Cognition following bilateral deep brain stimulation surgery of the subthalamic nucleus for Parkinson s disease

Transcription

1 INTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY Int J Geriatr Psychiatry 2009; 24: Published online 17 November 2008 in Wiley InterScience ( REVIEW ARTICLE Cognition following bilateral deep brain stimulation surgery of the subthalamic nucleus for Parkinson s disease Casey H. Halpern 1, Jacqueline H. Rick 2, Shabbar F. Danish 3, Murray Grossman 4 and Gordon H. Baltuch 1 * 1 Department of Neurosurgery, Neurology and Psychiatry, University of Pennsylvania, Philadelphia, PA, USA 2 Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA 3 Division of Neurosurgery, Robert Wood Johnson University Hospital University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA 4 Department of Neurology, University of Pennsylvania, Philadelphia, PA, USA SUMMARY Objective Parkinson s disease (PD) is a neurodegenerative disorder characterized by significant motor dysfunction and various non-motor disturbances, including cognitive alterations. Deep brain stimulation (DBS) is an increasingly utilized therapeutic option for patients with PD that yields remarkable success in alleviating disabling motor symptoms. DBS has additionally been associated with changes in cognition, yet the evidence is not consistent across studies. The following review sought to provide a clearer understanding of the various cognitive sequelae of bilateral subthalamic nucleus (STN) DBS while taking into account corresponding neuroanatomy and potential confounding variables. Design A literature search was performed using the following inclusion criteria: (1) at least five subjects followed for a mean of at least 3 months after surgery; (2) pre- and postoperative cognitive data using at least one standardized measure; (3) adequate report of study results using means and standard deviations. Results Two recent meta-analyses found mild post-operative impairments in verbal learning and executive function in patients who underwent DBS surgery. However, studies have revealed improved working memory and psychomotor speed in the on vs off stimulation state. A deficit in language may be a consequence of the surgical procedure. Conclusions While cognitive decline has been observed in some domains, our review of the data suggests that STN DBS is a worthwhile and safe method to treat PD. Copyright # 2008 John Wiley & Sons, Ltd. key words cognition; deep brain stimulation; neuropsychologic; subthalamic; Parkinson s disease INTRODUCTION *Correspondence to: Dr G. H. Baltuch, Department of Neurosurgery, 3 Silverstein, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA 19104, USA. gordon.baltuch@uphs.upenn.edu Copyright # 2008 John Wiley & Sons, Ltd. Parkinson s disease (PD) is a neurodegenerative disorder characterized by motor impairment including resting tremor, bradykinesia, postural instability and rigidity. Deep brain stimulation (DBS) alleviates many of these symptoms (Krack et al., 2003; Ford et al., 2004; Visser-Vandewalle et al., 2005). While a multiinstitutional, VA-NIH sponsored, randomized clinical trial has been initiated to determine the most effective neural target for DBS, the subthalamic nucleus (STN) has gained general preference in the United States. Although PD is traditionally considered a movement disorder, multiple studies have reported cognitive changes, including impairments in executive function, language, memory, vision, and psychomotor speed (Grossman et al., 2002; Lee et al., 2003; Pillon et al., 2003; Muslimovic et al., 2005). fmri studies and positron emission tomography (PET) activation studies have indicated that changes in the recruitment of the frontal striatal thalamic circuitry may explain Received 23 December 2007 Accepted 25 September 2008

