Neuropsychologia 49 (2011) Contents lists available at ScienceDirect. Neuropsychologia

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1 Neuropsychologia 49 (2011) Contents lists available at ScienceDirect Neuropsychologia journal homepage: Stimulation at dorsal and ventral electrode contacts targeted at the subthalamic nucleus has different effects on motor and emotion functions in Parkinson s disease Ian Greenhouse a, Sherrie Gould b, Melissa Houser b, Gayle Hicks b, James Gross c, Adam R. Aron a, a Department of Psychology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA , USA b Department of Neurology, Scripps Clinic, La Jolla, CA, USA c Department of Psychology, Stanford University, Stanford, CA, USA article info abstract Article history: Received 9 September 2010 Received in revised form 10 December 2010 Accepted 15 December 2010 Available online 22 December 2010 Keywords: Deep brain stimulation Mood Basal ganglia Emotion Motor Motor and emotion processing depend on different fronto-basal ganglia circuits. Distinct sub-regions of the subthalamic nucleus (STN) may modulate these circuits. We evaluated whether stimulation targeted at separate territories in the STN region would differentially affect motor and emotion function. In a double-blind design, we studied twenty Parkinson s disease patients who had deep brain stimulation (DBS) electrodes implanted bilaterally in the STN. We stimulated either dorsal or ventral contacts of the STN electrodes on separate days in each patient and acquired behavioral measures. Dorsal contact stimulation improved motor function by reducing scores on the Unified Parkinson s Disease Rating Scale and by reducing both reaction time and reaction time variability compared to ventral contact stimulation. By contrast, ventral contact stimulation led to an increase in positive emotion compared to dorsal contact stimulation. These results support the hypothesis that different territories within the STN region implement motor and emotion functions Elsevier Ltd. All rights reserved. 1. Introduction The subthalamic nucleus (STN) of the basal ganglia may be important for the regulation of diverse behaviors including simple sensorimotor function, higher-level cognitive function, and affective processing (Monakow, Akert, & Künzle, 1978; Temel, Blokland, Steinbusch, & Visser-Vandewalle, 2005). Such diversity is consistent with evidence from mainly non-human animal research for three separate sub-regions ( sensorimotor, associative, and limbic ) spanning a dorsolateral to ventromedial topography within the STN (Karachi et al., 2005; Monakow et al., 1978; Sudhyadhom et al., 2007; Zaidel, Spivak, Shpigelman, Bergman, & Israel, 2009) (Fig. 1). Yet, the functional relevance of these putative STN subregions in humans is only weakly established (Benedetti et al., 2004; Hershey et al., 2010; Mallet et al., 2007; Okun et al., 2009). Here we examine whether motor, cognitive and emotion functions are dissociable to different territories within the STN region. Deep brain stimulation (DBS) of the STN is an effective treatment for the motor symptoms of Parkinson s disease (PD). Many studies have examined the effectiveness of different STN stimulation sites for improving the motor symptoms of PD (for a review see Kuncel Corresponding author. address: adamaron@ucsd.edu (A.R. Aron). & Grill, 2004). In addition to clinical studies on how STN DBS affects motor function, many studies have examined how stimulation affects other functional domains such as cognition and emotion. Yet very few of these studies have examined the effect of stimulation on STN sub-regions. Instead they have contrasted the effects of stimulation against the absence of stimulation (either by turning off the stimulator or by comparing with a presurgical session where the stimulator was not yet implanted). The findings from these studies are complex, with some reporting that stimulation improves behavior and others reporting impairments. For example, STN DBS has been shown to disrupt the processing of negative and fearful emotional facial expressions (Dujardin, Defebvre, Krystkowiak, Blond, & Destée, 2001; Le Jeune et al., 2008), to impair spatial working memory and the ability to inhibit prepared motor responses (Campbell et al., 2008; Hershey et al., 2004; Ray et al., 2009), and to improve multiple measures of executive function while impairing Stroop task performance (Jahanshahi et al., 2000). STN DBS has also been associated with the onset of both depressive and hypomanic states (for reviews see Appleby, Duggan, Regenberg, & Rabins, 2007 and Temel et al., 2005). The diverse effects of STN DBS on cognitive and emotion functions and some of the inconsistency in the results from these previous studies could perhaps be explained by stimulation at different STN sub-regions. A very few studies have specifically looked at the effect of stimulating different putative STN sub-regions on cognition and emotion /$ see front matter 2010 Elsevier Ltd. All rights reserved. doi: /j.neuropsychologia

