Neural adaptive deep brain stimulation in treating freezing of gait in Parkinson's disease: explore the efficacy and mechanism

Freezing of gait (FoG) is a common, disabling motor symptom in patients with advanced Parkinson’s disease. It is defined as “brief, episodic absence of marked reduction of forward progression of the feet despite the intention to walk”. FoG often severely disrupts locomotion, causes falls and lead to loss of autonomy. The pathogenesis of FoG remains unclear. It is suggested that the motor cortex, basal ganglia and midbrain locomotor region (MRL) are responsible for the FoG. The therapeutic modulation for freezing is complex. Levodopa ameliorates FoG. However, in some cases, Levodopa paradoxically worsen this symptom. As the disease progresses, FoG becomes refractory to dopaminergic medication. Deep brain stimulation (DBS) at Subthalamic nucleus (STN) reduces FoG in off-medication state, but it might elicit FoG in a subgroup of PD patients. This implies that this structure is involved with the pathogenesis of freezing. The failure of STN DBS in ameliorating FoG has contributed to the exploration in alternative targets and low frequency stimulation. STN DBS is an effective therapy for advanced PD, ameliorating bradykinesia, rigidity and tremor and improves quality of life in PD. However, the therapeutic effectiveness is largely limited by incomplete treatment of motor impairments, unwanted side effects, such as brittle dyskinesia, speech and gait disturbance, and high cost of battery. It is suggested that the continuous, conventional DBS (cDBS) suppresses the pathological activities and inevitably disrupts the residual physiological activities and lead to the disruption of motor processing. Adaptive deep brain stimulation (aDBS) uses neuronal feedback signals that relate to the clinical states to control the stimulation instead of delivering fixed stimulation, as cDBS. aDBS has been proved to be more effective, less energy consumption with less adverse effects than cDBS in treating bradykinesia, rigidity and tremor. So far, very limited studies focus on the therapeutic modulation of aDBS in the treatment of FoG. The current project has three important aims. First is to compare the therapeutic efficacy of cDBS and aDBS at STN in treating FoG in PD. Second is to explore the different mechanism of action in conventional and adaptive stimulation and to test the hypothesis that two stimulation conditions reduce FoG through action on different motor circuits. Last is to test the effectiveness of cDBS and aDBS in freezing in daily actions. To this end, we will use a narrow β band (~18 Hz) in STN for feedback control in trials of aDBS, as previous studies have suggested elevation of this activity is associated with occurrence of FoG. The final goal of this project is to improve the therapeutic strategies in the treatment of FoG in PD.

Project ID:PG11105-0203
External Project ID:NHRI-EX111-11104NI