2 444 c. h. halpern ET AL. such cognitive difficulties (Owen et al., 1998; Grossman et al., 2003). Thus, there is growing interest in the non-motor implications of DBS. Many factors other than the direct effects of stimulation can explain cognitive changes following DBS surgery, including inadequately defined patient selection criteria (Saint-Cyr and Albanese, 2006), small sample sizes with inadequate power (Woods et al., 2006), surgical complications, and adjustments in pharmacologic regimens (Funkiewiez et al., 2004). The current literature review sought to provide a clearer understanding of cognitive impairments associated with stimulation of STN in PD while taking into account potential confounds noted above and PD neuroanatomy. In this way, we may better predict overall outcome in PD patients. DBS AND THE BASAL GANGLIA CIRCUITRY IN PARKINSON S DISEASE The choice of the best anatomic targets for DBS is based on a clear understanding of the direct and indirect neural circuitry of the basal ganglia (BG) (Bergman et al., 1990; Albin et al., 1995; Halpern et al., 2007). There is a normal physiologic balance between indirect projections from striatum to the globus pallidus internus (GPi) (via the external segment of globus pallidus and STN) and direct projections from striatum to GPi. Final output from the BG is a modulated inhibition through GPi to the motor nuclei of the thalamus (VA/VL complex) and then to motor and premotor cortex for execution of voluntary movement. Normally, STN s output to GPi is excitatory (onto an inhibitory assembly of neurons in the GPi), but in PD the output of STN is excessive secondary to upstream loss of inhibitory dopaminergic input (Albin et al., 1989). The net result is uncontrolled inhibitory output from GPi to thalamus and a cascade of physiologic suppression of movement through connecting synapses. DBS provides significant symptomatic improvement in parkinsonism in both animal and human studies (Krack et al., 2003; Fang et al., 2006), and at high frequencies ( Hz) mimics the clinical effects of tissue lesioning (Andy et al., 1963; Benabid et al., 1987; Bergman et al., 1990). However, in contrast to stereotactic lesions, DBS provides the added benefit of reversibility and titratability (Deuschl et al., 2006), as well as a very low risk of complications (Voges et al., 2006; Deogaonkar et al., 2007). Although the precise mechanism of action remains unclear, a remarkable improvement in parkinsonism with high frequency STN DBS supports functional inhibition of the aberrant STN in PD (Benabid et al., 1987). Indeed, some have shown that high frequency DBS has an inhibitory effect on STN (Toleikis et al., 2007). Alternatively, introducing the DBS lead into the STN may truly lesion this area (Hirashima et al., 2005), though this observation is debated in post-mortem literature (Haberler et al., 2000; Henderson et al., 2001). SELECTION CRITERIA FOR DEEP BRAIN STIMULATION SURGERY There is growing evidence to suggest that patient selection criteria for STN DBS surgery should include features that may impact cognition. Currently, bilateral STN DBS for PD is recommended for otherwise healthy patients who continue to respond to medical therapy but suffer from disabling motor complications of levodopa therapy and/or breakthrough severe tremor (Charles et al., 2002; Benabid, 2003; Montgomery, 2003). Most centers use the CAPSIT criteria for surgery, emphasizing an accurate diagnosis and response to pharmacological treatment (Defer et al., 1999). However, growing interest in the non-motor effects of STN DBS has led to a number of recent reports insisting that new guidelines be developed to include non-motor features of PD (Saint-Cyr and Albanese, 2006). Charles et al. (2002) showed that age correlated negatively with postoperative improvement following DBS. Because of the high prevalence of mild cognitive impairment in advanced PD, older patients with cognitive impairment may be vulnerable to decompensation postoperatively. Therefore, careful preoperative evaluation of cognition should be mandatory. Nevertheless, well-selected older patients in good general health with unimpaired cognitive function are appropriate surgical candidates (Benabid, 2003; Broggi et al., 2003; Krack et al., 2003). COGNITIVE EFFECTS OF SUBTHALAMIC NUCLEUS DEEP BRAIN STIMULATION Studies were reviewed (see Table 1) if they were published in the English language and met our minimum inclusion criteria: 1) at least five subjects followed for a mean of at least 3 months postoperatively; (2) pre- and post-operative cognitive data using at least one standardized measure; (3) adequate report of study results using means and standard deviations, as well as noting significant changes at p-values less than 0.05 or at values adjusted by Bonferroni correction. Table 2 summarizes the cognitive effects reported in these studies.