2 I. Greenhouse et al. / Neuropsychologia 49 (2011) Fig. 1. Putative functional sub-regions of the subthalamic nucleus are depicted with their respective cortico-basal ganglia loops. Benedetti et al. (2004) observed that two patients experienced pleasant sensations when bilateral stimulation was delivered at the ventral pole of the STN, bordering the substantia nigra pars reticulata, but only when patients were aware that they were being stimulated and not when patients were blind to stimulation. This effect was not observed when stimulation was delivered at the dorsal pole of the STN in the same patients. Mallet et al. (2007) reported that bilateral stimulation delivered at a ventral but not a dorsal DBS contact positioned within the STN resulted in transient and reproducible hypomanic states in two patients. However, another study found that 22 patients were less happy, less energetic and more confused when undergoing unilateral stimulation at a ventral STN target in comparison with stimulation at an optimal treatment target, a dorsal target, or Off stimulation (Okun et al., 2009). Together, these findings suggest that stimulation targeted at the ventral but not the dorsal STN influences limbic function. Regarding cognitive function, a recent study reported that while stimulation of both the ventral and dorsal STN improved PD motor symptoms, only stimulation of the ventral STN (but not the dorsal STN) decreased the number of correct responses and increased the number of false alarms during performance of a Go/No-Go task (Hershey et al., 2010). These findings suggest that some cognitive effects of STN-DBS are due to selective stimulation of the more ventral (associative) sub-region of the STN, and not the dorsal (sensorimotor) STN sub-region. Here we compared the effects of bilateral STN-DBS at different ventral and dorsal electrode contacts in the same individuals on tests of motor, cognitive and emotion function. By targeting stimulation at different areas of the STN region through these separate electrode contacts, we hoped to validate the hypothesis of different functional STN sub-regions. We expected that dorsal contact stimulation would affect the dorsal sensorimotor territory of the STN, and that ventral contact stimulation would affect the associative and/or limbic territory of the STN. We tested a moderately sized samples of patients with bilateral STN-DBS using a battery of computerized behavioral tasks in addition to rating scales. The tasks included reaction time (RT) indices of motor function, a test of cognitive control (the stop signal test) and a test of emotion function (using a film-based emotion elicitation procedure). We predicted that stimulation at the dorsal electrode contact would result in improved performance on motor tasks and would result in lower ratings of motor symptom severity, as several clinical studies have shown previously, albeit not usually with measures of RT (Kuncel & Grill, 2004). We also predicted that stimulation at the ventral electrode contact would induce changes in the response to emotional films. This is motivated by evidence for changes in affective function that were associated with stimulation of the ventral STN but not the dorsal STN (Benedetti et al., 2004; Mallet et al., 2007; Okun et al., 2009). The observation of separate effects on motor and emotion functions during stimulation at different electrode contacts within the same individuals would lend support to the concept of functionally dissociable territories within the STN region. We also examined if stimulation at different electrode contacts would affect cognitive performance, specifically on cognitive control as measured by the stop signal task (Logan, Cowan, & Davis, 1984). The STN appears important in a prefrontal cortex basal ganglia network for voluntarily stopping action, as suggested by high resolution functional imaging (Aron & Poldrack, 2006) and lesion studies in the rodent (Eagle et al., 2008). Consistent with this, a study that investigated the effects of STN-DBS on performance of the stop signal task reported improvement in stopping (faster stop signal reaction time, SSRT) for On vs. Off stimulation (van den Wildenberg et al., 2006) (but see Ray et al., 2009). One possible explanation for these inconsistent effects of stimulation on SSRT is that different STN sub-regions may have been stimulated in these different studies. Here we speculate that the associative sector is the best candidate sub-region for stopping action because it connects with dorsal (i.e. non-orbital) sectors of prefrontal cortex that are known to be important for stopping (Chambers, Garavan, & Bellgrove, 2009). In our study, the associative sector would be most