Unilateral vs. bilateral STN DBS effects on working memory and motor function in Parkinson disease☆
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.
Section snippets
Subjects
This study was approved by the Human Research Protection Office at Washington University School of Medicine and participants gave informed consent. These procedures are in compliance with national legislation and the Code of Ethical Principles for Medical Research Involving Human Subjects of the World Medical Association. Individuals with PD with previously implanted bilateral stimulators in the STN region were studied. Prior to implantation, all met diagnostic criteria for clinically definite
Subjects
Subjects had good clinical benefit from bilateral stimulation (mean improvement in UPDRS scores = 49%, SD = 23; t = 13.7, p < .001). The more affected side of the brain was the right hemisphere in 28 patients and the left hemisphere in 21 patients. These two groups did not differ in age, gender distribution or duration of disease (p values > .07). The average absolute difference between UPDRS motor scores on the more affected vs. less affected sides across the entire sample was 4 points (SD = 3). Degree of
Discussion
In this study, unilateral STN DBS differentially affected working memory and motor function depending primarily on disease asymmetry. Motor function improved more with DBS on the more affected side of the brain than with DBS on the less affected side of brain. In contrast, DBS on the more affected side of the brain impaired working memory, whereas DBS on the less affected side did not. These results suggest that clinical asymmetry interacts with STN DBS to determine behavioral responses.
There
Acknowledgments
Supported by: the Greater St. Louis Chapter of the American Parkinson Disease Association (APDA), NIH (NS41248; NS41509), American Academy of Neurology, APDA Advanced Center for PD Research at Washington University, and the Barnes-Jewish Hospital Foundation (Elliot Stein Family Fund and the Jack Buck Fund for PD Research).
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2017, NeuropsychologiaCitation Excerpt :Indeed, the pervasive and automatic nature of auditory rehearsal for short term recall in humans is thought to explain why irrelevant tones or speech interfere with memory, even when items are presented visually (Jones and Macken, 1993; Salame and Baddeley, 1982). In addition to supporting the basal ganglia's role as a domain-general WM resource, these results additionally shed light on the currently contentious question of whether the clinical application of STN-DBS affects visuospatial WM. Though PD patients generally show mild to moderate deficits in visuospatial WM compared to aged-matched controls (e.g. Lee et al., 2010), there have been conflicting accounts of the effects of STN-DBS state on spatial WM performance (Hershey et al., 2008; Mollion et al., 2011; Selzler et al., 2013; Ventre-Dominey et al., 2014), though even in the absence of behavioral effects, ERP components indexing WM processes are affected by STN-DBS (Selzler et al., 2013). Across these studies, the effect of distractors was not specifically or systematically examined, which may help in part to explain the inconsistencies in finding clear spatial WM deficits.
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2016, Brain StimulationCitation Excerpt :Although there is evidence of more enduring anatomical or functional changes associated with tDBS [53–55], the practical impact and clinical significance of such changes are unclear given that individual motor signs begin to recur within seconds to hours of deactivation [50–52,56,57]. The side-effects associated with traditional STN DBS also tend to be tightly coupled to stimulus delivery, to the extent that clinical DBS programming typically has the conceptual goal of maximizing coverage of the ‘target’ region(s) while minimizing or avoiding spread of current to adjacent non-motor sub-regions within the target nucleus itself or other structures outside of its borders [3–7,30,58–66]. One approach to this problem involves the development of new lead designs (e.g., split-band) that allow for greater ‘sculpting’ of the current fields created during stimulation [67,68].
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Disclosure: Dr. Karimi received partial fellowship funding from Medtronic, Inc, the manufacturer of the implanted stimulators. There are no other conflicts of interest.