3 stn dbs and cognition 445 Table 1. Summary of studies included in literature review Series N Mean age Mean disease duration (months) Mean follow-up period (months) Alegret et al. (2001) Ardouin et al. (1999) Castelli et al. (2006) Contarino et al. (2007) Daniele et al. (2003) De Gaspari et al. (2006) Dujardin et al. (2001) Erola et al. (2006) Funkiewiez et al. (2003) NR 12 a Funkiewiez et al. (2004) Gironell et al. (2003) Hälbig et al. (2004) NR Hershey et al. (2004) Hilker et al. (2004) Jahanshahi et al. (2000) Limousin et al. (1998) Moretti et al. (2003) Moro et al. (1999) Morrison et al. (2004) Perozzo et al. (2001) Pillon et al. (2000) b Saint-Cyr JA et al. (2000) c Saint-Cyr JA et al. (2006) Schupbach et al. (2005) Temel et al. (2006) Trepanier et al. (2000) Whelan et al. (2003) Witt et al. (2004) NR ¼ Not Reported. a Median follow-up period. b We only report findings from the STN1 group. c 9 12 month follow-up period. Language The STN is believed to regulate activity of thalamocortical projections via excitatory influences on basal ganglionic output nuclei (Parent and Hazrati, 1995a, 1995b). Subcortical participation in language has been hypothesized (Nadeau and Crosson, 1997; Smith et al., 1998; Whelan et al., 2004, 2005). STN hyperactivity in PD may disrupt thalamocortical projections dedicated to language production. Some studies have noted enhanced verbal function with STN DBS. For example, sustained improvements in language following bilateral STN DBS have been reported in studies in which PD patients who underwent DBS surgery are compared to an agematched control group in which surgery was not performed. Whelan et al. (2003) observed a greater proportion of improvement on a high-level linguistic task (Huisingh et al., 1990) during active stimulation (Whelan et al., 2003). Moretti et al. (2003) reported a significant decrease in the total number of mistakes in syntactic comprehension tasks relative to baseline and controls. Such sustained improvements in language function do support functional inhibition of the STN by DBS. We are unable to argue that STN DBS has an overall positive effect on language. Several studies have demonstrated postoperative impairments on measures of semantic and phonemic fluency (Ardouin et al., 1999; Funkiewiez et al., 2004). Two recent metaanalyses revealed a small to moderate language impairment with STN DBS (Parsons et al., 2006; Temel et al., 2006). However, diminished verbal fluency seems to occur immediately after surgery consistent with a surgical effect (Funkiewiez et al., 2004). While such reported declines in language could be secondary to a disruption of neural networks by STN DBS with the production of artificial nerve impulses (Benazzouz and Hallett, 2000), no further deterioration in verbal fluency was noted at 3 years follow-up.

4 446 c. h. halpern ET AL. Table 2. Summary Of Cognitive Changes Following Subthalamic Nucleus Deep Brain Stimulation For Parkinson s disease Series Cognitive improvements Cognitive declines No change Alegret et al. (2001) E, PS E, L, M, V None Ardouin et al. (1999) E L GC, E, PS Castelli et al. (2006) None E, L E, L, M Contarino et al. (2007) None E, L GC, E, A/C, M Daniele et al. (2003) GC, E L E, A/C, M De Gaspari et al. (2006) None L GC, E, L Dujardin et al. (2001) PS L, M GC, E, M, PS Erola