Neuroscience

Every year thousands of people in Europe are paralysed by a spinal cord injury. Many are young adults, facing the rest of their lives confined to a wheelchair. Although no medical cure currently exists, in the future they could be able to walk again thanks to a mind-controlled robotic exoskeleton being developed by EU-funded researchers.

The system, based on innovative ‘Brain-neural-computer interface’ (BNCI) technology - combined with a light-weight exoskeleton attached to users’ legs and a virtual reality environment for training - could also find applications in the rehabilitation of stroke victims and in assisting astronauts rebuild muscle mass after prolonged periods in space.

In the United Kingdom, every eight hours someone suffers a spinal cord injury, often leading to partial or full lower-body paralysis. In the United States, more than 250.000 people are living with paralysis as a result of damage to their spinal cord, usually because of a traffic accident, fall or sporting injury. Many are under the age of 50, and with no known medical cure or way of repairing damaged spinal nerves they face the rest of their lives in a wheelchair.

But by bypassing the spinal cord entirely and routing brain signals to a robotic exoskeleton, they should be able to get back on their feet. That is the ultimate goal of researchers working in the ‘Mind-controlled orthosis and VR-training environment for walk empowering' (Mindwalker) project, a three-year initiative supported by EUR 2.75 million in funding from the European Commission.

'Mindwalker was proposed as a very ambitious project intended to investigate promising approaches to exploit brain signals for the purpose of controlling advanced orthosis, and to design and implement a prototype system demonstrating the potential of related technologies,' explains Michel Ilzkovitz, the project coordinator at Space Applications Services in Belgium.

The team’s approach relies on an advanced BNCI system that converts electroencephalography (EEG) signals from the brain, or electromyography (EMG) signals from shoulder muscles, into electronic commands to control the exoskeleton.

The Laboratory of Neurophysiology and Movement Biomechanics at the Université Libre de Bruxelles (ULB) focused on the exploitation of EEG and EMG signals treated by an artificial neural network, while the Foundation Santa Lucia in Italy developed techniques based on EMG signals modelled by the coupling of neural and biomechanical oscillators.

One approach for controlling the exoskeleton uses so-called ‘steady-state visually evoked potential’, a method that reads flickering visual stimuli produced at different frequencies to induce correlated EEG signals. Detection of these EEG signals is used to trigger commands such as ‘stand’, ‘walk’, ‘faster’ or ‘slower’.

A second approach is based on processing EMG signals generated by the user’s shoulders and exploits the natural arm-leg coordination in human walking: arm-swing patterns can be perceived in this way and converted into control signals commanding the exoskeleton’s legs.

A third approach, ‘ideation’, is also based on EEG-signal processing. It uses the identification and exploitation of EEG Theta cortical signals produced by the natural mental process associated with walking. The approach was investigated by the Mindwalker team but had to be dropped due to the difficulty, and time needed, in turning the results of early experiments into a fully exploitable system.

Regardless of which method is used, the BNCI signals have to be filtered and processed before they can be used to control the exoskeleton. To achieve this, the Mindwalker researchers fed the signals into a ‘Dynamic recurrent neural network’ (DRNN), a processing technique capable of learning and exploiting the dynamic character of the BNCI signals.

'This is appealing for kinematic control and allows a much more natural and fluid way of controlling an exoskeleton,' Mr Ilzkovitz says.

The team adopted a similarly practical approach for collecting EEG signals from the user’s scalp. Most BNCI systems are either invasive, requiring electrodes to be placed directly into brain tissue, or require users to wear a ‘wet’ capon their head, necessitating lengthy fitting procedures and the use of special gels to reduce the electrical resistance at the interface between the skin and the electrodes. While such systems deliver signals of very good quality and signal-to-noise ratio, they are impractical for everyday use.

The Mindwalker team therefore turned to a ‘dry’ technology developed by Berlin-based eemagine Medical Imaging Solutions: a cap covered in electrodes that the user can fit themselves, and which uses innovative electronic components to amplify and optimise signals before sending them to the neural network.

'The dry EEG cap can be placed by the subject on their head by themselves in less than a minute, just like a swimming cap,' Mr Ilzkovitz says.

