Selectively Modulating Pathophysiological Biomaker to Improve Freezing of Gait in Parkinson' s Disease by Adaptive Subthalamic Stimulation

Selectively Modulating Pathophysiological Biomaker to Improve Freezing of Gait in Parkinson' s Disease by Adaptive Subthalamic Stimulation

Freezing of gait (FoG) is defined as a brief, episodic absence or reduction of forward progression of the feet despite the intention to walk. It is one of the most disabling and intractable motor symptoms in patients with Parkinson's disease (PD) as it often causes falls and loss of independence. The pathophysiology of FoG remains unclear but it seems differ from other cardinal motor symptoms in PD. The therapeutic efficacy of medical and surgical treatments for FoG are usually suboptimal. Deep brain stimulation (DBS) in the subthalamic nucleus (STN) is a well established treatment for advanced PD with motor fluctuation. It alleviates tremor, bradykinesia and rigidity and improved the quality of life. However, the therapeutic effects of DBS are impeded by high cost of device, stimulation induced adverse effects and partial treatment for some parkinsonism symptoms, particular gait disturbance and FoG. Recently, a new mode of stimulation is proposed. Differing from the conventional DBS which is operated in open loop so that stimulation remains fixed over time and is delivered at regular and high frequencies, the new adaptive DBS (aDBS) detects the pathological activities and only deliver stimulation when it is necessary. Recent studies in MPTP-primate and patients with PD demonstrate that the aDBS is superior to standard continuous DBS. However, the therapeutic efficacy is only shown in "appendicular symptoms" such as bradykinesia, rigidity and tremor. There is no report about the effect of aDBS on gait disturbance, particular FoG in PD so far.

The aim of the current project is to test whether the therapeutic efficacy of aDBS is superior to conventional DBS in PD patients with FoG. To this end, 20 advanced PD patients who undergo STN DBS implantation for the treatment of their disorders will be examined. The gait of patients will be assessed during conventional open loop stimulation and aDBS and the therapeutic efficacy for FoG will be defined. The results of this study will also contribute to better understanding of pathophysiology of FoG and to future development of embedded aDBS system for PD.

Inclusion Criteria:

1. Patients' age between 20 and 75 years old
2. Idiopathic PD with cardinal motor impairment (bradykinesia, rigidity, tremor and postural instability
3. Advanced PD as determined by Hoehn and Yahr stage or UPDRS part III motor score
4. Levodopa responsive
5. Disabling Parkinson's symptoms or drug side effects (dyskinesia, motor fluctuation or disabling "off"period) despite the best medical therapy.
6. Willingness and ability to cooperate during conscious operative and experimental procedure.
7. Normal MRI

Exclusion Criteria:

1. Non-idiopathic parkinsonism or "Parkinson's plus syndrome"
2. Impaired cognitive dysfunction (MMSE<26)
3. Moderate to severe depression (BDI≧30)
4. Depression (BDI≧30), or psychiatric disorder
5. Structure lesion such as stroke, tumor or severe brain atrophy revealed by MRI
6. Major medical disorders, such as hematological, heart disease or malignancy
7. Significant medical, surgical or neurological co-morbidities contraindicating DBS surgery or stimulation