In the beginning of the summer, we were able to meet two movement disorder researchers, Associate Professor Juho Joutsa from the University of Turku, and Dr. Daniel Corp from Deakin University in Australia. They have pooled their resources to study dystonia using lesion network mapping and brain stimulation (DBS, TMS).

The researchers met in 2016 at Harvard University, when both worked there as research fellows. In collaboration with Harvard professor Michael D. Fox, they applied a new approach to the study of movement disorders using lesion network mapping. Juho and Daniel are internationally respected researchers and have received several awards for their research work, including Juho’s Duodecim Young Researcher Award, which is given every two years to only one medical researcher, and Daniel’s Brainbox Initiative’s Young Investigator Award for exceptional research.

Early research career

Juho’s career as a neurology specialist and researcher has had many phases. He started his studies with mathematics, became interested in medicine and decided to change fields. As a young doctor, he became interested in neurology through a summer job. During his medical studies, Juho wasn’t sure whether he wanted to focus on clinical work or research.

“While in med school I always considered research as an option. During my post-doc fellowship in Harvard, being in that atmosphere with all the cool new discoveries, made me certain that research is the main thing for me”, ponders Juho.

Nowadays, research takes up most of his working time, but he also does clinical work on top of that. Treating patients with neurological disorders allows him to see what the main challenges are and what is important for patients. Research then allows for solving the unmet needs of the patients in a larger scale. So, both roles support each other, but they also take a lot of time from each other.

As a neurologist, Juho has been interested in movement disorders for a long time, and at Harvard he joined the world-famous imaging center to study the combination of brain stimulation methods and brain imaging. The center in which he worked was known for having invented functional MRI (fMRI), so Juho was learning brain imaging in excellent company.

Daniel’s background is in brain stimulation methods, and he has expertise especially in transcranial magnetic stimulation (TMS). Daniel didn’t particularly plan a research career, but his interest in neuroscience in particular developed gradually during his studies. Although, as a child, he did not dream of a career as a researcher, he considers his current job to be a dream job.

“As an undergraduate student I did a couple of courses on motor control. That is where I got interested in neuroscience and in the brain controlling the movement of the body”, Daniel recalls.

In search of the brain basis of dystonia

Daniel was involved in a project led by Prof. Michael D. Fox to find out the brain basis of cervical dystonia. He needed an expert in brain imaging, so Juho joined the same project at this point. The origin of dystonia in the brain was unknown until now. At times, dystonia may be caused by a local lesion, such as a lesion caused by a stroke. However, lesion-induced dystonia is so rare that it would be impossible to collect such a group of patients. Therefore, the group used previous studies on lesion-induced dystonia as their starting point, and then confirmed their findings by comparing the brain function of dystonia patients and healthy controls using fMRI. They found that lesions causing cervical dystonia hit a common network and that this network was also highly abnormal in idiopathic dystonia. The cerebellum and the somatosensory cortex turned out to be the most central areas of the dystonia brain network. The research results were published in 2019 in the journal Brain, which is one of the most prestigious scientific journals in the field of neurology and neuroscience.

“Based on these results, it is possible to apply treatment with transcranial magnetic stimulation to the right place in the brain. After that, there are still many other important issues to be decided in terms of treatment, such as whether we should inhibit or excite these brain areas”, Juho thinks.

“As a result of this research, we found a spot on the cerebral cortex, which we can stimulate using TMS. The next logical step is to focus the treatment on this area of the somatosensory cortex, Daniel says.

Daniel and Juho have also investigated the origin of other types of dystonia in the brain and noticed that the brain networks vary by type of dystonia. Again, the results were published this summer at one of the most prestigious journals in neurology, Neurology (DOI: https://doi.org/10.1212/WNL.0000000000201042).

New dystonia research in Turku

After his years at Harvard, Juho founded his own research in Turku in 2018. That was when Daniel also came to Finland for the first time to set up new TMS equipment. The purpose of the study was to find out the effects of magnetic stimulation in the brain using PET imaging. The research that started from this examined how TMS can be used to activate the brain network of the cervical dystonia, identified by these two researchers. In February this year, the research visits were completed, and currently the collected data is being analyzed.

“We can already say that activation can be seen in the brain areas where we target the TMS treatment, which means we are on the right track. That is as much as I can say at this point. It will take a little bit more time before we have analyzed all the data, and after that we will think about what the results mean in practice”, Juho sums up.

From research to treatment

New treatments for dystonia are urgently needed. Juho’s and Daniel’s research brilliantly shows the direction for new, non-invasive forms of treatment. However, research is long-term work and TMS is not yet in clinical use in the treatment of dystonia.

