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Journal of Parkinson’s Disease 5 (2015) 95–104 DOI 10.3233/JPD-140443 IOS Press
Research Report
Decline in Verbal Fluency After Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease: A Microlesion Effect of the Electrode Trajectory? Floriane Le Goffa , St´ephane Derreyb , Romain Lefaucheura , Alaina Bordena , Damien Fettera , Maryvonne Jana , David Wallona and David Maltˆetea,c,∗ a Department
of Neurology, Rouen University Hospital and University of Rouen, France of Neurosurgery, Rouen University Hospital and University of Rouen, France c INSERM U1079, Rouen Faculty of Medicine, France b Department
Abstract. Background: Decline in verbal fluency (VF) is frequently reported after chronic deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson disease (PD). Objective: We investigated whether the trajectory of the implanted electrode correlate with the VF decline 6 months after surgery. Methods: We retrospectively analysed 59 PD patients (mean age, 61.9 ± 7; mean disease duration, 13 ± 4.6) who underwent bilateral STN-DBS. The percentage of VF decline 6 months after STN-DBS in the on-drug/on-stimulation condition was determined in respect of the preoperative on-drug condition. The patients were categorised into two groups (decline and stable) for each VF. Cortical entry angles, intersection with deep grey nuclei (caudate, thalamic or pallidum), and anatomical extent of the STN affected by the electrode pathway, were compared between groups. Results: A significant decline of both semantic and phonemic VF was found after surgery, respectively 14.9% ± 22.1 (P < 0.05) and 14.2%±30.3 (P < 0.05). Patients who declined in semantic VF (n = 44) had a left trajectory with a more anterior cortical entry point (56 ± 53 versus 60 ± 55 degree, P = 0.01) passing less frequently trough the thalamus (P = 0.03). Conclusions: Microlesion of left brain regions may contribute to subtle cognitive impairment following STN-DBS in PD. Keywords: Verbal fluency, deep brain stimulation, subthalamic nucleus, parkinson’s disease, microlesion
INTRODUCTION Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for patients with a moderate or advanced Parkinson’s disease (PD), which improves motor functions and quality of life [1]. While there is no change in global cognitive performance after chronic STN-DBS [2], decline in verbal ∗ Correspondence to: David Maltˆ ete, M.D., Ph.D., Department of Neurology, Rouen University Hospital, 76031 Rouen Cedex, France. Tel.: +33 2 32 88 87 40; Fax: +33 2 32 88 87 41; E-mail: [email protected].
fluency (VF) is the most consistent neuropsychological adverse effect reported, both in phonemic and semantic tasks [2–6]. The mechanisms leading to this cognitive sequelae remain not fully understood. Since the intermediate part of the STN is involved in cognitive processes, it has been postulated that diffusion of the electrical current may affect cognitive performance, including VF [7]. Conversely, evidence suggests that post-operative cognitive impairment could be more linked to a surgical microlesion than to a stimulationinduced effect [2, 4, 5]. Thus, the decline in VF appears right after surgery in the absence of STN stimulation
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and then persists in comparison to PD patient treated by medication only [8]. Moreover, this decline have been found in the case of other targets such as the globus pallidus and thus cannot be attributed to the STN only [9]. Previous studies have shown that lead trajectories intersecting with caudate nuclei increased the risk of global cognitive decline and working memory performance after STN implantation [10]. VF is a composite function implying motor, executive, and language subcomponents. Its anatomical substrate involves frontotemporal networks [11], including anatomical structures that may be crossed by the electrode pathways, i.e. dorsolateral prefrontal cortex, caudate nuclei [10], left thalamus [12], and pallidum [9], during STN implantation procedure. Nevertheless, recent studies found no correlation between numbers of microelectrode passes or lead location and VF decline after surgery [13]. The aim of the current study was therefore to examine whether the trajectory of the definitive implanted quadripolar electrode correlates with the decline in VF 6 months after chronic STN-DBS. In particular, we focussed on the cortical entry angles (lateral and antero-posterior), the deep grey nuclei (caudate, thalamic or pallidum), and the anatomical extent of the STN affected by the definitive electrode pathway. PATIENTS AND METHODS Patients We retrospectively analysed data from patients with PD undergoing bilateral STN DBS in our centre between 2007 and 2013. Patients selected for DBS were clinically diagnosed with a PD, had severe levodopa-related complications despite optimal adjustment medication, no surgical contraindications, and no dementia or major ongoing psychiatric illness. Within this cohort, subjects were excluded if they were missing any baseline or post-operative measures, especially neuropsychological and/or imaging data. All participants were native French speakers. Neurological and neuropsychological evaluation A baseline clinical evaluation was performed 1 month before surgery based on the CAPIT protocol (Langston, 1992). The motor state was assessed by the UPDRS part III. Motor performance assessments were performed 6 months after surgery, under two conditions (off-drug/on-stimulation, on-drug/ on-stimulation) as previously described [14]. Percent-
age improvement in motor disability was determined in respect of the preoperative off-drug condition. Complications of levodopa therapy, i.e. dyskinesias (UPDRS part IVA score) and clinical fluctuations (UPDRS part IVB score), were also assessed pre- and postoperatively. All the patients underwent standardized cognitive assessments, i.e. Mattis Dementia Rating scale (MDRS), VF tasks and Stroop test, both before surgery (baseline) in the on-drug condition, and after surgery at six months in the on-drug/on-stimulation condition. Phonemic VF was determined by the number of words beginning with letter “p” produced in two minutes. Semantic VF was determined by the number of animal names produced in two minutes. The GREFEX version of the Stroop test was administered. Total time to complete word reading (WR) and color word (CW) naming was measured. All dopaminergic drugs, expressed in dopaequivalent daily dose, were recorded before and after surgery. Stimulation parameters were also recorded at the time of testing. Surgical procedures All the procedures we performed by the same neurosurgeon (SD). Prior to surgery, a stereotactic CT scan and a nonstereotactic MRI (1.5 Tesla) were fused using Framelink software on the stealth station. The trajectory was planned from the cortical surface to the NST target avoiding vessels, sulci and ventricles. The location of the visually-selected target was compared with standardized location of the STN using the following coordinates: 12 mm lateral from the midsagittal plane, 4 mm posterior to the middle of the Anterior Commisure-Posterior Commisure (AC-PC) line and 4 mm below the AC-PC plane. To determine the optimal position for the quadripolar permanent electrode (DBS type 3389, Medtronic, Minneapolis, Mn, USA), several guidances were used: 1-stereotactic guidance, 2-two to five parallel microelectrodes recordings starting 10 mm above the anatomical target until the substantia nigra, 3-clinical examination with macro electrode stimulations focusing on motor improvement and limited side effects, 4-per-operative imaging with X-ray films and stereoplan software [15]. The electrode was then connected to a programmable pulse generator (Kinetra, Medtronic). Image analysis All patients had a pre-operative MRI (Magneton Symphony 1.5 Telsa, Siemens, Erlangen, Germany;