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According to a 2012 World Health Organization report, over 35 million people worldwide currently have dementia, a number that is expected to double by 2030 (66 million) and triple by 2050 (115 million). Alzheimer’s disease, the most common form of dementia, has no cure and there are currently only a handful of approved treatments that slow, but do not prevent, the progression of symptoms.

New drug development, no matter the disease, is a slow, expensive, and risky process. Thus, innovative techniques to study and assess the possibilities of already-existing drugs for different diseases can be used to alleviate the traditional burdens of cost and time. Detailed in their new article in Biological Psychiatry, researchers from the University of Washington, led by Dr. Brian Kraemer, have developed an exciting new approach to screening potential new treatments for Alzheimer’s disease using C. elegans, a small transparent worm.

Their focus was on tau, a protein involved in maintaining brain cell structure. In Alzheimer’s disease and related disorders, tau protein becomes abnormally modified and forms clumps of protein called aggregates. These aggregates are a hallmark of the dying nerve cells in Alzheimer’s disease and other related disorders. Diseases with abnormal tau are called tauopathies.

Dr. Kraemer’s lab previously developed a worm model for tauopathy by expressing human tau in C. elegans nerve cells. This model has behavioral abnormalities, accumulates abnormal tau protein, and exhibits loss of nerve cells—all of which are general features of Alzheimer’s disease.

Using their worm model for this study, they screened a library of 1,120 drugs approved for human use and tested each at three different concentrations to identify compounds that suppress the effects of abnormal tau aggregation.

“We have identified six compounds capable of reliably alleviating tau induced behavioral abnormalities in our C. elegans model for tauopathy. In a human cultured cell model for abnormal tau protein, we have also seen that azaperone treatment can decrease the amount of abnormal tau,” said Kraemer.

Azaperone, an antipsychotic drug, normally binds to certain dopamine receptors found in nerve cells. They demonstrated that removing those receptors in either C. elegans or human cells has the same effect as azaperone treatment, indicating that azaperone and related drugs should alter abnormal tau accumulation. Other antipsychotic drugs also have a similar effect to azaperone.

Tests of these compounds for anti-tau properties are now underway in existing mouse models of Alzheimer’s disease.

“This study is an exemplary instance of how a simple C. elegans model system may be used to rapidly screen drugs for diseases and evaluate mechanism of action,” said Drs. Sangeetha Iyer and Jonathan Pierce-Shimomura, authors of a commentary that accompanies this article.

Dr. John Krystal, Editor of Biological Psychiatry, agrees and added: “Studying the worm, C. elegans, has already provided us with fundamental insights into how the brain develops. The new approach described by McCormick and colleagues suggests that this animal model may be a powerful new approach to studying novel treatments that prevent its decline.”

Last month, the National Institutes of Health announced a new collaborative initiative that aims to accelerate the search for biomarkers — changes in the body that can be used to predict, diagnose or monitor a disease — in Parkinson’s disease, in part by improving collaboration among researchers and helping patients get involved in clinical studies. As part of this program, launched by the National Institute of Neurological Disorders and Stroke (NINDS), part of the NIH, Clemens Scherzer, MD, a neurologist and researcher at Brigham and Women’s Hospital (BWH), was awarded $2.6 million over five years to work on the development of biomarkers and facilitate NINDS-wide access to one of the largest data and biospecimens bank in the world for Parkinson’s available at BWH. This NINIDS initiative is highlighted in an editorial in the March issue of Lancet Neurology.

"There is a critical gap in the research that leads to lack of treatment for diseases like Parkinson’s," said Scherzer. "Biomarkers are desperately needed to make clinical trials more efficient, less expensive and to monitor disease and treatment response. We are hopeful that this initiative will fast track new discoveries in this area."

According to Scherzer, most of our knowledge of the human brain is based on the analysis of just 1.5 percent of the human genome that encodes proteins. The first part of Scherzer’s project will examine the function of the remaining 98.5 percent of the genome that, so far, has been unexplored in the human brain. While this remainder had been previously dismissed as “junk”, it is now becoming clearer that parts of it actively regulate cell biology.  Scherzer and colleagues believe that “dark matter” RNA transcribed from stretches of so called “junk” DNA is active in brain cells and contributes to the complexity of normal dopamine neurons and, when corrupted, Parkinson’s disease.

