Lithium in the brain

Experiments with neutrons at the Technische Universität München (TUM) show that the antidepressant lithium accumulates more strongly in white matter of the brain than in grey matter. This leads to the conclusion that it works differently from synthetic psychotropic drugs. The tissue samples were examined at the Research Neutron Source Heinz Maier-Leibnitz (FRM II) with the aim of developing a better understanding of the effects this substance has on the human psyche.

At present lithium is most popular for its use in rechargeable batteries. But for decades now, lithium has also been used to treat various psychological diseases such as depressions, manias and bipolar disorders. But, the exact biological mode of action in certain brain regions has hardly been understood. It is well known that lithium lightens moods and reduces aggression potential.

Because it is so hard to dose, doctors have been reluctant to prescribe this “universal drug”. Nonetheless, a number of international studies have shown that a higher natural lithium content in drinking water leads to a lower suicide rate in the general population. Lithium accumulates in the brains of untreated people, too. This means that lithium, which has so far been regarded as unimportant, could be an essential trace element for humans.

Lithium detection with neutrons

This is what Josef Lichtinger is studying in his doctoral thesis at the Chair for Hadron and Nuclear Physics (E12) at the Technische Universität München. From the Institute for Forensic Medicine at the Ludwig-Maximilians-Universität Munich (LMU) he received tissue samples taken from patients treated with lithium, untreated patients and healthy test persons. The physicist exposed these to a focused cold neutron beam of greatest intensity at the measuring station for prompt gamma activation analysis at FRM II.

Lithium reacts with neutrons in a very specific manner and decays to a helium and a tritium atom. Using a special detector developed by Josef Lichtinger, traces as low as 0.45 nanograms of lithium per gram of tissue can be measured. “It is impossible to make measurements as precise as those using the neutrons with any other method,” says Jutta Schöpfer, forensic scientist at the LMU in charge of several research projects on lithium distribution in the human body.

Lithium concentrates at the nerve-tracts

Lichtinger’s results are surprising: Only in the samples of a depressive patient treated with lithium did he observe a higher accumulation of lithium in the so-called white matter. This is the area in the brain where nerve tracts run. The lithium content in the neighboring grey matter was 3 to 4 times lower. Lithium accumulation in white matter was not observed in a number of untreated depressive patients. This points to the fact that lithium does not work in the space between nerve cells, like other psychotropic drugs, but within the nerve tracts themselves.

In a next step Josef Lichtinger plans to examine further tissue samples at TUM’s Research Neutron Source in order to confirm and expand his results. The goal is a space-resolved map showing lithium accumulation in the brain of a healthy and a depressive patient. This would allow the universal drug lithium to be prescribed for psychological disorders with greater precision and control. The project is funded by the German Research Foundation (DFG).

Publication:

J. Lichtinger et. al, „Position sensitive measurement of lithium traces in brain tissue with neutrons“, Med. Phys. 40, 023501 (2013)

Predicting Who Will Have Chronic Pain

Abnormalities in brain axons predispose people to chronic back pain after injury

Abnormalities in the structure of the brain predispose people to develop chronic pain after a lower back injury, according to new Northwestern Medicine® research. The findings could lead to changes in the way physicians treat patients’ pain.

Most scientists and clinicians have assumed chronic back pain stems from the site of the original injury.

“We’ve found the pain is triggered by these irregularities in the brain,” said A. Vania Apkarian, senior author of the study and a professor of physiology at Northwestern University Feinberg School of Medicine. “We’ve shown abnormalities in brain structure connections may be enough to push someone to develop chronic pain once they have an injury.”

Based on MRI brain scans of people who had a new lower back injury, Northwestern scientists could predict with about 85 percent accuracy which patients’ pain would persist. The predictor was a specific irregularity or marker the scientists identified in the axons, pathways in the brain’s white matter that connect brain cells so they can communicate with each other.

The findings provide a new view of treating chronic pain, which affects nearly 100 million Americans and costs up to $635 billion a year to treat.