F. Le Goff et al. / Decline in Verbal Fluency After Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease
T1, T2 spin echo and (CISS) and a post-operative CTscan (Light speed, General electric, Milwaukee, Minn., USA) within 72 hours after surgery. The electrode trajectory was determined using a CT-MRI fusion created by Framelink software (Framelink v 4.0, Medtronic, Minneapolis, USA) in the Stealth Station (Stealth Station, Medtronic, Minneapolis, USA). The fusion was visually confirmed on 5 slices to ensure accuracy. Using all three planes, the volumes were realigned to AC-PC points and three marked midline points. The target was determined with the most inferior slice showing the tip of the electrode, for both sides. The entry point was determined by the intersection of the electrode with the cortex. The surgical pathway was then traced between the target and the cortical entry point, referring consistently to the electrode pathway. An analysis of six centres of interest of the electrode pathway was performed: 1-the lateral angle, calculated in degrees according to a midsagittal plane, 2-the antero-posterior angle, calculated in degrees according to the AC-PC plan, 3-the intersection with the caudate nucleus, 4-the intersection with the pallidum, 5-the intersection with the thalamus, 6-the distance through the STN in mm. These analyses were performed separately for each hemisphere. Statistical analysis The different scores were expressed as mean value ± SD. The effects of stimulation of the STN were evaluated by comparison of different scores obtained before (baseline) and six months after surgery using a Wilcoxon signed-rank test. The percentage of VF decline 6 months after STN-DBS in the on-drug/onstimulation condition was determined with respect to the preoperative on-drug condition. The patients were then categorised into two groups for each VF: the first group included patients who declined while the second included the patients who remained stable. The decline was defined as a reduction of more than 5% of the pre-operative VF value. This value was chosen according to the test-related variability between two testing time [16]. Firstly, we analysed the difference of trajectory between both groups (decline versus stable) using a Mann and Whitney test for quantitative values and a Fisher’s exact test for the qualitative ones. We compared both cortical entry angles, the deep grey nuclei (number of electrode crossing caudate, thalamic or pallidum), and the anatomical extent of the STN affected by the definitive electrode pathway (distance through the STN in mm). Secondly, we compared the clinical
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and neuropsychological data between the two groups at baseline using a Mann and Whitney test for quantitative values and a Fisher’s exact test for the qualitative ones to evaluate confusing factors. All these analyses were performed separately for each VF. P < 0.05 were considered statistically significant. Statistic analysis was performed with the NCSS software, version 6.0. RESULTS Characteristics of the population Fifty-nine patients (mean age, 61.9 ± 7.1 years old; range, 40–73 years; mean disease duration, 13.1 ± 4.6 years; range, 7–30 years) were included. Twentyseven were excluded because of missing imaging data (n = 14), missing neuropsychological data (n = 8), electrode withdrawal for hematoma (n = 3) and postoperative pneumencephalia (n = 2). After 6 months of DBS, the total score of UPDRS part III in the off-drug/on-stimulation and on-drug/onstimulation conditions improved from the baseline value respectively by 62.5% (range, 0–95.5%) and 80.7% (range, 16–100%) (P < 0.05). Moreover, the severity of motor fluctuations and dyskinesia as assessed by the UPDRS IV was significantly reduced Table 1 Characteristics of global population Baseline Number Male/female Age at surgery (y) PD duration before surgery (y) UPDRS III Off-drug On-drug Off-drug/on stimulation On-drug/on stimulation UPDRS IV Dopaminergic drugs MDRS Verbal fluency Semantic fluency Phonemic fluency Stroop test Word reading (s) Color word naming (s)
6 Months
59 33/26 61.9 ± 7.1 13.1 ± 4.6 40.6 ± 15.4 10.7 ± 6.9 8.3 ± 3.2 1227 ± 681 136 ± 7.8
14.2 ± 8.2∗∗ 7.4 ± 5.8∗∗ 2.4 ± 2.6∗∗ 567 ± 263∗∗ 135 ± 9.5
26.6 ± 7.7 19.9 ± 8.5
22.7 ± 8.25∗∗ 16.1 ± 7.1∗∗
79.1 ± 26.1 152.3 ± 55.8
87.9 ± 29.1∗ 185.8 ± 77.3∗∗
PD: Parkinson Disease; UPDRS: Unified Parkinson Disease Rating Scale; MDRS: Mattis Dementia Rating Scale; Dopaminergic drugs, are expressed in dopa-equivalent daily dose (mg/day). Values are given as mean ± standard deviation. (y) = years; (s) = seconds. Comparison of scores obtained before surgery and respectively six months after surgery used a Wilcoxon signed-rank test (∗ P < 0.05, ∗∗ P < 0.0001).
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by 70% (range, −100–100%). Dopaminergic drugs were reduced by 46% (range, −150–100%) (Table 1). Semantic fluency Six months after DBS-STN the number of total words in the semantic fluency was significantly reduced by 14.9% in the on-drug/on-stimulation conditions in the global population (P < 0.001). Forty-four patients declined more than 5% (group decline) while 15 patients remained stable (group stable performer). The clinical characteristics of both groups are summarized in Table 2a. There were no significant differences between groups with respect to age, gender, disease duration, L-dopa-equivalent daily dose, stimulation parameters and pre-operative cognitive performances (P > 0.05). Patients who declined in semantic fluency had a trajectory with a more anterior cortical entry point Table 2a Comparison of the trajectories between both groups decline versus stable performer in semantic fluency Trajectories
Right Hemisphere Cortical entry angles Antero-posterior angle (degree) Lateral angle (degree) Intersection with deep grey nuclei No. of trajectories Caudate nucleus Thalamus Pallidum Anatomical extent of the STN Distance through the STN (mm) Left Hemisphere Cortical entry angles Antero-posterior angle (degree) Lateral angle (degree) Intersection with deep grey nuclei No. of trajectories Caudate nucleus Thalamus Pallidum Anatomical extent of the STN Distance through the STN (mm)
Decline
P-values
(n = 44)
Stable performer (n = 15)
57 ± 6.9
59 ± 6.5
0.36
22 ± 3.7
21 ± 2.3
0.25
7 17 15
1 8 4
0.67 0.37 0.75
4.4 ± 1.7
4.4 ± 1.7
0.96
55 ± 6.9
59 ± 5.9
0.03
23 ± 4.4
22 ± 5
0.28
18 16 13
8 11 1
0.55 0.02 0.09
4.2 ± 1.5
4.6 ± 1.3
0.52
Values are given as mean ± standard deviation. Comparison of both groups used a Mann and Whitney test for quantitative data and a Fisher’s exact test for qualitative ones. P < 0.05 was considered statistically significant.