"This offers a potentially ground breaking opportunity for biomarker development. Initially, the team will search for these RNAs associated in brain tissue of individuals at earliest stages of the disease. Then, this team will look for related biomarkers in the bloodstream and cerebrospinal fluid in both healthy brains and those with Parkinson’s," Scherzer said.

Scherzer’s lab has been spearheading biomarker research in this field since 2004 and the team already has 2,000 patients enrolled and being followed in a longitudinal study with rich clinical data and one of the largest biobanks in the world for Parkinson’s tissue with support from the Harvard NeuroDiscovery Center. The biobank was designed as an incubator for Parkinson’s research and until now was chiefly available for research collaborations within the Harvard-affiliated community. As part of this new project, this vast resource will be open to all NIH-funded investigators.

"Our ultimate goal is to personalize treatment for our patients with Parkinson’s." said Scherzer. "By opening up this vast collection of specimens, we are exploding the resources that are available to NIH-funded investigators looking at this disease. We hope to harness the power of collaboration to speed up biomarkers discovery."

Researchers from Plymouth University Peninsula Schools of Medicine and Dentistry are part of an international team which has for the first time identified the role of a tumour suppressor in peripheral neuropathy in those suffering multiple tumours of the brain and nervous system.

One in 25,000 people worldwide is affected by neurofibromatosis type 2 (NF2), a condition where the loss of a tumour suppressor called Merlin results in multiple tumours in the brain and nervous system.

Sufferers may experience 20 to 30 tumours at any one time and such numbers often lead to hearing loss, disability and eventually death. Those with NF2 may also experience peripheral neuropathy, which is when the nerves carrying messages to and from the brain and spinal column to the rest of the body do not work.

Peripheral neuropathy leads to further complications for NF2 sufferers, such as pain and numbness, muscle problems, problems with body organs and other symptoms of nerve damage, such as bladder problems, uncontrollable sweating and sexual dysfunction.

Researchers from Plymouth University Peninsula Schools of Medicine and Dentistry are part of an international research team which has for the first time identified the role of a tumour suppressor called Merlin in regulating the integrity of axons. Axons are nerve fibres which transmit information around the body and it is these are that damaged in peripheral neuropathy.

The research team showed that Merlin regulates a protein called neurofilament which supplies structural support for the axon. A better understanding of this mechanism could lead to effective drug therapies to alleviate the symptoms of peripheral neuropathy in patients with NF2.

The results of the research is published this week in Nature Neuroscience.

Researchers at Boston University School of Medicine (BUSM) have, for the first time, identified a specific group of cells in the brainstem whose activation during rapid eye movement (REM) sleep is critical for the regulation of emotional memory processing. The findings, published in the Journal of Neuroscience, could help lead to the development of effective behavioral and pharmacological therapies to treat anxiety disorders, such as post-traumatic stress disorder, phobias and panic attacks.

There are two main stages of sleep – REM and non-REM – and both are necessary to maintain health and to regulate multiple memory systems, including emotional memory. During non-REM sleep, the body repairs tissue, regenerates cells and improves the function of the body’s immune system. During REM sleep, the brain becomes more active and the muscles of the body become paralyzed. Additionally, dreaming generally occurs during REM sleep, as well as physiological events including saccadic eye movements and rapid fluctuations of respiration, heart rate and body temperature. One particular physiological event, which is a hallmark sign of REM sleep, is the appearance of phasic pontine waves (P-waves). The P-wave is a unique brain wave generated by the activation of a group of glutamatergic cells in a specific region within the brainstem called the pons.

Memories of fearful experiences can lead to enduring alterations in emotion and behavior and sleep plays a natural emotional regulatory role after stressful and traumatic events. Persistence of sleep disturbances, particularly of REM sleep, is predictive of developing symptoms of anxiety disorders. A core symptom of these disorders frequently reported by patients is the persistence of fear-provoking memories that they are unable to extinguish. Presently, exposure therapy, which involves controlled re-exposure to the original fearful experience, is considered one of the most effective evidence-based treatments for anxiety disorders. Exposure therapy produces a new memory, called an extinction memory, to coexist and compete with the fearful memory when the fearful cue/context is re-encountered.

