Neurophysiological Correlates of Motor and Working Memory Performance Following Subthalamic Nucleus Stimulation

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 cortical EEG while 10 PD and 20 control participants performed two versions of a visual serial probe recognition task. We hypothesized that putative behavioral effects of DBS would Table 1. Participant Characteristics (Means and SDs) be reflected in the N200 response. We found that N200 Younger Older responses of PD patients without DBS occurred signifi- Control Control PD cantly later and were of greater amplitude than the controls and these were related to poorer overall working memory n (sex) 10 (8 m/2 f ) 10 (8 m/2 f ) 10 (9 m/1 f ) performance. With DBS, clinical ratings of motor disability Age (years) 25 (3.9) 68.8 (6.9) 63.1 (8.7) improved and N200 responses became significantly slower Handedness Right (10) Right (10) Right (9), Left (1) and the amplitude was significantly reduced such that they no longer differed from the age-matched control group on m = male; f = female.

38 Journal of Cognitive Neuroscience Volume 25, Number 1 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00306 by guest on 26 September 2021 Table 2. PD Participant Clinical Characteristics

Time since Initial Duration of Levodopa Equivalent Participant Sex Age Hand Programming (years) PD (years) UPDRS ON UPDRS OFF Daily Dose 1 M 55 R 0.4 12.0 40 45 550 2 M 59 R 1.2 4.5 21 36 0 3 F 81 R 1.1 16.0 19 36 350 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 4 M 63 R 7.2 15.5 16 21 850 5 M 65 R 5.3 16.0 34 40 875 6 M 63 R 0.3 16.5 19 29 320 7 M 68 L 9.1 24.5 48 55 750 8 M 59 R 9.3 20.5 20 30 1560 9 M 49 R 3.9 12.0 16 29 1255 10 M 69 R 0.4 4.5 22 36 780

M = male; F = female; R = right; L = left.

Table 3. PD DBS Characteristics

Participant Side Voltage (V) Pulse Width (μs) Frequency (Hz) Electrode Configuration 1 R 2.6 60 130 C+, 10− L 2.4 90 130 C+, 0− 2 R 2 60 125 C+, 8− L 1 3 90 125 C+, 0− L2a 0.5 60 125 C+, 3− 3 R 2.3 60 135 C+, 4−,5− L 3.1 60 135 C+, 0−,1− 4 R 3 120 185 6+, 4− L 3.4 90 185 3+, 1− 5 R 3.5 60 145 C+, 0− L 2.9 90 145 C+, 2− 6 R 2.2 60 125 C+, 9− L 1 1.8 60 125 C+, 0− L 2 0.8 60 125 C+, 3− 7 R 3.3 60 130 C+, 1− L 2.6 60 130 C+, 1− 8 R 1.6 60 130 2+, 3− L 1.3 60 135 1+, 0− 9 R 1.8 90 130 C+, 1−,2− L 2.6 90 130 C+, 2− 10 R L 5.0 90 125 C+, 10− L 1 3.6 90 125 C+, 2− L 2 1.6 90 125 C+, 0−

R = right; L = left. aTwo settings per side indicate interleaved stimulation via Activa PC implantable pulse generator.

