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.

New headway in battle against neurodegenerative diseases

Conditions which may accelerate the spread of Parkinson’s disease, and a potential means of enhancing naturally-occurring defences against neurodegenerative disorders, have been identified in two new studies.

Two significant breakthroughs which could inform future treatments for neurodegenerative diseases such as Alzheimer’s and Parkinson’s, have been announced by scientists.

The research, published in two separate studies this week, advances understanding of the early development of such disorders and how they might be prevented – in particular by identifying the biological areas and processes that could be pinpointed by future drugs.

Both sets of results have emerged from collaborations between the research groups led by Chris Dobson, Tuomas Knowles and Michele Vendruscolo at the University of Cambridge, who focus on understanding protein “misfolding” diseases. These include Alzheimer’s and Parkinson’s diseases, as well as numerous others.

The first study provides evidence that the early spread of the protein aggregates associated with Parkinson’s appears to happen at an accelerated rate in mildly acidic conditions. This suggests that particular compartments within brain cells, which are slightly more acidic than others, may turn out to be appropriate targets for future treatments fighting the disease.

Meanwhile, researchers behind the second study appear to have identified a way in which the effectiveness of so-called molecular “chaperones”, responsible for limiting the damage caused by misfolded proteins, can be significantly enhanced.

The papers appear in the latest issue of Proceedings of the National Academy of Sciences of the USA.

As the term suggests, protein misfolding diseases stem from the fact that proteins, which need to fold into a particular shape to carry out their assigned function in the body, can sometimes misfold. In certain cases these misfolded proteins then clump together into fibre-like threads, called amyloid fibrils, potentially becoming toxic to other cells.

How this formation begins at a molecular level is still not completely understood, but comprehending the process will be fundamental to the development of future therapies and is the subject of extensive current research.

The first of the new studies builds on research published in 2013, which showed that in Alzheimer’s sufferers, the initial “nucleation” between proteins, which leads to amyloid formation, is followed by an amplification process called secondary nucleation. In these secondary events, the existing amyloid structures facilitate the formation of new aggregates, leading to their exponential increase. This process is likely to be at the heart of the development and spread of the disease in affected brains.

Using the same techniques, the researchers behind the latest study identified a similar process that is relevant in the early stage development of Parkinson’s Disease. Their work focused on a protein called α-synuclein, which is associated with the disorder, and simulated different conditions in which this protein might misfold and form clumps.

As with the previous study on Alzheimer’s, the research identified that Parkinson’s could spread through a series of secondary nucleation events. In addition, however, it showed that in the case of α-synuclein, this happens at a highly accelerated rate only in solutions which are mildly acidic, with a pH below 5.8. The finding is important because certain sub-compartments within cells are more acidic than others, meaning that these may be particularly productive areas for future treatments to target.

Dr Tuomas Knowles, from the Department of Chemistry and a Fellow of St John’s College, Cambridge, said: “This tells us much more about the molecular mechanisms underlying protein aggregation in Parkinson’s and suggests that mildly acidic microenvironments within cells may enhance that process by several orders of magnitude. Not every sub-cellular compartment offers these conditions, so it takes us much closer to understanding how the disease might spread.”

The second study meanwhile suggests a potential route to improving the effectiveness of a particular molecular “chaperone” – a loose classification for proteins which assist in the folding of others, thereby preventing them from causing damage when they misfold.

The researchers focused on a chaperone called α2-macroglobulin (α2M), which is found outside cells themselves. This is important because neurodegenerative diseases often stem from a process which begins with extracellular misfolding. The α2M was tested on a substrate of the amyloid-beta peptide associated with Alzheimer’s Disease.

Typically, the potency of α2M is limited. The new study, however, found that when it comes into contact with the oxidant hypochlorite – the same chemical found in household bleach, which also naturally occurs in our immune systems – its structure is modified in a manner that makes it into a much more dynamic defence.

In their report, the researchers suggest that this increased effectiveness stems from the fact that α2M, which is usually found in a four-part, “tetrameric” form, breaks down into “dimeric”, two-part forms when it comes into contact with hypochlorite.

The chaperone usually plays its role by preventing a misfolded protein from interacting with the membranes that surround and protect cells. Once in its dimeric form, however, receptor binding sites within the α2M are exposed, leading to specific interactions with receptors on the cell itself. If the α2M has already interacted with misfolded proteins, this connection triggers the cell to break the potentially harmful protein down.

“It’s almost like a warning flag for the cell, telling it that something is wrong,” Dr Janet Kumita, from the Department of Chemistry, explained. “It triggers the cell to react in a way that subjects the cargo of misfolded protein to a degradation pathway.”

“Increasing its potency in this way is an exciting prospect. If we could find a way of developing a drug that introduces the same structural alterations, we would have a therapeutic intervention capable of increasing this protective activity in patients with Alzheimer’s Disease.”

Professor Christopher Dobson, from the University’s Department of Chemistry and Master of St John’s College, said: “These studies add very substantially to our detailed understanding of the molecular origins of neurodegenerative diseases, which are now becoming one of the greatest threats to healthcare in the modern world.”

“We are beginning to understand exactly how a single, aberrant event can lead to the proliferation and spreading of toxic species throughout the brain, and the manner in which our sophisticated defence mechanisms do their best to suppress such phenomena. It will undoubtedly provide vital clues to the development in due course of new and effective drugs to combat these debilitating and increasingly common disorders.”

