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.

Healthcare professionals must be aware of the signs, symptoms and appropriate response to rarer causes of headaches in pregnancy, suggests new review

Most headaches in pregnancy and the postnatal period are benign, but healthcare professionals must be alert to the rarer and more severe causes of headaches, suggests a new review published in The Obstetrician & Gynaecologist (TOG).

(Image caption: Given an opportunity to spread in cells, prion-like proteins taken from the brains of patients with (from top) Alzheimer’s disease, corticobasal degeneration and Pick’s disease form distinctly shaped clumps (green in this image) in different parts of the cells. Credit: David W. Sanders)

Alzheimer’s disease, other conditions linked to prion-like proteins

A new theory about disorders that attack the brain and spinal column has received a significant boost from scientists at Washington University School of Medicine in St. Louis.

The theory attributes these disorders to proteins that act like prions, which are copies of a normal protein that have been corrupted in ways that cause diseases. Scientists previously thought that only one particular protein could be corrupted in this fashion, but researchers in the laboratory of Marc Diamond, MD, report that another protein linked to Alzheimer’s disease and many other neurodegenerative conditions also behaves very much like a prion.

The findings appear online May 22 in Neuron.

Diamond’s lab found that the protein, known as tau, could be corrupted in different ways, and that these different forms of corruption — known as strains — were linked to distinct forms of damage to the brain.

“If we think of these different tau strains as different pathogens, then we can begin to describe many human disorders linked to tau based on the strains that underlie them,” said senior author Diamond, the David Clayson Professor of Neurology. “This may mean that certain antibodies or drugs, for example, will work better against certain disorders than others.”

The study was led by co-first authors David Sanders and Sarah Kaufman, who are graduate students.

Prions are composed of normal proteins that have folded into an abnormal shape. They aren’t alive, but their effects can be similar to infectious microbes such as bacteria or viruses. Their unusual structure lets prions replicate themselves through a kind of molecular peer pressure: When a prion interacts with identical but normally folded proteins, it can cause these proteins to become prions, which are small aggregates, or clumps, that can spread from cell to cell.

Prions first came to popular attention in the 1990s with the emergence of mad cow disease, a disorder that destroys the brains of cattle. Scientists linked a few cases of a similar condition in people to consumption of meat from infected cows. Researchers eventually determined that the disorder was caused by a distinct strain of prions made by the sickened cattle.

Scientists had suspected that prion-like forms of a protein called alpha-synuclein contribute to Parkinson’s disease and other conditions, and prion-like versions of proteins known as SOD1 and TDP43 may cause amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease.

Scientists also had identified tau clumps in 25 different neurodegenerative disorders, known collectively as tauopathies. This hinted at potential prion-like behavior on the part of tau. In 2009, Diamond’s group found that tau misfolds into several different shapes in a test tube.

“When we infected a cell with one of these misshapen copies of tau and allowed the cell to reproduce, the daughter cells contained copies of tau misfolded in the same fashion as the parent cell,” Diamond said. “Further, if we extracted the tau from an affected cell, we could reintroduce it to a naïve cell, where it would recreate the same aggregate shape. This proves that each of these differently shaped copies of the tau protein can form stable prion strains, like a virus or a bacteria, that can be passed on indefinitely.”

Diamond used the tau prions made in cells to infect mouse brains, showing that differently shaped strains caused different levels of brain damage. He isolated the prions from the mice, grew them in cell culture, and then infected other mice. Throughout these transfers, each particular prion strain continued to be misfolded in the same shape and to cause damage in the same fashion.

Finally, the researchers examined clumps of tau from the brains of 28 patients after they died. Each of the patients was known to have one of five forms of tauopathy.

“Each disease had a unique tau prion strain or combination of strains associated with it,” he said. “For example, we isolated the same tau prion strain from nearly every patient with Alzheimer’s disease we examined.”

Brain samples from patients with the progressive neurological disorderscorticobasal degeneration and Pick’s disease also typically had the same tau prion strains or mixtures of strains.