Selzler et al. 39 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00306 by guest on 26 September 2021 order was randomized across the PD participants, with a ficult to verbally encode (Ragland et al., 2002; Miyashita, 30-min wash-in/wash-out period after stimulation change Higuchi, Sakai, & Masui, 1991). We anticipated that the before the second session. We measured motor disabil- fractal SPR task would be more difficult and that by using ity in the PD patients using the clinician administered both tasks we would cover the range of performance for motor subscale of the Unified Parkinson Disease Rating the three participant groups. Participants completed a total Scale (UPDRS; Fahn, Elton, & UPDRS Program Members, of 32 trials in each task (eight trials each at the two-, four-, 1987). six-, and eight-item list lengths). The list length for each We used a two-alternative forced-choice modification trial was randomized and the order of the images in each of the serial probe recognition (SPR) task described by task was randomized. Two equivalent versions of each task 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 Sternberg (1966) to measure working memory. Partici- (object and fractal) were used for the two testing sessions pants viewed a series of two, four, six, or eight stimuli of the PD participants, and the order of these was counter- followed by a probe stimulus, which was indicated by balanced across subjects. a red perimeter (Figure 1). Using their dominant hand, During the SPR tasks, we simultaneously recorded corti- participants indicated if the probe stimulus was in the cal EEG using a SynAmps system (NeuroScan Compu- just-viewed series by pressing the right button on a two- medics USA, Charlotte, NC). The EEG was recorded using button response box and the left button if it was not. RT a 32-channel QuikCap with 30 nonpolarizable Ag/AgCl elec- (msec) and accuracy were recorded. Stimuli were pre- trodes. Electrodes were located at the standard Interna- sented using the NeuroScan STIM (Compumedics USA, tional 10–20 sites and included two referentially linked Charlotte, NC) platform and displayed on an LCD monitor mastoids and a ground electrode near midline of the fore- 24 in. in front of the participants. SPR stimuli were dis- head. In addition, four electrodes were attached separately played for 1000 msec with an ISI of 1000 msec. To mini- around the eyes to identify vertical and horizontal eye mize the effects of slowed RTs in the PD patients, all movement artifacts. Continuous EEG was recorded at a participantsweregivenasmuchtimeasneededtore- rate of 1 kHz with all impedances ≤10 kΩ (for controls spond to the probe and were required to initiate each trial and PD participants off stimulation) and a band-pass filter with a button press. between 0.3 and 100 Hz. We chose to sample at 1 kHz to We administered two versions of the SPR task that dif- limit harmonic artifacts of stimulation in the lower fre- fered primarily in how easily the stimuli could be named. quency ranges of interest (Jeck et al., 2006). All data were One version included line drawings of common objects collectedinanenclosedlaboratorywithminimalambient (450 × 360 pixels in size and 300 dpi resolution) and a light and extraneous noise. EEG data were analyzed off- second version contained grayscale fractal images (512 × line in the MATLAB environment (Mathworks, Natick, MA) 384pixelsinsizeand72dpiresolution)thataremoredif- using the EEGLAB toolbox (Delorme & Makeig, 2004).

Figure 1. Example of four-item set of the SPR task used to assess working memory. The object set included easily named objects (A) and the fractal set used fractal images (B). Stimuli remained on the screen for 1000 msec and the interstimulus interval was 1000 msec. The probe item was indicated with a red box in the task, and subjects responded to whether the probe was in the shown series with a two-alternative forced-choice button press.