et al. (2006) None L GC, E, PS Funkiewiez et al. (2003) None None GC, E Funkiewiez et al. (2004) None L GC, E, M, PS Gironell et al. (2003) None L E, A/C, M, V, PS Hälbig et al. (2004) M, PS M GC, E, L Hershey et al. (2004) None E None Hilker et al. (2004) M None GC, E, L, A/C, M, V Jahanshahi et al. (2000) E, A/C, PS M None Limousin et al. (1998) None None E,L,V,PS Moretti et al. (2003) L E, L E, L, A/C, M, V Moro et al. (1999) None None GC, E, L, M Morrison et al. (2004) None L, A/C, M E, M,V Perozzo et al. (2001) None None E, A/C, M, PS Pillon et al. (2000) E, PS L, M None Saint-Cyr JA et al. (2000) None E, L, M, A/C None Saint-Cyr JA et al. (2006) PS E, L, A/C, M, PS None Schupbach et al. (2005) None GC,E None Temel et al. (2006) PS None None Trepanier et al. (2000) None E, L, M E, L, A/C Whelan et al. (2003) L None None Witt et al. (2004) None E GC A/C ¼ Attention/Concentration; E ¼ Executive; GC ¼ Global Cognition; L ¼ language; M ¼ Memory; PS ¼ Psychomotor/Processing Speed; V ¼ Visual. A/C ¼ Digit Span Forward, WAIS III Arithmetic, Corsi Span Forward, Paced Auditory Serial Addition Task. E ¼ Trail Making Test Part B, Stroop Color/Word, Wisconsin Card Sorting Test, Raven s Progressive Matrices, Digit Span Backward, Frontal Assessment Battery, Spatial Span, Word Span, Baddeley s Doors Test, Tower of London, Tower of Hanoi. GC ¼ Mattis Dementia Rating Scale, Mini Mental State Examination. L ¼ Category and Letter Fluency, The Word Test Revised Language Battery. M ¼ Rey Auditory Verbal Learning Test, Corsi Block Tapping, Delay Recall, Sternberg, Memo Test, WMS Logical Memory, Visual Association Memory, Bisyllabic Word Recognition. PS ¼ Trail Making Test Part A, Graphic and Motor Series, Simple and Choice Reaction Time, Visual and Auditive Reaction Time. Visual ¼ Judgment of Line Orientation, Rey Complex Figure Test, Benton Visual Retention Test. We only report findings from the STN1 group. Two studies to our knowledge have examined language in the on and off stimulation conditions (Pillon et al., 2000; Morrison et al., 2004). A comparison of patients at 3 and 12 months postoperatively revealed impairment in category fluency with or without stimulation, supporting a consequence of surgery, or more specifically, the parasagittal trajectory taken for electrode implantation (Pillon et al., 2000). Indeed, an fmri study has demonstrated functional activation of the paracingulate and cingulate sulci during word generation (Crosson et al., 1999). Such verbal deterioration postoperatively has been noted consistently in both ablation and DBS of GPi, supporting a consequence of the procedure itself (Troster et al., 1997, 2002). Of note, one study has directly compared the cognitive sequelae of STN DBS to GPi DBS and showed no overall differential effects, further supporting the direct effects of the surgical procedure. Nevertheless, a study of 41 PD patients undergoing bilateral STN DBS noted that none of the patients, family members, or members of the medical staff reported postoperative changes in language, or any other domain of cognition, suggesting that any change revealed by cognitive tests was subtle (Ardouin et al., 1999). This supports that the majority of patients are not dissatisfied with this surgical procedure given the dramatic improvements in their motor function and ADLs.

