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The effect of deep brain stimulation of the subthalamic nucleus on executive functions: impaired verbal fluency and intact updating, planning and conflict resolution in Parkinson's disease
Accepted Manuscript Title: The effect of deep brain stimulation of the subthalamic nucleus on executive functions: Impaired verbal fluency and intact updating, planning and conflict resolution in Parkinson’s disease Author: Gyula Demeter Istv´an Val´alik P´eter Pajkossy Agnes ´ Sz˝oll˝osi Agnes Luk´acs Ferenc Kem´eny Mih´aly Racsm´any PII: DOI: Reference:
S0304-3940(17)30247-1 http://dx.doi.org/doi:10.1016/j.neulet.2017.03.026 NSL 32714
To appear in:
Neuroscience Letters
Received date: Revised date: Accepted date:
13-1-2017 2-3-2017 15-3-2017
´ Sz˝oll˝osi, A. ´ Please cite this article as: G. Demeter, I. Val´alik, P. Pajkossy, A. Luk´acs, F. Kem´eny, M. Racsm´any, The effect of deep brain stimulation of the subthalamic nucleus on executive functions: impaired verbal fluency and intact updating, planning and conflict resolution in Parkinson’s disease, Neuroscience Letters (2017), http://dx.doi.org/10.1016/j.neulet.2017.03.026 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
*Highlights
Highlights The effect of bilateral STN DBS on executive functions was tested in PD
The focus was on three different executive functions known to be involved in PD
Results were compared to a DBS wait-listed PD control group
Impaired fluency and intact updating, planning and conflict resolution was found
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*Manuscript
Running title: DBS effect on cognitive functions in PD The effect of deep brain stimulation of the subthalamic nucleus on executive functions: impaired verbal fluency and intact updating, planning and conflict resolution in
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Parkinson’s disease
Gyula Demetera,b, István Valálikc, Péter Pajkossya,b, Ágnes Szőllősib, Ágnes Lukácsb, Ferenc
Frontostriatal System Research Group, Hungarian Academy of Sciences, Budapest, Hungary
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Department of Cognitive Science, Budapest University of Technology and Economics,
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Keményd & Mihály Racsmánya,b
Budapest, Hungary
Department of Neurosurgery, St. John's Hospital, Budapest, Hungary Institute for Psychology, University of Graz, Graz, Austria
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Corresponding author
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Gyula Demeter
Department of Cognitive Science Budapest University of Technology and Economics Egry József utca 1 1111 Budapest, Hungary [email protected]
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Abstract
Although the improvement of motor symptoms in Parkinson’s disease (PD) after Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is well documented, there are open
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questions regarding its impact on cognitive functions. The aim of the present study was to assess the effect of bilateral DBS of the STN on executive functions in PD patients using a
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DBS wait-listed PD control group. Ten PD patients with DBS implantation (DBS group) and
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ten PD wait-listed patients (Clinical control group) participated in the study. Neuropsychological tasks were used to assess general mental ability and various executive
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functions. Each task was administered twice to each participant: before and after surgery (with the stimulators on) in the DBS group and with a matched delay between the two task
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administration points in the control group. There was no significant difference between the DBS and the control groups’ performance in tasks measuring the updating of verbal, spatial or
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visual information (Digit span, Corsi and N-back tasks), planning and shifting (Trail Making B), and conflict resolution (Stroop task). However, the DBS group showed a significant
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decline on the semantic verbal fluency task after surgery compared to the control group, which is in line with findings of previous studies. Our results provide support for the relative cognitive safety of the STN DBS using a wait-listed PD control group. Differential effects of
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the STN DBS on frontostriatal networks are discussed.
Keywords: Deep Brain Stimulation; Parkinson’s disease; executive functions; verbal fluency
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Introduction
In Parkinson’s disease (PD), beside the motor symptoms, several cognitive domains are also affected: in 20 to 40% of patients in the early stage of the disease mild cognitive impairment
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(MCI) is also present [1]. Based on previous studies it seems that the central cognitive deficit in PD is related to executive dysfunction [2].