(mean antero-posterior angle, 56 ± 53 versus 60 ± 55 degree) passing less frequently trough the thalamus on the left hemisphere (P = 0.03), as shown in Table 2b. After DBS, both time of WR and CW naming of the Stroop test increased significantly in the group decline (respectively 78 ± 29 versus 88 ± 31 seconds and 157 ± 66 versus 200 ± 92 seconds, P < 0.001) while it remained stable in the group stable performer (P > 0.05). The MDRS score decreased significantly in the group decline after DBS (136 ± 6.2 versus 134 ± 9.1, P = 0.02) while it remained stable in the group stable performer (P > 0.05) (Table 2a). Phonemic fluency Six months after DBS-STN the number of total words in the phonemic fluency was significantly reduced by 14.2% in the on-drug/on-stimulation conditions in the global population (P < 0.05). Forty-four patients (34 similar, 10 different from the group semantic fluency decline) declined more than 5% (group decline) while 15 patients remained stable (group stable performer). The clinical characteristics of both groups are summarized in Table 3a. There were no significant differences between groups with respect to age, gender, disease duration, L-dopa-equivalent daily dose and stimulation parameters (P > 0.05). The analysis of the trajectory showed no significant differences between the groups (Table 3b). The mean number of words in phonemic fluency at baseline was significantly higher in the decline group than in the stable performer group (22.2 ± 7.3 versus 13 ± 8.2 words, P < 0.001). After DBS, both time WR and CW naming of the Stroop test increased significantly in the group decline, (respectively 72 ± 22 versus 81.2 ± 17.4 seconds and 142.6 ± 39 versus 185.3 ± 81.3 seconds, P < 0.001) while it remained stable in the group stable performer (P > 0.05). The MDRS score did not significantly change in both groups. DISCUSSION Recent evidence indicates that cognitive deterioration following DBS-STN in PD may be related to a microlesion due to the electrode trajectories [8, 10]. However, the existing literature fails to clearly explain whether surgery and stimulation differentially contribute to this deleterious effect. The present study examines the relationship between the VF decline after STN-DBS and the stereotactic lead trajectory. The results suggest that PD patients who decline in
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Table 2b Semantic fluency. Motor and cognitive assessments before and after STN stimulation in decline versus stable performer groups Scoring factor
Decline (n = 44) Baseline
Gender (M/F) Age at surgery (y) PD duration (y) UPDRS III off-drug off-drug/on-stimulation on-drug/on-stimulation UPDRS IV Dopaminergic drugs Stimulation parameters R Voltage L Voltage R Frequency L Frequency R Pulse width L Pulse width MDRS Verbal fluency Semantic Fluency Phonemic Fluency Stroop test Word reading (s) Color word naming (s)
Stable performer (n = 15)
6 Months
23/21 62.3 ± 6.6 13.3 ± 4.7 40.3 ± 14.2
Baseline
6 Months
10/5 60.5 ± 8.6 12.4 ± 4 41.4 ± 19
8.2 ± 3.2 1154 ± 393
15.2 ± 8.3∗∗ 8 ± 5.6∗∗ 2.7 ± 2.8∗∗ 563 ± 276∗∗
8.9 ± 3,1 1455 ± 1209
11.4 ± 7.3∗∗ 5.7 ± 6.2∗∗ 1.8 ± 1.6∗ 580 ± 226∗∗
136 ± 6.2
2.9 ± 0.4 3.1 ± 0.4 148 ± 28 148 ± 28 61.4 ± 6.4 62.3 ± 8.8 134 ± 9.1∗
3 ± 0,4 3 ± 0,4 147 ± 24 147 ± 24 64 ± 10 60.7 ± 2.6 135 ± 11.4
137 ± 10.7
27 ± 8 20 ± 8.3
21 ± 7.8∗∗ 16 ± 6.9∗∗
78 ± 29 157 ± 66
88 ± 31∗∗ 200 ± 92∗∗
25 ± 6.3 19 ± 9.4 80 ± 14.5 148 ± 40
28 ± 7.4∗∗ 16 ± 8.1∗ 84 ± 17.9 168 ± 43.6
PD: Parkinson disease; UPDRS: Unified Parkinson Disease Rating Scale; MDRS: Mattis Dementia Rating Scale; R: Right; L: Left Dopaminergic drugs, are expressed in dopa-equivalent daily dose (mg/day). Values are given as mean ± standard deviation. (y) = years; (s) = seconds. Comparison of scores obtained before surgery and respectively six months after surgery for each group used a Wilcoxon signed-rank test (∗ P < 0.05, ∗∗ P < 0.0001).
semantic VF have a left trajectory with a more anterior cortical entry point. Conversely, post-operative semantic VF is more stable when trajectories pass more frequently through the left thalamus. Finally, we found no correlation between phonemic VF decline and lead trajectories. The trajectory or approach angle used to reach the STN may vary considerably among surgeons. However, most centres orient their tracks in a double oblique manner (lateral and antero-posterior cortical entry angles) for several reasons. First, a lateral-tomedial orientation in the coronal plane avoids the ventricle, which minimizes brain shift due to loss of cerebrospinal fluid or possible intraventricular hemorrhage. This also places the cortical entry point more lateral with respect to the sagittal sinus, thereby theoretically minimizing the risk of venous complications. Second, the anterior-to-posterior orientation in the sagittal plane ensures entry through the precoronal region, thus sparing the motor cortex from injury. Finally, the double oblique track happens to be closer to the long axis of the STN, maximizing the length of electrode within the target nucleus. In general, electrode tracks traversed the dorsolateral prefrontal cortex, the
thalamus pars reticularis or ventral anterior, passed through the white matter tracts of the thalamic fasciculus, the anterior limb of the internal capsule, the zone incerta and lenticular fasciculus before entering the STN [10, 17]. Disruption of cells and/or fibres within the penetrated region may concern cortical areas and subcortical structures involved in VF networks [18]. The classic verbal generation task takes two forms, phonemic or semantic word fluency, each of which requires the generation of multiple single words from a single cue within a given time. Underlying cortical neural systems commonly identified in VF performances include the left inferior frontal gyrus, anterior cingulate gyrus, and supramarginal gyrus [19, 20]. Based on its role in sequencing information in working memory, the role of prefrontal areas is essential for VF. Dorsolateral regions are involved in monitoring and selecting goalrelevant representations, whereas ventrolateral regions are involved in maintaining these representations [21, 22]. On the other hand, the anterior cingulate gyrus has an important role in vocalization within an emotional context [23], and a key role in allocating attentional resources, both of which are important processes for language.
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Table 3a Comparison of the trajectories between both groups decline versus stable performer in VF phonemic fluency Trajectories
Decline (n = 44)
Right Hemisphere Cortical entry angles Antero-posterior angle (degree) Lateral angle (degree) Intersection with deep grey nuclei No. of trajectories Caudate nucleus Thalamus Pallidum Anatomical extent of the STN Distance through the STN (mm) Left Hemisphere Cortical entry angles Antero-posterior angle (degree) Lateral angle (degree) Intersection with deep grey nuclei No. of trajectories Caudate nucleus Thalamus Pallidum Anatomical extent of the STN Distance through the STN (mm)
57.3 ± 7
Stable P-values performer (n = 15)
57.9 ± 6.3
0.99
22.3 ± 3.6 21.3 ± 2.9
0.49
5 18 16
3 7 3
0.41 0.77 0.34
4.6 ± 1.5 3.9 ± 2.2
0.12
55.4 ± 7.2 58.5 ± 5.3
0.2
22.7 ± 4.9
0.73
22 18 11
22 ± 3.4
4 9 3
4.3 ± 1.5 4.2 ± 1
0.14 0.24 1
0.53
Values are given as mean ± standard deviation. Comparison of both groups used a Mann and Whitney test for quantitative data and a Fisher’s exact test for qualitative ones. P < 0.05 was considered statistically significant.
