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.

Technical Abstract:
A significant proportion of PD patients develop severe axial problems within 5 years of STN-DBS. The primary objectives of this investigative study are to establish 1) whether these axial symptoms can be alleviated by altering stimulation parameters, 2) whether the optimal parameters are the same for different motor functions for individual patients, and 3) to what extent the optimised settings for each motor function varies across a cohort of patients with emergence of gait and/or balance problems and who have received STN-DBS for 3 years or more. To achieve this we will develop a series of laboratory-based tests to statistically determine for individual patients small changes that may occur in gait, freezing of gait, balance, posture, and upper limb movements. Motor performance will be measured using CODA motion analysis system, which determines the 3D whole body position in space. In an initial study, we will apply these methods to a cohort of 15 non-operated PD patients, studied on and off levodopa, and a group of age-matched healthy control subjects. Patients' clinical state will be rated using UPDRS. These data will establish a spectrum of values for each test and demonstrate they are sufficiently sensitive to reflect clinical state. We then will apply the tests to the cohort of 15 implanted patients with emerging axial symptoms in the following three stages: 1) Varying stimulation frequency from 50 to 150 Hz in 20 Hz steps using voltages with equivalent energy; 2) varying stimulation frequency in 10 Hz steps centred on the two 'best' frequencies from stage 1 tailored for each patient; 3) varying the stimulation voltage using frequencies determined in stages 1 and 2 for each patient. At each stage the patient and experimenter will be blinded to the DBS parameters until the data are measured. These data will provide a detailed picture of the relationship between STN-DBS parameters and motor function and will lead to improvements in PD management.

Potential Impact:
The beneficiaries of this research will include:
1. Parkinson's disease patients with DBS implants. The research will have immediate and direct benefit by providing a methodology for optimizing stimulation parameters for individual patients. It will also provide information about how deep brain stimulation frequency precisely affects different motor functions. These advances will lead to better management of symptoms, which in turn will increase quality of life and improve health through minimizing immobility and risk of falls and will reduce social isolation caused by inability or fear of leaving the home.
2. Patients with movement disorders. The development of a new methodology for optimizing stimulation parameters across a wide range of motor functions can also be used for testing the efficacy of other existing or new forms of treatment for Parkinson's disease or other movement disorders.
3. Health service. The research will improve the spending efficiency of DBS therapy by solving the emerging medical problem of axial symptoms using the existing stimulators and electrodes and negate the need for additional spending on alternative therapies.
4. Industry. The research will provide basic information that will inform the manufacturers of DBS equipment. It will also be valuable for manufacturers of motion capture equipment as it will extend the current applications into new research areas, and will increase publicity of the technology through dissemination of results.