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One interesting possibility to gain further data regarding the nature of executive dysfunctions
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in PD focuses on the differential effect of Deep Brain Stimulation (DBS) on specific executive functions. In the past decades DBS became a widely used and accepted procedure
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in the symptomatic treatment of PD [3].
DBS of the subthalamic nucleus (STN) in PD is associated with a clear motor benefit, and
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with minimal or no changes in cognitive functions [4,5]. There are studies reporting declines in certain executive [6-8] and memory tasks after STN DBS [4,8-10], studies reporting
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improvement on certain executive [4,6,10] and memory tasks [11] and studies reporting no change in specific tasks measuring these cognitive domains [7,12-14]. One of the most
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systematically reported decline is in verbal fluency tasks after STN DBS surgery [6,9,14] with this pattern of performance deteriorating further in the long term [8,15]. Our aim in this study was twofold. First, we hoped to gather further evidence regarding the
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effect of STN DBS on the three main executive components (updating, conflict resolution and planning) [16], within one experimental study. Second, we wanted to overcome the methodological problems faced in the majority of previous studies regarding the use of a relevant clinical control group. In general, we can find two main approaches in the literature regarding control groups in the study of DBS effects on cognitive outcomes: a) those comparing the performance of PD patients after DBS with the stimulators switched on either to the preoperative or to the postoperative state without DBS stimulation [4,6,10,13], and b)
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those comparing the performance of PD patients after DBS with the stimulators turned on to the performance of a clinical control group with PD diagnosis, but without a planned DBS intervention [7,17]. To overcome some of these methodological problems (e.g. deterioration of cognitive
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functions with time in PD, differences in symptoms, medication dosage, applied treatment methods across patients, etc.) we designed a study with a so called wait-listed PD control
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group. In this group, PD patients with DBS indication were investigated twice during the
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period between their referral to DBS and surgery. This way we could control cognitive changes related to both (a) cognitive deterioration over time and (b) different patient
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populations, and thus this design enables us to focus more closely on possible changes related to the DBS procedure in itself. In sum, the aim of the present study was to asses the effect of
Participants
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Materials and methods
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using a DBS wait-listed PD control group.
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bilateral STN DBS on executive functions with widely used cognitive tasks in PD patients
Patients were recruited from the St. John's Hospital, Budapest, Hungary and were assessed by
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a neurosurgeon (I.V.) and a neurologist (L.F.), both specialized in movement disorders. Only patients who met the UK Parkinson’s Disease Society Brain Bank clinical diagnostic criteria for PD were included. All patients were assessed first and then those who had surgical intervention during the 4-6 month period between the two assessment points were assigned to the experimental group. The remaining participants (with no surgical intervention) were assigned to the control group. Ten PD patients with bilateral DBS implantation (STN DBS group) and 10 PD wait-listed patients (Clinical control group) participated in the study.
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Parkinsonian motor symptoms were rated using the motor part III of the Unified Parkinson’s Disease Rating Scale (UPDRS) [18] by the same specialist at the first and at the second assessment points in both groups. Daily doses of medications were standardized by a formula for L-dopa-equivalent doses (LED). As inclusion criteria we used a cutoff score of > 24 on the
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Mini Mental State Examination (MMSE) [19] and a cutoff score of > 19 on the Beck Depression Inventory (BDI Hungarian version) [20]. Anxiety was assessed by the Spielberger
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State and Trait Anxiety Inventory (STAI Hungarian version) [21]. We did not include in the
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study those participants who had a lifetime history of alcohol or drug dependence and who met the criteria for any psychiatric or neurological diagnosis other than PD (see Table 1 for
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sample characteristics).
The research protocol was approved by the hospital’s ethical review board and it was carried
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out in accordance with the latest version of the Declaration of Helsinki. All patients were assured that participation in the study would not interfere with their clinical treatment and all
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patients received a detailed description of the study before they signed the informed consent
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forms.