Many studies have demonstrated reduced phonemic and semantic fluencies following frontal lobes lesions [24, 25], whereas patients with temporal injuries showed a larger semantic than phonemic deficit [26]. In our study, we found that a more anterior left trajectory increases the risk of a decline in semantic VF. This left-lateralization is in line with previous reports suggesting that word fluency is more reduced following left as compared to right frontal lesions [27], especially for semantic VF [28, 29]. Additionally, both time to read of CW and WR of the Stroop test increased after STN-DBS in our study, suggesting a prefrontal dysfunction. Indeed, L-dopa uptake in the area of the medial frontal cortex and the anterior cingulate in PD correlated with Stroop test performances [30]. Since temporal cortex support word retrieval constrained by semantic VF, we postulated that left electrode trajectory may disrupt corticocortical pathways linking
specific more anterior prefrontal or cingulated areas to distinct temporal lobe regions. Further functional or structural neuroimaging studies investigating precisely the neural system affected by the electrode may be warranted to corroborate this hypothesis. The output of the basal ganglia that project to frontal cortices has a key role in motor functions, including speech production, which depends on coordination of multiple cortical areas to translate sound into the complex process of speech. Especially, the role of the basal ganglia may be in cognitive control, assisting language function by generally enhancing selected activities while suppressing competing ones [31, 32]. Hence, neuroimaging studies of healthy adults suggest that the striatum is implicated in a wide variety of language tasks, including word generation [31]. Furthermore, thalamic nuclei have connections with frontal language and the prefrontal cortex, which also have an integral role in VF processing [33, 34]. Indeed, many PD patients, especially those in the later stages of the disease, have difficulty in initiating speech, which may be rooted to disruption of a loop through the basal ganglia, its projection to the thalamic nuclei ventral anterior/ventral lateral and mediodorsal and projection to premotor, and dorsal prefrontal cortices and the anterior cingulated gyrus [34]. In the present study, we found no correlation between the post-operative decline in semantic or phonemic VF and the number of electrode crossing grey nuclei. Accordingly, previous study found no relationship between electrode trajectories crossing caudate nuclei and the risk of VF decline [10]. Moreover, we assumed that the microlesion of the pallidal outflow coursing dorsally to the STN through the lenticular fasciculus and ansa lenticularis is subtle, and thereby without consequence on the cognitive post-operative outcome. On the other hand, we determined that PD patients with stable post-operative semantic VF performances were implanted with a trajectory crossing more frequently the left thalamus. Since typical more posterior tracks usually pass into the thalamus, especially the reticular formation and, or the anterior ventral thalamic neurons; this finding is in accordance with our result concerning the left cortical entry angle. Nevertheless, it seems difficult to consider that an intersection with the thalamus protects against post-operative VF decline. Therefore, we postulate that anterior trajectories might affect neural structures different from grey nuclei involved in semantic VF. In particular, we hypothesize that posterior trajectory spares more commonly the anterior limb of the internal capsule. Recent diffusion tensor
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Table 3b Phonemic fluency. Motor and cognitive assessments before and after STN stimulation in decline versus stable performer groups Scoring factor
Decline (n = 44) Baseline
Gender (M/F) Age at surgery (y) PD duration (y) UPDRS III off-drug off-drug/on-stimulation on-drug/on-stimulation UPDRS IV Dopaminergic drugs Stimulation parameters R Voltage L Voltage R Frequency L Frequency R Pulse width L Pulse width MDRS Verbal fluency Semantic Fluency Phonemic Fluency Stroop test Word reading (s) Color word naming (s)
Stable performer (n = 15)
6 Months
62.7 ± 7.5 13.2 ± 5
6 Months
59.5 ± 5.4 12.6 ± 3
40.8 ± 16.4 8.5 ± 3 1210 ± 742
15.2 ± 8.2∗∗ 7.7 ± 5.7∗∗ 2.6 ± 2.7∗∗ 544 ± 260∗∗
136.7 ± 8
40 ± 11.7 7 ± 3.8 1285 ± 426
10.6 ± 7.2∗∗ 7 ± 6.4∗∗ 1.9 ± 1.9∗∗ 647 ± 271∗∗
2.9 ± 0.4 3 ± 0.4 149 ± 28 149 ± 28 62.8 ± 8.8 63 ± 8.9 136 ± 7.8
134 ± 6.9
2.9 ± 0.4 3 ± 0.4 145 ± 25 144 ± 25 60 ± 0 60 ± 0 131 ± 13.2
23.3 ± 7.9∗∗ 16.4 ± 6.6∗∗
23.8 ± 9.9 13 ± 8.2†
20.7 ± 9∗ 15.5 ± 8.8∗∗
81.2 ± 17.4∗∗ 185.3 ± 81.3∗∗
96 ± 28.9† 193.3 ± 93.5
27.5 ± 6.6 22.2 ± 7.3 72 ± 22 142.6 ± 39
Baseline
103.7 ± 43.7 213.8 ± 90.5
PD: Parkinson disease; UPDRS: Unified Parkinson Disease Rating Scale; MDRS: Mattis Dementia Rating Scale; R: Right; L: Left Dopaminergic drugs, are expressed in dopa-equivalent daily dose (mg/day). Values are given as mean ± standard deviation. (y) = years; (s) = seconds. Comparison of scores obtained before surgery and respectively six months after surgery for each group used a Wilcoxon signed-rank test (∗ P < 0.05, ∗∗ P < 0.0001). Comparison of the baseline characteristics between decline and stable performer used a Mann–Whitney test for quantitative data and a Fisher’s exact test for qualitative data († P < 0.05).
imaging studies demonstrating that linguistic performance highly correlated with the region of the left anterior limb of internal capsule in PD corroborated this hypothesis [35]. Additionally, we cannot exclude that a more posterior trajectory decreased the likelihood of the anterior non-motor territories of the STN to be affected by the electrode microlesion. Deep brain stimulation of the posterior sensorimotor area of the STN results in the best motor outcome in advanced levodopa-responsive form of PD. Nevertheless, both human and non-human primate studies have revealed functional non-motor territories of the STN consisting of a more intermediate associative territory and a smaller anteromedial limbic area [36, 37]. Since the electrode lead may be placed through the associative portion of the STN, several studies suggest that post-operative VF decline reflects a STN cognitive microlesion effect [5, 8, 38]. Conversely, high frequency stimulation itself has been reported to influence VF performances, especially with most ventral contacts [38]. In the present study, we considered the distance crossed by the electrode through the STN as the optimal value to reflect the target associated
cognitive microlesion effect. Thereby, we postulated that the probability to disrupt STN associative area could increase with the distance of track within the STN. However, we found no correlation between the anatomical extent of the STN affected by the definitive electrode pathway and the post-operative decline in VF. This might be the consequence of a methodological limitation. In fact, a best definition of the lesion volume using a voxel-based lesion-symptom mapping would likely improve our ability to correlate STN associative areas and VF performances. Finally, it is crucial to remember that there is an inherent risk profile for decline in cognitive functions after chronic DBS, which includes advanced age, higher severity of PD based on axial motor symptoms, and levodopa resistant symptoms [13, 39]. Moreover, the electrical stimulation itself has been reported to influence the VF performances, depending on the tissue volume affected by current spreading [38]. Since there were no significant differences between groups (decline versus stable performer) with respect to age, disease duration, pre-operative levodopa responsiveness and electrical parameters, we considered that
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cognitive post-operative changes depend particularly on the surgical procedure. Several limitations of this study need to be pointed out. First, the artefact of the electrode on the CT scan to determine the trajectory measures 2 mm while the actual electrode measures 1.27 mm, which overestimates the real lesion and the potential intersection with grey nuclei. Likewise, the distance through the STN may have been misestimated. Second, the definitive electrode pathway was determined by one rater using only imaging data, without other tools used such as electrophysiological recordings during surgery. Third, we found a slight difference (four degrees) in the mean antero-posterior angle between groups (decline versus stable performers). This result strongly suggests that a smaller specific frontal region may contain all the processes required for semantic fluency. However, we did not compare a set of frontal regions only with each other. Then, it may be argued that this difference of cortical microlesion between groups is not sufficient to explain the decline of verbal fluency performance. Fourth, we did not assess the impact of the number of electrodes used during the electrophysiological procedure. Hence, previous studies demonstrated that multiple tracks could increase the risk of memory function deterioration [40]. Nevertheless, recent studies demonstrated no correlation between VF decline and the number of microelectrode passes [13, 41]. Finally, we found no correlation between phonemic VF decline and lead trajectories. However, the mean number of words in phonemic fluency at baseline was significantly higher in the decline group than in the stable performer group. Therefore the subtle difference of the electrode trajectory may be negligible with respect to the greater difference of baseline number of words.
CONFLICTS OF INTEREST/DISCLOSURE OF ALL AUTHORS Floriane Le Goff reports no disclosures. Damien Fetter reports no disclosures. Romain Lefaucheur reports no disclosures. St´ephane Derrey reports no disclosures. Alaina Borden reports no disclosures. Maryvonne Jan reports no disclosures. David Wallon reports no disclosures. David Maltˆete reports no disclosures. FINANCIAL DISCLOSURE OF ALL AUTHORS None. REFERENCES [1]
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CONCLUSION Consistent with prior neuroimaging studies, we confirmed that microlesion of left-brain regions may contribute to subtle cognitive impairment following STN-DBS in PD. More specifically, we demonstrated that semantic VF decline correlates with more anterior left trajectories sparing the thalamus. This highlights additional internal landmark for refining optimal STN targeting to avoid post-operative cognitive impairment.
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ACKNOWLEDGMENTS [8]
None.
