Unilateral vs. bilateral STN DBS effects on working memory and motor function in Parkinson disease

Abstract

Bilateral subthalamic nucleus deep brain stimulation (STN DBS) can reduce working memory while improving motor function in Parkinson disease (PD), but findings are variable. One possible explanation for this variability is that the effects of bilateral STN DBS on working memory function depend in part on functional or disease asymmetry. The goal of this study was to determine the relative contributions of unilateral DBS to the effects seen with bilateral DBS. Motor (Unified Parkinson Disease Rating Scale Part III, UPDRS) and working memory function (Spatial Delayed Response, SDR) were measured in 49 PD patients with bilateral STN DBS while stimulators were Both-off, Left-on, Right-on and Both-on in a randomized, double-blind manner. Patients were off PD medications overnight. Effects of unilateral DBS were compared to effects of bilateral STN DBS. Mean UPDRS and SDR responses to Left-on vs. Right-on conditions did not differ (p > .20). However, improvement in contralateral UPDRS was greater and SDR performance was more impaired by unilateral DBS in the more affected side of the brain than in the less affected side of the brain (p = .008). The effect of unilateral DBS on the more affected side on contralateral UPDRS and SDR responses was equivalent to that of bilateral DBS. These results suggest that motor and working memory function respond to unilateral STN DBS differentially depending on the asymmetry of motor symptoms.

Introduction

Working memory, the ability to maintain, monitor and use internal information to guide behavior, is a fundamental cognitive skill underlying other more complex “executive” functions (Baddeley, 1992), and is known to be affected by Parkinson disease (PD). Individuals with PD are particularly impaired on spatial working memory tasks, even at the early stages of the disease (Gabrieli et al., 1996, Lewis et al., 2005), perhaps due to altered basal ganglia output or changes in mesocortical dopaminergic pathways (Carbon and Marie, 2003). The degree of impairment in spatial working memory may depend in part on which hemisphere of the brain is more affected by PD, since worse left-sided motor dysfunction in PD is associated with worse spatial (right hemisphere) tasks and worse right-sided motor dysfunction is associated with more impairment on verbally mediated (left-hemisphere) tasks (Taylor et al., 1986, Starkstein et al., 1987, Spicer et al., 1988, Blonder et al., 1989, Huber et al., 1992, Amick et al., 2006).

Recent work has suggested that bilateral deep brain stimulation of the subthalamic nucleus (STN DBS), apart from any effects of the surgical procedure itself, can impair spatial working memory below already suboptimal levels of function while simultaneously improving motor symptoms of PD (Hershey et al., 2004). For example, STN DBS decreases response inhibition performance under conditions of strong response conflict challenges (Jahanshahi et al., 2000, Schroeder et al., 2002, Hershey et al., 2004, Witt et al., 2004, Temel et al., 2004). Similar findings have been reported for working memory performance, particularly under conditions with higher demand on cognitive control processes (Hershey et al., 2004). In contrast, there have also been reports of improved working memory with STN DBS (Rivaud-Pechoux et al., 2000, Pillon et al., 2000) . However, neither study withdrew levodopa before testing, although levodopa is known to influence working memory and possibly other cognitive skills (Gotham et al., 1988). Other studies have reported that STN DBS improves extinction task and non-declarative memory performance, worsens declarative memory and causes no changes in a gambling task (Halbig et al., 2004, Funkiewiez et al., 2004). The emerging pattern of results suggests that tasks with greater cognitive control demands are most susceptible to the negative effects of STN DBS. These effects may be mediated through the STN's connections to the prefrontal cortex (Nakano et al., 2000, Baunez et al., 2001, Chudasama et al., 2003).

Despite the overall trends observed, findings are variable both across studies and across individuals, driving some controversy in the field. One possible explanation for some of this variability is that clinical factors such as disease asymmetry may modify the effect of bilateral STN DBS on working memory and other cognitive functions. To determine the influence of disease asymmetry on bilateral STN DBS-induced changes in working memory, responses to unilateral STN DBS must be examined. We measured working memory and motor responses to unilateral and bilateral STN DBS in a within-subjects design to address whether responses differed depending on which hemisphere (left vs. right; more affected vs. less affected side of the brain) was stimulated. This information may shed light on the neuropathophysiology of cognitive dysfunction in PD, and help us understand the contributing factors to effects of bilateral STN DBS on working memory.