Could you provide insight into the history of deep brain stimulation (DBS)? How has it developed as a neurological therapy over the years?

Some people say that DBS as a treatment originated with hyperkinetic patients, but there is also evidence to suggest that it was applied to psychiatric problems before being brought to the field of movement disorders. I would say that DBS developed more or less in parallel in both of these areas of medicine. As a practice, it arose out of lesion surgery, whereby distinct tissues in the brain were destroyed to repair the overall electrical circuits. Testing the organ piece by piece, it was discovered that some areas, when destroyed, produced a great clinical benefit in certain disorders, such as motor disorders like Parkinson’s disease. It was also observed that by using electrical stimulation, one could achieve a similar effect to lesioning an area of the brain without destroying the tissue.

What led you to study DBS for movement disorders?

The reason we started with movement disorders was that this was the main field for DBS in everyday practice when we initiated our studies more than 10 years ago. To date, there is the highest level of clinical evidence for the usefulness of DBS in these disorders. When the treatment itself was first implemented, surgical lesions and stimulation were commonly performed in a psychiatric context – but due to the development of

pharmacology in the 1950s and 1960s, a growing trend of managing psychiatric disorders using medication arose. Combined with historical malpractice in psychosurgery, it had become almost taboo to perform electrical stimulation in psychiatric patients by the time we entered the field. As a result, we studied the potential of DBS in movement disorders. Throughout our investigations, we noticed a side effect from the treatment – DBS was also having an impact on patients’ mood and cognition. These findings have pushed us to look at DBS in the context of psychiatric disorders.

Can you outline both the challenges and benefits associated with using DBS to treat movement disorders?

The benefits are clear: we have seen huge improvements in motor function and quality of life – even in the judgement of the patients themselves. Admittedly, there are some inconsistencies between patient responses, and in some cases, there are cognitive and emotional side-effects.

However, there are two main challenges: how do we choose the right patients who can benefit from this treatment? Also, how do we determine over the course of the disease, the right time for the intervention? In addition, it is important to figure out an acceptable ratio of cognitive and emotional side-effects compared to motor function benefits; while DBS can repair some motor function, there is also the potential to cause other problems.

Did you come across any obstacles or challenges over the course of your investigation?

Yes. We don’t have the technical capability at the moment to stimulate two areas at different frequencies; if we want to improve cognitive function, we might use a specific frequency – but at the same time, this same frequency could worsen motor function. This is a tricky complication that we are currently working on, as the ability to fine-tune the precise area and frequency of stimulation would be ideal. One very big target is to develop a closed-loop stimulation device that could directly record activity, and then feed back to the pacemaker, which would change stimulation patterns based on this input.

Where will you be focusing your research efforts next? Do you have any exciting plans in the pipeline?

We have a new research grant that just started called ERA-NET NEURON from the EC. Our project within that is called TYMON, and it is a collaborative endeavour involving partners in Paris and Lisbon. Here, we are looking at the mechanisms of DBS in treating obsessive compulsive disorder (OCD). We are trying to disentangle the mechanisms of DBS’s impact on the subthalamic nucleus.

More broadly, in light of our new knowledge that we can influence emotion and cognition, we are now moving into the treatment of psychiatric disorders. In addition, we hope to compare the impact of DBS in the same area of brains under different conditions, such as Parkinson’s and OCD. This work started just four weeks ago, but it will be one main focus for the next three years.

Expert neurologist and clinician-researcher Dr Lars Wojtecki explains the finer points of his work to explore deep brain stimulation, not only as a treatment for motor disorders, but also for neuropsychiatric conditions such as obsessive compulsive disorder and dementia

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42 INTERNATIONAL INNOVATION

Acting on impulseA team of neurologists, neurophysiologists and psychologists at Heinrich-Heine University in

Düsseldorf, Germany, is investigating the operation of the human brain; with the help of several cohorts

of movement disorders patients and deep brain stimulation, several novel discoveries have been made

DR LARS WOJTECKI

WWW.INTERNATIONALINNOVATION.COM 43

TREATMENTS THAT TARGET the brain directly with surgical interventions are always going to be controversial. People consider the brain as the physical seat of the mind, and one of the most complex organs in the body; as such, alterations to it might have unexpected and radical impacts on a subject’s behaviour and personality. The common definition of a person includes, at least to some extent, psychological continuity – the thoughts and attitudes of an individual are expected to either remain consistent, or change incrementally under the influence of experience. Some would argue, therefore, that when a person’s behaviour is radically altered in an instant – as it can be when surgical procedures are conducted on the brain – his or her psychological continuity, and therefore identity, is disrupted.