5 stn dbs and cognition 447 Executive function The effect of bilateral STN DBS on executive function has been shown to be both beneficial and detrimental though a meta-analysis supports an adverse effect overall (Parsons et al., 2006; Temel et al., 2006). Nine of the studies included in our review reported executive impairment following bilateral STN DBS. Moretti et al. (2003) reported declines in executive function relative to controls, as measured by the interference condition from the Stroop test (Stroop, 1935), 3, 6 and 12 months postoperatively. It is worth noting that the PD patients included in this study already demonstrated a significant increase in time required for Stroop execution preoperatively. Hershey et al. (2004) noted executive deficits associated with both higher demands in memory and inhibitory control, suggesting that STN DBS may compromise these processes specifically. One recent study noted a postoperative impairment on Raven s progressive matrices (Contarino et al., 2007). However, when the raw scores obtained by each patient 5 years after surgery were adjusted for age and educational level, only two out of 11 impaired patients performed slightly below the normal range. Interestingly, most of these patients performed below the normal range preoperatively (Contarino et al., 2007). Saint-Cyr et al. (2000) suggested that bilateral STN DBS can have a negative impact on executive function, particularly in patients older than 69 years. The mean age of patients in Saint-Cyr s study (67 years) was approximately nine years older than the mean age of the patients in some studies where postoperative executive improvement was observed. Four out of five patients older than 69 years in Trepanier and colleauges study (2000) suffered a decline in many aspects of cognitive functioning, including mental slowing. Thus, cognitive outcome following bilateral STN DBS for PD may be influenced not only by the surgery and stimulation but also by patient characteristics such as age and preoperative cognitive status (Trepanier et al., 2000). Trepanier et al. (2000) likened the cognitive changes observed in their group of PD patients to Progressive Supranuclear Palsy (PSP). This may specifically be due to long-term STN stimulation, given the STN s involvement in PSP neuropathology (Parent and Hazrati, 1995a,b). On the other hand, microtrauma to the frontal lobe and thalamic trajectories during target localization and lead placement may also contribute to the cognitive disturbances associated with STN DBS. Five studies that met our criteria for review reported enhanced executive functioning post-dbs manifested by improved performance on measures such as the Stroop test, Trail-Making B Test (cognitive shifting), and the Wisonson Card Sorting Test. Authors from one study hypothesized that in PD DBS alters excessive inhibitory outflow from BG, releasing the brake from frontal cortex and improving both the motor and cognitive functions dependent on these frontal areas (Jahanshahi et al., 2000). Improvements in executive function for example may indicate a positive effect of STN-DBS on dorsolateral prefrontal cortex (DLPFC). Indeed, a PET study showed greater DLPFC activation associated with effective STN DBS (Limousin et al., 1998). Studies directly comparing executive function in both the on and off stimulation conditions reported improvements on the Trail Making B test with STN DBS (Jahanshahi et al., 2000; Pillon et al., 2000). Importantly, subjects did not show improvements on the Trail Making A Test (simple tracking). Since the motor demands for both tasks are roughly equivalent, it is difficult to attribute improved executive function to enhanced psychomotor speed. Of interest, this improvement in executive function was not found in patients undergoing GPi DBS (Jahanshahi et al., 2000). Attention and concentration Only one study included in this review noted improvements in attention and concentration despite the fact that similar brain regions are involved in these tasks as in tests of executive function. Jahanshahi et al. (2000) utilized two attentional tasks including the missing digit task and the paced auditory serial addition test, and observed improvements on both in the on vs off stimulation condition. PET studies have shown that the missing digit task specifically activates the DLPFC (Broadmann areas 9 and 46) and posterior premotor cortex bilaterally (Petrides et al., 1993). Thus, an improvement on measures of attention with DBS may relate to alterations in activity of the lateral and medial premotor cortices, which are cortical sites of projection from the STN to the motor circuit. Studies have reported adverse effects of bilateral STN DBS on measures of attention span and mental tracking ability (Morrison et al., 2004; Saint-Cyr and Albanese, 2006). Morrison et al. (2004) reported a dramatic post-surgical decline in one patient who at the time of surgery was 14 years older than the mean age of patients included in their study. However, Morrison et al. (2004) in addition to other on-off studies failed to show a difference in attention in the stimulation on vs off states (Pillon et al., 2000;

