Brain imaging reveals clues about chronic fatigue syndrome

A brain imaging study shows that patients with chronic fatigue syndrome may have reduced responses, compared with healthy controls, in a region of the brain connected with fatigue. The findings suggest that chronic fatigue syndrome is associated with changes in the brain involving brain circuits that regulate motor activity and motivation.

Compared with healthy controls, patients with chronic fatigue syndrome had less activation of the basal ganglia, as measured by fMRI (functional magnetic resonance imaging). This reduction of basal ganglia activity was also linked with the severity of fatigue symptoms.

According to the Centers for Disease Control and Prevention, chronic fatigue syndrome is a debilitating and complex disorder characterized by intense fatigue that is not improved by bed rest and that may be worsened by exercise or mental stress.

The results are scheduled for publication in the journal PLOS One.

"We chose the basal ganglia because they are primary targets of inflammation in the brain," says lead author Andrew Miller, MD. "Results from a number of previous studies suggest that increased inflammation may be a contributing factor to fatigue in CFS patients, and may even be the cause in some patients."

Miller is William P. Timmie professor of psychiatry and behavioral sciences at Emory University School of Medicine. The study was a collaboration among researchers at Emory University School of Medicine, the CDC’s Chronic Viral Diseases Branch, and the University of Modena and Reggio Emilia in Italy. The study was funded by the CDC.

The basal ganglia are structures deep within the brain, thought to be responsible for control of movements and responses to rewards as well as cognitive functions. Several neurological disorders involve dysfunction of the basal ganglia, including Parkinson’s disease and Huntington’s disease, for example.

In previous published studies by Emory researchers, people taking interferon alpha as a treatment for hepatitis C, which can induce severe fatigue, also show reduced activity in the basal ganglia. Interferon alpha is a protein naturally produced by the body, as part of the inflammatory response to viral infection. Inflammation has also been linked to fatigue in other groups such as breast cancer survivors.

"A number of previous studies have suggested that responses to viruses may underlie some cases of CFS," Miller says. "Our data supports the idea that the body’s immune response to viruses could be associated with fatigue by affecting the brain through inflammation. We are continuing to study how inflammation affects the basal ganglia and what effects that has on other brain regions and brain function. These future studies could help inform new treatments."

Treatment implications might include the potential utility of medications to alter the body’s immune response by blocking inflammation, or providing drugs that enhance basal ganglia function, he says.

The researchers compared 18 patients diagnosed with chronic fatigue syndrome with 41 healthy volunteers. The 18 patients were recruited [not referred] based on an initial telephone survey followed by extensive clinical evaluations. The clinical evaluations, which came in two phases, were completed by hundreds of Georgia residents. People with major depression or who were taking antidepressants were excluded from the imaging study, although those with anxiety disorders were not.

For the brain imaging portion of the study, participants were told they’d win a dollar if they correctly guessed whether a preselected card was red or black. After they made a guess, the color of the card was revealed, and at that point researchers measured blood flow to the basal ganglia.

The key measurement was: how big is the difference in activity between a win or a loss? Participants’ scores on a survey gauging their levels of fatigue were tied to the difference in basal ganglia activity between winning and losing. Those with the most fatigue had the smallest changes, especially in the right caudate and the right globus pallidus, both parts of the basal ganglia.

Ongoing studies at Emory are further investigating the impact of inflammation on the basal ganglia, including studies using anti-inflammatory treatments to reduce fatigue and loss of motivation in patients with depression and other disorders with inflammation including cancer.

(Image caption: A series of three MRI images (top row) shows how dopamine concentrations change over time in the brain’s ventral striatum. Photocollage: Christine Daniloff/MIT, with images courtesy of the researchers)

Delving deep into the brain

MRI sensor allows neuroscientists to map neural activity with molecular precision

Launched in 2013, the national BRAIN Initiative aims to revolutionize our understanding of cognition by mapping the activity of every neuron in the human brain, revealing how brain circuits interact to create memories, learn new skills, and interpret the world around us.

Before that can happen, neuroscientists need new tools that will let them probe the brain more deeply and in greater detail, says Alan Jasanoff, an MIT associate professor of biological engineering. “There’s a general recognition that in order to understand the brain’s processes in comprehensive detail, we need ways to monitor neural function deep in the brain with spatial, temporal, and functional precision,” he says.

Jasanoff and colleagues have now taken a step toward that goal: They have established a technique that allows them to track neural communication in the brain over time, using magnetic resonance imaging (MRI) along with a specialized molecular sensor. This is the first time anyone has been able to map neural signals with high precision over large brain regions in living animals, offering a new window on brain function, says Jasanoff, who is also an associate member of MIT’s McGovern Institute for Brain Research.

