Differences in the complexity of the EEG signal (yellow and red colors) in a specific brain area between the group with advanced multiple sclerosis and the control group, and multifractal spectra calculated for the group of patients (red line) and for the control group (blue line). CREDIT Source: IFJ PAN
What was it we were going to tell you about? Oh!! About the research into the complexity of electrical brain signals in patients with multiple sclerosis, a disease mainly associated with the slowing-down of information processing and a lack of motor coordination. These signals are beginning to show traces of multifractality, according to a scientific project carried out with the participation of the Institute of Nuclear Physics of the Polish Academy of Sciences in Cracow.
Multiple sclerosis is an incurable disease that leads to degeneration of the central nervous system, manifesting as motor and sensory disturbances. Its course can only be mitigated, the more effectively the earlier the disease is detected. A promising tool for early detection of the severity of this neurological disease appears to be multifractal analyses of electrical signals flowing from the brain, as has just been demonstrated by researchers carrying out the “Biologically inspired neural networks” project of the Foundation for Polish Science, funded by the European Regional Development Fund. The achievement is the result of collaboration between researchers from four scientific institutions: the Jagiellonian University (UJ), Cracow University of Technology, SWPS University (USWPS) in Katowice and the Institute of Nuclear Physics of the Polish Academy of Sciences (IFJ PAN) in Cracow, where the multifractal analyses were carried out.
“The search for multifractal relationships is computationally demanding and has only started to become more widespread in the last decade or so, together with the increase in computing power of computers and the development of software. As a result, in many areas of scientific activity multifractals are only at the stage of ‘taking their first steps’. One such area is the analysis of the complexity of electrical signals emitted by the human brain, especially in the context of degenerative changes taking place in it,” says Dr. Pawel Oswiecimka from the Department of Complex Systems Theory at the Institute of Computer Science, Polish Academy of Sciences, introducing to the subject.
The patients for the studies that formed the basis of the project were strictly selected by researchers and doctors from the Department of Neurology at the UJ Medical College and the Department of Neurology at the UJ Hospital. The group with diagnosed, early-stage multiple sclerosis was eventually reduced to 38 subjects – and the control group to 27. Electroencephalographic (EEG) data were collected several times over a two-year period, each time involving the subjects in different tasks. The electrical activity of the brain was measured using 256 electrodes, each sampled one thousand times per second. Before the actual analysis, the signals were cleaned, removing, for example, artefacts caused by eye blinks, and, according to generally accepted convention, were combined into groups corresponding to 20 brain areas.
“The total amount of data collected is so large that it will take our team years to complete a full set of multifractal analyses. Therefore, the paper we have just published in ‘Biomedical Signal Processing and Control’ discusses only the readings collected during the earliest phase of the measurements, concerning the situation when the subjects taking one of the two prescribed pharmaceuticals did not perform any activity during the measurements,” explains Dr. Oswiecimka.
The basic feature of ‘ordinary’ fractals is their self-similarity: by enlarging them, sooner or later we see a structure very similar to the initial one, or even identical. And what happens when we combine several fractals in a simple manner? The result is generally noise. However, there are mathematical operations that weave fractals into complex structures that retain the capacity for self-similarity. In ordinary fractals, self-similarity appears when we scale any fragment by a factor that is always constant for that fractal, whereas different fragments of multifractals must be scaled in different ways. This feature means that, while analyses using ordinary fractals allow linear correlations, such as trends, to be picked up, multifractals can reveal the existence of less obvious, non-linear correlations.
At the fractal analysis stage, the IFJ PAN specialists noticed that the electrical signals emanating from the brains of healthy people show the presence of certain long-range trends, which makes the graphs of their electrical activity visually smoother than in patients with multiple sclerosis, whose brains send out more ‘jagged’ signals. But when multifractals are involved, the situation changes: the electrical signals emitted by the brains of healthy people have less structural complexity than in patients.
“It seems that in people with early-stage multiple sclerosis, the communication between neurons is more complex. However, the neurons are not fully independent of each other, as they are still jointly responsible for the formation of the EEG signal, and therefore we observe a tangle of fractals, i.e. multifractals,” says Dr. Oswiecimka and adds: “In contrast, in the control, healthy group the individual fractal components are more regular, fit together better and the multifractal structure becomes more difficult to see.”