The risks involved in brain surgery of any kind are regarded by some as serious – but even more critical are the problems that such interventions are implemented to counteract. Movement disorders like Parkinson’s disease, idiopathic dystonia and psychiatric disorders including obsessive compulsive disorder (OCD) can be extremely debilitating, and the physical manipulation of the brain represents an expedient and promising route to therapy and treatment. In fact, the limits of what could be achieved with this kind of intervention are still unknown – and as the complexities of the brain are unravelled, the risks associated with increasingly daring treatments will be reduced and eventually eradicated. With neuropsychiatric and movement disorders taking an increasing toll on the global population, the time to examine this type of procedure is now.

GOING DEEP

One surgical intervention that has proven extremely useful in the context of motor dysfunction is deep brain stimulation (DBS). Sometimes referred to as a ‘brain pacemaker’, this setup allows physicians to influence the function of the organ through the generation of controlled electrical impulses – a process that does not cure conditions like Parkinson’s, but which can significantly alleviate symptoms and improve quality of life for patients. Despite its facility, the mechanisms behind DBS’s efficacy are still not completely understood, and it has only been approved as a treatment for some motor disorders worldwide and additionally for OCD in Europe.

Based at Heinrich-Heine University is one team dedicated to unravelling the mysteries surrounding DBS. Dr Lars Wojtecki is a senior physician in the University Hospital’s Neurology Clinic and leader of the Perioperative Neurophysiology and Neuropsychology (PERIPHYS) group, which aims to understand the cognitive and emotional functions of the subthalamic nucleus and other basal ganglia structures. “We perform a combination of behavioural and neuropsychological studies, in addition to electrophysiological recordings,” Wojtecki explains. For example, in some studies the researchers stimulate subjects with a DBS device while they perform psychological tests, simultaneously recording electroencephalographic (EEG) data to generate a complete picture of how DBS interacts with the brains of patients suffering from a range of motor and neuropsychiatric diseases.

In addition to this approach, the German neurologists use an invasive technique in which they target specific areas of the brain with an externalised lead. The lead is led out of the skull and directly reports the neural activity it registers. Recently, the researchers have been combining the invasive and non-invasive techniques, collecting data from inside and outside the brain in tandem – and this additional information has made all the difference to their work.

WORDS AND EXPECTATIONS

As part of his goal to understand and modulate cognitive and emotional functions of the basal ganglia using DBS, Wojtecki has partnered with several researchers, scientists and clinicians across Germany. Recently, Wojtecki and his colleagues have demonstrated that stimulation at a certain frequency can improve verbal fluency, a cognitive ability often impaired in Parkinson’s disease. Cognitive functions were also investigated in Huntington´s disease, which is a debilitating movement and dementia disorder that causes changes in the brain that affect movement, mood and critical thinking skills. Using DBS to stimulate the dorsal pallidum – the area of the brain that functions in the cognitive processes that control motor activities – the neuroscience team provided clinical evidence and data from EEG recordings that show DBS can restore cognitive control.

In two further studies, both of which were published last year, Wojtecki and his collaborators turned their attention to the relation of deterioration in motor control, cognitive function and speech in Parkinson’s disease. Although DBS can be very helpful in the context of this disease as it has been shown to reduce movement symptoms such as slowness, stiffness and tremors, it has also been associated with a range of negative side-effects including speech deterioration. One of the group’s studies set out to examine the impact of DBS on speech in 38 Parkinson’s patients. It found that eight of the total cohort produced worse speech samples while undergoing stimulation; interestingly, these were the same eight patients whose speech was worst without DBS.