40 Journal of Cognitive Neuroscience Volume 25, Number 1 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00306 by guest on 26 September 2021 Continuous EEG data were low-pass filtered (short infi- Cpz, and Pz) for any dependent measure on either SPR nite impulse response filter) at 50 Hz and then high-pass task and there were no significant interactions between filtered (basic finite impulse response filter) at 0.5 Hz to Group and Channel for any of the three dependent mea- further limit potential harmonic artifacts of the stimulating sures, so all five midline channels were included in the electrodes. Other artifacts including eye blinks, muscle analysis of the neurophysiological data to increase overall contamination, and cardiac signals were removed using power. For the neurophysiological data, we conducted independent component analysis (Jung et al., 2000). All two separate multivariate ANOVAs, one for each version components were individually inspected and rejected if of the SPR task (object, fractal) to compare Groups (YCS, necessary. Although we collected data throughout the trial, OCS, PD OFF) for each dependent variable (N200 peak 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 we were most interested in the retrieval phase of the SPR amplitude, N200 latency, and N200 mean amplitude). List task. The retrieval phase was defined from the onset of length was not included as a within-subject factor because the probe stimulus and lasted 1 sec. Baseline activity data across all list lengths were combined to derive the included the 200 msec before probe onset. ERP-dependent measures. We used repeated-measures From the EEG data, we first created time–frequency ANOVA to examine the effects of Stimulation (OFF, ON) plots for each group to visually examine frequency-specific on peak amplitude, latency, and mean amplitude in the neurophysiological responses during the retrieval phase PD group for the object and fractal SPR tasks. We then of the SPR tasks. Time–frequency plots were created by repeated the multivariate ANOVAs to examine DBS effects synchronizing neurophysiological activity from the EEG relative to the other groups (YCS, OCS, PD ON). using a trigger pulse coincident with the onset of the probe Finally, we used step-wise linear regression to examine stimulus at each trial. We collapsed these ERPs across list the relationships between the behavioral and neuro- length for each participant and averaged these to create physiological data. The dependent measures were accu- group time–frequency plots. racy and RT for the object and fractal tasks. Independent We used the ERPLAB toolbox (www.erpinfo.org/erplab/) variables were the corresponding N200 peak amplitude, to create averaged ERP data sets for each SPR task. EEG N200 latency, and N200 mean amplitude. All post hoc activity was synchronized to the probe onset trigger pulse comparisons used Tukeyʼs procedure and significance and lasted for 1 sec. We filtered the ERP data sets at 10 Hz for all tests was set to p < .05. All statistical analyses were to minimize PD related pathological frequency artifacts that performed in SPSS v.17 (SPSS, Inc., Chicago, IL). are known to be present in the low beta (12–18 Hz) range (Sagliocco, Meistrowitz, Schwendemann, Herrmann, & Basar-Eroglu, 2005; Green et al., 1996). All filtered ERP RESULTS data sets were grand averaged and appended for group comparisons. From the ERP data, we extracted N200 peak Behavioral Measures amplitude, N200 latency, and N200 mean amplitude from The YCS, OCS, and PD OFF groups differed significantly midline channels (Fz, FCz, Cz, CPz, and Pz) in the time in both accuracy, F(2, 948) = 11.347, p < .001, and RT, frame 200–350 msec following probe onset (after Nobre, F(2, 861) = 77.479, p < .001, for the object version of Griffin, & Rao, 2007; Kusak, Grune, Hagendorf, & Metz, the task (Figure 1A). The three groups also differed sig- 2000) for analysis. nificantly in both accuracy, F(2, 948) = 20.249, p < .001, and RT, F(2, 948) = 45.180, p < .001, on the fractal version of the task (Figure 1B). In both versions of the task, the control groups were significantly more accurate and Data Analyses faster to respond than the PD OFF group (all ps < .05). We used the nonparametric sign test to examine the ef- Whereas the control groups did not differ from each other fects of DBS (ON, OFF) for the UPDRS. We conducted four in accuracy or RT for the object task, the YCS group was separate analyses of variance (ANOVAs) to examine effects significantly more accurate ( p < .05) and faster to respond of Group (YCS, OCS, PD OFF) and Stimulus Load (two, ( p < .001) than the OCS group in the fractal task. four, six, or eight items) for the dependent variables (RT, Length of the SPR list significantly affected RT for both accuracy) for each of the two versions of the SPR task the object, F(3, 861) = 3.359, p < .05, and fractal, F(3, (object, fractal). We used only correct trials for RT analyses. 651) = 2.729, p < .05, tasks; however, the effects were We also conducted four repeated-measures ANOVAs to in opposite directions. All participants were slower to the examine the effect of Stimulation (OFF, ON) and Stimulus two-item list compared with the four- and six-item lists Load (two, four, six, or eight items) on RT and accuracy in the object task ( p < .05 each) and faster to the two- in the PD group for both SPR tasks. Finally, we repeated item list compared with the four-item list in the fractal the RT and accuracy univariate ANOVAs to examine DBS task ( p < .05). List length significantly affected accu- effects relative to the other Groups (YCS, OCS, PD ON) racy in the fractal task only, F(3, 948) = 6.418, p < by Stimulus Load (two, four, six, or eight items). .001; all groups were more accurate on the less demand- In a preliminary analysis, we found no significant differ- ing two-item list compared with the four-, six-, and eight- ences between the five midline electrodes (Fz, FCz, Cz, item lists ( p < .05 for all). There were no interactions