likely affected by ventral contact stimulation. Thus we expected that ventral contact stimulation would speed SSRT more than dorsal contact stimulation. This prediction was also motivated by effects of ventral vs. dorsal STN stimulation on Go/No-Go task performance (Hershey et al., 2010) and also a study that reported increased firing rates of neurons in the ventral STN of monkeys when countermanding prepotent response tendencies (Isoda & Hikosaka, 2008). Thus we compared the effects of stimulation targeted at the STN through either dorsal or ventral electrode contacts on motor, cognitive and emotion functions in the same individuals. This is a powerful double-blind approach that controls for non-specific effects of stimulation. 2. Methods 2.1. Participants Twenty PD patients with bilateral STN-DBS were recruited from Scripps Clinic, La Jolla, California (18 male; mean age: 62.4 ± 8.96; all right-handed; time since DBS implantation: ± months; Mini-Mental State Examination Score: ± 0.66). All patients had been screened for psychiatric illness and dementia prior to DBS surgery. Participant characteristics are presented in Table Deep brain stimulation localization and adjustment procedure Each patient had bilaterally implanted STN electrodes (Medtronic, Kinetra Model 3389). Each quadripolar electrode contains four 1.5 mm contacts spaced 0.5 mm apart. By convention, the contacts are numbered from ventral to dorsal 0, 1, 2, 3 (left hemisphere) and 4, 5, 6, 7 (right hemisphere). The standard method for electrode localization now involves fusing a preoperative MRI with a postoperative CT scan (Paek et al., 2008; Schrader, Hamel, Weinert, & Mehdorn, 2002). Such data were available to us in just five of our twenty patients. For these patients we localized the electrode contacts by fusing preoperative structural MRI images and postoperative CT images using iplan software (BrainLAB, Germany). The fused images were then coregistered to corresponding plates from the Schaltenbrand and Wahren Atlas for Stereotaxy of the Human Brain (1977). This allowed us to visualize the placement of the electrode contacts for each individual

3 530 I. Greenhouse et al. / Neuropsychologia 49 (2011) Table 1 Patient characteristics, rating scale scores, simple RT, choice RT, and stop (choice) RT. Stop (choice) RT (ms) Choice RT (ms) Simple RT (ms) BDI MMSE LEDD (mg/day) YMRS dorsal YMRS ventral UPDRS dorsal UPDRS ventral Months with DBS DBS treatment settings left/right Patient Age Sex Age of onset Ventral Dorsal Ventral Dorsal Ventral Dorsal 1 51 M 48 1 c+/5 c M 80 (0,1) 3+/5 c M 53 0 c+/6 c M 60 1 c+/5 c M 69 2 c+/5 c M 54 1 c+/5 c M 55 1 c+/5 c M 65 1 c+/5 c M 63 (1,2) 3+/(5,6) M 60 (1,2) 3+/(5,6) M 41 (1,2) c+/(5,6) F 66 1 c+/5 c M /(5,6) M 53 (1,2) 3+/(5,6) M 42 1 c+/ F 54 1 c+/5 c M 68 0 c+/(4,5) c M 58 1 c+/4 c M 55 1 c+/6 c M 67 2 c+/ Note. UPDRS = Unified Parkinson s Disease Rating Scale part III, YMRS = Young Mania Rating Scale, dorsal = dorsal contact stimulation, and ventral = ventral contact stimulation, BDI = Beck Depression Inventory, MMSE = Mini-Mental State Examination, LEDD = Levodopa Equivalent Daily Dose. in a common atlas space. For these five patients we found that the ventral electrode contact was positioned in and around the ventral STN and that the dorsal electrode contact was above the STN, either in the white matter (i.e. zona incerta) or the ventral thalamus (Fig. 2). Despite the fact that the dorsal contacts were placed above the STN, we note that studies have reported that the dorsal border of the STN or the white matter above the STN are the most effective targets for treating PD motor symptoms (Kuncel & Grill, 2004). Moreover, stimulation of the input pathways to the STN has been shown to account for the therapeutic effects of DBS in animal models of PD (Gradinaru, Mogri, Thompson, Henderson, & Deisseroth, 2009). We note, in any case, that the field of stimulation can have a spread of up to 2 mm within the brain (Maks, Butson, Walter, Vitek, & McIntyre, 2009). Therefore, in order to maximize the likelihood of finding functional differences between stimulation sites and because we do not have precise localization information in every patient, we chose to stimulate at the dorsal-most and ventral-most contacts in all patients. We also had access to neurophysiological recording diagrams attained during surgery for all patients. These diagrams were created using intraoperative recordings overlaid onto a corresponding plate from the Schaltenbrand-Wahren atlas (1977). In brief, as the microelectrode was lowered into the nucleus, the rate and density of neural firing was used to identify the border between the STN and substantia nigra. The microelectrode recordings were made in the patients stereotaxic space and were coregistered to the Schaltenbrand Wahren atlas space. The coregistered mappings were consequently used to