Diamond and others now are working to find a way to isolate tau prions non-invasively from individuals for diagnostic purposes.

Options for stopping prions include monoclonal antibodies, which could label prions for inactivation or immune system attack and removal (described in a paper by Diamond and David Holtzman, MD, Chair of Neurology (Neuron, 2013)). Diamond and others also are developing ways to block tau prion movement between cells and to stop cells from making new copies of the prion proteins.

First Non-Study Site to Implant Device for Stopping Uncontrolled Seizures

NYU Langone Medical Center last month became the first hospital outside of a clinical trial site to implant a pacemaker-like device in the brain that may be a game-changer for patients with epilepsy.

The device, called the RNS System, was implanted April 17, 2014 in a patient with seizures that previously could not be controlled with medication, or intractable epilepsy, by Werner Doyle, MD, an associate professor in the Department of Neurosurgery at NYU Langone. The patient has recovered completely from the surgery.

The first-of-its-kind device is similar to an implantable cardioverter-defibrillator (ICD), which delivers electrical pulses to the heart to prompt it to beat a normal rhythm and provides a new alternative treatment to vagus nerve stimulation and surgical removal of the focus site – parts in the brain where the seizures originate — for people with intractable epilepsy.

Prior to last month’s surgery, the only implants of the seizure-reducing medical device took place at U.S. medical centers that had previously researched the device’s effectiveness and safety, making NYU Langone the first non-study hospital in the U.S. and New York metropolitan area to offer the RNS System to patients.

"Medically intractable epilepsy is often a debilitating disorder that puts sufferers at risk from sudden loss of consciousness and uncontrolled movements. It stigmatizes patients and restricts their independence," said Dr. Doyle. "Epilepsy surgery is an important therapeutic option for patients, which can significantly or completely control their seizures and return their lives to normal. The RNS device improves our ability to control seizures with surgery and now offers patients who may not have been surgical candidates in the past a surgical option."

According to the Centers for Disease Control and Prevention, about 2.3 million Americans suffer from epilepsy, with about one in 26 people expected to be diagnosed in their lifetimes. Approximately one-third of patients do not respond to medications and face major challenges with daily living. Uncontrolled seizures may interfere with normal activities such as working, going to school and driving. Patients also face increased risk for anxiety, depression, injury, brain damage, and in rare cases, death.

The RNS System, manufactured by NeuroPace Inc. of Mountain View, Calif., is a responsive stimulation device that’s implanted in the skull along with brain electrodes to detect abnormal electrical activity in the brain associated with seizures. After two or more weeks of recording the activity, doctors program the device to specifically respond to these abnormal signals by delivering imperceptible electrical pulses to the brain that normalize the activity. The device essentially “reboots” the portion of the brain where the seizure is originating, thereby effectively interrupting the abnormal electrical activity before it spreads or causes its unwanted effects.

The RNS System received pre-market approval from the Food and Drug Administration in November 2013 to treat patients’ seizures that have not been controlled by two or more antiepileptic medications.

In clinical trials performed at medical centers across the U.S., including at Saint Barnabas Medical Center in New Jersey by Dr. Doyle and Orrin Devinsky, MD, director of the Comprehensive Epilepsy Center at NYU Langone, 55 percent of patients experienced a 50 percent or greater reduction in seizures two years post implantation.

"The RNS System represents one of the most important and innovative therapies to treat people with epilepsy," says Dr. Devinsky. "This new surgical therapy uses information to target and shut down points in the brain where seizures start without removing tissue, providing a novel option for patients with uncontrolled seizures."

For more information:

Neurology, Morrell et al, 2011.

Epilepsia, Heck et al, 2014.

NeuroPace

Fruit flies ‘think’ before they act

Oxford University neuroscientists have shown that fruit flies take longer to make more difficult decisions.

In experiments asking fruit flies to distinguish between ever closer concentrations of an odour, the researchers found that the flies don’t act instinctively or impulsively. Instead they appear to accumulate information before committing to a choice.

Gathering information before making a decision has been considered a sign of higher intelligence, like that shown by primates and humans.

