Clinical effects of deep brain stimulation on gait disorders in Parkinson’s disease

Bilateral stimulation of the subthalamic nucleus (STN) has been established to provide long-term improvement for the cardinal symptoms of Parkinson s disease (PD) and for the dyskinesias induced by long-term use of dopaminergic drugs [1]. However, the effect of STN stimulation on postural instability and gait disability (PIGD) in PD has been a more complex and challenging question that is an important area of research. Any clinical benefit of deep brain stimulation (DBS) on PIGD appears dependent upon several factors, including the type of gait disorder and whether or not it is responsive to dopamine ( levodopa-responsive ), the location of the stimulating electrode, and the stimulation parameters. What do we know so far? The assessment of PIGD in DBS studies involves the use of the Unified Parkinson s Disease Rating Scale and the PIGD subscale (items 13, 14, 15, 27, 28, 29, and 30), timed tests (timed walking or stand-walk-sit test), or more elaborate techniques such as posturography. Bilateral STN stimulation significantly improves PIGD [2], increases stride length and gait velocity comparable to an optimal dose of levodopa [3] and improves kinematics related to the hip, knee, and ankle joints [3]. In addition, it improves the abnormal sensory aspects of postural instability and movement velocity better than medication alone [4]. However, in a large study from the Grenoble group, bilateral STN stimulation provided an initial benefit in postural instability and gait, but the benefit declined and by 5 years, there was progression of postural instability and gait disturbances in the best on conditions [1]. Freezing of gait (FOG) and postural instability that are stimulation resistant thus eventually become a common and disabling symptom of PD that significantly impact the quality of life. Moreover, FOG and gait disorders can be an adverse effect of the surgery or stimulation in some patients [5]. What effect on PIGD can be expected from bilateral STN stimulation? The efficacy of STN stimulation has been demonstrated to depend on the degree of preoperative responsiveness to levodopa [6]. Therefore, patients have been selected for surgery on the basis of levodopa-responsivity. Effective stimulation is highly dependent upon an optimal site of stimulation, a matter of continuing debate. Some groups regard the optimal stimulation site as the dorsolateral part of the STN, others dorsal/dorsomedial to the STN in the region of the pallidofugal fibers and the rostral zona incerta, whilst still others believe the optimal target lies between the dorsolateral part of the STN and the region dorsal/ dorsomedial to it [7]. Lee et al. [8] have recently demonstrated, using novel neurochemical recording techniques, that the therapeutic benefit of STN stimulation is provided, at least in part, by activation of surviving nigrostriatal dopaminergic neurons, subsequent striatal dopamine release, and resumption of striatal target control by dopamine. In addition, they observed that stimulation of the medial forebrain bundle dorsal to the STN causes substantially greater release of striatal dopamine than STN stimulation, which may correspond well to the previous clinical findings of the optimal sites of stimulation. Thus, verification of the stimulation site and the subsequent effects on PIGD are important. Johnsen et al. [9], in this issue, examined the clinical outcomes on motor function and gait performance in relation to the stimulation site. They report that step velocity, stride length, and balance during gait were improved significantly more with stimulation of the dorsal STN compared to ventral stimulation, findings consistent with previous work. Efforts such as this continue to improve our knowledge of the optimal site of stimulation for maximal clinical benefit of PD symptoms that are dopamine responsive. Whilst further studies designed to optimize the clinical effects of DBS on gait disorders in PD are needed, another frontier for research is to understand more clearly the pathophysiology of those features of PD that are resistant to levodopa and current stimulation therapy targets. This will require focus on the progressive multiple-system neurodegeneration in PD in addition to the consequences of nigrostriatal dopamine deficiency to develop more effective treatments. Such efforts thus far have included anecdotal experience with bilateral DBS of the pedunculopontine (PPN) and STN nuclei using lower stimulation frequencies for PPN stimulation [10], and the recent novel finding that spinal cord stimulation restores locomotion in one animal model of parkinsonism [11]. Much more work is needed to determine the safety and efficacy of such approaches in patients with PD suffering from PIGD despite our best medical and surgical therapies.