Fall 2011 - Institute of Medical Science - University of Toronto

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SPOTLIGHT Transcranial magnetic stimulation An investigational tool and potential therapeutic option in movement disorders By Nina Bahl Arguably the most important organ in the body, the brain is also the least understood; comprised of a staggering one hundred billion neurons, the complexity of the connectivity between these cells seems nearly incomprehensible. Accordingly, our understanding of human neurophysiology has benefited tremendously from the advent of sophisticated investigational tools, including transcranial magnetic stimulation (TMS) – a non-invasive method of stimulating the brain. For Dr. Robert Chen, a senior scientist and movement disorders specialist at Toronto Western Hospital, the utility of TMS has proven invaluable to his investigations of motor cortex functionality and of the pathophysiology and associated treatments of movement disorders. Stimulation is produced by generating a brief, high-current pulse in a magnetic coil that is placed on the scalp of the subject. This transient current induces a large and changing magnetic field, which subsequently produces an electric current in the underlying brain 1,2 . For studies involving the motor cortex, as in Chen’s lab, TMS pulses are typically administered to the region of the brain that controls a specific hand muscle. Here, stimulation produces a focal twitch in the target muscle, which is measured with surface electrodes placed on the hand, and visualized on an electromyogram. This muscle response to TMS is termed the motor-evoked potential, the amplitude of which is thought to reflect motor cortex excitability 2,3 . Thus, human cortical excitability can be assessed using a number of specific TMS measures that are based on this fundamental principle. While using TMS techniques during a research fellowship at the National Institutes of Health, Chen quickly appreciated the versatility and uniqueness of TMS as a neurophysiological probe. “It really is a fascinating way to study the brain,” he affirms. “By stimulating neural regions without any sort of invasive method, you can measure a subject’s response in a number of ways and reveal fairly specific information about their [cortical] physiology. There aren’t many other methods that can offer such a direct investigation in humans, so [TMS] is a very powerful tool.” Upon establishing his laboratory at the Toronto Western Research Institute in 1998, Chen predominantly adopted TMS techniques for use in his lab, which currently focuses its studies on patient populations to elucidate pathological mechanisms in a number of movement disorders. One of the most commonly studied pathologies in the lab is Parkinson’s disease (PD), a neurodegenerative disorder that causes a variety of debilitating motor symptoms, including bradykinesia, rigidity, and tremor. “Our [studies] have revealed several cortical changes in PD patients – as one example, we see a reduction in one form of motor cortical inhibition,” he notes. By understanding details such as these, the hope is to be able to piece together how neuronal degeneration in a disorder like PD translates into its overt symptoms, which is currently not well understood. Chen’s team has also used TMS techniques to explore deep-brain stimulation (DBS), which is one of the most remarkable neurosurgical advances for PD and a handful of other movement disorders. “When DBS emerged as a new treatment around 2000, our lab began investigating it soon after. One of the challenges is that we still don’t know how it works.” Chen aims to reveal potential mechanisms of action of DBS, and specifically, explore how deep-brain nuclei (where DBS implants are located) may be modulating the motor cortex to produce clinical improvements in patients with disordered motor control. Other major TMS investigations in his lab include studies of normal human motor physiology, including the examination of how different neuronal circuits interact with one another in the motor cortex. As well, his lab uses genetic techniques as an adjunct to examine the effects of selected single nucleotide polymorphisms on brain functionality and its ability to undergo plasticity and learning. Undeniably, for Dr. Chen, TMS has proven Photo by Paulina Rzeczkowska 25 | IMS MAGAZINE FALL 2011 PROSTATE CANCER
SPOTLIGHT itself as a versatile and invaluable research tool. Magnetic Stimulation for the Treatment of Motor and Mood Symptoms of Parkinson’s disease (MASTER-PD): A multicentre clinical trial Beyond its use as a neural probe, TMS has also been studied for its therapeutic potential. A recent meta-analysis by Chen’s team involving small pilot trials has revealed a reduction of motor symptoms in Parkinson’s disease patients following high-frequency repetitive TMS (rTMS) to the motor cortex. High-frequency rTMS is known to induce long-lasting, enhanced excitation in the brain. Thus, the clinical benefit seen in PD supports the hypothesis that rTMS may modulate underactive brain regions to improve symptoms of the disease 4 . Larger clinical trials have shown high-frequency rTMS to also be effective in reducing symptoms of depression when administered regularly to the left dorsolateral prefrontal cortex (DLPFC), a region of hypometabolism in depressed patients 2,3 . With depression as one of the most common and incapacitating non-motor symptoms in PD, these results are also critical for the PD patient population. “There have been a number of studies proving rTMS efficacy in treating depression, including a large randomized controlled clinical trial,” notes Chen. “It is an approved treatment for depression in Canada, and more recently, in the US as well.” Despite the promising rTMS results in PD, however, Chen realizes that its effectiveness is not yet as conclusive and explains its lack of approval as a treatment option. “The problem [with regards to PD] is that there has not yet been any large-scale clinical trial. The sample sizes so far have been small – typically only 10 to 20 patients per study,” he explains. “Our metaanalysis tells us there are encouraging results, but we need to build on that.” and the Cleveland Clinic – Chen is leading the sole Canadian site at the University of Toronto. MASTER-PD’s researchers hope to recruit 160 PD patients experiencing depressive symptoms to participate in a randomized, double-blinded, placebo-controlled study. Participants will be randomly assigned to receive either real or sham (placebo) rTMS via four possible treatment combinations: 1) rTMS to bilateral motor cortex + sham rTMS to the left DLPFC, 2) rTMS to left DLPFC + sham rTMS to bilateral motor cortex, 3) rTMS to both bilateral motor cortex and left DLPFC, or 4) sham rTMS to both bilateral motor cortex and left DLPFC. The rTMS interventions will be administered over the course of two weeks, and all subjects will undergo a comprehensive assessment of motor, mood, cognition and quality of life at different intervals for up to 6 months posttreatment. “Certainly, this will be the largest study of rTMS in PD. Hopefully it will be able to address whether rTMS can be used for the treatment of motor and mood symptoms in this patient population.” And with that, we are reminded of the ultimate goals of Chen’s TMS investigations: to disentangle the complexities of the brain, and more pointedly, to use this knowledge to better serve those who suffer from neurological disease. *The MASTER-PD trial is supported by the Michael J Fox Foundation. References 1. Hallett M. (2000). Transcranial magnetic stimulation and the human brain. Nature, 406(6792): 147-150. 2. Chen R. (2000). Studies of human motor physiology with transcranial magnetic stimulation. Muscle& Nerve, S9: S26-S32. 3. Hallett M. (2007). Transcranial magnetic stimulation: a primer. Neuron, 55(2): 187-189. 4. Elahi B, Elahi B, Chen R. (2009). Effect of transcranial magnetic stimulation on Parkinson motor function – systematic review of controlled clinical trials. Movement Disorders, 24(3): 357-363. Photo by Paulina Rzeczkowska To that end, Chen is currently involved in a North American multicentre clinical trial, termed MASTER-PD, that aims to determine the efficacy of rTMS in modulating brain activity to treat both motor and mood symptoms in PD. Of the five centres participating – including Harvard, the University of Florida, the University of California Los Angeles, The versatility of TMS has allowed Dr. Robert Chen to examine human motor cortex physiology, the pathological disruptions that can lead to movement disorders, and potential therapeutic options. IMS MAGAZINE FALL 2011 PROSTATE CANCER | 26
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