- Table 1 about here -
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Experimental design and procedure
A mixed factorial design was used with group (STN DBS vs. Clinical control) as a betweensubjects factor and assessment points (1st vs. 2nd) as a within-subjects factor. Each patient in the DBS group was assessed twice with the same cognitive and neuropsychological task battery: before surgery on medication and after surgery on medication with the stimulators on. Patients in the control group were also assessed twice before the DBS surgery with the same
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task battery. We made an attempt to maintain a similar time interval between the two assessment points as in the DBS group and this time interval varied between 4 and 6 months. The position of the implanted electrodes was confirmed on the post-operative CT-scan, and the active contacts’ relationship to the STN was confirmed by fusion of the postoperative CT
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to the preoperative MRI data set on custom-developed Vister-3D planning software. The active contact was positioned 1-2 mm posterior, 10.8-12.0 mm lateral, and 1-2 mm below the
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mid-comissural point. Eight patients were treated with monopolar stimulation at 130 Hz with
Cognitive and neuropsychological assessment
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delivered through two pairs of contacts on both sides.
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60 or 90 μs pulse duration and 2.6-3.9 mA. In 2 patients interleaving bipolar stimulation was
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General mental ability was assessed by the MMSE [19]. Widely used neuropsychological tasks were used to assess executive functions, including the updating of verbal (Digit span
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forward and backward) [22], spatial (Corsi block-tapping task) [23] and visual (letter N-back task with two- and three-back conditions) [22] information. Conflict resolution was tested by
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the Stroop task [16], while planning and shifting were assessed by the Trail Making Test B [24]. The fluency of information processing was measured by phonemic and semantic verbal
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fluency tasks [25].
Statistical analysis
Due to technical problems, the results of one participant in the Clinical control group were not recorded in the Stroop test and in the N-back task. During data analysis, non-parametric statistical methods were used. A change score was determined for each participant and for each task by calculating the difference between scores obtained at the first and second
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assessment points. Then change scores were compared between the groups (STN DBS vs. Clinical control) by conducting a series of Mann-Whitney U Tests. For within-subject comparisons (1st vs. 2nd assessment point), a series of Wilcoxon signedrank tests was conducted in the two groups separately. For between-subjects comparisons
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(STN DBS vs. Clinical control), a series of Mann-Whitney U Tests was conducted for the two assessment points separately. A Spearman’s rank correlation was conducted between the
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Semantic fluency task change score and the time (in months) elapsed between the two
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assessment points and age.
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Results
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Characteristics of the STN DBS and Clinical control groups
The main results regarding the characteristics of the two groups are summarized in Table 1.
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The patients in the two groups did not differ significantly at baseline in the duration of illness, years of education, symptom severity, in daily L-dopa equivalent dose, but there was a
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significant difference in age: the clinical control group was older. Both groups had significantly lower UPDRS part III ratings on medication than off medication (STN DBS group: z = -2.81, p < 0.01, r = -0.89; Clinical control group: z = -2.81,
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p < 0.01, r = -0.89).
There was no significant difference between the two groups at baseline on self-reported depression as measured by the BDI, on the level of anxiety as measured by the STAI total scores and in general cognitive ability as measured by the MMSE (see Table 2 for details). The results on the memory and executive tasks are summarized in Table 3.
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Table 2 and Table 3 about here –
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The effect of STN DBS on motor and clinical scores The patients were assessed after DBS surgery with the stimulators turned on. STN DBS led to a significant decrease in the UPDRS motor scores with medication ON (z = -2.82, p < 0.01, r
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= 0.89) and in the medication OFF condition as well (z = -2.81, p < 0.01, r = 0.89). The mean daily LED was significantly (z = -2.7, p < 0.01, r = -0.85) reduced after surgery from
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606.7±250.2 mg to 129.1±295.7 mg, and complete elimination of dyskinesias was observed.