The strength of the extinction memory determines the efficacy of exposure therapy. A demonstrated prerequisite for the successful development of an extinction memory is adequate sleep, particularly REM sleep, after exposure therapy. However, adequate or increased sleep alone does not universally guarantee its therapeutic efficacy.

"Given the inconsistency and unpredictability of exposure therapy, we are working to identify which process(es) during REM sleep dictate the success or failure of exposure therapy," said Subimal Datta, PhD, director and principle investigator at the Laboratory of Sleep and Cognitive Neuroscience at BUSM who served as the study’s lead author.

The researchers used contextual fear extinction training, which works to turn off the conditioned fear, to study which brain mechanisms play a role in the success of exposure therapy. The study results showed that fear extinction training increased REM sleep. Surprisingly, however, only 57 percent of subjects retained fear extinction memory, meaning that they did not experience the fear, after 24 hours. There was a tremendous increase of phasic P-wave activity among those subjects. In 43 percent of subjects, however, the wave activity was absent and they failed to retain fear extinction memory, meaning that they re-experienced fear.

"The study results provide direct evidence that the activation of phasic P-wave activity within the brainstem, in conjunction with exposure therapy, is critical for the development of long-term retention of fear extinction memory," said Datta, who also is a professor of psychiatry and neurology at BUSM. In addition, the study indicates the important role that the brainstem plays in regulating emotional memory.

Future research will explore how to activate this mechanism in order to help facilitate the development of new potential pharmacological treatments that will complement exposure therapy to better treat anxiety and other psychological disorders.

According to the National Institute of Mental Health, anxiety disorders affect approximately 40 million American adults each year. While anxiety can sometimes be a normal and beneficial reaction to stress, some people experience excessive anxiety that they are unable to control, which can negatively impact their day to day life.

Reducing fear and stress following a traumatic event could be as simple as providing a protein synthesis blocker to the brain, report a team of researchers from McLean Hospital, Harvard Medical School, McGill University, and Massachusetts General Hospital in a paper published in the March 4 issue of Proceedings of the National Academy of Sciences.

“This is an important basic neuroscience finding that has the potential to have clinical implications for the way individuals with posttraumatic stress disorder are treated,” said Vadim Bolshakov, PhD, director of the Cellular Neurobiology Laboratory at McLean Hospital. “We used a well-known behavioral paradigm that we think models PTSD, fear conditioning, to explore how fearful memories are formed. In our study, the level of fear exhibited by experimental subjects was significantly reduced as a result of decreased signal transfer between cells in the amygdala, a key brain region in fear-related behaviors.”

Influenced by the original findings of Karim Nader, PhD, professor of Psychology at McGill University, whose pioneering work showed that old memories should be un-stored in their brain after their recollection in order to last, Bolshakov’s team exposed rats to auditory stimulus that the animals learned to associate with a mildly traumatic event. After a single exposure to the training procedures, the rats exhibited fear during subsequent exposures to auditory stimuli. The researchers then provided the animals with rapamycin, a protein synthesis blocker, immediately after memory was retrieved in order to control bonding between the cells in the brain. The animals exhibited significantly less fear in response to the fear-invoking stimulus when retested the next day.

“The animals showed stereotypical signs of fear after the initial exposure to the auditory stimulus,” explained Nader, a co-author on the paper. “Following the administration of rapamycin, we show a significant decrease in fear, but not a complete elimination. We were surprised to note that activity between cells was significantly affected by postsynaptic mechanisms.”

The findings of this study, which was funded by a grant from the United States Department of Defense spearheaded by Roger Pitman, suggest that different plasticity rules within cells in the brain are recruited during the formation of the original fear memory and after  fear memory was reactivated.

“Although further work at the molecular level needs to be completed, we are hopeful that this unexpected discovery is the foundation needed to identify ways in which we can better treat anxiety disorders in which fear condition plays a role, such as post-traumatic stress disorder,” said Bolshakov.