“We think the people who are vulnerable need to be treated aggressively with medication early on to prevent their pain from becoming chronic,” Apkarian said. “Last year, we showed people who take medication early on had a better chance of recovering. Medication does help.” Apkarian also is a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

The research, funded by the National Institutes of Health, was published Sept. 16 in the journal Pain.

Brain abnormalities have been observed in other long-term chronic pain conditions. Apkarian’s study is the first to show brain structure abnormalities are a marker of a predisposition to the chronic pain, not a result of living with it.

The lead author of the study is Ali Mansour, M.D., formerly a postdoctoral fellow in Apkarian’s lab.

Apkarian’s research focuses on the relationship between chronic pain and the brain. One of his previous studies showed chronic pain patients lose gray matter volume over time.

Chronic pain is one of the most expensive health care conditions in the U.S. and takes an enormous toll on quality of life, yet there still is not a scientifically validated therapy for the condition. Lower back pain represents 28 percent of all causes of pain in the U.S.; about 23 percent of these patients suffer long-term pain.

The abnormalities identified in the study were found in multiple white matter axon bundles, some surrounding the nucleus accumbens and medial prefrontal cortex, two brain regions involved in processing emotion and pain. Last year, the Apkarian group showed that the physiological properties of these two regions identify which patients will persist with back pain. The new results identify a pre-existing culprit for these physiological responses to the injury.

“The brain abnormalities exist in the general population, but only those people with a back injury go on to develop the chronic pain,” Apkarian said.

For the study, Apkarian and his colleagues scanned the brains of 46 people who had an episode of lower back pain for at least four weeks and had not experienced any pain for at least one year before that. Their pain had to be rated at least five out of 10 on a pain scale for them to be included in the study.

Scientists followed the patients for a year, scanning their brains at the onset of study and one year later. After a year about half of them had improved, regardless of whether they took anything to treat the pain, and half of them continued to have pain. Those with the persistent pain had the same structural abnormalities in their white matter at the onset of the injury and after one year.

“The abnormality makes them vulnerable and predisposes them to enhanced emotional learning that then amplifies the pain and makes it more emotionally significant,” Apkarian said.

“Pain is becoming an enormous burden on the public,” said Linda Porter, the pain policy advisor at National Institute of Neurological Disorders and Stroke (NINDS) and a leader of the National Institutes of Health (NIH) Pain Consortium. “The U.S. government recently outlined steps to reduce the future burden of pain through broad-ranging efforts, including enhanced research. This study is a good example of the kind of innovative research we hope will reduce chronic pain, which affects a huge portion of the population.”

(Image: Shutterstock)

Multiple Sclerosis Appears to Originate in Different Part of Brain Than Long Believed

The search for the cause of multiple sclerosis, a debilitating disease that affects up to a half million people in the United States, has confounded researchers and medical professionals for generations. But Steven Schutzer, a physician and scientist at Rutgers New Jersey Medical School, has now found an important clue why progress has been slow – it appears that most research on the origins of MS has focused on the wrong part of the brain. 

Look more to the gray matter, the new findings published in the journal PLOS ONE suggest, and less to the white. That change of approach could give physicians effective tools to treat MS far earlier than ever before.   

Until recently, most MS research has focused on the brain’s white matter, which contains the nerve fibers. And for good reason: Symptoms of the disease, which include muscle weakness and vision loss, occur when there is deterioration of a fatty substance called myelin, which coats nerves contained in the white matter and acts as insulation for them. When myelin in the brain is degraded, apparently by the body’s own immune system, and the nerve fiber is exposed, transmission of nerve impulses can be slowed or interrupted. So when patients’ symptoms flare up, the white matter is where the action in the brain appears to be.

But Schutzer attacked the problem from a different direction. He is one of the first scientists to analyze patients’ cerebrospinal fluid (CSF) by taking full advantage of a combination of technologies called proteomics and high-resolution mass spectrometry. “Proteins present in the clear liquid that bathes the central nervous system can be a window to physical changes that accompany neurological disease,” says Schutzer, “and the latest mass spectrometry techniques allow us to see them as never before.” In this study, he used that novel approach to compare the cerebrospinal fluid of newly diagnosed MS patients with that of longer term patients, as well as fluid taken from people with no signs of neurological disease.