determine the target locus for the tip of the DBS lead. See Hutchison et al. (1998) for a more complete description. The spatial coordinates for the ventral and dorsal electrode contacts derived from the neurophysiological diagrams for all patients are presented in Supplementary Table 1. These diagrams provide approximate information about electrode location. In the five patients for whom we had both structural imaging and neurophysiological recording there was strong correspondence between the two methods. Using either method, ventral contacts were estimated to be within or below the STN while dorsal contacts were estimated to be within the white matter bordering the dorsal STN or within the ventral thalamus for all patients (Fig. 2). During the study, a nurse practitioner administered monopolar stimulation (60 s pulse width; 185 Hz frequency) once at the ventral contacts (0 and 4) and once at the dorsal contacts (3 and 7), with order randomly assigned across two visits (26.3 ± days apart). At each visit, stimulation was set as close to 3.2 V as possible at the two (left and right) prescribed electrode contacts for that visit, while not producing any discomfort. This specific voltage setting was selected because, first, it produced detectable effects in our sample when prescribed as part of standard treatment settings and second, it helped to limit variability across patients. The mean and SD of the stimulation voltages were: 2.83 ± 0.5 V for left ventral, 3.03 ± 0.3 V for left dorsal, 2.92 ± 0.34 V for right ventral, and 2.90 ± 0.5 V for right dorsal contacts. The patients and test-battery experimenter remained blind to stimulation settings. Patients maintained their regular medication schedule, and medications remained stable throughout the study. 3. Materials and procedure The tasks were run on a 13.3 MacBook (Apple, Cupertino, CA) using the Psychtoolbox version 3.0 (running under Matlab, R2007a). The right hand was used to make response on an USBinterfaced button box Simple reaction time task Patients made a speeded right index finger response to a target stimulus. Each trial (96 total) began with a fixation cross which was presented for ms (mean 1000 ms). This was followed by an imperative target (an asterisk) presented for up to 1000 ms or until a button was pressed. A blank-screen inter-trial interval lasted 1500 ms. Three measures were computed: mean RT, the standard deviation of the RT and the number of premature responses (i.e. those with an RT of less than 100 ms) Choice reaction time task Patients used the index or the middle finger of the right hand to make a speeded response to a leftward or rightward pointing arrow, respectively. The arrow directions were equiprobable. Each trial (96 total) began with a fixation cross for 500 ms. This was followed by a leftward or rightward pointing arrow presented for up to 1000 ms, or until a button was pressed, and then a 1500 ms blank-screen. Four measures were computed: mean RT, the standard deviation of

4 I. Greenhouse et al. / Neuropsychologia 49 (2011) Fig. 2. Diagrams of electrode location were constructed based upon intraoperative neurophysiological recordings (squares) and fused preoperative MRI and postoperative CT images (dots) in five patients. Left dorsal, right dorsal, left ventral, and right ventral electrode contact locations are presented on sagittal plates from the Schaltenbrand Wahren Atlas determined to be closest to the mean lateral distance from the AC-PC line across patients for each electrode contact. The lateral distance in mm from the AC-PC line is displayed in the bottom right corner of each plate. The subthalamic nucleus is outlined with a dashed line. The numbers correspond to the patient numbers in Table 1. the RT, the number of errors in response selection, and the number of premature responses Stop-signal reaction time task (Aron & Poldrack, 2006) We used a task with 192 trials total; two-thirds were go trials (no stop signal) and one-third were stop trials. Go trials were identical to the choice RT task above (and are referred to as choice (stop)). Stop trials began in the same way, however at some delay after the go (arrow) stimulus, an auditory stop signal (500 Hz, 400 ms) was presented. The patient was instructed to try to stop the response when the stop signal occurred. The stop signal delay (SSD) changed dynamically to achieve a 50% stopping rate (for full details see Aron & Poldrack, 2006). Five measures were computed: the mean Go RT, the standard deviation of Go RT, the number of discrimination errors on Go trials, the number of premature responses, and the stop signal reaction time (SSRT). SSRT was calculated by subtracting the average of the last 12 SSDs derived from each of four staircases from the mean correct Go RT (Verbruggen & Logan, 2008) Emotion reactivity task The emotion reactivity task and the film stimuli have been