His team used this molecular imaging approach, described in the May 1 online edition of Science, to study the neurotransmitter dopamine in a region called the ventral striatum, which is involved in motivation, reward, and reinforcement of behavior. In future studies, Jasanoff plans to combine dopamine imaging with functional MRI techniques that measure overall brain activity to gain a better understanding of how dopamine levels influence neural circuitry.

“We want to be able to relate dopamine signaling to other neural processes that are going on,” Jasanoff says. “We can look at different types of stimuli and try to understand what dopamine is doing in different brain regions and relate it to other measures of brain function.”

Tracking dopamine

Dopamine is one of many neurotransmitters that help neurons to communicate with each other over short distances. Much of the brain’s dopamine is produced by a structure called the ventral tegmental area (VTA). This dopamine travels through the mesolimbic pathway to the ventral striatum, where it combines with sensory information from other parts of the brain to reinforce behavior and help the brain learn new tasks and motor functions. This circuit also plays a major role in addiction.

To track dopamine’s role in neural communication, the researchers used an MRI sensor they had previously designed, consisting of an iron-containing protein that acts as a weak magnet. When the sensor binds to dopamine, its magnetic interactions with the surrounding tissue weaken, which dims the tissue’s MRI signal. This allows the researchers to see where in the brain dopamine is being released. The researchers also developed an algorithm that lets them calculate the precise amount of dopamine present in each fraction of a cubic millimeter of the ventral striatum.

After delivering the MRI sensor to the ventral striatum of rats, Jasanoff’s team electrically stimulated the mesolimbic pathway and was able to detect exactly where in the ventral striatum dopamine was released. An area known as the nucleus accumbens core, known to be one of the main targets of dopamine from the VTA, showed the highest levels. The researchers also saw that some dopamine is released in neighboring regions such as the ventral pallidum, which regulates motivation and emotions, and parts of the thalamus, which relays sensory and motor signals in the brain.

Each dopamine stimulation lasted for 16 seconds and the researchers took an MRI image every eight seconds, allowing them to track how dopamine levels changed as the neurotransmitter was released from cells and then disappeared. “We could divide up the map into different regions of interest and determine dynamics separately for each of those regions,” Jasanoff says.

He and his colleagues plan to build on this work by expanding their studies to other parts of the brain, including the areas most affected by Parkinson’s disease, which is caused by the death of dopamine-generating cells. Jasanoff’s lab is also working on sensors to track other neurotransmitters, allowing them to study interactions between neurotransmitters during different tasks.

Deep Brain Stimulation for Obsessive-Compulsive Disorder Releases Dopamine in the Brain

Some have characterized dopamine as the elixir of pleasure because so many rewarding stimuli – food, drugs, sex, exercise – trigger its release in the brain. However, more than a decade of research indicates that when drug use becomes compulsive, the related dopamine release becomes deficient in the striatum, a brain region that is involved in reward and behavioral control.

New research now published in Biological Psychiatry from the Academic Medical Center in Amsterdam suggests that dopamine release is increased in obsessive-compulsive disorder (OCD) and may be normalized by the therapeutic application of deep brain stimulation (DBS).

To conduct the study, the authors recruited clinically stable outpatients with OCD who had been receiving DBS therapy for greater than one year. The patients then underwent three single photon emission computerized tomography (SPECT) imaging scans to measure dopamine availability in the brain.

In order to evaluate the effect of DBS, these scans were conducted during chronic DBS, 8 days after DBS had been discontinued, and then after DBS was resumed. Designing the study in this manner also allowed the researchers to measure the relationship between dopamine availability and symptoms.

During the chronic DBS phase, patients showed increased striatal dopamine release compared to healthy volunteers. When DBS was turned off, patients showed worsening of symptoms and reduced dopamine release, which was reversed within one hour by the resumption of DBS. This observation suggests that enhancing striatal dopamine signaling may have some therapeutic effects for treatment-resistant symptoms of OCD.

First author Dr. Martijn Figee further explained, “DBS of the nucleus accumbens decreased central dopamine D2 receptor binding potential indicative of DBS-induced dopamine release. As dopamine is important for reward-motivated behaviors, these changes may explain why DBS is able to restore healthy behavior in patients suffering from OCD, but potentially other disorders involving compulsive behaviors, such as eating disorders or addiction.”