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Journal of Parkinson’s Disease 5 (2015) 95–104 DOI 10.3233/JPD-140443 IOS Press
Research Report
Decline in Verbal Fluency After Subthalamic Nucleus Deep Brain Stimulation in Parkinson’s Disease: A Microlesion Effect of the Electrode Trajectory? Floriane Le Goffa , St´ephane Derreyb , Romain Lefaucheura , Alaina Bordena , Damien Fettera , Maryvonne Jana , David Wallona and David Maltˆetea,c,∗ a Department
of Neurology, Rouen University Hospital and University of Rouen, France of Neurosurgery, Rouen University Hospital and University of Rouen, France c INSERM U1079, Rouen Faculty of Medicine, France b Department
Abstract. Background: Decline in verbal fluency (VF) is frequently reported after chronic deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson disease (PD). Objective: We investigated whether the trajectory of the implanted electrode correlate with the VF decline 6 months after surgery. Methods: We retrospectively analysed 59 PD patients (mean age, 61.9 ± 7; mean disease duration, 13 ± 4.6) who underwent bilateral STN-DBS. The percentage of VF decline 6 months after STN-DBS in the on-drug/on-stimulation condition was determined in respect of the preoperative on-drug condition. The patients were categorised into two groups (decline and stable) for each VF. Cortical entry angles, intersection with deep grey nuclei (caudate, thalamic or pallidum), and anatomical extent of the STN affected by the electrode pathway, were compared between groups. Results: A significant decline of both semantic and phonemic VF was found after surgery, respectively 14.9% ± 22.1 (P < 0.05) and 14.2%±30.3 (P < 0.05). Patients who declined in semantic VF (n = 44) had a left trajectory with a more anterior cortical entry point (56 ± 53 versus 60 ± 55 degree, P = 0.01) passing less frequently trough the thalamus (P = 0.03). Conclusions: Microlesion of left brain regions may contribute to subtle cognitive impairment following STN-DBS in PD. Keywords: Verbal fluency, deep brain stimulation, subthalamic nucleus, parkinson’s disease, microlesion
INTRODUCTION Deep brain stimulation (DBS) of the subthalamic nucleus (STN) is an effective treatment for patients with a moderate or advanced Parkinson’s disease (PD), which improves motor functions and quality of life [1]. While there is no change in global cognitive performance after chronic STN-DBS [2], decline in verbal ∗ Correspondence to: David Maltˆ ete, M.D., Ph.D., Department of Neurology, Rouen University Hospital, 76031 Rouen Cedex, France. Tel.: +33 2 32 88 87 40; Fax: +33 2 32 88 87 41; E-mail: [email protected].
fluency (VF) is the most consistent neuropsychological adverse effect reported, both in phonemic and semantic tasks [2–6]. The mechanisms leading to this cognitive sequelae remain not fully understood. Since the intermediate part of the STN is involved in cognitive processes, it has been postulated that diffusion of the electrical current may affect cognitive performance, including VF [7]. Conversely, evidence suggests that post-operative cognitive impairment could be more linked to a surgical microlesion than to a stimulationinduced effect [2, 4, 5]. Thus, the decline in VF appears right after surgery in the absence of STN stimulation
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and then persists in comparison to PD patient treated by medication only [8]. Moreover, this decline have been found in the case of other targets such as the globus pallidus and thus cannot be attributed to the STN only [9]. Previous studies have shown that lead trajectories intersecting with caudate nuclei increased the risk of global cognitive decline and working memory performance after STN implantation [10]. VF is a composite function implying motor, executive, and language subcomponents. Its anatomical substrate involves frontotemporal networks [11], including anatomical structures that may be crossed by the electrode pathways, i.e. dorsolateral prefrontal cortex, caudate nuclei [10], left thalamus [12], and pallidum [9], during STN implantation procedure. Nevertheless, recent studies found no correlation between numbers of microelectrode passes or lead location and VF decline after surgery [13]. The aim of the current study was therefore to examine whether the trajectory of the definitive implanted quadripolar electrode correlates with the decline in VF 6 months after chronic STN-DBS. In particular, we focussed on the cortical entry angles (lateral and antero-posterior), the deep grey nuclei (caudate, thalamic or pallidum), and the anatomical extent of the STN affected by the definitive electrode pathway. PATIENTS AND METHODS Patients We retrospectively analysed data from patients with PD undergoing bilateral STN DBS in our centre between 2007 and 2013. Patients selected for DBS were clinically diagnosed with a PD, had severe levodopa-related complications despite optimal adjustment medication, no surgical contraindications, and no dementia or major ongoing psychiatric illness. Within this cohort, subjects were excluded if they were missing any baseline or post-operative measures, especially neuropsychological and/or imaging data. All participants were native French speakers. Neurological and neuropsychological evaluation A baseline clinical evaluation was performed 1 month before surgery based on the CAPIT protocol (Langston, 1992). The motor state was assessed by the UPDRS part III. Motor performance assessments were performed 6 months after surgery, under two conditions (off-drug/on-stimulation, on-drug/ on-stimulation) as previously described [14]. Percent-
age improvement in motor disability was determined in respect of the preoperative off-drug condition. Complications of levodopa therapy, i.e. dyskinesias (UPDRS part IVA score) and clinical fluctuations (UPDRS part IVB score), were also assessed pre- and postoperatively. All the patients underwent standardized cognitive assessments, i.e. Mattis Dementia Rating scale (MDRS), VF tasks and Stroop test, both before surgery (baseline) in the on-drug condition, and after surgery at six months in the on-drug/on-stimulation condition. Phonemic VF was determined by the number of words beginning with letter “p” produced in two minutes. Semantic VF was determined by the number of animal names produced in two minutes. The GREFEX version of the Stroop test was administered. Total time to complete word reading (WR) and color word (CW) naming was measured. All dopaminergic drugs, expressed in dopaequivalent daily dose, were recorded before and after surgery. Stimulation parameters were also recorded at the time of testing. Surgical procedures All the procedures we performed by the same neurosurgeon (SD). Prior to surgery, a stereotactic CT scan and a nonstereotactic MRI (1.5 Tesla) were fused using Framelink software on the stealth station. The trajectory was planned from the cortical surface to the NST target avoiding vessels, sulci and ventricles. The location of the visually-selected target was compared with standardized location of the STN using the following coordinates: 12 mm lateral from the midsagittal plane, 4 mm posterior to the middle of the Anterior Commisure-Posterior Commisure (AC-PC) line and 4 mm below the AC-PC plane. To determine the optimal position for the quadripolar permanent electrode (DBS type 3389, Medtronic, Minneapolis, Mn, USA), several guidances were used: 1-stereotactic guidance, 2-two to five parallel microelectrodes recordings starting 10 mm above the anatomical target until the substantia nigra, 3-clinical examination with macro electrode stimulations focusing on motor improvement and limited side effects, 4-per-operative imaging with X-ray films and stereoplan software [15]. The electrode was then connected to a programmable pulse generator (Kinetra, Medtronic). Image analysis All patients had a pre-operative MRI (Magneton Symphony 1.5 Telsa, Siemens, Erlangen, Germany;
