Developmental Clinical Studies - Optimising STN-DBS stimulation for late-emerging

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Deep brain stimulation of the subthalamic nucleus (STN-DBS) is a powerful and effective treatment for symptoms of Parkinson's disease (PD). However, a number of research groups have reported that a significant proportion of patients start to develop severe axial and gait problems within 5 years of implantation even though the stimulation continues to alleviate their symptoms of tremor, akinesia and rigidity. These axial symptoms are very disabling and can lead to falls and severe mobility problems. Some recent research has reported that the disruption of gait can be improved by lowering the stimulation frequency from 130 Hz to 60-80 Hz and increasing the stimulation voltage. This suggests that in these patients the classical stimulation parameters are no longer optimised for their disease management. When optimising parameters, the clinician has to consider the effects the stimulation has on a range of motor functions as well as on the positive symptoms of tremor and rigidity. This is problematic because clinical rating scales are relatively blunt tools of functional assessment and there are a large number of possible stimulator settings that can be tested with no guarantee that all motor functions will respond in the same way. The current proposal plans to develop a series of laboratory-based methods for measuring specific motor functions that can be used to quantify precisely the effects of changing stimulator parameters on each function and to establish whether the observed changes are statistically significant at the level of an individual patient. These methods will target the disorders of axial functions including gait and freezing of gait, balance control and posture control, as well as disorders of upper limb movements involving distal and proximal muscle groups. In an initial study the measures of axial and limb functions will be assessed on a cohort of 15 PD patients studied on and off levodopa, and a group of age-matched healthy control subjects. This will provide a broad spectrum of baseline reference data and by contrasting responses on and off medication and comparing with UPDRS clinical ratings will establish that the methods are sufficiently sensitive to reflect clinical change. In a second study a group of 15 patients who have been receiving STN-DBS for 3 years or more and with emergence of gait and/or balance problems will be studied using the newly developed laboratory-based methods. This will be done in three stages. In the first stage we will investigate 6 frequencies of stimulation ranging from 50 Hz to 150 Hz at steps of 20 Hz, with the voltage set at levels to have equivalent energy at all frequencies. In the second stage, 6 frequencies will be studied with a finer grain of 10 HZ centred on the 2 'best' frequencies obtained in the first stage and tailored to each individual patient. In the third stage, the effect of voltage adjustment will be studied using 2 frequencies of stimulation based on the results from stages 1 and 2. Three voltages will be studied at each frequency using the highest voltage without adverse effects tailored to individual subjects and 1V and 2V below. These data will provide a detailed picture of how stimulation frequency and voltage affects specific axial and appendicular motor functions and how the optimum stimulator settings vary across this cohort of PD patients.