described and validated previously (Rottenberg, Ray, & Gross, 2007). At each visit the patient viewed three movie clips of different valence: (a) neutral (3.03 min nature film of Denali National Park), (b) sad (2.82 min clip of The Champ ), and (c) amusing (2.58 min of Bill Cosby s solo standup comedy). The same film clips were presented in a random order at each visit. After viewing each clip the patient completed a questionnaire. In keeping with prior film research (Brücke et al., 2007; Rottenberg et al., 2007; Vicente et al., 2009), a broad range of 22 emotion items was assessed. Each item was rated on a nine-point Likert scale (i.e. 0 = none [not experienced] to 8 = extremely [experienced in the extreme]) (see Supplementary Table 2 for complete results). When the ratings were averaged over the two stimulation conditions, a subset of five items showed the greatest sensitivity to differences in film valence. These were: positive, negative, happiness, amusement, and sadness. As positive and negative affect are the most consistent factors in self-report of mood (Watson & Tellegen, 1985), we focused on these two items alone for the orthogonal analysis of dorsal vs. ventral contact stimulation Psychiatric and motor rating scales The Mini-Mental State Examination was administered at the initial research visit only, while patients were at treatment stimulation settings. At each visit, while the patients were at the experimental stimulation settings, we administered the Unified Parkinson s Disease Rating Scale III Motor Examination (UPDRS) and the Young Mania Rating Scale (Young, Biggs, Ziegler, & Meyer, 1978). Only the Motor Examination of the UPDRS was administered due to time constraints Statistical analysis Because the stimulation voltages were not normally distributed, a Friedman s two-way ANOVA by ranks test was performed to rule out differences in voltage between the stimulation conditions. For mean RT and RT variability separately, two-way, repeatedmeasures ANOVAs were performed with the factors task (simple, choice, or choice (stop)) and stimulation site (ventral or dorsal contact). Including these RT measures together in a single ANOVA reduces the number of statistical comparisons. For error rates, a related-samples Friedman s two-way ANOVA by ranks was run with the factors task (choice, choice (stop)) and stimulation site. The rates of premature responding were too low to perform a meaningful comparison between stimulation conditions. For the SSRT measure, a paired t-test compared between stimulation conditions. For the emotion ratings, a three-way, repeated-measures

5 532 I. Greenhouse et al. / Neuropsychologia 49 (2011) ANOVA was performed with the factors questionnaire item (positive or negative), stimulation site (ventral or dorsal contact) and valence of film (positive, negative and neutral). 4. Results 4.1. Stimulation parameters The voltage at dorsal and ventral contacts was not significantly different ( 2 (3) = 4.56, p = 0.21) Reaction time tests The ANOVA for the RT measures revealed a main effect of stimulation condition for both mean RT (F(1,19) = 5.80, p = 0.026) and RT variability (F(1,19) = 11.78, p = 0.003) (Table 2 and Fig. 3A and B). This showed that mean RT was faster and RT variability was less for dorsal than ventral contact stimulation. There were no interactions between task and stimulation condition. There was no main effect or interaction for error rates. For the stop signal task, SSRT did not differ significantly between the two stimulation conditions (t(19) = 0.25, p = 0.81) Rating scales UPDRS motor scores improved significantly for dorsal vs. ventral contact stimulation (t(19) = 2.62, p = 0.017, see Table 2 and Fig. 3D). Young Mania Rating Scale scores did not differ significantly between the two stimulation conditions (t(19) = 0.64, p = 0.53, see Table 2). Correlations between UPDRS measures and other measures of interest are discussed in the Supplementary Materials Emotion reactivity task There was a significant interaction between stimulation site and questionnaire item (F(1,19) = 10.73, p = 0.004)(Table 2 and Fig. 3C). There were no significant main effects or further interactions. Posthoc tests comparing the two stimulation conditions revealed a significant difference for the positive (F(1,19) = 5.96, p < 0.025, Bonferroni corrected) but not the negative (F(1,19) = 2.02, p = 0.17) items. Table 2 Mean measures of interest for reaction time tasks, rating scales, and film ratings. Measure of interest Dorsal contact mean (SD) Ventral contact mean (SD) Simple RT (ms) 415 (101) 442 (115) Standard deviation of simple RT (ms) 111 (44) 145 (62) Simple errors (number) 0.30 (0.5) 1.75 (3.3) Choice RT (ms) 566 (104) 599 (143) Standard deviation of choice RT (ms) 119 (49) 134 (63) Choice errors (number) 4.60 (4.7) 3.35 (2.5) Choice (stop) RT (ms) 711 (173) 751 (206) Standard deviation of choice (stop) RT (ms) 163 (54) 178 (77) Stop errors (number) 3.55 (4.9) 2.55 (3.0) SSRT (ms) 263 (163) 256 (100) p(inhibit) following convergence 52.5 (14.6) 61.3 (9.3) Failed stop RT (ms) 619 (182) 637 (181) UPDRS score 11.9 (6.0) 14.7 (7.4) YMRS score 2.6 (3.3) 2.1 (2.4) Positive rating of films 3.8 (1.2) 4.4 (1.5) Negative rating of films 2.0 (1.1) 1.7 (1.3) Note. Film ratings were averaged across three film types. SSRT = stop signal reaction time, UPDRS = Unified Parkinson s Disease Rating Scale part III, YMRS = Young Mania Rating Scale. 