Melting freezing of gait with non-invasive cerebellar stimulation

Summary: Freezing of Gait (FOG) is a devastating symptom of Parkinson's disease (PD), causing regular falls and nursing home placement. Unfortunately, clinical management of FOG is very challenging with no current treatment completely alleviating FOG. As such, this study sets out to reduce FOG by using a safe stimulation technique called intermitted Theta Burst Stimulation (iTBS) of the cerebellum, which is a structure known to be involved with Parkinsonian gait disorders. iTBS is a form of Transcranial Magnetic Stimulation (TMS). This potential treatment has the advantage of non-invasively accessing a promising target for one of the most debilitating symptoms of PD, without the surgical risks associated with invasive brain stimulation techniques like deep brain stimulation. Study design: This is a single-blind sham controlled cross-over study. Aims: The aim of this study is to test the effects of intermitted Theta Burst Stimulation (iTBS) of the lateral cerebellum (Active 1), of the cerebellar vermis (Active 2) and of a control sham stimulation condition (Sham) of the neck muscles on Freezing of Gait in Parkinson's disease to be assessed on three separate mornings with a minimum washout period of 48 hours between visits. Subjects will be tested on standardised Timed-up-and-Go (Gait performance) and will be assessed on section 3 of the Unified Parkinson's Disease Rating Scale (UPDRS) before and after stimulation. Each subject's Active Motor Threshold (AMT) will be obtained, as further described below. The active stimulation parameters will be set to 80% of the subject's AMT as per TMS safety guidelines (Rossi et al. 2009). Participants will be blinded to treatment allocation and the order of stimulation will be randomized across participants. Materials: iTBS will be applied using a Magpro bi-phasic figure-of-eight coil connected to a MagPro R30 (MagVenture) stimulator with theta-burst option. Stimulation protocol: Subjects will first have their active motor thresholds determined by the first visible twitching of the FDI muscle which is actively contracted, related to single pulse TMS to the primary motor cortex controlling their dominant hand as per TMS safety guidelines (Rossi et al. 2009). The active motor threshold is the minimum amount of power necessary to make the subject's thumb twitch, and varies from individual to individual. The cerebellar stimulations will be set at 80% of active motor threshold, as per safety guidelines (Rossi et al. 2009). The two active stimulations will be set to 3 pulses at 50Hz, repeated at 5Hz (e.g. an inter-burst interval of 200 milliseconds) during a train of 2 seconds, repeated 20 times every 10 seconds administering a total of 600 pulses, as per previous investigation and safety guidelines (Koch et al. 2008; Rossi et al. 2009). In addition, during one of the three visits patients will undergo a brief (190 seconds) and low intensity (20% of active motor threshold) sham stimulation of the neck muscles to act as a control condition (Bologna et al. 2015). Procedures: iTBS stimulation The coil will be positioned tangentially to the scalp, with the handle pointing upwards as per previous investigations showing that this orientation is able to modulate contralateral M1 excitability (Koch et al. 2008). The targets for active stimulation are the ipsilateral cerebellum (1cm below and 3cm lateral to inion), corresponding to the most affected side; and the cerebellar vermis (1 cm below inion) (Bologna et al. 2015; Hardwick et al. 2014). A sham stimulation of the neck muscles will also be applied (Bologna et al. 2015; Koch et al. 2008). This sham stimulation will induce the same auditory stimuli and a mild subjective sensation of neck muscle contraction similar to that obtained with real stimulation but does not stimulate the cerebellum and does not produce neurophysiological changes of the cerebellar connectivity, thus acting as a control condition (Bologna et al. 2015). Each stimulation protocol only takes little over three minutes and will be applied during a separate visit several days apart to account for wash-out effects. The study coordinator, who completed extensive training on applicability and safety of Transcranial Magnetic Stimulation will apply the stimulation. A licensed medical officer will always be present during each visit to ensure participant safety. The Chief Medical Officer, a Neurologist and Movement Disorder Specialist, will also be available for medical supervision during each study visit. Behavioural measures: During each visit (3 visits in total) the subjects will be assesses on standardised Timed-up-and-Go tasks and the motor section of the UPDRS immediately before and after iTBS stimulation. During the Timed-up-and-Go tasks subjects will be asked to stand up from a chair, walk 5 meters towards a square taped box on the floor, turn around and walk back towards the starting position. A total of eight trials will be performed where subjects are asked to make the following turns: -2x 180 degrees, once left and once right; -2x 540 degrees turns, once left and once right; -2x shuffling around the outside of the taped box, once left and once right; -2x 180 degrees turn while performing a cognitive dual task, once left and once right. A researcher will always walk alongside the participants to reduce the risk for falls. The motor section of the Unified Parkinson's Disease Rating Scale will be used to assess motor symptom severity associated with Parkinson's disease, such as bradykinesia, rigidity and tremor. Location: This study will be conducted at the Brain and Mind Centre, The University of Sydney.