The interpretation of the obtained results is presented by Prof. Tadeusz Marek, from the USWPS Department of Psychology: “The existence of complex signal organisation in multiple sclerosis sufferers may indicate compensatory processes in the brain’s neural networks. The brain attempts to compensate for the deficit created by the disease and seeks ways around damaged areas, leading to a reorganisation of the network. The functions of these areas try to be taken over by other, still efficiently working groups of neurons, which manifests itself in an increase in the complexity of electrical activity.”
In summarising the results of the analysis of multifractal EEG recordings, Prof. Marek emphasises that they are proving to be a highly sensitive tool for detecting compensatory processes occurring in the neural networks of the brain in the early phase of multiple sclerosis development.
The results of the work of the team of physicists from the IFJ PAN are the first step towards developing more accurate techniques for assessing the progression of multiple sclerosis in patients. Currently, a questionnaire survey, which is highly subjective by nature, is used for this purpose, while more objective examinations require the use of magnetic resonance imaging and are therefore not only invasive but also highly cost-intensive. Discovering the relationship between a patient’s condition and the multifractal complexity of their brain’s electrical activity would allow for an objective assessment, using an easy to use measurement technique that is non-invasive and not too troublesome for the patient.
The reported results are the first phase of analyses of the EEG signals collected during this scientific project, with the remaining electroencephalographic data currently being processed. However, the scope of the research was broader and also included brain imaging using structural and functional magnetic resonance techniques. These resulted in a series of images showing cross-sections from which the structure of the brain and changes in the blood supply and oxygenation of its various areas can be reconstructed. The search for multifractal heralds of multiple sclerosis will therefore continue – no longer in one, but in four dimensions.
Combining pelvic floor exercises with behavioural therapy could be more effective than current medical treatments at helping men with frequent urges to urinate, new research in men has found.
The results reveal that an app-based therapy significantly improves the lower urinary tract symptoms that many millions of men experience—hesitancy, straining, frequent urges to urinate, and effective bladder emptying. The full trial results are expected to be published later this year.
This could be useful to people with multiple sclerosis, diabetes, rheumatoid arthritis, and other conditions, as well as to the general population.
Carried out in Germany, this is the world’s first randomised controlled trial to look at combining pelvic floor training, behavioural therapy and bladder control techniques for mild, moderate and severe bladder emptying disorders in men, all delivered as an app-based therapeutic.
Bladder emptying disorders can start to appear from the age of 30 and typically affect a large proportion of men aged over 50.
While clinical guidelines recommend physiotherapy, behavioural therapy and lifestyle changes as a first-line treatment, clinicians often neglect them due to a lack of available evidence. Several unpleasant side effects are associated with the few drugs available, and surgery is only advised for those with severe symptoms.
Professor Christian Gratzke, from University Hospital Freiburg in Germany, who co-led the trial, explains: “Frequent urges to urinate and issues emptying the bladder are the most prevalent urinary conditions we see in men after urinary tract infections. While some drugs are available, they don’t tend to be effective, and up until now, there’s been little data available to back physiotherapy. We’re confident that we now have that data, and making this form of therapy available digitally could be a game changer for the millions of men who struggle day-to-day with issues emptying their bladder.”
The researchers recruited 237 men aged 18 across Germany into their 12-week study. Half the men were randomised to receive standard medical care, while the other half were given access to the Kranus Lutera app-based therapy alongside standard care. These participants were asked to record a urination diary, which was used to inform their treatment, and complete questionnaires about their symptoms’ severity and overall quality of life.
After 12 weeks, the trial found significant and clinically meaningful improvements in symptoms and quality of life measures from participants given the app-based therapy, who reported an average seven-point increase in symptom scores compared to those in the control group.
The study found that app-based therapy was more effective than medical therapy. No patients reported any side effects or challenges accessing the smartphone app.
The findings challenge the dogma of the 1980s and 1990s, when prostrate surgery was the first line of treatment for an overactive bladder, and offer a welcome alternative to drugs, say the researchers.
“Many men with bladder emptying disorders are ageing and have other medical conditions that require drug treatments,” says Professor Gratzke. “The limited drugs we have available aren’t suitable for these patients due to their side effects. For those with mild-to-moderate urinary symptoms, this digital therapy is without side effects and improves symptoms by a magnitude we have not seen before. Simply strengthening the pelvic floor makes all the difference, it’s a no brainer.”