The patients selected for participation in this study had previously been non-responsive to traditional pharmacological therapies that target the dopamine system. These findings suggest that the effectiveness of DBS for OCD may be related to its ability to compensate for an underlying dysfunction of the dopaminergic system. The DBS-related stimulatory increase in dopamine appears to aid patients by improving their control over obsessive-compulsive behaviors.

“It is exciting to see circuit-based DBS linked to molecular brain imaging. This is a strategy that may shed light into the mechanisms through which this treatment can produce positive clinical change,” said Dr. John Krystal, Editor of Biological Psychiatry.

He also noted, “It would be interesting to know whether the patients who do respond to dopamine-blocking antipsychotic medications commonly prescribed for OCD symptoms have a different underlying disturbance in dopamine function than the patients enrolled in this study who failed to respond to these medications. Nonetheless, the findings of this study raise the possibility that some deficits in dopamine signaling in the brain that might be targeted by novel treatments may prevent adequate response to conventional treatments for this disorder.”

(Image: © Thom Graves)

Seeking the Causes of Hyperactivity

The 60 trillion cells that comprise our bodies communicate constantly.  Information travels when chemical compounds released by some cells are received by receptors in the membrane of another cell. In a paper published in the Journal of Neuroscience, the OIST Cell Signal Unit, led by Professor Tadashi Yamamoto, reported that mice lacking an intracellular trafficking protein called LMTK3, are hyperactive.  Hyperactivity is a behavioral disorder that shows symptoms including restlessness, lack of coordination, and aggressive behavior. Identifying the genetic factors that contribute to such behaviors may help to explain the pathological mechanisms underlying autism and Attention Deficit Hyperactivity Disorder, ADHD, in humans.

LMTK3 is abundant in two brain regions: the cerebral cortex, which coordinates perception, movement, and thought, and the hippocampus, which governs memory and learning. In the brain, neurons communicate via connections called synapses. To send a message, a nerve terminus in the pre-synapse releases neurotransmitters to be received by the post-synaptic receptors. Yamamoto’s team discovered that LMTK3 regulates trafficking of neurotransmitter receptors at synapses. In neurons of mice deficient in LMTK3, internalization of receptors are augmented in the post-synapse, suggesting that synaptic communication is impaired. The LMTK3-deficient mice exhibited various hyperactive behaviors such as restlessness and hypersensitivity to sound. Interestingly, their dopamine levels were elevated. Dopamine is a neurotransmitter known to be involved in regulation of movement and hormone levels, motivation, learning, and expression of emotion. Excessive dopamine secretion results in schizophrenia, causing a loss of integrity of neuronal activity, and abnormal thoughts and emotions. The relationships between regulation of neurotransmitter receptor expression by LMTK3, dopamine turnover, and the biochemical pathways that induce hyperactivity, remain unknown.

Functions of many human proteins are still not understood. The Cell Signal Unit continues genetic studies of intracellular proteins that maintain and regulate complex functions such as behaviors, through their activities inside cells. “We hope to advance our research in order to elucidate genetic defects that result in behavioral abnormalities,” Yamamoto said.

(Image caption: A solar flare erupts on the far right side of the sun, in this image captured by NASA’s Solar Dynamics Observatory. The flare peaked at 6:34 p.m. EDT on March 12, 2014. Credit: NASA)

Some Astronauts at Risk for Cognitive Impairment

Johns Hopkins scientists report that rats exposed to high-energy particles, simulating conditions astronauts would face on a long-term deep space mission, show lapses in attention and slower reaction times, even when the radiation exposure is in extremely low dose ranges.

The cognitive impairments — which affected a large subset, but far from all, of the animals — appear to be linked to protein changes in the brain, the scientists say. The findings, if found to hold true in humans, suggest it may be possible to develop a biological marker to predict sensitivity to radiation’s effects on the human brain before deployment to deep space. The study, funded by NASA’s National Space Biomedical Research Institute, is described in the April issue of the journal Radiation Research.

When astronauts are outside of the Earth’s magnetic field, spaceships provide only limited shielding from radiation exposure, explains study leader Robert D. Hienz, Ph.D., an associate professor of behavioral biology at the Johns Hopkins University School of Medicine. If they take space walks or work outside their vehicles, they will be exposed to the full effects of radiation from solar flares and intergalactic cosmic rays, he says, and since neither the moon nor Mars have a planet-wide magnetic field, astronauts will be exposed to relatively high radiation levels, even when they land on these surfaces.

But not everyone will be affected the same way, his experiments suggest. “In our radiated rats, we found that 40 to 45 percent had these attention-related deficits, while the rest were seemingly unaffected,” Hienz says. “If the same proves true in humans and we can identify those more susceptible to radiation’s effects before they are harmfully exposed, we may be able to mitigate the damage.”