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T1, T2 spin echo and (CISS) and a post-operative CTscan (Light speed, General electric, Milwaukee, Minn., USA) within 72 hours after surgery. The electrode trajectory was determined using a CT-MRI fusion created by Framelink software (Framelink v 4.0, Medtronic, Minneapolis, USA) in the Stealth Station (Stealth Station, Medtronic, Minneapolis, USA). The fusion was visually confirmed on 5 slices to ensure accuracy. Using all three planes, the volumes were realigned to AC-PC points and three marked midline points. The target was determined with the most inferior slice showing the tip of the electrode, for both sides. The entry point was determined by the intersection of the electrode with the cortex. The surgical pathway was then traced between the target and the cortical entry point, referring consistently to the electrode pathway. An analysis of six centres of interest of the electrode pathway was performed: 1-the lateral angle, calculated in degrees according to a midsagittal plane, 2-the antero-posterior angle, calculated in degrees according to the AC-PC plan, 3-the intersection with the caudate nucleus, 4-the intersection with the pallidum, 5-the intersection with the thalamus, 6-the distance through the STN in mm. These analyses were performed separately for each hemisphere. Statistical analysis The different scores were expressed as mean value ± SD. The effects of stimulation of the STN were evaluated by comparison of different scores obtained before (baseline) and six months after surgery using a Wilcoxon signed-rank test. The percentage of VF decline 6 months after STN-DBS in the on-drug/onstimulation condition was determined with respect to the preoperative on-drug condition. The patients were then categorised into two groups for each VF: the first group included patients who declined while the second included the patients who remained stable. The decline was defined as a reduction of more than 5% of the pre-operative VF value. This value was chosen according to the test-related variability between two testing time [16]. Firstly, we analysed the difference of trajectory between both groups (decline versus stable) using a Mann and Whitney test for quantitative values and a Fisher’s exact test for the qualitative ones. We compared both cortical entry angles, the deep grey nuclei (number of electrode crossing caudate, thalamic or pallidum), and the anatomical extent of the STN affected by the definitive electrode pathway (distance through the STN in mm). Secondly, we compared the clinical
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and neuropsychological data between the two groups at baseline using a Mann and Whitney test for quantitative values and a Fisher’s exact test for the qualitative ones to evaluate confusing factors. All these analyses were performed separately for each VF. P < 0.05 were considered statistically significant. Statistic analysis was performed with the NCSS software, version 6.0. RESULTS Characteristics of the population Fifty-nine patients (mean age, 61.9 ± 7.1 years old; range, 40–73 years; mean disease duration, 13.1 ± 4.6 years; range, 7–30 years) were included. Twentyseven were excluded because of missing imaging data (n = 14), missing neuropsychological data (n = 8), electrode withdrawal for hematoma (n = 3) and postoperative pneumencephalia (n = 2). After 6 months of DBS, the total score of UPDRS part III in the off-drug/on-stimulation and on-drug/onstimulation conditions improved from the baseline value respectively by 62.5% (range, 0–95.5%) and 80.7% (range, 16–100%) (P < 0.05). Moreover, the severity of motor fluctuations and dyskinesia as assessed by the UPDRS IV was significantly reduced Table 1 Characteristics of global population Baseline Number Male/female Age at surgery (y) PD duration before surgery (y) UPDRS III Off-drug On-drug Off-drug/on stimulation On-drug/on stimulation UPDRS IV Dopaminergic drugs MDRS Verbal fluency Semantic fluency Phonemic fluency Stroop test Word reading (s) Color word naming (s)
6 Months
59 33/26 61.9 ± 7.1 13.1 ± 4.6 40.6 ± 15.4 10.7 ± 6.9 8.3 ± 3.2 1227 ± 681 136 ± 7.8
14.2 ± 8.2∗∗ 7.4 ± 5.8∗∗ 2.4 ± 2.6∗∗ 567 ± 263∗∗ 135 ± 9.5
26.6 ± 7.7 19.9 ± 8.5
22.7 ± 8.25∗∗ 16.1 ± 7.1∗∗
79.1 ± 26.1 152.3 ± 55.8
87.9 ± 29.1∗ 185.8 ± 77.3∗∗
PD: Parkinson Disease; UPDRS: Unified Parkinson Disease Rating Scale; MDRS: Mattis Dementia Rating Scale; Dopaminergic drugs, are expressed in dopa-equivalent daily dose (mg/day). Values are given as mean ± standard deviation. (y) = years; (s) = seconds. Comparison of scores obtained before surgery and respectively six months after surgery used a Wilcoxon signed-rank test (∗ P < 0.05, ∗∗ P < 0.0001).
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by 70% (range, −100–100%). Dopaminergic drugs were reduced by 46% (range, −150–100%) (Table 1). Semantic fluency Six months after DBS-STN the number of total words in the semantic fluency was significantly reduced by 14.9% in the on-drug/on-stimulation conditions in the global population (P < 0.001). Forty-four patients declined more than 5% (group decline) while 15 patients remained stable (group stable performer). The clinical characteristics of both groups are summarized in Table 2a. There were no significant differences between groups with respect to age, gender, disease duration, L-dopa-equivalent daily dose, stimulation parameters and pre-operative cognitive performances (P > 0.05). Patients who declined in semantic fluency had a trajectory with a more anterior cortical entry point Table 2a Comparison of the trajectories between both groups decline versus stable performer in semantic fluency Trajectories
Right Hemisphere Cortical entry angles Antero-posterior angle (degree) Lateral angle (degree) Intersection with deep grey nuclei No. of trajectories Caudate nucleus Thalamus Pallidum Anatomical extent of the STN Distance through the STN (mm) Left Hemisphere Cortical entry angles Antero-posterior angle (degree) Lateral angle (degree) Intersection with deep grey nuclei No. of trajectories Caudate nucleus Thalamus Pallidum Anatomical extent of the STN Distance through the STN (mm)
Decline
P-values
(n = 44)
Stable performer (n = 15)
57 ± 6.9
59 ± 6.5
0.36
22 ± 3.7
21 ± 2.3
0.25
7 17 15
1 8 4
0.67 0.37 0.75
4.4 ± 1.7
4.4 ± 1.7
0.96
55 ± 6.9
59 ± 5.9
0.03
23 ± 4.4
22 ± 5
0.28
18 16 13
8 11 1
0.55 0.02 0.09
4.2 ± 1.5
4.6 ± 1.3
0.52
Values are given as mean ± standard deviation. Comparison of both groups used a Mann and Whitney test for quantitative data and a Fisher’s exact test for qualitative ones. P < 0.05 was considered statistically significant.
