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New combination therapy for treating stroke patients

30 to 40 percent of all stroke patients suffer from persistent signs of paralysis that prevents them from using the affected hand. The innovative combination of two non-invasive treatment methods is a therapeutic approach with considerable potential for treating severely impaired patients.

Researchers and medical doctors from Tübingen have developed a new treatment approach for severely impaired stroke patients. “Many of these patients can no longer extend their fingers and so cannot open up their hands. This can affect up to 100,000 patients a year in Germany alone,” says Prof. Dr. Alireza Gharabaghi from the Department of Neurosurgery at Tübingen University Hospital. Gharabaghi and his team have charted new territory by combining two innovative, non-invasive methods in a completely new way.

Prof. Dr. Alireza Gharabaghi has been the head of the Neuroprothetics research group at the DFG-funded Centre for Integrative Neuroscience (CIN) at the University of Tübingen since 2009. He has also been the head of the Division of Functional and Restaurative Neurosurgery at the Department of Neurosurgery at the University of Tübingen since 2012. © Gharabaghi

The two methods have been used for many years in clinic and research. One of them, transcranial magnetic stimulation, TMS for short, is used for the targeted stimulation of certain brain regions. The procedure involves holding magnetic coils near to the patient’s scalp. The other method involves the use of a neurorobotic device that can be controlled by a patient’s brain activity using a brain-machine interface (BMI). It works as follows: a patient imagines opening his or her hand, for example. Sensors attached to the patient’s scalp receive the electrical signals generated by the patient’s thoughts and translate them into real movement. The hand opens. The two methods are already used separately. However, a sustainable breakthrough has not yet been achieved. A brain-machine interface combining TMS with a robotic device that controls hand movement may therefore be beneficial for patients who have lost voluntary muscle control.

The smart combination of the devices is an important factor for stimulating unused nerves in paralysed patients. “In order to restore communication between the brain and muscles, it is important to properly time brain stimulation,” says Gharabaghi. “We use robotic hand orthoses like those purchased by rehabilitation clinics. The TMS equipment we use is also freely available on the market.” The scientists have combined the devices in such a way that they are able to trigger concerted actions, thus making the devices “smarter”. The IT experts and engineers in Gharabaghi’s team brought to the development project the same skills that they used to optimise TMS for application in neurotherapy.

Glossary

  • Being lytic is the feature of a bacteriophage leading to the destruction (lysis) of the host cell upon infection.
  • Translation in a biological context is the process in which the base sequence of mRNA is translated into the amino acid sequence of a protein. This process takes place in the ribosomes. Based on a single mRNA molecule, many protein molecules can be synthesised.
  • A neuron is a nerve cell. A nerve cell consists of a body, an axon and dendrites.
  • Physiology is the study of the biochemical and physical processes in cells, tissues and organs of creatures.
  • The transcranial magnetic stimulation (TMS) is a non-invasive method used to stimulate parts of the brain with strong magnetic fields. This method is applied in some cases in neurological diagnosis and, more uncommonly, in the therapy of certain neurological diseases like tinnitus, apoplexy, epilepsy, Parkinson's disease or depressions.
  • Biomolecules which can bind active agents are called targets. They can be receptors, enzymes or ion channels. If agent and target interact with each other the term agent-target-specific effect is used. The identification of targets is very important in biomedical and pharmaceutical research because a specific interaction can help to understand basic biomolecular processes. This is essential to identify new points of application.

Remote signalling pathways become a motorway

The new approach has been tested in healthy volunteers and in a number of stroke patients, and has already delivered positive results. The basic principle is that neural pathways connecting the motor brain areas and the periphery, in this case the hand, that are unaffected by the stroke can be sustainably strengthened with the new procedure. “It is like using a secondary road when the motorway is congested,” says Gharabaghi. But how do the doctors know where to find “secondary roads”? “We use MR images of the brain and physiological methods such as TMS to identify these secondary roads. Magnetic stimulation is not just used for therapy, but also for diagnosis by mapping various brain areas like a chess board and setting pulses. We use a sensor on the patient’s hand to measure whether and when a signal arrives,” says Gharabaghi.

The simultaneous use of a neurorobotic device and transcranial magnetic stimulation (TMS) stimulates previously unused nerves. © Work group Gharabaghi, University Hospital ofTübingen

Some residual nerve activity needs to be available in order for the method to work. In addition, the patient’s motivation and ability to imagine opening his or her hand are central to the success of the therapy. This generates a measurable signal that can be transmitted to the robotic device that then converts the patient’s thoughts into real movement. At the same time, i.e. as the robotic device opens and closes the patient’s fingers, magnetic pulses stimulate the hand area of the brain. Gharabaghi and his co-workers have already found in their initial investigations that these pulses need to be transmitted at the same time the robotic device initiates hand movement. Further investigations are needed to obtain information on optimal time duration and frequency. “We can use different types of pulses and pulse patterns. We have yet have to find out whether it is better to use single or multiple pulses,” says Gharabaghi. In addition, the researchers and doctors are developing and optimising training plans for patients. Controlled, prospective studies involving an as large a patient group as possible will help them achieve this.

Important success factors: a patient's willingness and perseverance

The preliminary tests have already shown that the more the patient participates, the better the treatment outcome. “A passive patient will not benefit much from the approach. It is vitally important that the patient is actively involved and focused on the processes,” says Gharabaghi. In general, Gharabaghi has had the best experience with highly motivated and disciplined patients, especially patients who are able to stay motivated and disciplined over a period of several weeks. The patients should also be able to tolerate frustration. “There is no guarantee of success, but we can create the best possible conditions for it,” says Gharabaghi summing up his group’s findings. Gharabaghi’s team is currently investigating potential study participants. Only volunteers who experienced a stroke more than six months ago and who have so far not experienced any notable improvement of hand movement will be enrolled in the study.

In the medium and long term, the combined use of the two methods has the potential to be extended to other functional failures. Theoretically, there is nothing standing in the way of combining BMI with deep brain stimulation to treat other malfunctions. However, Gharabaghi does not want to take the second step before the first has been achieved. This means that Gharabaghi and his group of researchers will continue investigating and bringing to application the combination of non-invasive TMS and BMI. “We can achieve a lot with this combination. We will only carry out surgery if further improvements can be expected.”

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