If a biomarker can be identified for humans, it could have even broader implications in determining the best course of treatment for patients receiving radiotherapy for brain tumors or identifying which patients may be more at risk from radiation-based medical treatments, the investigators note.

Previous research has tested how well radiation-exposed rats do with basic learning tasks and mazes, but this new Johns Hopkins study focused on tests that closely mimic the self-tests of fitness for duty currently used by astronauts on the International Space Station prior to mission-critical events such as space walks. Similar fitness tests are also used for soldiers, airline pilots and long-haul truckers.

In one such test, an astronaut sees a blank screen on a handheld device and is instructed to tap the screen when an LED counter lights up. The normal reaction time should be less than 300 milliseconds. The rats in the experiment are similarly taught to touch a light-up key with their noses and are then tested to see how quickly they react.

To conduct the new study, rats were first trained for the tests and then taken to Brookhaven National Laboratory on Long Island in Upton, N.Y., where a collider produces the high-energy proton and heavy ion radiation particles that normally occur in space. The rats’ heads were exposed to varying levels of radiation that astronauts would normally receive during long-duration missions, while other rats were given sham exposures.

Once the rats returned to Johns Hopkins, they were tested every day for 250 days. The radiation-sensitive animals (19 of 46) all showed evidence of impairment that began at 50 to 60 days post–exposure and remained through the end of the study.

Lapses in attention occurred in 64 percent of the sensitive animals, elevations in impulsive responding occurred in 45 percent and slower reaction times occurred in 27 percent. The impairments were not dependent on radiation dose. Additionally, some of the rats didn’t recover at all from their deficits over time, while others showed some recovery over time.

The radiation-sensitive rats that received higher doses of radiation had a higher concentration of transporters for the neurotransmitter dopamine, which plays a role in vigilance and attention, says Catherine M. Davis, Ph.D., a postdoctoral fellow in the Department of Psychiatry and Behavioral Sciences and the study’s first author.

The dopamine transport system appears impaired in radiation-sensitive rats because the neurotransmitter is most likely not removed in the manner it should be for the brain to function properly, she says. Humans with genetic differences related to dopamine transport, she adds, have been shown to do worse on the type of mental fitness tests given to the astronauts and rats alike.

Davis says she wouldn’t want to see radiation-sensitive astronauts kept from future missions to the moon or Mars, but she would want those astronauts to be prepared to take special precautions to protect their brains, such as wearing extra shielding or not performing space walks.

“As with other areas of personalized medicine, we would seek to create individual treatment and prevention plans for astronauts we believe would be more susceptible to cognitive deficits from radiation exposure,” she says.

Current astronauts are not as exposed to the damaging effects of radiation, Davis says, because the International Space Station flies in an orbit low enough that the Earth’s magnetic field continues to provide protection.

While the Johns Hopkins team studies the likely effects of radiation on the brain during a deep space mission, other NASA-funded research groups are looking at the potential effects of radiation on other parts of the body and on whether it increases cancer risks.

Novel compound halts cocaine addiction and relapse behaviors

A novel compound that targets an important brain receptor has a dramatic effect against a host of cocaine addiction behaviors, including relapse behavior, a University at Buffalo animal study has found.

The research provides strong evidence that this may be a novel lead compound for treating cocaine addiction, for which no effective medications exist.

The UB research was published as an online preview article in Neuropsychopharmacology last week.

In the study, the compound, RO5263397, severely blunted a broad range of cocaine addiction behaviors.

“This is the first systematic study to convincingly show that RO5263397 has the potential to treat cocaine addiction,” said Jun-Xu Li, MD, PhD, senior author and assistant professor of pharmacology and toxicology in the UB School of Medicine and Biomedical Sciences.

“Our research shows that trace amine associated receptor 1 – TAAR 1—holds great promise as a novel drug target for the development of novel medications for cocaine addiction,” he said.

TAAR 1 is a novel receptor in the brain that is activated by minute amounts of brain chemicals called trace amines.

The findings are especially important, Li added, since despite many years of research, there are no effective medications for treating cocaine addiction.

The compound targets TAAR 1, which is expressed in key drug reward and addiction regions of the brain.

“Because TAAR 1 anatomically and neurochemically is closely related to dopamine – one of the key molecules in the brain that contributes to cocaine addiction – and is thought to be a ‘brake’ on dopamine activity, drugs that stimulate TAAR 1 may be able to counteract cocaine addiction,” Li explained.

The UB research tested this hypothesis by using a newly developed TAAR 1 agonist RO5263397, a drug that stimulates TAAR 1 receptors, in animal models of human cocaine abuse. 