“The development of treatment for dystonia is a good example of how long the journey is from research findings to treatment. We found a clear treatment target almost five years ago, but after this many more studies have to be done before we can demonstrate the possible benefits of the treatment, first with small pilot tests and finally with large clinical trials. All this requires time and funding”, Juho says.

Daniel is currently starting a clinical trial in Australia, where he intends to treat dystonia patients with a protocol pilot tested in Turku. This research is first of its kind in the world. This should have started already two years ago, but coronavirus postponed the start of the study.

“We have a clear gap in the treatment of dystonia: there are few good options between the most commonly used botulinum toxin injection treatment and the deep brain stimulation treatment that requires brain surgery. Often, patients’ symptoms are not severe enough to warrant deep brain stimulation therapy, but on the other hand, botulinum toxin may not help enough with the symptoms. This is why the patients are very interested in the research and are happy to participate in this new study”, Daniel says.

In movement disorders the patients’ symptoms vary a lot, and the future direction is to treat symptoms individually, not a specific disease. For example, tremor in Parkinson’s disease and tremor in essential tremor are relieved by the same deep brain stimulation treatment, i.e. we should find a specific place in the brain for each neurological symptom and then target the treatment there. Although these new treatments are not curative, eliminating symptoms is the key to improving the patients’ quality of life.

“Parkinson’s disease is a good example of how effective symptomatic treatments can be in improving quality of life”, Juho says.

Winds of the future

Juho’s research team is currently collecting its own lesion data for brain network analyses from the Hospital District of Southwest Finland. The limited lesion data available makes it difficult to utilize the method, so the data being collected now brings many new opportunities to study the origin of various neurological and psychiatric diseases in the brain. Patients with stroke are recruited for the study straight from the hospital. In Turku, approximately 1,000 infarction patients are treated each year, and approximately 400 of them are included in this study each year. The purpose is to collect data for about 3 years and the patients’ symptoms are monitored regularly.

“Previously, we used brain network analysis to elucidate the brain basis of a very rare neurological disease, Holmes tremor. I hope to find at least one patient here in Finland who has Holmes tremor, so that we can study the neurobiology of this disease in more detail”, Juho says.

Daniel says that their most important future research direction is to conduct different clinical studies on the effectiveness of TMS in different types of dystonia. They also study other movement disorders and are currently investigating the use of TMS in the treatment of Parkinson’s disease as well.

“We have already shown that stimulating the motor cortex with TMS could be effective in the treatment of Parkinson’s disease”, says Daniel.

“In Parkinson’s disease, as well as in dystonia, other treatments are initially very effective, but over time the effectiveness of the medication fades and new treatment options are needed in addition to deep brain stimulation”, adds Juho.

Dystonia research elsewhere in the world

Research into rare diseases is always difficult and the sample sizes are often very small. Research into the use of non-invasive brain stimulation (such as TMS) in the treatment of dystonia has increased in recent years. Daniel led a systematic literature review on the use of non-invasive magnetic stimulation in the treatment of dystonia. Just under 30 studies had been conducted until last year 2020, and the results would show that the treatments had, on average, little benefit in terms of symptoms (DOI 10.1101/2021.11.02.21265839). Since the brain basis of dystonia has not been identified, the treatments have been directed to very different parts of the brain using different treatment protocols, and the sample sizes have been small. Therefore, based on these results, it is not yet possible to draw very far-reaching conclusions about the effectiveness of brain stimulation in the treatment of dystonia. Juho mentions that the somatosensory cortex is now the newest promising treatment target that many research groups want to try in the future.

“In Germany, a research team was about to start a study in which they planned to target TMS treatments to the motor cortex, but after hearing about our new findings, they put the study on hold and are now waiting to see what kind of results our research will produce”, says Juho.

What new could health technology bring to the field of research?

Today, health technology is used to develop many new devices for monitoring the symptoms and treatment of movement disorders. Currently, they are mainly used for groups of patients, who are unable to express their symptoms themselves.

“Technological devices could be useful in research in the future because they can be used to obtain reliable data about the patient’s symptoms in a measurable form”, thinks Juho.

Daniel has been involved in the development of a new video analysis system using machine learning, which can be used to objectively measure the symptoms of dystonia at a more precise level. Also, deep brain stimulation treatment is being developed ever more toward automation. For example, a device mounted on the wrist or belt could monitor symptoms and the stimulator device would automatically adjust its settings accordingly. Research into the materials used in deep brain stimulators is also currently being carried out in order to develop electrodes that are even better compatible with the body.

Cooperation is power

Cooperation between researchers is important because no one can do everything. Juho and Daniel are a good example of how high-quality research can be achieved by combining different areas of expertise. Juho mentions that there are exceptional opportunities for world-class research in movement disorder in Turku, because a lot of movement disorders research is concentrated here, and the patient organization is also located in Turku.

Image by: Emmi Nuppula, Parkinsonliitto