'Freedom of action from automatic impulses is considered a hallmark of cognition or intelligence,' says Professor Gero Miesenböck, in whose laboratory the new research was performed. 'What our findings show is that fruit flies have a surprising mental capacity that has previously been unrecognised.'

The researchers also showed that the gene FoxP, active in a small set of around 200 neurons, is involved in the decision-making process in the fruit fly brain.

The team reports its findings in the journal Science. The group was funded by the Wellcome Trust, the Gatsby Charitable Foundation, the US National Institutes of Health and the Oxford Martin School.

The researchers observed Drosophila fruit flies make a choice between two concentrations of an odour presented to them from opposite ends of a narrow chamber, having been trained to avoid one concentration.

When the odour concentrations were very different and easy to tell apart, the flies made quick decisions and almost always moved to the correct end of the chamber.

When the odour concentrations were very close and difficult to distinguish, the flies took much longer to make a decision, and they made more mistakes.

The researchers found that mathematical models developed to describe the mechanisms of decision making in humans and primates also matched the behaviour of the fruit flies.

The scientists discovered that fruit flies with mutations in a gene called FoxP took longer than normal flies to make decisions when odours were difficult to distinguish – they became indecisive.

The researchers tracked down the activity of the FoxP gene to a small cluster of around 200 neurons out of the 200,000 neurons in the brain of a fruit fly. This implicates these neurons in the evidence-accumulation process the flies use before committing to a decision.

Dr Shamik DasGupta, the lead author of the study, explains: ‘Before a decision is made, brain circuits collect information like a bucket collects water. Once the accumulated information has risen to a certain level, the decision is triggered. When FoxP is defective, either the flow of information into the bucket is reduced to a trickle, or the bucket has sprung a leak.’

Fruit flies have one FoxP gene, while humans have four related FoxP genes. Human FoxP1 and FoxP2 have previously been associated with language and cognitive development. The genes have also been linked to the ability to learn fine movement sequences, such as playing the piano.

'We don't know why this gene pops up in such diverse mental processes as language, decision-making and motor learning,' says Professor Miesenböck. However, he speculates: 'One feature common to all of these processes is that they unfold over time. FoxP may be important for wiring the capacity to produce and process temporal sequences in the brain.'

Professor Miesenböck adds: ‘FoxP is not a “language gene”, a “decision-making gene”, even a “temporal-processing” or “intelligence” gene. Any such description would in all likelihood be wrong. What FoxP does give us is a tool to understand the brain circuits involved in these processes. It has already led us to a site in the brain that is important in decision-making.’

Training brain patterns of empathy using functional brain imaging

An unprecedented research conducted by a group of neuroscientists has demonstrated for the first time that it is possible to train brain patterns associated with empathic feelings – more specifically, tenderness. The research showed that volunteers who received neurofeedback about their own brain activity patterns whilst being scanned inside a functional magnetic resonance (fMRI) machine were able to change brain network function of areas related to tenderness and affection felt toward loved ones. These significant findings could open new possibilities for treatment of clinical situations, such as antisocial personality disorder and postpartum depression.

In Ridley Scott’s film “Blade Runner”, based on the science fiction book ‘Do androids dream of electric sheep?’ by Philip K. Dick, empathy-detection devices are employed to measure tenderness or affection emotions felt toward others (called “affiliative” emotions). Despite recent advances in neurobiology and neurotechnology, it is unknown whether brain signatures of affiliative emotions can be decoded and voluntarily modulated.

The article entitled “Voluntary enhancement of neural signatures of affiliative emotion using fMRI neurofeedback” published in PLOS ONE is the first study to demonstrate through a neurotechnology tool, real-time neurofeedback using functional Magnetic Resonance Imaging (fMRI), the possibility to help the induction of empathic brain states.

The authors conducted this research at the D’Or Institute for Research and Education where a sophisticated computational tool was designed and used to allow the participants to modulate their own brain activity related to affiliative emotions and enhance this activity. This method employed pattern-detection algorithms, called “support vector machines” to classify complex activity patterns arising simultaneously from tenths of thousands of voxels (the 3-D equivalent of pixels) inside the participants’ brains.