What Schutzer found startled one of his co-investigators, Patricia K. Coyle of Stony Brook University in New York, one of the leading MS clinicians and researchers in the country. The proteins in the CSF of the new MS patients suggested physiological disruptions not only in the white matter of the brain where the myelin damage eventually shows up. They also pointed to substantial disruptions in the gray matter, a different part of the brain that contains the axons and dendrites and synapses that transfer signals between nerves.   

Several scientists had in fact hypothesized that there might be gray matter involvement in early MS, but the technology needed to test their theories did not yet exist. Schutzer’s analysis, which Coyle calls “exquisitely sensitive,” provides the solid physical evidence for the very first time. It includes a finding that nine specific proteins associated with gray matter were far more abundant in patients who had just suffered their first attack than in longer term MS patients or in the healthy controls. “This evidence indicates gray matter may be the critical initial target in MS rather than white matter,” says Coyle. “We may have been looking in the wrong area.”

According to Coyle, that realization presents exciting possibilities. One, she says, is that patients who suffer attacks that appear related to MS could have their cerebrospinal fluid tested quickly. If proteins that point to early MS are found, helpful therapy could begin at once, before the disease can progress further. 

Coyle says Schutzer’s findings may also lead one day to more effective treatments for MS with far fewer side effects. Without specific knowledge of what causes multiple sclerosis, patients now need to take medications that can broadly weaken their immune systems. These drugs slow the body’s destruction of myelin in the brain, but also degrade the immune system’s ability to keep the body healthy in other ways. By suggesting an exciting new direction for MS research, Schutzer and his team may have set the stage for more targeted treatments that attack MS while preserving other important immune functions.     

Schutzer sees an even broader future for the work he is now doing. He also has used advanced analysis of cerebrospinal fluid to identify physical markers for neurological ailments that include Lyme disease, in which he has been a world leader in research for many years, as well as chronic fatigue syndrome. He says, “When techniques are refined, more medical conditions are examined, and costs per patient come down, one day there could be a broad panel of tests through which patients and their doctors can get early evidence of a variety of disorders, and use that knowledge to treat them both more quickly and far more effectively than is possible now. “

Migraine May Permanently Change Brain Structure

Migraine may have long-lasting effects on the brain’s structure, according to a study published in the August 28, 2013, online issue of Neurology®, the medical journal of the American Academy of Neurology.

“Traditionally, migraine has been considered a benign disorder without long-term consequences for the brain,” said study author Messoud Ashina, MD, PhD, with the University of Copenhagen in Denmark. “Our review and meta-analysis study suggests that the disorder may permanently alter brain structure in multiple ways.”

The study found that migraine raised the risk of brain lesions, white matter abnormalities and altered brain volume compared to people without the disorder. The association was even stronger in those with migraine with aura.

For the meta-analysis, researchers reviewed six population-based studies and 13 clinic-based studies to see whether people who experienced migraine or migraine with aura had an increased risk of brain lesions, silent abnormalities or brain volume changes on MRI brain scans compared to those without the conditions.

The results showed that migraine with aura increased the risk of white matter brain lesions by 68 percent and migraine with no aura increased the risk by 34 percent, compared to those without migraine. The risk for infarct-like abnormalities increased by 44 percent for those with migraine with aura compared to those without aura. Brain volume changes were more common in people with migraine and migraine with aura than those with no migraines.

“Migraine affects about 10 to 15 percent of the general population and can cause a substantial personal, occupational and social burden,” said Ashina. “We hope that through more study, we can clarify the association of brain structure changes to attack frequency and length of the disease. We also want to find out how these lesions may influence brain function.”

(Image: Getty images)

High-Flying Pilots at Increased Risk of Brain Lesions

A new study suggests that pilots who fly at high altitudes may be at an increased risk for brain lesions. The study is published in the August 20, 2013, print issue of Neurology®, the medical journal of the American Academy of Neurology.