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According to our results STN DBS did not cause a significant change in self reported depressive (z = -0.06, p > 0.05, r = -0.02) and anxiety symptoms (z = -0.3, p > 0.05, r = -
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The effect of STN DBS on executive functions
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0.09).
To analyze the effect of surgical intervention on executive functions we calculated change
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scores for each task (the difference between the second assessment task scores and baseline scores) and we compared the change scores between the two groups. Mann-Whitney U test
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showed a significant difference only in the Semantic fluency task score (U = 21.5, p < .05, r = -.49) between the two groups. No other group differences were significant. The detailed
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results for all tasks are summarized in Table 4.
- Table 4 about here -
Due to the difference between the groups regarding time elapsed between the assessment points (U = 20, p < 0.05, r = -0.52), we calculated the Spearman’s correlation coefficients for the semantic fluency change score and the time elapsed for the whole sample (r = -0.35, p > 0.05) and for the STN DBS (r = -0.06, p > 0.05) and Clinical control groups (r = -0.26, p >
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0.05) separately. Due to the significant age differences between the two groups we conducted control analyses. We calculated the Spearman’s correlation coefficients for the semantic fluency change score and age for the whole sample (r = 0.09, p > 0.05) and for the STN DBS (r = -0.52 p > 0.05) and Clinical control groups (r = -0.21, p > 0.05) separately. None of the
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correlations were significant.
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Discussion
In accordance with main findings in the literature, we found evidence in support of the
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relative cognitive safety of STN DBS. We addressed the methodological problems we identified in the literature by using a wait-listed patient group as a clinical control group.
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There was no significant difference between the two groups at the baseline level according to the main motor symptoms assessed by the UPDRS motor scale, medication (L-dopa
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equivalent dose), main clinical symptoms - anxiety and depression - assessed by the STAI and BDI, respectively, and education. The clinical effect of DBS on the motor UPDRS score and
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on daily LED changes in the patients was consistent with previous reports [5]. Our findings suggest that STN DBS does not affect the main executive functions. The DBS group performed at the same level as the control group on tasks measuring updating of verbal
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(Digit span tasks), spatial (Corsi block tapping task) and visual (N-back task) information. Similarly, we found no significant difference between the two groups on the Stroop task (conflict resolution), on the Trail Making Test – B version (planning and shifting) either at baseline or in changes between the two assessment points (change scores). Taken together, our results based on comparisons with a wait-listed control group support previous findings that describe no substantial cognitive change after the surgical intervention [7,13,14] and contradict others arguing for beneficial effects of the STN DBS on memory and
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executive functions [4]. Contradictory findings are probably due to different factors. The differences in the sensitivity of the different tasks used to measure these cognitive functions can lead to conflicting results which could be further complicated by the presence of confounding variables such as the severity of the symptoms, the presence of different
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comorbid disorders and medication use. Our results from verbal fluency tasks are consistent with previous results on a postoperative
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decline in verbal fluency [6]. This decline seems to be unrelated to changes in psychomotor
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speed, given that most PD patients showed similar or improved performance on word-reading tasks [4].
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We found impaired semantic verbal fluency after STN DBS, and this impairment was not present in the clinical control group as the time passed by. This pattern of performance in the
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DBS group could be seen in the case of phonological fluency, but the difference did not reach statistical significance probably due to the small sample size. Verbal fluency is taken to be a
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measure of executive functions, and to provide an index of the ability to get controlled and flexible access of verbal information stored in memory [26]. The neural mechanisms
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underlying verbal fluency performance are not fully understood; imaging studies revealed the activation of the left inferior frontal gyrus during word generation [27] and plausible assumptions were also outlined regarding the role of STN in language functions [28].