(mean antero-posterior angle, 56 ± 53 versus 60 ± 55 degree) passing less frequently trough the thalamus on the left hemisphere (P = 0.03), as shown in Table 2b. After DBS, both time of WR and CW naming of the Stroop test increased significantly in the group decline (respectively 78 ± 29 versus 88 ± 31 seconds and 157 ± 66 versus 200 ± 92 seconds, P < 0.001) while it remained stable in the group stable performer (P > 0.05). The MDRS score decreased significantly in the group decline after DBS (136 ± 6.2 versus 134 ± 9.1, P = 0.02) while it remained stable in the group stable performer (P > 0.05) (Table 2a). Phonemic fluency Six months after DBS-STN the number of total words in the phonemic fluency was significantly reduced by 14.2% in the on-drug/on-stimulation conditions in the global population (P < 0.05). Forty-four patients (34 similar, 10 different from the group semantic fluency decline) declined more than 5% (group decline) while 15 patients remained stable (group stable performer). The clinical characteristics of both groups are summarized in Table 3a. There were no significant differences between groups with respect to age, gender, disease duration, L-dopa-equivalent daily dose and stimulation parameters (P > 0.05). The analysis of the trajectory showed no significant differences between the groups (Table 3b). The mean number of words in phonemic fluency at baseline was significantly higher in the decline group than in the stable performer group (22.2 ± 7.3 versus 13 ± 8.2 words, P < 0.001). After DBS, both time WR and CW naming of the Stroop test increased significantly in the group decline, (respectively 72 ± 22 versus 81.2 ± 17.4 seconds and 142.6 ± 39 versus 185.3 ± 81.3 seconds, P < 0.001) while it remained stable in the group stable performer (P > 0.05). The MDRS score did not significantly change in both groups. DISCUSSION Recent evidence indicates that cognitive deterioration following DBS-STN in PD may be related to a microlesion due to the electrode trajectories [8, 10]. However, the existing literature fails to clearly explain whether surgery and stimulation differentially contribute to this deleterious effect. The present study examines the relationship between the VF decline after STN-DBS and the stereotactic lead trajectory. The results suggest that PD patients who decline in
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Table 2b Semantic fluency. Motor and cognitive assessments before and after STN stimulation in decline versus stable performer groups Scoring factor
Decline (n = 44) Baseline
Gender (M/F) Age at surgery (y) PD duration (y) UPDRS III off-drug off-drug/on-stimulation on-drug/on-stimulation UPDRS IV Dopaminergic drugs Stimulation parameters R Voltage L Voltage R Frequency L Frequency R Pulse width L Pulse width MDRS Verbal fluency Semantic Fluency Phonemic Fluency Stroop test Word reading (s) Color word naming (s)
Stable performer (n = 15)
6 Months
23/21 62.3 ± 6.6 13.3 ± 4.7 40.3 ± 14.2
Baseline
6 Months
10/5 60.5 ± 8.6 12.4 ± 4 41.4 ± 19
8.2 ± 3.2 1154 ± 393
15.2 ± 8.3∗∗ 8 ± 5.6∗∗ 2.7 ± 2.8∗∗ 563 ± 276∗∗
8.9 ± 3,1 1455 ± 1209
11.4 ± 7.3∗∗ 5.7 ± 6.2∗∗ 1.8 ± 1.6∗ 580 ± 226∗∗
136 ± 6.2
2.9 ± 0.4 3.1 ± 0.4 148 ± 28 148 ± 28 61.4 ± 6.4 62.3 ± 8.8 134 ± 9.1∗
3 ± 0,4 3 ± 0,4 147 ± 24 147 ± 24 64 ± 10 60.7 ± 2.6 135 ± 11.4
137 ± 10.7
27 ± 8 20 ± 8.3
21 ± 7.8∗∗ 16 ± 6.9∗∗
78 ± 29 157 ± 66
88 ± 31∗∗ 200 ± 92∗∗
25 ± 6.3 19 ± 9.4 80 ± 14.5 148 ± 40
28 ± 7.4∗∗ 16 ± 8.1∗ 84 ± 17.9 168 ± 43.6
PD: Parkinson disease; UPDRS: Unified Parkinson Disease Rating Scale; MDRS: Mattis Dementia Rating Scale; R: Right; L: Left Dopaminergic drugs, are expressed in dopa-equivalent daily dose (mg/day). Values are given as mean ± standard deviation. (y) = years; (s) = seconds. Comparison of scores obtained before surgery and respectively six months after surgery for each group used a Wilcoxon signed-rank test (∗ P < 0.05, ∗∗ P < 0.0001).
semantic VF have a left trajectory with a more anterior cortical entry point. Conversely, post-operative semantic VF is more stable when trajectories pass more frequently through the left thalamus. Finally, we found no correlation between phonemic VF decline and lead trajectories. The trajectory or approach angle used to reach the STN may vary considerably among surgeons. However, most centres orient their tracks in a double oblique manner (lateral and antero-posterior cortical entry angles) for several reasons. First, a lateral-tomedial orientation in the coronal plane avoids the ventricle, which minimizes brain shift due to loss of cerebrospinal fluid or possible intraventricular hemorrhage. This also places the cortical entry point more lateral with respect to the sagittal sinus, thereby theoretically minimizing the risk of venous complications. Second, the anterior-to-posterior orientation in the sagittal plane ensures entry through the precoronal region, thus sparing the motor cortex from injury. Finally, the double oblique track happens to be closer to the long axis of the STN, maximizing the length of electrode within the target nucleus. In general, electrode tracks traversed the dorsolateral prefrontal cortex, the
thalamus pars reticularis or ventral anterior, passed through the white matter tracts of the thalamic fasciculus, the anterior limb of the internal capsule, the zone incerta and lenticular fasciculus before entering the STN [10, 17]. Disruption of cells and/or fibres within the penetrated region may concern cortical areas and subcortical structures involved in VF networks [18]. The classic verbal generation task takes two forms, phonemic or semantic word fluency, each of which requires the generation of multiple single words from a single cue within a given time. Underlying cortical neural systems commonly identified in VF performances include the left inferior frontal gyrus, anterior cingulate gyrus, and supramarginal gyrus [19, 20]. Based on its role in sequencing information in working memory, the role of prefrontal areas is essential for VF. Dorsolateral regions are involved in monitoring and selecting goalrelevant representations, whereas ventrolateral regions are involved in maintaining these representations [21, 22]. On the other hand, the anterior cingulate gyrus has an important role in vocalization within an emotional context [23], and a key role in allocating attentional resources, both of which are important processes for language.
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Table 3a Comparison of the trajectories between both groups decline versus stable performer in VF phonemic fluency Trajectories
Decline (n = 44)
Right Hemisphere Cortical entry angles Antero-posterior angle (degree) Lateral angle (degree) Intersection with deep grey nuclei No. of trajectories Caudate nucleus Thalamus Pallidum Anatomical extent of the STN Distance through the STN (mm) Left Hemisphere Cortical entry angles Antero-posterior angle (degree) Lateral angle (degree) Intersection with deep grey nuclei No. of trajectories Caudate nucleus Thalamus Pallidum Anatomical extent of the STN Distance through the STN (mm)
57.3 ± 7
Stable P-values performer (n = 15)
57.9 ± 6.3
0.99
22.3 ± 3.6 21.3 ± 2.9
0.49
5 18 16
3 7 3
0.41 0.77 0.34
4.6 ± 1.5 3.9 ± 2.2
0.12
55.4 ± 7.2 58.5 ± 5.3
0.2
22.7 ± 4.9
0.73
22 18 11
22 ± 3.4
4 9 3
4.3 ± 1.5 4.2 ± 1
0.14 0.24 1
0.53
Values are given as mean ± standard deviation. Comparison of both groups used a Mann and Whitney test for quantitative data and a Fisher’s exact test for qualitative ones. P < 0.05 was considered statistically significant.
