Neurophysiological Correlates of Motor and Working Memory Performance following Subthalamic Nucleus Stimulation Katherine Selzler, Michelle Burack, Ryan Bender, and Mark Mapstone Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/37/1778613/jocn_a_00306.pdf by MIT Libraries user on 17 May 2021 Abstract ■ Subthalamic nucleus (STN) deep brain stimulation (DBS) tion, along with 20 normal controls on a visual working mem- has become an accepted treatment for the motor manifesta- ory task while simultaneously recording cortical EEG. In the tions of Parkinson disease (PD). The beneficial motor effects OFF state, PD patients had poor motor function, were slower of STN DBS are likely due to modulation of BG output to frontal and less accurate in performing the working memory task, and cortical regions associated with motor control, but the under- had greater amplitudes and shorter latencies of the N200 ERP lying neurophysiology of STN DBS effects, especially at the response. DBS improved clinical motor function, reduced N200 level of the cortex, is not well understood. In this study, we ex- amplitudes, and increased N200 latencies but had little effect on amined the effects of STN DBS on motor disability and visual working memory performance. We conclude that STN DBS nor- working memory, a cognitive process supported by pFC. We malizes neurophysiological activity in fronto striatal circuits and tested 10 PD participants off medications, ON and OFF stimula- this may independently affect motor and cognitive function. ■ INTRODUCTION Parkinson disease (PD) is a disorder of BG circuit Working memory is the temporary storage and manipula- function, and cognitive impairments, including working tion of information necessary for many higher order cog- memory deficits in PD, are thought to result from loss of nitive tasks (Baddeley, 1986). Working memory consists ascending dopaminergic projections to pFC terminal fields, of several component processes including initial sensory particularly those in lateral pFC (Alexander, DeLong, & processing, short-term storage, continuous upgrade of in- Strick, 1986). The first line approach to treating the car- formation, and an executive control system for manipula- dinal motor manifestations of PD involves dopaminergic tion or retrieval (Baddeley, 2000). Executive components pharmacotherapy. Dopaminergic medications can also of working memory, especially those related to response ameliorate cognitive and affective deficits (e.g., Cools, selection, appear to rely critically on the pFC (Rowe, Barker, Sahakian, & Robbins, 2001; Owen, Iddon, Hodges, Toni, Josephs, Frackowiak, & Passingham, 2000), which Summers, & Robbins, 1997). However, the effects of dopa- are linked, perhaps by attentional control (Postle, 2006), mine replacement on non-motor features are not consis- to distributed cortical regions in a functional network tent across studies (Lange et al., 1992; Gotham, Brown, & (Mesulam, 2000). Most of pFC participates in mixed paral- Marsden, 1988; Girotti et al., 1986) and the reasons for this lel and integrative BG-cortical circuits in which informa- are not fully understood. Similarly, modulation of cortical- tion from functionally distinct regions of pFC (Haber, BG circuits by chronic deep brain electrical stimulation Kim, Mailly, & Calzavara, 2006; Haber, Fudge, & McFarland, (DBS) of the STN can significantly improve motor func- 2000) and other regions of cortex converge to inform such tion and reduce motor disability in PD patients (Moro behaviors as response selection (Schroll, Vitay, & Hamker, et al., 2010; Weaver et al., 2009; Deuschl et al., 2006; 2012; Aron et al., 2007) and working memory (McNab Rodriguez-Oroz et al., 2005), but again, effects on cogni- & Klingberg, 2008). The subthalamic nucleus (STN) is tive function, particularly working memory, are mixed. part of the hyperdirect pathway, which connects regions Whereas some investigators have reported working memory of frontal cortex to the BG and may be critical in support- improvements (Mollion, Dominey, Broussolle, & Ventre- ing integrative functions of BG-thalamo-cortical circuits Dominey, 2011; Jahanshahi et al., 2000), others have shown through rapid inhibition of thalamo-cortical pathways either no change (Heo et al., 2008; Ardouin et al., 1999) (Mink, 1996). or worsening of working memory (Hershey et al., 2004, 2008; Saint-Cyr, Trépanier, Kumar, Lozano, & Lang, 2000). These contradictory behavioral findings may be partially The University of Rochester School of Medicine and Dentistry explained by PET studies of pFC following STN DBS (see © 2012 Massachusetts Institute of Technology Journal of Cognitive Neuroscience 25:1, pp. 37–48 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00306 by guest