Selzler et al. 41 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00306 by guest on 26 September 2021 between Group and List Length for either accuracy or RT frequency suppression initially, but there was less over- for either task. all power in the theta range and it was of much shorter duration, diminishing by approximately 400 msec. There was also a small band of low beta power (12–20 Hz) pres- DBS Effects on Behavior ent immediately after the probe appeared in the PD As expected, DBS improved motor function in the PD OFF group that was not present in the control groups (Fig- participants. There was DBS-related improvement in ure 3). ERP waveforms of both SPR tasks showed peak clinical ratings of motor disability with lower UPDRS amplitude of the N200 within a time window of 200– scores (reduced motor disability) for all PD participants 350 msec after the appearance of the probe for all groups 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 (nonparametric sign test, p < .01). DBS also improved confirming this time window was appropriate for analyses motor RTs on the most difficult eight-item list length of (Figure 4). the fractal task, F(3, 119) = 2.879, p < .05. There were no In the object task, the YCS, OCS, and PD OFF groups significant effects of DBS on accuracy in either working differed significantly on N200 peak latency, F(2, 147) = memory task. However, the statistically significant differ- 7.845, p < .001, N200 peak amplitude, F(2, 147) = 6.034, ences between the PD group without stimulation and p < .05, and N200 mean amplitude, F(2, 147) = 29.872, their age-matched controls on measures of accuracy were p < .001 (Figure 4A). In the fractal task, the groups dif- no longer present with stimulation (Figure 1, bottom). fered on N200 peak amplitude, F(2, 146) = 8.030, p < The PD group remained significantly less accurate and .001, and N200 mean amplitude, F(2, 146) = 19.261, p < slower than the YCS group on both tasks even after .001, but not peak latency (Figure 4B). In the object task, stimulation (Figure 2). the N200 response of the YCS group occurred significantly sooner after the probe onset than both the OCS ( p <.001) and PD OFF groups ( p < .05), but the OCS and PD OFF Neurophysiological Measures groups did not differ significantly in N200 response la- In both SPR tasks, a strong band of low frequency power, tency. In the fractal task, the PD OFF participants had a primarily theta (4–8 Hz) appeared, and there was relative faster N200 peak latency than the OCS group, but the three suppression of higher frequency power (>8 Hz) immedi- groups did not differ significantly on this measure. On ately after the probe onset. This pattern of activity was both SPR tasks, the PD OFF peak N200 amplitude was sig- sustained for approximately 1 sec in the YCS group and nificantly greater than both control groups (all ps<.05). 600 msec in the OCS group. The PD OFF group showed In addition, the PD OFF group had a larger mean N200 a similar pattern of low-frequency activation and higher- amplitude than both control groups on the object (both

Figure 2. Behavioral results from the object (A) and fractal (B) SPR tasks. RT (top) and accuracy for each of the four different list lengths (2, 4, 6 and 8) are plotted. Error bars represent SEMs. Note the overall poorer accuracy of the PD OFF group relative to the controls on both tasks improves with stimulation (PD ON). Also note that RTs for the PD group did not significantly improve with stimulation.