One of the ways that researchers test the rewarding effects of cocaine in animals is called conditioned place preference. In this type of test, the animal’s persistence in returning to, or staying at, a physical location where the drug was given, is interpreted as indicating that the drug has rewarding effects.

In the UB study, RO5263397 dramatically blocked cocaine’s rewarding effects.  

“When we give the rats RO5263397, they no longer perceive cocaine rewarding, suggesting that the primary effect that drives cocaine addiction in humans has been blunted,” said Li.

The compound also markedly blunted cocaine relapse in the animals.

“Cocaine users often stay clean for some time, but may relapse when they re-experience cocaine or hang out in the old cocaine use environments,” said Li. “We found that RO5263397 markedly blocked the effect of cocaine or cocaine-related cues for priming relapse behavior.

“Also, when we measured how hard the animals are willing to work to get an injection of cocaine, RO5263397 reduced the animals’ motivation to get cocaine,” said Li. “This compound makes rats less willing to work for cocaine, which led to decreased cocaine use.”

The UB researchers plan to continue studying RO5263397, especially its effectiveness and mechanisms in curbing relapse to cocaine addiction.

(Image: Shutterstock)

Common links between neurodegenerative diseases identified

Diseases of the central nervous system are a big burden to society. According to estimates, they cost €800 billion per year in Europe. And for most of them, there is no definitive cure. This is true, for example, for Parkinson disease. Although good treatments exist to manage its symptoms, they become more and more ineffective as the disease progresses. Now, the EU-funded REPLACES project, completed in 2013, which associated scientists with clinicians, has shed light on the abnormal working of a particular brain circuitry related to Parkinson’s disease. The results of the project suggest that these same circuits are implicated in different forms of pathologies. And this gives important insights into the possible common links between neurodegenerative diseases such as Parkinson and intellective disabilities or autism.

Existing treatments for Parkinson are very effective at the beginning. When the disease progresses, however, drugs, such as levodopa and so-called dopamine agonists, produce side effects that are sometimes even worse than the initial symptoms of the condition. In particular, they cause a complication called dyskinesia, characterised by abnormal involuntary movements. Therapies are therefore sought that allow better management of symptoms.

The project focused on the study of a highly plastic brain circuitry, which connects regions of the cerebral cortex with the basal ganglia. It is involved in very important functions such as learning and memory. “This system, based onglutamate as a mean of signalling between neurons, has also been discovered to be damaged in Parkinson disease,” says Monica Di Luca, professor of neuropharmacology at the University of Milan, Italy, and the project coordinator. She adds: “Parkinson’s more well-known and characteristic trait is the selective loss of cells producers of neurotransmitter dopamine.”

Researchers involved into the project studied the function and plasticity of this circuit in different animal models of Parkinson disease, from mice to non-human primates. They found that exactly the same alterations were present and conserved. This makes it an interesting and alternative target for trying to re-establish the correct functioning and reverse the symptoms of the disease.

One expert agrees with the need to target alternative target systems. “What researchers are trying to do is to intervene to modulate other systems that do not involve dopamine and obtain a better symptoms management,” explains Erwan Bezard, a researcher at the Neurodenerative Diseases Institute at the University of Bordeaux, in France. He also works on alternative targets in Parkinson disease. In monkeys, compounds that target glutamate receptors, used in combination with traditional drugs, have previously shown to improve some deficits in voluntary motor control.

But the research has also shed some light into apparently unrelated diseases. It is becoming more and more obvious that the same alterations in the working of the communication systems among neurons are shared among different diseases. “This is why we speak about ‘synaptopathies’: there are common players among Parkinson disease, autism and other forms of intellectual disabilities and even schizophrenia. Several of the mutated genes are the same, and affect the signalling systems through common molecules,” says Claudia Bagni, who works on synaptic plasticity in the context of intellectual disabilities at the University of Leuven, in Belgium and University of Rome Tor Vergata, in Italy. “For example, the glutamatergic system is also affected in the X-fragile syndrome, the most common form of inherited intellectual disability.”

Progress is in sight thanks to a much better understanding of the working of the abnormal synapses in Parkinson disease, and experiments performed in monkeys showing encouraging results. Indeed, “the team studied human primates, the model system closest to humans, and therefore their findings are relevant to human health.” says Bagni. Project researchers hope the door is now opened for the first clinical trials in humans. “We have identified a potential new target for treatment, and tested a couple of molecules in animals,” says Di Luca, the “next step would be to find a partnership with pharmaceutical industries interested in pursuing this research.”