For the study, 102 U-2 United States Air Force pilots and 91 non-pilots between the ages of 26 and 50 underwent MRI brain scans. The scans measured the amount of white matter hyperintensities, or tiny brain lesions associated with memory decline in other neurological diseases. The groups were matched for age, education and health factors.

“Pilots who fly at altitudes above 18,000 feet are at risk for decompression sickness, a condition where gas or atmospheric pressure reaches lower levels than those within body tissues and forms bubbles,” said study author Stephen McGuire, MD, with the University of Texas in San Antonio, the US Air Force School of Aerospace Medicine and a Fellow of the American Academy of Neurology. “The risk for decompression sickness among Air Force pilots has tripled from 2006, probably due to more frequent and longer periods of exposure for pilots. To date however, we have been unable to demonstrate any permanent clinical neurocognitive or memory decline.”

Symptoms affecting the brain that sometimes accompany decompression sickness include slowed thought processes, confusion, unresponsiveness and permanent memory loss.

The study found that pilots had nearly four times the volume and three times the number of brain lesions as non-pilots. The results were the same whether or not the pilots had a history of symptoms of decompression sickness.

The research also found that while the lesions in non-pilots were mainly found in the frontal white matter, as occurs in normal aging, lesions in the pilots were evenly distributed throughout the brain.

“These results may be valuable in assessing risk for occupations that include high-altitude mountain climbing, deep sea diving and high-altitude flying,” McGuire said.

Chocolate may help keep brain healthy, sharp in old age, study says

Older chocoholics may have a new excuse to indulge their cravings: The dark stuff not only soothes the soul, but might also sharpen the mind. 

In a study published Wednesday in the journal Neurology, researchers reported that chocolate may help improve brain health and thinking skills in the elderly. The Boston-based team found that older people who initially performed poorly on a memory and reasoning test and also had reduced blood flow to their brains showed improvement after drinking two cups of cocoa every day for a month.  

The researchers had set out to test whether chocolate could increase blood flow to the brain during problem solving, boosting performance, after finding in earlier studies that consuming chocolate high in the antioxidant flavanol was associated with better brain and blood vessel functioning. They recruited 60 elderly subjects for the new study. Since they suspected that flavanol would improve the subjects’ thinking skills and blood flow, they randomly assigned subjects to drink either flavanol-rich or flavanol-poor hot chocolate.

The participants drank two cups of hot chocolate every day for 30 days. Before and after the study period, they completed a memory and reasoning test, which assessed their ability to recognize patterns in a series of letters on a computer screen. Additionally, the researchers used ultrasound to indirectly measure the blood flow to subjects’ brains, as well as magnetic resonance imaging, or MRI,  to examine subjects’ white matter — the nerve fibers that connect different parts of the brain.

People who performed poorly on the initial cognitive test — about a third of the participants — also had reduced blood flow to their brains and widespread white matter damage. Those who scored high on the test had signficantly better blood flow and more intact white matter, indicating that blood flow, cognitive functioning and brain structure were linked.

At the end of the 30 days, the team found that drinking hot chocolate benefited only the subjects who had poor cognitive and neurovascular function to begin with. After the hot cocoa regimen, those individuals showed an 8% improvement in blood flow and a roughly 1 minute faster reaction time on the cognitive task. There was barely any improvement among those who had started out with normal blood flow and cognitive skills.

To the scientists’ surprise, there weren’t significant differences in the neurovascular or cognitive changes between the flavanol-rich and flavanol-poor groups — suggesting that something else in the chocolate was causing the improvements. The researchers plan to identify and test this component in future trials, said study leader Dr.  Farzaneh A. Sorond, a neurologist at Brigham and Women’s Hospital in Boston.

After identifying the substance, the researchers may even be able to produce it in pill form, said Dr. Costantino Iadecola, a neurologist at Weill Cornell Medical College in New York City, who was not involved in the study.

By showing that blood flow to the brain is associated with cognitive function, the study helps explain earlier findings that people with high blood pressure and other cardiovascular conditions were prone to developing dementia. This, in turn, suggests that the cognitive functioning test and other measures used in the trial may one day serve as cheap, noninvasive methods to screen people for risk of dementia.