42 Journal of Cognitive Neuroscience Volume 25, Number 1 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00306 by guest on 26 September 2021 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

Figure 3. Group-averaged time–frequency plots during the object and fractal SPR tasks at channel Fz. All plots have a frequency scale ( y axis) from 3 to 25 Hz, a color bar scale from −2.5 to 2.5 μV, and a timescale from −200 to 1200 msec. The dotted red line represents the onset of the probe stimulus for all list lengths (2, 4, 6, and 8 items). Note the relatively greater amplitude of power in the theta (4–8 Hz) band with relative suppression of alpha activity (8–12 Hz) in the two control groups and increased beta activity (12–25 Hz) in the PD groups.

p < .001) and fractal ( p < .001 each) tasks. The control tions in N200 peak latency in the object task made these groups did not differ in the size of the peak or mean N200 responses faster than the OCS group and increased N200 amplitude. peak latency in the fractal task made these responses equivalent to the OCS group (Figure 4). DBS Effects on Neurophysiology Relationships between Neurophysiology In general, DBS led to neurophysiological activity that and Behavior was more similar to that seen in the age-matched OCS group. In the N200 time window, there was qualitatively Collapsed across all groups, response latency was signifi- less overall suppression of activity in frontal regions and cantly related to the mean N200 amplitude, F(1, 38) = greater activation in posterior regions (Figure 4, right). 16.19, p < .001, R2 = .28, in the object task alone. There In addition, DBS led to significant reductions in the PD were no significant relationships between accuracy and groupʼs N200 peak amplitude for both the object, F(1, any neurophysiological measures for either task. Linear 49) = 16.239, p < .001, and fractal, F(1, 49) = 59.259, regressions performed at the group level were more in- p < .001, tasks and reduced N200 mean amplitude in the formative. For the OCS group mean N200 amplitude was object, F(1, 49) = 15.071, p < .001, and fractal, F(1, 49) = related to accuracy in the object task, F(1, 38) = 6.21, 26.398, p < .001, tasks (Figure 4). Furthermore, DBS- p < .05, R2 = .37. In the PD OFF group, response speed related reduction in N200 peak amplitude made these re- was significantly related to mean N200 amplitude, F(1, sponses equivalent to both control groups in the fractal 38) = 6.55, p < .05, R2 = .38, in the object task. In task. With regard to the latency of responses, DBS in- the more difficult fractal task, accuracy in the PD OFF creased N200 latency on the fractal task by an average of group was significantly relatedtoN200peaklatency, 25 msec, F(1, 49) = 14.692, p < .001. DBS-related reduc- F(1, 38) = 64.30, p < .001, R2 = .88, such that faster

Selzler et al. 43 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00306 by guest on 26 September 2021 Figure 4. ERP waveforms averaged across all working memory loads (2–8) and all five channels (Fz, FCz, Cz, CPz, Pz) for all four groups on the object (A) and fractal (B) tasks. The x axis represents the time from −200 msec before probe onset (0 msec)

to 1000 msec. The y axis 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 represents voltage in microvolts. The gray box from 200 to 350 msec represents the N200 time frame used in the analyses. To the right of each averaged ERP plot are topographic head plots showing the mean N200 amplitude for each group during the N200 time window. The head plot color bar scale is −7.0 to 7.0 μV. Note the larger negative deflection in the N200 time frame for the PD group compared with the controls. Also note the head plots showing greater posterior power during the time window for the control groups and greater frontal suppression in the PD group.