5. Discussion Using a double-blind design, we found dissociable effects of dorsal and ventral STN contact stimulation on motor compared to emotion function. Dorsal contact stimulation was associated with faster and less variable motor responding and with improved UPDRS motor ratings. These improvements in motor function were likely achieved by selectively modulating activity within the sensorimotor territory of the STN (Yokoyama, Ando, Sugiyama, Akamine, & Namba, 2006) or afferent projections to the STN (Gradinaru et al., 2009). Ventral contact stimulation was associated with an increase in positive ratings in response to films of different valences. This suggests that ventral stimulation led to a general increase in positive affect. Taken together these results support the hypothesis of dissociable functional territories in the STN region in humans. We found that ventral contact stimulation led to increased ratings of positive emotion compared to dorsal stimulation. This is consistent with a possible role for the ventral sector of the STN in limbic function (Mallet et al., 2007; Saleh & Okun, 2008; Temel et al., 2005) although we cannot rule out effects on adjacent structures or fibres of passage (Coenen et al., 2009; Yokoyama et al., 2006). Moreover, this effect occurred irrespective of film type (i.e. positive, negative or neutral clips), indicating a general and lasting shift towards positive emotion which may be better characterized as a change in mood. This fits the so-called Affect-Level theory (Gross, Sutton, & Ketelaar, 1998), wherein changes in affect occur at a general level, separate from changes to individual stimuli. Notably, the stimulation effects observed here occurred without any changes in Young Mania Rating Scale scores. It is thus possible that the emotion reactivity test used here (Rottenberg et al., 2007) has greater sensitivity than the psychiatric instrument. There have been studies measuring the effects of dorsal vs. ventral STN-DBS on mood. One of these observed decreased happiness (Okun et al., 2009) and the other observed hypomania (Mallet et al., 2007) for ventral relative to dorsal stimulation. Inconsistencies between these results may be due to the fact that Okun et al. (2009) only used unilateral stimulation and Mallet et al. (2007) reported effects with bilateral stimulation (moreover in only two patients). In contrast to these studies, we measure the effects of dorsal vs. ventral stimulation in bilateral STN-DBS in a moderately large sample of patients for an emotion elicitation task. We show a contactspecific change in affect, which is dissociable from improvements in motor function in the same individuals. Although several lines of evidence point to the importance of the STN for stopping action (Aron & Poldrack, 2006; Eagle et al., 2008; Hershey et al., 2004, 2010; Kühn et al., 2005; Ray et al., 2009; van den Wildenberg et al., 2006), SSRT values were not significantly different for dorsal vs. ventral contact stimulation. However, SSRT was similar to that of healthy controls of a similar age (Williams, Ponesse, Schachar, Logan, & Tannock, 1999) and faster than reported for PD patients in an Off stimulation condition (van den Wildenberg et al., 2006). Thus, although we did not include an Off stimulation condition, STN-DBS in the current study might have affected SSRT in both ventral and dorsal stimulation conditions. It is possible that the stopping function is more broadly represented in the STN and/or its connected functional networks than simple motor and emotion functions. It is also possible that the stopping function is implemented by the associative STN, as we predicted, yet both dorsal and ventral contact stimulation could have affected this region. Future studies with greater spatial specificity of stimulation, or recording, could resolve this question. This study had two limitations. First, we did not include an Off stimulation condition or a comparison group of healthy agematched controls. The inclusion of an Off stimulation condition would have permitted us to evaluate the clinical benefit to motor function and emotion as well as any general effects of DBS on stop-