Brain inflammation a recipe for chronic fatigue

Patients with chronic fatigue syndrome (CFS), also known as myalgic encephalomyelitis, experience severe and often disabling exhaustion. Other symptoms include cognitive dysfunction, pain and depression. Although brain inflammation is thought to be involved in the development of these symptoms, direct evidence of this relationship has proved elusive. 

Yasuyoshi Watanabe, Yasuhito Nakatomi, Kei Mizuno and colleagues from the RIKEN Center for Life Science Technologies and other institutes in Japan have now shown using a noninvasive brain imaging technique that the neuropsychological symptoms of patients with CFS are closely associated with widespread inflammation in the brain.

Positron emission tomography (PET) is a brain imaging technique that uses radioactive tracers attached to particular cell types or molecules to noninvasively track changes in the brain in disease states. To examine the effect of CFS, the researchers used a radioactive tracer that labels activated glial cells, which tend to be associated with neuroinflammation. They performed PET imaging studies on nine CFS sufferers and ten healthy individuals to identify the extent to which brain inflammation plays a role in CFS. They found that the levels of tracer binding were much higher in multiple brain regions in the CFS patients compared with the same brain regions in the healthy participants.

The investigation also found correlations between tracer binding in various brain regions and the severity of symptoms in the CFS patients. The researchers found that inflammation in the thalamus—a region of the brain responsible for relaying motor and sensory information to and from the cerebral cortex—correlated with the severity of both cognitive impairment and pain in the CFS patients. They also identified a correlation between inflammation in the amygdala—a part of the brain linked to emotional memory—and the severity of cognitive impairment. The severity of depression in CFS patients, on the other hand, was linked to the extent of inflammation in the hippocampus, which is a part of the brain known to be associated with depression.

The findings suggest that inflammation in the brain plays a key role in CFS in humans. Drugs that fight inflammation in the brain may therefore offer promising therapies to prevent or treat CFS and its related symptoms of pain, depression and cognitive dysfunction.

“Because CFS is diagnosed based on subjective symptoms such as fatigue, pain, sleep problems and cognitive impairment,” says Mizuno, “neuroinflammation as observed by PET imaging could be helpful as a more objective biomarker for diagnosis of the disorder.”

Don’t beat yourself up, you’ll live longer

Brandeis researchers explore the relationship between self-compassion and health

We all have stress in our lives, whether it’s a daily commute, workplace pressures or relationship troubles. But how we deal with that stress could impact our health and longevity.

In a recently published paper in Brain, Behavior and Immunity, Brandeis University researchers report they found a connection between a self-compassionate attitude and lower levels of stress-induced inflammation. The discovery could lead to new techniques to lower stress and improve health.

The paper was authored by psychology professor Nicolas Rohleder, with postdoctoral fellows Juliana Breines and Myriam Thoma, and graduate students Danielle Gianferante, Luke Hanlin and Xuejie Chen.

It’s long known that psychological stress can trigger biological responses similar to the effects of illness or injury, including inflammation. While regulated inflammation can help stave off infection or promote healing, unregulated inflammation can lead to cardiovascular disease, cancer and Alzheimer’s.

Self-compassion describes behaviors such as self-forgiveness or, more colloquially, cutting yourself some slack. A person with high levels of self-compassion may not blame themselves for stress beyond their control or may be more willing to move on from an argument, rather than dwelling on it for days.

To understand the connection between self-compassion and inflammatory responses to stress, Rohleder and his team asked 41 participants to rank their levels of self-compassion. The participants ranked their agreement to statements such as, “I try to be understanding and patient toward aspects of my personality I do not like” and “I’m disapproving and judgmental about my own flaws and inadequacies.”

Then, the participants took one stress test a day for two days and their levels of interleukin-6 (IL-6), an inflammatory agent linked to stress, were recorded before and after each test. After the first stress test, participants with higher self-compassion had significantly lower levels of IL-6.

On the second day, Rohleder and his team found something unexpected. Those with low self-compassion had higher base levels of IL-6 before the test, suggesting that they may have been carrying the stress they experienced the day before.

“The high responses of IL-6 on the first day and the higher baseline levels on the second day suggest that people with low self-compassion are especially vulnerable to the adverse effects of this kind of stress,” Rohleder says.

The research illustrates how easy it is for stress to build over time and how a seemingly small daily stressor, such as traffic, can impact a person’s health if they don’t have the right strategies to deal with it.

“Hopefully, this research can provide more effective ways to cope with stress and reduce disease, not only by relieving negative emotions but by fostering positive ideas of self compassion,” Rohleder says.

Scientists catch brain damage in the act

Scientists have uncovered how inflammation and lack of oxygen conspire to cause brain damage in conditions such as stroke and Alzheimer’s disease.

The discovery, published today in Neuron, brings researchers a step closer to finding potential targets to treat neurodegenerative disorders.

Chronic inflammation and hypoxia, or oxygen deficiency, are hallmarks of several brain diseases, but little was known about how they contribute to symptoms such as memory loss.

The study used state-of-the-art techniques that reveal the movements of microglia, the brain’s resident immune cells. Brain researcher Brian MacVicar had previously captured how they moved to areas of injury to repair brain damage.

The new study shows that the combination of inflammation and hypoxia activates microglia in a way that persistently weakens the connection between neurons. The phenomenon, known as long-term depression, has been shown to contribute to cognitive impairment in Alzheimer’s disease.

“This is a never-before-seen mechanism among three key players in the brain that interact together in neurodegenerative disorders,” says MacVicar with the Djavad Mowafaghian Centre for Brain Health at UBC and Vancouver Coastal Health Research Institute.

“Now we can use this knowledge to start identifying new potential targets for therapy.”