6 448 c. h. halpern ET AL. Morrison et al., 2004). Of note, Pillon et al. (2000) denied any change in attention postoperatively in the off condition. No difference was found between the STN DBS patients and GPi DBS patients (Pillon et al., 2000). Given the trajectory of the DBS leads through frontal regions, such sequelae are not surprising. While DBS surgery may compromise attentive processes, stimulation alone does not appear to directly affect these functions. Memory The majority of studies in the current review that included memory measures in their analyses utilized tests of verbal memory. Thus, a review of the memory changes following STN DBS surgery is potentially confounded by the language effects noted above. Nevertheless, two studies reported memory improvements in PD patients following bilateral STN DBS (Halbig et al., 2004; Hilker et al., 2004). Halbig et al. distinguished between declarative and non-declarative memory and found differential effects of DBS surgery (Halbig et al., 2004). Although language impairments have been observed in PD, PD is characterized by a degeneration of dopaminergic neurons, which animal studies have shown modulate synaptic strength during non-declarative memory (Schultz, 1982; Setlow and McGaugh, 2000). In addition, the STN has direct and indirect projections to the dorsal striatum (Parent and Smith, 1987), which has been demonstrated to be involved in non-declarative memory (Squire and Zola, 1996). Thus, changes in non-declarative memory may be mediated by STN DBS-induced improvements of striatal dopaminergic transmission in PD patients. Others have reported a decline in declarative memory performance after STN DBS (Faglioni et al., 1997; Halbig et al., 2004). For example, Alegret et al. (2001) reported a postoperative decrease in verbal learning ability, using the Rey Auditory Verbal Learning Test, although no change was noted in the immediate condition. The STN appears to have projections to cortical and subcortical regions known to be involved in declarative memory (Aggleton and Brown, 1999; Maurice et al., 1999). Hilker et al. (2004) reported that PD patients who underwent bilateral STN DBS significantly demonstrated improvements in both verbal and nonverbal longterm memory associated with enhanced metabolic activation in memory relevant areas (i.e. right DLPFC in PET studies) (Hilker et al., 2004). Interestingly, subthalamotomy has been shown to have a detrimental effect on verbal learning (McCarter et al., 2000), much like pallidotomy and DBS of the globus pallidus (Trepanier et al., 2000). All of these surgical procedures may be associated with verbal learning deficits, and thus, further investigation is warranted to elucidate the influence of STN DBS on memory. Meta-analyses have demonstrated some deterioration in memory following DBS, although this finding is not universal. Nevertheless, comparisons of patients preoperatively and postoperatively as well as in the stimulation on vs off conditions, using measures of free and cued recall revealed no deterioration of memory function with the surgery or DBS itself (Pillon et al., 2000). Further, no difference was found in the STN DBS group relative to the GPi group (Pillon et al., 2000). Visual function Six studies evaluated visuo-spatial performance in PD patients with STN DBS. The majority reported no significant change in visual function consistent with previous studies (Parsons et al., 2006). One report, however, noted a decline on a line orientation test (Alegret et al., 2001). To our knowledge, this was the first investigation that found detrimental effects of STN-DBS on visuospatial function. Indeed, a comparison of the on vs off conditions revealed no significant change at 12 months following surgery in visuoconstruction, discrimination, or orientation (Pillon et al., 2000; Morrison et al., 2004). No difference was found in visual function in patients who underwent STN DBS or GPi DBS (Pillon et al., 2000). Visual function is an area that requires further research in light of a recent report that demonstrated significant deficits on visual sensory function, visual attention, spatial perception, and visuoconstructional abilities in PD (Uc et al., 2006). Psychomotor and processing speed Psychomotor slowing is commonly observed in PD (Muslimovic et al., 2005). Multiple studies demonstrated enhancement of psychomotor speed as evidenced by reduction in response times on simple and choice reaction time tasks (Pillon et al., 2000; Dujardin et al., 2001; Halbig et al., 2004). While many studies use the Trail Making A Test to assess selective KEY POINTS STN DBS is associated with at least mild cognitive change

