brain damage do not lose any of their senses and often have preserved motor and language abilities, but they may manifest social abnormalities or difficulties with high-level planning in everyday life situations.

"In this review, we aimed to highlight a blend of new studies using cutting edge research techniques to investigate brain damage, but also to relate these new studies to original studies, some of which were published more than a century ago," said lead author Dr. Sara Szczepanski, of the University of California, Berkeley. "There is currently a large push to better understand the functions of the prefrontal cortex, and we believe that our review will make an important contribution to this understanding."

In addition to revealing the functions of different areas within the prefrontal cortex, studies have also demonstrated the flexibility of the region, which has helped experts optimize cognitive therapy techniques to enable patients with brain damage to learn new skills and compensate for their impairments.

The review indicates that by studying patients with damage to the prefrontal cortex, investigators can gain insights into this still-mysterious region of the brain that is critical for complex human skills and behavior.

This is Your Brain’s Blood Vessels on Drugs

A new method for measuring and imaging how quickly blood flows in the brain could help doctors and researchers better understand how drug abuse affects the brain, which may aid in improving brain-cancer surgery and tissue engineering, and lead to better treatment options for recovering drug addicts. The new method, developed by a team of researchers from Stony Brook University in New York, USA and the U.S. National Institutes of Health, was published today in The Optical Society’s (OSA) open-access journal Biomedical Optics Express.

The researchers demonstrated their technique by using a laser-based method of measuring how cocaine disrupts blood flow in the brains of mice. The resulting images are the first of their kind that directly and clearly document such effects, according to co-author Yingtian Pan, associate professor in the Department of Biomedical Engineering at Stony Brook University. “We show that quantitative flow imaging can provide a lot of useful physiological and functional information that we haven’t had access to before,” he says.

Drugs such as cocaine can cause aneurysm-like bleeding and strokes, but the exact details of what happens to the brain’s blood vessels have remained elusive—partly because current imaging tools are limited in what they can see, Pan says. But using their new and improved methods, the team was able to observe exactly how cocaine affects the tiny blood vessels in a mouse’s brain. The images reveal that after 30 days of chronic cocaine injection or even after just repeated acute injection of cocaine, there’s a dramatic drop in blood flow speed. The researchers were, for the first time, able to identify cocaine-induced microischemia, when blood flow is shut down—a precursor to a stroke.

Measuring blood flow is crucial for understanding how the brain is working, whether you’re a brain surgeon or a neuroscientist studying how drugs or disease influence brain physiology, metabolism and function, Pan said. Techniques like functional magnetic resonance imaging (fMRI) provide a good overall map of the flow of deoxygenated blood, but they don’t have a high enough resolution to study what happens inside tiny blood vessels called capillaries. Meanwhile, other methods like two-photon microscopy, which tracks the movement of red blood cells labeled with fluorescent dyes, have a small field of view that only measures few vessels at a time rather than blood flow in the cerebrovascular networks.

In the last few years, researchers including Pan and his colleagues have developed another method called optical coherence Doppler tomography (ODT). In this technique, laser light hits the moving blood cells and bounces back. By measuring the shift in the reflected light’s frequency—the same Doppler effect that causes the rise or fall of a siren’s pitch as it moves toward or away from you—researchers can determine how fast the blood is flowing.

It turns out that ODT offers a wide field of view at high resolution. “To my knowledge, this is a unique technology that can do both,” Pan said. And, it doesn’t require fluorescent dyes, which can trigger harmful side effects in human patients or leave unwanted artifacts—from interactions with a drug being tested, for example—when used for imaging animal brains.

Two problems with conventional ODT right now, however, are that it’s only sensitive to a limited range in blood-flow speeds and not sensitive enough to detect slow capillary flows, Pan explained. The researchers’ new method described in today’s Biomedical Optics Express paper incorporates a new processing method called phase summation that extends the range and allows for imaging capillary flows.

Another limitation of conventional ODT is that it doesn’t work when the blood vessel is perpendicular to the incoming laser beam. In an image, the part of the vessel that’s perpendicular to the line of sight wouldn’t be visible, instead appearing dark. But by tracking the blood vessel as it slopes up or down near this dark spot, the researchers developed a way to use that information to interpolate the missing data more accurately.

ODT can only see down to 1-1.5 millimeters below the surface, so the method is limited to smaller animals if researchers want to probe into deeper parts of the brain. But, Pan says, it would still be useful when the brain’s exposed in the operating room, to help surgeons operate on tumors, for example.

The new method is best suited to look at small blood vessels and networks, so it can be used to image the capillaries in the eye as well. Bioengineers can also use it to monitor the growth of new blood vessels when engineering tissue, Pan said. Additionally, information about blood flow in the brain could also be applied to developing new treatment options for recovering drug addicts.

Researchers publish first study of brain activation in MS using fNIRS

Using functional near infrared spectroscopy (fNIRS), Kessler Foundation researchers have shown differential brain activation patterns between people with multiple sclerosis (MS) and healthy controls. This is the first MS study in which brain activation was studied using fNIRS while participants performed a cognitive task. The article, “Neuroimaging and cognition using functional near infrared spectroscopy (fNIRS) in multiple sclerosis,” was published online on June 11 by Brain Imaging and Behavior. Authors are Jelena Stojanovic-Radic, PhD, Glenn Wylie, DPhil, Gerald Voelbel, PhD, Nancy Chiaravalloti, PhD, and John DeLuca, PhD.

Researchers compared 13 individuals with MS with 12 controls for their performance on a working memory task with four levels of difficulty. Most such studies have employed functional magnetic resonance imaging (fMRI); fNIRS has been used infrequently in clinical populations, and has not been applied previously to neuroimaging research in MS.  Studies comparing fMRI findings with those of fNIRS, however, show broad agreement in terms of activation patterns.

Results showed differences in activation between the groups that were dependent on task load. The MS group had an increase in activation at low task difficulty and a decrease in activation at high task difficulty. Conversely, in the control group, activation decreased with low task difficulty and increased with high task difficulty. Performance accuracy was lower in the MS group for low task load; there were no differences between the groups at the higher task loads.  

“The data we obtained via fNIRS are consistent with fMRI data for clinical populations. We demonstrated that fNIRS is capable of detecting neuronal activation with a reasonable degree of detail,” noted Glenn Wylie, DPhil, associate director of Neuroscience and the Neuroimaging Center at Kessler Foundation. “We attribute the differences in brain activation patterns to the effort expended during the working memory task rather than to differences in speed of processing,” he added. “Because fNIRS is more portable and easier to use that fMRI, it may offer advantages in monitoring cognitive interventions that require frequent scans.”

In addition to working memory, future research in clinical populations should focus on processing speed and episodic memory, cognitive functions that are also affected in MS.

(Image credit)