Jean-Nicolas Cornu, Professor of Urology at the Charles Nicolle Hospital in France and member of the EAU Scientific Congress Office, said: “There has been little to no evidence to support training men to better control their bladders, despite this being recommended in clinical guidelines. This is the first randomised controlled trial looking at physiotherapy and behavioural therapy for bladder emptying disorders, and it shows a very positive effect over conventional drug treatment.
“We now need a bigger trial looking at the longer-term effect of this app-based therapy after 12 weeks for different forms of bladder emptying disorders. If offered widely, this treatment could dramatically change clinical practice, and could relieve symptoms without exposing patients to drugs. We could save a lot of unnecessary prescriptions for drugs that tend to be of little benefit.”
The researchers compared data from men whose symptoms were due to overactive bladder with those whose symptoms were due to an enlarged prostate. They found that both groups benefited from the therapy. However, it did not compare the effect of therapy on different forms of bladder emptying disorder.
The test was developed using an existing diagnostic procedure as its basis and has the potential to be applied in clinical trials that target the Epstein Barr Virus
A team of research scientists at Trinity College Dublin have developed a new and unique blood test to measure the immune response to the Epstein Barr Virus (EBV) which is the leading risk factor for developing multiple sclerosis (MS). Their findings are published in the journal Neurology Neuroimmunology and Neuroinflammation and have implications for future basic research in further understanding the biology of EBV in MS, but also has the potential to be applied in clinical trials that target the virus.
MS is a chronic neurological disease with no known cure. It affects approximately three million people worldwide and is the second leading cause of disability in young adults. There is a pressing need for better treatments.
A range of viruses relating to MS have been studied in the past but none have had such compelling evidence as EBV. The question the team considered was why do some people have known MS have a rogue immune response to EBV, a common viral infection that is generally asymptomatic?
To answer this, scientists measured the cellular response of MS patients to EBNA-1, a part of the EBV that can mimic the myelin coating of nerves which are the principal site of attack of the immune system in MS. The team found that the immune response is higher to EBNA-1 in people with MS compared to those with epilepsy, or the healthy control group. The team also showed that this cellular response is impacted by currently approved medications for MS which target the immune system, but not the virus. The immune response to EBNA-1 was found to be lower in people who are taking B cell depleting medications compared to people with MS not taking medication and the level recorded was equivalent to healthy controls.
B cell depleting medications are effective for reducing MS disease activity. It is not known however, how exactly they work. Many people believe that reducing B cells reduces EBV levels, as EBV can lie dormant within B cells. The scientists do not prove this theory, but do show that the immune response to EBV in MS is equal to healthy controls when these medications are used. The team believe that this supports the need for more selective reduction in EBV rather than targeting all B cells. This is of importance as B cells play an important role in fighting infection and an unselective approach can lead to unwanted side effects.
The Trinity researchers are the first team of scientists to capture the immune response to EBNA-1 using whole blood samples carried out exclusively with equipment that is used in the hospital laboratory day to day. This builds on previous research that used extensive pre-processing in research laboratories. We believe this is of importance as it shows the ability for the test to be run elsewhere and at scale without a need for new equipment or personnel.
This research is important because a standard blood test that was processed in a hospital laboratory provides important information on the immune system’s response to EBNA-1. This response appears to be at the heart of the pathogenesis of MS. The ability to measure this in a scalable test, that was developed using an existing diagnostic test as its basis, has implications for future basic research in further understanding the biology of EBV in MS. But the test also has the potential to be applied in clinical trials that target the virus. This would mean that there is the potential to directly measure the immune response to any potential antiviral treatments, rather than measuring MS outcome measures alone.
Speaking on the potential benefits of this research, Dr Hugh Kearney, Neurologist, School of Medicine, Trinity College and lead author said:
“In the short term the benefit of this research is likely to be for the research community in MS. We believe the approach adopted in this test that uses whole blood samples on a robust hospital-based platform will facilitate adoption in other centres and also replication of the results with a view towards validation. In the medium term, if validated, then this would be of benefit to researchers involved in clinical trials in MS. Long term benefits will be for people with MS, who live with a chronic neurological illness as new treatments tested in clinical trials have the potential to reduce the burden of this potentially disabling disease.
The next step for our team is to develop a longitudinal study. We aim to do this by recruiting newly diagnosed people with MS and measuring this blood test before treatment has started and then repeating the blood test at an interval to show that B cell depletion directly impacts on the cellular response to EBNA-1 in MS.”