Scientists have focused more on treating than on preventing age-related cognitive decline, Sorond said.

“By the time people develop these problems, it’s too late to initiate the drugs we have,” she said. “If we could diagnose them earlier, before they have clinical symptoms, using physiological markers … maybe we could prevent the disease or lessen its impact.”

The study has its limitations. The ultrasound technique the researchers used offered only an estimate of blood flow to the brain – a precise measurement would require a more invasive method. “This was an easy way to get this information, but not the most accurate way,” Iadecola said.

He added that the study was small, and that it was unclear how long the chocolate’s effects would last.

“Will these changes persist after a month of cocoa or go back to where they were before? Would you take the cocoa forever?” Iadecola said. “We don’t know.”

Although the study results may tempt some to add chocolate to their diet,  Sorond noted that the participants’ food intake was strictly regulated to offset the excess fat and sugar in hot chocolate. For people seeking to keep their brains healthy, she recommends an intervention already known to improve cognitive function: exercise.

FASD impacts brain development throughout childhood and adolescence not just at birth

Medical researchers at the University of Alberta recently published findings showing that brain development is delayed throughout childhood and adolescence for people born with Fetal Alcohol Spectrum Disorder (FASD).

Christian Beaulieu and Carmen Rasmussen, the two primary investigators in the research study, recently published the results of their work in the peer-reviewed journal, The Journal of Neuroscience. Their team scanned 17 people with FASD, and 27 people without the disorder, who were between 5 and 15 years old. Each participant underwent two to three scans, with each scan taking place two to four years apart. This is the first research study involving multiple scans of the same FASD study participants.

Researchers used an advanced MRI method that examines white matter in the brain. White matter forms connections between various regions of the brain and usually develops significantly during childhood and adolescence. Those who took part in the study were imaged multiple times, to see what kinds of changes occurred in brain development as the participants aged. Those without the disorder had marked increases in brain volume and white matter – growth that was lacking in those with FASD. However, the advanced MRI method revealed greater changes in the brain wiring of white matter in the FASD group, which the authors suggest may reflect compensation for delays in development earlier in childhood.

“These findings may suggest that significant brain changes happened earlier in the study participants who didn’t have FASD,” says the study’s first author, Sarah Treit, who is a student in the Centre for Neuroscience at the U of A. “This study suggests alcohol-induced injury with FASD isn’t static – those with FASD have altered brain development, they aren’t developing at the same rate as those without the disorder. And our research showed those with FASD consistently scored lower on all cognitive measures in the study.”

Treit said the research team also made other important observations. Children with FASD who demonstrated the greatest changes in white matter development also made the greatest gains in reading ability – “so the connection seems relevant.” And those with the most severe FASD showed the greatest changes in white matter brain wiring. Scans also confirmed those with FASD have less overall brain volume – this issue neither rectified itself nor worsened throughout the course of the study.

Beaulieu is a researcher in the Department of Biomedical Engineering, while Rasmussen works in the Department of Pediatrics. Their research was funded by the Canadian Institutes of Health Research.

The team is continuing their research in this area, in hopes of finding a biomarker for FASD, and to examine how the brain changes from adolescence into adulthood in those with the disorder. The advanced MRI imaging the team used can pinpoint brain damage present in those with FASD, and could one day guide medical interventions for those with the disorder, which affects one in every 100 Canadians.

Breakthrough Study Reveals Biological Basis for Sensory Processing Disorders in Kids

Sensory processing disorders (SPD) are more prevalent in children than autism and as common as attention deficit hyperactivity disorder, yet it receives far less attention partly because it’s never been recognized as a distinct disease.

In a groundbreaking new study from UC San Francisco, researchers have found that children affected with SPD have quantifiable differences in brain structure, for the first time showing a biological basis for the disease that sets it apart from other neurodevelopmental disorders.

One of the reasons SPD has been overlooked until now is that it often occurs in children who also have ADHD or autism, and the disorders have not been listed in the Diagnostic and Statistical Manual used by psychiatrists and psychologists.