6 I. Greenhouse et al. / Neuropsychologia 49 (2011) Fig. 3. Dorsal vs. ventral deep brain stimulation of the subthalamic nucleus modulates motor function differently from emotion function. Dorsal stimulation is depicted in blue and ventral stimulation in red. Error bars represent one standard error of the mean. (A) Improved simple, choice, and choice (stop) RT for dorsal vs. ventral stimulation. (B) Decreased variability of simple, choice, and choice (stop) RT for dorsal vs. ventral stimulation. (C) Increased positive and decreased negative emotion ratings for ventral vs. dorsal stimulation. (D) Improved Unified Parkinson s Disease Rating Scale scores for dorsal vs. ventral stimulation. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.) ping behavior. The inclusion of a healthy control group would also have enabled us to assess the degree of clinical benefit. For example, the current study shows that ventral stimulation increased positive emotion ratings in a manner consistent with possibly improved mood. However, without an Off condition or healthy-matched controls it is unclear if this positive effect has clinical significance. Notwithstanding this limitation, the current study was clearly able to address the cognitive neuroscience hypotheses of interest by harnessing the power of a double-blind design. Moreover, there is some clinical implication of our study for the DBS programmer who traditionally attempts to optimize motor function but has little guidance regarding emotion. The behavioral methods used here could help develop testing batteries in the DBS outpatient suite, where motor and emotion processing could be quickly and repeatedly evaluated. Such a battery of behavioral tasks may be sensitive to stimulation-induced changes in behavior that are not detectable with conventional psychiatric rating scale measures. A second limitation was that we opted to stimulate all patients at the ventral-most and dorsal-most contacts rather than targeting the contacts in each patient on the basis of localization information. Since we began this study, the current state-of-the-art is to use preoperative and postoperative imaging to localize the dorsal and ventral STN contacts on a subject-by-subject basis (Hershey et al., 2010) something that is clearly recommended for future studies. Thus, the lack of precise electrode localization prevents us from making strong claims about the importance of specific dorsolateral and ventromedial sub-regions within the STN. However, the congruence between our imaging data and neurophysiological recording diagrams in five patients, and the fact that we had neurophysiological recording diagrams in the remaining 15 patients, allows us to be confident that the dorsal contact was stimulating an area in the vicinity of the dorsal STN (most likely the white matter above the STN, which has been shown to have optimal clinical benefit) while the ventral contact was stimulating an area in the vicinity of the ventral STN. Moreover, given the hypothesized 2 mm spread of current within the brain (Maks et al., 2009), we note that the spatial precision of stimulation is limited for any study. In summary, we demonstrated dissociable effects on motor and emotion functioning for dorsal vs. ventral electrode contact stimulation of the STN. Stimulation at the dorsal electrode contact resulted in improved performance on simple motor tasks and stimulation at the ventral electrode contact resulted in generally more positive ratings of emotion (possibly consistent with increases in positive mood). These differences in behavior lend support to the hypothesis that sub-regions within the STN in humans participate in functionally distinct circuits. Moreover, the findings have possible clinical implications. If our observation is substantiated that stimulation of the ventral STN sub-region leads to generally increased positive emotion (mood) then it may be possible to use the emotion elicitation methods harnessed here to try to optimized DBS treatment programming to simultaneously improve motor and emotion function.

7 534 I. Greenhouse et al. / Neuropsychologia 49 (2011) Acknowledgements We thank the patients for participating and Nader Pouratian for helpful advice regarding image registration. This study was supported by the National Association for Research into Schizophrenia and Depression (NARSAD), A.R.A (PI) and an Alfred P Sloan Award to A.R.A. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi: /j.neuropsychologia References Appleby, B. S., Duggan, P. S., Regenberg, A., & Rabins, P. V. (2007). Psychiatric and neuropsychiatric adverse events associated with deep brain stimulation: A meta-analysis of ten years experience. Movement Disorders, 22(12), Aron, A. R., & Poldrack, R. A. (2006). Cortical and subcortical contributions to Stop signal response inhibition: Role of the subthalamic nucleus. Journal of Neuroscience, 26(9), Benedetti, F., Colloca, L., Lanotte, M., Bergamasco, B., Torre, E., & Lopiano, L. (2004). 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