Volunteers who received real time information of their ongoing neural activity could change brain network function among connected areas related to tenderness and affection felt toward loved ones, while the control group who performed the same fMRI task without neurofeedback did not show such improvement.

Thus, it was demonstrated that those who received a “real” feedback were able to “train” specific brain areas related to the experience of affiliative emotions that are key for empathy. These findings can lead the way to new opportunities to investigate the use of neurofeedback in conditions associated with reduced empathy and affiliative feelings, such as antisocial personality disorders and post-partum depression.

The authors point out that this study may represent a step towards the construction of the ‘empathy box’, an empathy-enhancing machine described by Philip K. Dick’s novel.

(Image caption: These are mature nerve cells generated from human cells using enhanced transcription factors. Credit: Fahad Ali)

Functional nerve cells from skin cells

A new method of generating mature nerve cells from skin cells could greatly enhance understanding of neurodegenerative diseases, and could accelerate the development of new drugs and stem cell-based regenerative medicine.

The nerve cells generated by this new method show the same functional characteristics as the mature cells found in the body, making them much better models for the study of age-related diseases such as Parkinson’s and Alzheimer’s, and for the testing of new drugs.

Eventually, the technique could also be used to generate mature nerve cells for transplantation into patients with a range of neurodegenerative diseases.

By studying how nerves form in developing tadpoles, researchers from the University of Cambridge were able to identify ways to speed up the cellular processes by which human nerve cells mature. The findings are reported in the May 27th edition of the journal Development.

Stem cells are our master cells, which can develop into almost any cell type within the body. Within a stem cell, there are mechanisms that tell it when to divide, and when to stop dividing and transform into another cell type, a process known as cell differentiation. Several years ago, researchers determined that a group of proteins known as transcription factors, which are found in many tissues throughout the body, regulate both mechanisms.

More recently, it was found that by adding these proteins to skin cells, they can be reprogrammed to form other cell types, including nerve cells. These cells are known as induced neurons, or iN cells. However, this method generates a low number of cells, and those that are produced are not fully functional, which is a requirement in order to be useful models of disease: for example, cortical neurons for stroke, or motor neurons for motor neuron disease.

In addition, for age-related diseases such as Parkinson’s and Alzheimer’s, both of which affect millions worldwide, mature nerve cells which show the same characteristics as those found in the body are crucial in order to enhance understanding of the disease and ultimately determine the best way to treat it.

"When you reprogramme cells, you’re essentially converting them from one form to another but often the cells you end up with look like they come from embryos rather than looking and acting like more mature adult cells," said Dr Anna Philpott of the Department of Oncology, who led the research. "In order to increase our understanding of diseases like Alzheimer’s, we need to be able to work with cells that look and behave like those you would see in older individuals who have developed the disease, so producing more ‘adult’ cells after reprogramming is really important."

By manipulating the signals which transcription factors send to the cells, Dr Philpott and her collaborators were able to promote cell differentiation and maturation, even in the presence of conflicting signals that were directing the cell to continue dividing.

When cells are dividing, transcription factors are modified by the addition of phosphate molecules, a process known as phosphorylation, but this can limit how well cells can convert to mature nerves. However, by engineering proteins which cannot be modified by phosphate and adding them to human cells, the researchers found they could produce nerve cells that were significantly more mature, and therefore more useful as models for disease such as Alzheimer’s.

Additionally, very similar protein control mechanisms are at work to mature important cells in other tissues such as pancreatic islets, the cell type that fails to function effectively in type 2 diabetes. As well as making more mature nerves, Dr Philpott’s lab is now using similar methods to improve the function of insulin-producing pancreas cells for future therapeutic applications.

"We’ve found that not only do you have to think about how you start the process of cell differentiation in stem cells, but you also have to think about what you need to do to make differentiation complete - we can learn a lot from how cells in developing embryos manage this," said Dr Philpott.