“Until now, SPD hasn’t had a known biological underpinning,” said senior author Pratik Mukherjee, MD, PhD, a professor of radiology and biomedical imaging and bioengineering at UCSF. “Our findings point the way to establishing a biological basis for the disease that can be easily measured and used as a diagnostic tool,” Mukherjee said.

The work is published in the open access online journal NeuroImage:Clinical.

‘Out of Sync’ Kids

Sensory processing disorders affect 5 to 16 percent of school-aged children.

Children with SPD struggle with how to process stimulation, which can cause a wide range of symptoms including hypersensitivity to sound, sight and touch, poor fine motor skills and easy distractibility. Some SPD children cannot tolerate the sound of a vacuum, while others can’t hold a pencil or struggle with social interaction. Furthermore, a sound that one day is an irritant can the next day be sought out.  The disease can be baffling for parents and has been a source of much controversy for clinicians, according to the researchers.

“Most people don’t know how to support these kids because they don’t fall into a traditional clinical group,” said Elysa Marco, MD, who led the study along with postdoctoral fellow Julia Owen, PhD. Marco is a cognitive and behavioral child neurologist at UCSF Benioff Children’s Hospital, ranked among the nation’s best and one of California’s top-ranked centers for neurology and other specialties, according to the 2013-2014 U.S. News & World Report Best Children’s Hospitals survey.

“Sometimes they are called the ‘out of sync’ kids. Their language is good, but they seem to have trouble with just about everything else, especially emotional regulation and distraction. In the real world, they’re just less able to process information efficiently, and they get left out and bullied,” said Marco, who treats affected children in her cognitive and behavioral neurology clinic.

“If we can better understand these kids who are falling through the cracks, we will not only help a whole lot of families, but we will better understand sensory processing in general. This work is laying the foundation for expanding our research and clinical evaluation of children with a wide range of neurodevelopmental challenges – stretching beyond autism and ADHD,” she said.

Imaging the Brain’s White Matter

In the study, researchers used an advanced form of MRI called diffusion tensor imaging (DTI), which measures the microscopic movement of water molecules within the brain in order to give information about the brain’s white matter tracts. DTI shows the direction of the white matter fibers and the integrity of the white matter. The brain’s white matter is essential for perceiving, thinking and learning.

The study examined 16 boys, between the ages of eight and 11, with SPD but without a diagnosis of autism or prematurity, and compared the results with 24 typically developing boys who were matched for age, gender, right- or left-handedness and IQ. The patients’ and control subjects’ behaviors were first characterized using a parent report measure of sensory behavior called the Sensory Profile. 

The imaging detected abnormal white matter tracts in the SPD subjects, primarily involving areas in the back of the brain, that serve as connections for the auditory, visual and somatosensory (tactile) systems involved in sensory processing, including their connections between the left and right halves of the brain. 

“These are tracts that are emblematic of someone with problems with sensory processing,” said Mukherjee. “More frontal anterior white matter tracts are typically involved in children with only ADHD or autistic spectrum disorders. The abnormalities we found are focused in a different region of the brain, indicating SPD may be neuroanatomically distinct.” 

The researchers found a strong correlation between the micro-structural abnormalities in the white matter of the posterior cerebral tracts focused on sensory processing and the auditory, multisensory and inattention scores reported by parents in the Sensory Profile. The strongest correlation was for auditory processing, with other correlations observed for multi-sensory integration, vision, tactile and inattention.

The abnormal microstructure of sensory white matter tracts shown by DTI in kids with SPD likely alters the timing of sensory transmission so that processing of sensory stimuli and integrating information across multiple senses becomes difficult or impossible.

“We are just at the beginning, because people didn’t believe this existed,” said Marco. “This is absolutely the first structural imaging comparison of kids with research diagnosed sensory processing disorder and typically developing kids. It shows it is a brain-based disorder and gives us a way to evaluate them in clinic.”

Future studies need to be done, she said, to research the many children affected by sensory processing differences who have a known genetic disorder or brain injury related to prematurity.