In these investigations, German scientists also found that the expectation of treatment success makes a difference to the effi cacy of DBS in counteracting some symptoms of the disease. A cohort of 24 tremor-dominant Parkinson’s patients were infl uenced by either positive, negative or neutral suggestions about the impact DBS treatment would have on tremor and motor control. While these suggestions had no impact on the group as a whole, the study found that resting tremor improvements and deteriorations under DBS were modulated by the patient’s expectation. Furthermore, when patients exhibited a negative or nocebo response to the treatment whereby their tremor grew worse, they also showed deterioration in their verbal fl uency.

TIME OUT OF MIND

In a 2011 study Wojtecki and his colleagues brought the approach of different stimulation frequency settings to the modulation of time processing. The brain generates humans’ perception of time through many factors, and the disease state induced by Parkinson’s impacts on these factors, altering patients’ perception of time. While medications exists that can help patients correct their distorted recognition of time, the German researchers were keen to discover whether DBS in the subthalamic nucleus could also infl uence interval recognition, as the treatment alleviates many of the other symptoms of Parkinson’s disease.

The subjects were given a number of tests to perform, which all involved gauging the length of a period of time and/or reproducing that length of time by the coordinated manipulation of buttons. Four conditions were tested: healthy controls, Parkinson’s patients with no DBS, patients with 10Hz DBS and patients with 130Hz DBS. The results were intriguing: all subjects overestimated the short interval of fi ve seconds and underestimated the long interval of 15 seconds, but underestimation of the 15-second period was signifi cantly higher in Parkinson’s patients without DBS than the controls, highlighting a disease effect. Moreover, this same time production error was mitigated by high-frequency DBS, but worsened by low-frequency stimulation.

REDEEMING DBS

As well as using the technique to glean basic information about the function of the brain and its various constituent structures, the work of Wojtecki and his collaborators has begun to elucidate the potential of DBS to achieve positive outcomes for patients – improving both motor and cognitive function, and boosting quality of life. In the future, the German neurologists plan to expand their studies to include neuropsychiatric conditions, even using the emotion and cognitive side-effects DBS produces in Parkinson’s patients to counteract these problems. Much has already been accomplished – but the possibilities are electrifying.

Wojtecki and his colleagues have

demonstrated that stimulation at

a certain frequency can improve

verbal fl uency, a cognitive

ability often impaired in

Parkinson’s disease

44 INTERNATIONAL INNOVATION

INTELLIGENCETREATING COGNITIVE AND EMOTIONAL FUNCTIONS AND MOVEMENT DISORDERS WITH THERAPEUTIC NEUROMODULATION

OBJECTIVE

To use behavioural experiments and interventional neurophysiology in the context of neuromodulation techniques to examine cognitive and emotional functions of the basal ganglia.

KEY COLLABORATORS

Professor Dr Jan Vesper; Professor Dr Tobias Kalenscher, University of Düsseldorf, Germany • Professor Dr Luc Mallet, Behaviour, Emotion & Basal Ganglia, Brain and Spine Institute, France • Dr Sabine Skodda, Ruhr University Bochum, Germany • Professor Dr Christian Beste, Dresden University of Technology, Germany • European Huntington’s Disease Network (EHDN)

FUNDING

German Research Foundation (DFG) • German Federal Ministry of Education and Research (BMBF)

CONTACT

Dr Lars Wojtecki Consultant Neurologist and Group Leader

Department of Neurology/Institute of Clinical Neuroscience and Medical Psychology Heinrich-Heine University DüsseldorfMoorenstrasse 540225 Düsseldorf, Germany

T +49 211 8107337E wojtecki@neurologie.uni-duesseldorf.de

www.larswojtecki.dehttp://bit.ly/LarsWojteckiwww.periphys.de

LARS WOJTECKI completed his Dr Med degree in Stereotactic Neurorsurgery, and since 2008, has been a Board Certifi ed Consultant Neurologist at the Center for Movement Disorders and Neuromodulation at the University Hospital Düsseldorf, Germany. In 2014, he rose to the position of Head of the Cognitive Neurology Unit at the Department of Neurology. He is currently Principal Investigator of the Perioperative Neurophysiology and Neuropsychology (PERIPHYS) research group at the Institute of Clinical Neuroscience and Medical Psychology.