latencies were related to poorer accuracy (Figure 5A). tencies during both working memory tasks and reducing Also for the PD OFF group, RT was related to both peak N200 peak and mean amplitudes in the fractal task. Our andmeanN200amplitude,F(1, 38) = 9.75, p <.01, data suggest that DBS normalizes task-related neuro- R2 = .66, with larger peak and mean amplitudes related physiological function with dissociable effects on motor to slower RTs (Figure 5B). function and working memory. The main finding from this study is that DBS altered PD task-related N200 latencies and amplitudes to be more like those of age-matched normal controls. Normal- DISCUSSION izing effects of DBS on cortical EEG have been reported In this study, we examined the neurophysiological effects previously, however, earlier studies have generally ex- of STN DBS on motor disability and working memory. amined motor related behavior and none have looked Because DBS is used to treat the severe motor disability specifically at the neural effects of stimulation on work- of PD, we first sought to determine the effects of DBS ing memory. In a previous EEG study, Gerschlager and on motor function. DBS significantly improved motor dis- colleagues (1999) reported beneficial effects of STN ability and also improved response speed on the most DBS on the contingent negative variation, an early cogni- difficult condition of a working memory task. We then tive process associated with planning a motor response. sought to determine the effects of DBS on working They found increased contingent negative variation am- memory, a nonmotor behavior which also relies on fron- plitudes with DBS over frontal and fronto-central re- tal cortex. Here, DBS did not significantly alter working gions. However, a more recent study by the same group memory performance. From the neurophysiological data (Gerschlager et al., 2001) found no evidence that DBS collected during the working memory task, we found that improved pathologically slowed P300 latencies in PD without stimulation, PD participants with worse accuracy subjects during an auditory oddball paradigm. Another had faster N200 responses (peak latencies), and slower study showed no effects of STN DBS on the N2/PC ERP RTswererelatedtogreaterN200peakandmeanam- response during a stop suppression task (Swann et al., plitudes. Although DBS did not have a significant effect 2011). on working memory performance, it did significantly In our study, we found that the PD OFF N200 peak alter the N200 response; significantly slowing N200 la- latencies were significantly related to accuracy in the

44 Journal of Cognitive Neuroscience Volume 25, Number 1 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00306 by guest on 26 September 2021 more difficult fractal SPR task with longer latencies asso- allow more flexible deployment of task-specific oscillatory ciated with better accuracy. We found that DBS increased activity. This normalization of neural activity may be the N200 latencies, which might suggest a corresponding mechanism by which STN DBS allows for the recruitment improvement in working memory performance that we of fronto-striatal networks for specific tasks. did not find. Overall slower ERP latencies are commonly Recent imaging studies would seem to support this reported in PD and other neurological and psychiatric dis- mechanistic explanation for DBS effects on pFC. One ease states, likely reflecting poorer neural efficiency, and study found decreases in rCBF in motor regions of frontal are generally associated with diminished behavioral per- cortex following STN DBS (Ceballos-Baumann et al., 1999) formance (e.g., Eusebio et al., 2009; Caviness et al., 2007). and others have reported reductions in FDG PET activity 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 We found that accuracy was numerically better, but not in pFC and other regions of heteromodal cortex (Hershey statistically better in subjects with DBS-induced slower et al., 2003). Reduction in pathological hypersynchrony N200 responses, which suggests that these PD participants by DBS could account for the reduced metabolic activity were able to make more thoughtful and accurate decisions seen in functional imaging studies and the observation of about the contents of working memory. This notion is normalized electrophysiological activity we observed with supported by results from a recent study demonstrating cortical EEG in the current study may link these processes. that STN DBS improves the fidelity of executive processes In this study, we observed effects of DBS on motor func- related to stopping a planned motor action in a Stop Sig- tion with faster RTs in the most difficult 8-item condition nal Suppression Task (Swann et al., 2011). In this study, of the fractal task and reduced motor disability as measured the authors also report that oscillatory activity in the beta bytheUPDRS.Thesefindingsarenotunexpected.For band (16–20 Hz) over the right pFC increased during stim- the majority of carefully selected PD patients, STN DBS ulation. The disruption of PD pathological beta synchrony greatly improves motor function and reduces disability by STN DBS (Brown & Eusebio, 2008; Brown, 2003) may (Moro et al., 2010; Weaver et al., 2009; Deuschl et al.,

Figure 5. Results of the linear regressions for the PD OFF group on the more difficult fractal SPR task on accuracy (A) and RT (B). Linear regression model for PD OFF accuracy selected the N200 latency as the sole independent variable (Beta = .943, t =8.02, p < .001) with an adjusted R2 of .876. Linear regression revealed two neurophysiological variables, N200 peak and mean amplitudes combining to predict RT with an adjusted R2 of .660.