Many studies have demonstrated reduced phonemic and semantic fluencies following frontal lobes lesions [24, 25], whereas patients with temporal injuries showed a larger semantic than phonemic deficit [26]. In our study, we found that a more anterior left trajectory increases the risk of a decline in semantic VF. This left-lateralization is in line with previous reports suggesting that word fluency is more reduced following left as compared to right frontal lesions [27], especially for semantic VF [28, 29]. Additionally, both time to read of CW and WR of the Stroop test increased after STN-DBS in our study, suggesting a prefrontal dysfunction. Indeed, L-dopa uptake in the area of the medial frontal cortex and the anterior cingulate in PD correlated with Stroop test performances [30]. Since temporal cortex support word retrieval constrained by semantic VF, we postulated that left electrode trajectory may disrupt corticocortical pathways linking
specific more anterior prefrontal or cingulated areas to distinct temporal lobe regions. Further functional or structural neuroimaging studies investigating precisely the neural system affected by the electrode may be warranted to corroborate this hypothesis. The output of the basal ganglia that project to frontal cortices has a key role in motor functions, including speech production, which depends on coordination of multiple cortical areas to translate sound into the complex process of speech. Especially, the role of the basal ganglia may be in cognitive control, assisting language function by generally enhancing selected activities while suppressing competing ones [31, 32]. Hence, neuroimaging studies of healthy adults suggest that the striatum is implicated in a wide variety of language tasks, including word generation [31]. Furthermore, thalamic nuclei have connections with frontal language and the prefrontal cortex, which also have an integral role in VF processing [33, 34]. Indeed, many PD patients, especially those in the later stages of the disease, have difficulty in initiating speech, which may be rooted to disruption of a loop through the basal ganglia, its projection to the thalamic nuclei ventral anterior/ventral lateral and mediodorsal and projection to premotor, and dorsal prefrontal cortices and the anterior cingulated gyrus [34]. In the present study, we found no correlation between the post-operative decline in semantic or phonemic VF and the number of electrode crossing grey nuclei. Accordingly, previous study found no relationship between electrode trajectories crossing caudate nuclei and the risk of VF decline [10]. Moreover, we assumed that the microlesion of the pallidal outflow coursing dorsally to the STN through the lenticular fasciculus and ansa lenticularis is subtle, and thereby without consequence on the cognitive post-operative outcome. On the other hand, we determined that PD patients with stable post-operative semantic VF performances were implanted with a trajectory crossing more frequently the left thalamus. Since typical more posterior tracks usually pass into the thalamus, especially the reticular formation and, or the anterior ventral thalamic neurons; this finding is in accordance with our result concerning the left cortical entry angle. Nevertheless, it seems difficult to consider that an intersection with the thalamus protects against post-operative VF decline. Therefore, we postulate that anterior trajectories might affect neural structures different from grey nuclei involved in semantic VF. In particular, we hypothesize that posterior trajectory spares more commonly the anterior limb of the internal capsule. Recent diffusion tensor
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Table 3b Phonemic fluency. Motor and cognitive assessments before and after STN stimulation in decline versus stable performer groups Scoring factor
Decline (n = 44) Baseline
Gender (M/F) Age at surgery (y) PD duration (y) UPDRS III off-drug off-drug/on-stimulation on-drug/on-stimulation UPDRS IV Dopaminergic drugs Stimulation parameters R Voltage L Voltage R Frequency L Frequency R Pulse width L Pulse width MDRS Verbal fluency Semantic Fluency Phonemic Fluency Stroop test Word reading (s) Color word naming (s)
Stable performer (n = 15)
6 Months
62.7 ± 7.5 13.2 ± 5
6 Months
59.5 ± 5.4 12.6 ± 3
40.8 ± 16.4 8.5 ± 3 1210 ± 742
15.2 ± 8.2∗∗ 7.7 ± 5.7∗∗ 2.6 ± 2.7∗∗ 544 ± 260∗∗
136.7 ± 8
40 ± 11.7 7 ± 3.8 1285 ± 426
10.6 ± 7.2∗∗ 7 ± 6.4∗∗ 1.9 ± 1.9∗∗ 647 ± 271∗∗
2.9 ± 0.4 3 ± 0.4 149 ± 28 149 ± 28 62.8 ± 8.8 63 ± 8.9 136 ± 7.8
134 ± 6.9
2.9 ± 0.4 3 ± 0.4 145 ± 25 144 ± 25 60 ± 0 60 ± 0 131 ± 13.2
23.3 ± 7.9∗∗ 16.4 ± 6.6∗∗
23.8 ± 9.9 13 ± 8.2†
20.7 ± 9∗ 15.5 ± 8.8∗∗
81.2 ± 17.4∗∗ 185.3 ± 81.3∗∗
96 ± 28.9† 193.3 ± 93.5
27.5 ± 6.6 22.2 ± 7.3 72 ± 22 142.6 ± 39
Baseline
103.7 ± 43.7 213.8 ± 90.5
PD: Parkinson disease; UPDRS: Unified Parkinson Disease Rating Scale; MDRS: Mattis Dementia Rating Scale; R: Right; L: Left Dopaminergic drugs, are expressed in dopa-equivalent daily dose (mg/day). Values are given as mean ± standard deviation. (y) = years; (s) = seconds. Comparison of scores obtained before surgery and respectively six months after surgery for each group used a Wilcoxon signed-rank test (∗ P < 0.05, ∗∗ P < 0.0001). Comparison of the baseline characteristics between decline and stable performer used a Mann–Whitney test for quantitative data and a Fisher’s exact test for qualitative data († P < 0.05).
imaging studies demonstrating that linguistic performance highly correlated with the region of the left anterior limb of internal capsule in PD corroborated this hypothesis [35]. Additionally, we cannot exclude that a more posterior trajectory decreased the likelihood of the anterior non-motor territories of the STN to be affected by the electrode microlesion. Deep brain stimulation of the posterior sensorimotor area of the STN results in the best motor outcome in advanced levodopa-responsive form of PD. Nevertheless, both human and non-human primate studies have revealed functional non-motor territories of the STN consisting of a more intermediate associative territory and a smaller anteromedial limbic area [36, 37]. Since the electrode lead may be placed through the associative portion of the STN, several studies suggest that post-operative VF decline reflects a STN cognitive microlesion effect [5, 8, 38]. Conversely, high frequency stimulation itself has been reported to influence VF performances, especially with most ventral contacts [38]. In the present study, we considered the distance crossed by the electrode through the STN as the optimal value to reflect the target associated
cognitive microlesion effect. Thereby, we postulated that the probability to disrupt STN associative area could increase with the distance of track within the STN. However, we found no correlation between the anatomical extent of the STN affected by the definitive electrode pathway and the post-operative decline in VF. This might be the consequence of a methodological limitation. In fact, a best definition of the lesion volume using a voxel-based lesion-symptom mapping would likely improve our ability to correlate STN associative areas and VF performances. Finally, it is crucial to remember that there is an inherent risk profile for decline in cognitive functions after chronic DBS, which includes advanced age, higher severity of PD based on axial motor symptoms, and levodopa resistant symptoms [13, 39]. Moreover, the electrical stimulation itself has been reported to influence the VF performances, depending on the tissue volume affected by current spreading [38]. Since there were no significant differences between groups (decline versus stable performer) with respect to age, disease duration, pre-operative levodopa responsiveness and electrical parameters, we considered that
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cognitive post-operative changes depend particularly on the surgical procedure. Several limitations of this study need to be pointed out. First, the artefact of the electrode on the CT scan to determine the trajectory measures 2 mm while the actual electrode measures 1.27 mm, which overestimates the real lesion and the potential intersection with grey nuclei. Likewise, the distance through the STN may have been misestimated. Second, the definitive electrode pathway was determined by one rater using only imaging data, without other tools used such as electrophysiological recordings during surgery. Third, we found a slight difference (four degrees) in the mean antero-posterior angle between groups (decline versus stable performers). This result strongly suggests that a smaller specific frontal region may contain all the processes required for semantic fluency. However, we did not compare a set of frontal regions only with each other. Then, it may be argued that this difference of cortical microlesion between groups is not sufficient to explain the decline of verbal fluency performance. Fourth, we did not assess the impact of the number of electrodes used during the electrophysiological procedure. Hence, previous studies demonstrated that multiple tracks could increase the risk of memory function deterioration [40]. Nevertheless, recent studies demonstrated no correlation between VF decline and the number of microelectrode passes [13, 41]. Finally, we found no correlation between phonemic VF decline and lead trajectories. However, the mean number of words in phonemic fluency at baseline was significantly higher in the decline group than in the stable performer group. Therefore the subtle difference of the electrode trajectory may be negligible with respect to the greater difference of baseline number of words.
CONFLICTS OF INTEREST/DISCLOSURE OF ALL AUTHORS Floriane Le Goff reports no disclosures. Damien Fetter reports no disclosures. Romain Lefaucheur reports no disclosures. St´ephane Derrey reports no disclosures. Alaina Borden reports no disclosures. Maryvonne Jan reports no disclosures. David Wallon reports no disclosures. David Maltˆete reports no disclosures. FINANCIAL DISCLOSURE OF ALL AUTHORS None. REFERENCES [1]
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CONCLUSION Consistent with prior neuroimaging studies, we confirmed that microlesion of left-brain regions may contribute to subtle cognitive impairment following STN-DBS in PD. More specifically, we demonstrated that semantic VF decline correlates with more anterior left trajectories sparing the thalamus. This highlights additional internal landmark for refining optimal STN targeting to avoid post-operative cognitive impairment.
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