7 stn dbs and cognition 449 attention and cognitive flexibility, it also measures psychomotor speed. Reports comparing the on vs off states consistently have reported postoperative enhancements of response time on multiple tests, further suggesting more efficient cognitive processing associated with bilateral STN DBS (Jahanshahi et al., 2000; Pillon et al., 2000). Again, in one study no difference was found comparing STN DBS patients to GPi DBS patients (Pillon et al., 2000). Global cognition The majority of studies included in the current review deny any change in global cognition consistent with two recent meta-analyses. Only one study revealed a significant decline in global cognitive function using the Mattis Dementia Rating Scale. Schüpach et al. (2005) showed that despite sustained improvement of parkinsonian motor symptoms, patients experienced a decline in activities of daily living (ADLs) from preoperative values at 5-year follow-up (Schupbach et al., 2005). The authors attributed this deterioration in part to a deficit in global cognition. However, no change in cognition was noted at 6- or 24-month follow-up. Thus, this decline may be secondary to normal disease progression. Other long-term followup studies have not found a significant change in global cognition (Krack et al., 2003), and in fact, improvements in Mini-Mental State Exam (MMSE) scores have been noted (Daniele et al., 2003). CONCLUSION Bilateral STN DBS surgery is associated with cognitive changes, and elderly PD patients with mild cognitive impairment preoperatively appear to be at the greatest risk. Recent meta-analyses have revealed deficits in executive function and verbal fluency. A review of the effects of DBS on cognitive function is hindered by many of the neuropsychological tests we administer which measure more than one area of cognition. The findings of the meta-analyses are potentially biased by the multitude of studies included that do not compare patients cognition in the on and off conditions. Thus, from this data it is challenging to make conclusions regarding the precise effect of bilateral STN DBS on each cognitive domain. Perhaps the most reliable data stem from reports of on vs off conditions, providing direct comparisons of the stimulatory effects while controlling for surgical effects and yielding greater power since patients serve as their own controls. In agreement with metaanalyses, DBS surgery does appear to compromise language. However, we believe that this deficit is secondary either to lead implantation with disruption of frontal striatal thalamic circuitry because there was no verbal deterioration in the stimulation on condition. On the other hand, comparisons of on and off states revealed improvements in both working memory and psychomotor speed with stimulation. Given remarkable relief in parkinsonism, our review supports STN DBS as the first-line surgical approach in the management of PD. CONFLICT OF INTEREST None known. ACKNOWLEDGEMENT We would like to thank Dr Paul Moberg for his invaluable guidance in the preparation of our manuscript. REFERENCES Aggleton JP, Brown MW Episodic memory, amnesia, and the hippocampal-anterior thalamic axis. Behav Brain Sci 22: ; Discussion Albin RL, Young AB, Penney JB The functional anatomy of basal ganglia disorders. Trends Neurosci 12: Albin RL, Young AB, Penney JB The functional anatomy of disorders of the basal ganglia. Trends Neurosci 18: Alegret M, Junque C, Valldeoriola F, et al Effects of bilateral subthalamic stimulation on cognitive function in Parkinson disease. Arch Neurol 58: Andy OJ, Jurko MF, Sias FR Jr Subthalamotomy in treatment of Parkinsonian tremor. J Neurosurg 20: Ardouin C, Pillon B, Peiffer E, et al Bilateral subthalamic or pallidal stimulation for Parkinson s disease affects neither memory nor executive functions: a consecutive series of 62 patients. Ann Neurol 46: Benabid AL Deep brain stimulation for Parkinson s disease. Curr Opin Neurobiol 13: Benabid AL, Pollak P, Louveau A, et al Combined thalamotomy and stimulation. stereotactic surgery of the vim thalamic nucleus for bilateral Parkinson disease. Appl Neurophysiol 50: Benazzouz A, Hallett M Mechanism of action of deep brain stimulation. Neurology 55: S13 S16. Bergman H, Wichmann T, Delong MR Reversal of experimental Parkinsonism by lesions of the subthalamic nucleus. Science 249: Broggi G, Franzini A, Marras C, et al Surgery of Parkinson s disease: inclusion criteria and follow-up. Neurol Sci 24(Suppl 1): S38 S40. Charles PD, Van Blercom N, Krack P, et al Predictors of effective bilateral subthalamic nucleus stimulation for PD. Neurology 59: Contarino MF, Daniele A, Sibilia AH, et al Cognitive outcome five years after bilateral chronic stimulation of subthalamic

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