Selzler et al. 45 Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn_a_00306 by guest on 26 September 2021 2006). The underlying mechanisms of DBS on motor func- such as complex attention, selective attention, processing tion are not entirely clear but are similar to those seen in speed, conceptualization, and response inhibition; all dopamine replacement. Indeed, DBS can extend thera- ofwhichhavebeenreportedtobeimprovedbySTN peutic efficacy of dopamine replacement, reducing the DBS (e.g., Swann et al., 2011; Frank, Samanta, Moustafa, amount of medication required for motor benefit and & Sherman, 2007; Alegret et al., 2001; Jahanshahi et al., in a minority of patients, dopamine replacement can be 2000; Saint-Cyr et al., 2000). We find the lack of an effect eliminated altogether (Rodriguez-Oroz et al., 2005). In of DBS on working memory interesting given the clear our nonmedicated subjects, the observed motor effects are effect on motor function and the alteration of underlying attributable to direct effects of DBS. The beneficial motor neurophysiology. These dissociable effects underscore 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 effects of STN DBS are greatest when the stimulation field the complexity of these mixed parallel and integrative is restricted to the dorsal sensorimotor region of the STN, striato-frontal networks (Haber et al., 2006). which sends efferent signals to primary and supplementary In this study, we attempted to address several possible motor cortex. The encroachment of the stimulation field confounds often not accounted for in previous studies to on the more ventrally located cognitive subregion of the increase the specificity of our results. All PD participants STN may underlie the frequently reported cognitive effects were tested after overnight PD medication withdrawal, so of STN DBS. we would be more confident that any observed effects Despite the clear effects of DBS on cortical neuro- were due to DBS alone. We also attempted to minimize physiology and motor function, we found little evidence practice or familiarity effects that can result from admin- to suggest that DBS meaningfully alters working memory istering the same tests in a short span of time commonly performance. Reports of DBS effects on executive func- used in DBS ON versus OFF studies by randomizing the tions including working memory are inconsistent. Most order of stimulator condition (ON/OFF) and using paral- studies report a negative impact on working memory lel versions of the SPR task. However, a major limitation (see Tröster, McTaggart, & Heber, 2008, for a review) to our study and interpretation of the results is the fact and fewer report beneficial effects (Mollion et al., 2011; that we do not know the exact location of the electrodes Jahanshahi et al., 2000; Pillon et al., 2000). Our results and stimulation fields in our patients. This would appear are somewhat similar to those reported by Mollion and to be a critical piece of information, because the STN colleagues (2011), in which PD participants without stim- is a neuroanatomically dense hub of information process- ulation were found to be significantly impaired on a visual ing and between-subject variation in location of active working memory task compared with controls. Their re- stimulation could significantly impact outcomes. Valid sults suggest that, although DBS significantly improved and reliable methods for determining lead placement working memory performance relative to the OFF state, and stimulation fields postoperatively are paramount their subjects remained significantly impaired relative to for determining STN DBS effects at the individual level the control group. We also find that PD participants OFF and for truly understanding the role of the STN in fronto- stimulation differed significantly from controls, but in the striatal circuitry and cognition. We anticipate that future ON comparison with controls, they no longer differed. work will attempt to more rigorously link the location of However, we did not find a significant main effect of DBS stimulation field in the STN with nonmotor outcomes. on working memory accuracy within the PD group; thus, we should not conclude that the elimination of this sig- Reprint requests should be sent to Mark Mapstone, Department nificant difference was due to DBS. of Neurology, University of Rochester, 601 Elmwood Avenue, There are a few possible reasons why we did not ob- Box 673, Rochester, NY 14642, or via e-mail: mark_mapstone@ urmc.rochester.edu. serve an effect of DBS on working memory performance (either improvement or worsening), whereas other groups have. One reason may be related to our working memory task and the use of rehearsal. For example, the spatial REFERENCES delayed response task used by Hershey et al. 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