on 26 September 2021 Ballanger, Jahanshahi, Broussolle, & Thobois, 2009, for a re- the more difficult working memory task. We conclude that view). Several PET studies have demonstrated increased STN DBS normalizes neurophysiological characteristics of blood flow to dorsolateral and motor regions of pFC in BG-thalamo-cortical circuits with dissociable effects on addition to the anterior cingulate following STN stimula- motor and cognitive function. tion (Sestini et al., 2002; Limousin et al., 1997), which may account for the common motor benefits and also observa- tions of working memory improvement following DBS. On the other hand, a more recent study (Hershey et al., 2003) METHODS Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/25/1/37/1778613/jocn_a_00306.pdf by MIT Libraries user on 17 May 2021 showed that STN stimulation increased blood flow to mid- Participants brain regions, but this was associated with reduced blood The study participants included 10 PD patients receiving flow to regions of bilateral frontal, parietal, and temporal bilateral STN stimulation and 20 healthy control partici- cortex. These findings suggest that STN DBS may increase pants. The control participants were volunteers from the inhibitory output from BG to thalamo-cortical circuits and local community or from the University of Rochester and may underlie working memory impairments following included 10 younger control (YCS; mean age = 25 ± STN DBS. 3.9 years) and 10 older control participants (OCS; mean An alternate approach to understanding DBS effects on age = 68.8 ± 6.9 years) who did not differ in mean age working memory is to measure the electrophysiology of from the PD group (mean age = 63.7 ± 8.1 years). All cortical regions known to support this behavior. During participants were right-handed except for one PD partici- visual working memory tasks ERP activity beginning pant, and all had normal or corrected-to-normal vision. around 200 msec post stimulus may reflect early, post PD participants were all at least 3 months post stimulator sensory processes associated with stimulus unfamiliarity activation and were on stable medication and stimulation (Daffner et al., 2000) and may be important for encoding parameters for at least two weeks before participation. All to and retrieval from the working memory buffer (Palva, PD participants were programmed for optimum motor Kulashekhar, Hamalainen, & Palva, 2011). The negative benefit before enrollment in the study. This typically in- deflection occurring around 200 msec following the visual volves targeting therapy for best motor symptom control stimulus (N200) may be selectively modulated with the with stimulator settings that minimize acutely evoked side earlier P200 or later P300 deflection (Missonnier et al., effects (e.g., paresthesias, weakness of the limb or face, 2003; Daffner et al., 2000) or may represent the earliest or visual changes). All participants provided informed negativity associated with a more diffuse negative slow consent and all study procedures were approved by the wave, a relative suppression of positive deflections, which University of Rochester Research Subjects Review Board. starts around 200 msec post stimulus (Ruchkin, Johnson, Participant characteristics can be found in Table 1, PD clini- Grafman, Canoune, & Ritter, 1997). Recent work has cal characteristics in Table 2, and PD stimulation param- shown that these negativities, including the well-known eters in Table 3. contralateral delay activity, may reflect the maintenance of working memory in posterior cortical regions (Vogel & Machizawa, 2004). In these studies, the N200 peak ob- Procedure served during encoding is also seen at retrieval (Vogel & All participants completed the experimental paradigm in Machizawa, 2004) and the amplitude of the N200 is related a single visit to the laboratory. Control participants com- to the working memory load (Palva et al., 2011). These ob- pleted testing in one session, whereas PD participants servations suggest that early components of the visual required two sessions separated by a 30-min rest period. working memory ERP, particularly the N200, may be strong PD participants were tested after withholding PD medi- markers of the underlying neurophysiological processes cations for at least 12 hr to nominally dissociate effects of involved in working memory response selection. dopamine replacement from direct effects of stimulation. In this study, we examined neurophysiological and be- PD participants were tested with bilateral stimulators ON havioral effects of DBS on motor function and working in one session and OFF in the other. Stimulator activation memory performance. We simultaneously recorded corti- cal EEG while 10 PD and 20 control