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A possible explanation of the impaired verbal fluency performance after STN DBS could be that DBS intervention affects those cortico-basal ganglia circuits that play a crucial role in word retrieval processes [29]. This finding is also in line with the assumption that DBS affects the basal ganglia outflow to frontal areas [30], which leads to impaired performance on certain executive tasks, as well as in verbal fluency tasks. Alternatively, Schroeder et al. [31] argue that STN stimulation might reduce the activity in the temporal and inferior frontal areas contributing to the impaired verbal fluency performance.
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Further studies are needed to understand the role of STN in language processing and its connectivity with areas involved in linguistic, especially lexical processes. Previous studies described a reduction in self-reported symptoms of anxiety and depression after STN DBS [10] in PD, which the authors attributed to the high frequency stimulation on
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prefrontal-subcortical circuity, to the improvement in motor functioning or to the reduction in dopaminergic medication. We did not find evidence for the STN DBS beneficial effect on
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affective symptoms. There was no significant difference between the first and second
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assessment points in the DBS group in the level of anxiety as measured by the STAI and depression as measured by the BDI. One explanation could be that those patients who were in
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the moderate and severe range in terms of anxiety and depression measures were not included in our sample. Further studies are needed to clarify the complex relationship between self-
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reported affective states, motor symptoms and cognitive functions. By including a wait-listed surgical control group, our study represents an important step
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towards overcoming some of the methodological issues faced by DBS research with Parkinson’s patients. This initiative also has its difficulties and matching the DBS group to
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wait-listed patients is still far from the experimental ideal. The interpretation of the results must factor in the limitations mentioned above. The heterogeneity of the patient groups, the small sample size, and the lack of further follow-up
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could be among the limitations of our study, as of most DBS studies. Further studies or metaanalyses should clarify whether some of our non-significant nominal differences might signal a real population-based effect. Keeping this in mind, we believe that future studies with similar designs should focus on evaluating the clinical significance of the effect of the STN DBS in other cognitive domains and non-motor symptoms, together with assessing the changes in the quality of life of PD patients and possible relationships between these factors, contributing to a more comprehensive understanding of this procedure and its effects.
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Conclusions Our results provide further support for the relative cognitive safety of the STN DBS using a wait-listed PD control group. After the surgical intervention the only difference we found was
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impaired semantic verbal fluency performance in the STN DBS.
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Author contributions
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MR, GYD and ÁL designed the study and wrote the protocol; GYD collected, analyzed, interpreted the data and wrote the first and final draft of the manuscript; IV organized the
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study, discussed the data and commented the first and final draft of the manuscript; PP, ÁSZ, ÁL, FK discussed the data and commented the first and final draft of the manuscript; MR
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discussed the data and revised the final draft of the manuscript. All authors have approved the
Acknowledgments
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final manuscript.
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This study was supported by a grant from the Hungarian National Academy of Sciences (KTIA_NAP_13-2-2014-0020 to Mihály Racsmány). Gyula Demeter was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The authors are
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grateful to Lehel Finta for neurological assessment of PD patients. We also thank Zsófia Budai, Gyöngyi Oláh and Annamária Tóth for their assistance in data collection.
Conflicts of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Table
Table 1. Sample characteristics
STN DBS
Clinical control
(n=10)
(n=10)
Characteristics
Mann-Whitney U test
SD
Age (years)
54.8
5.9
64.2
10
Education (years)
13.5
2.4
13.2
3.5
4/6
5/5
8.6
2.5
8.1
Hoehn & Yahr stage
3.6
0.5
3.8
606.7
250.2
Postop daily LED (mg)
129.1
295.7
UPDRS-III score MedOFF
48.2
10.4
UPDRS-III score MedON
23.7
10.9
UPDRS-III score MedOFF StimON
18.5
UPDRS-III score MedON StimON
17.8
821.1
M
16
0.01
46.5
0.78
r -0.57 -0.06
46
0.76
-0.07
0.4
40
0.34
-0.21
33
0.2
-0.29
389.6
---
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Daily LED (mg)
p
3.8
us
Disease duration (years)
U
---
cr
Sex (M/F)
Mean SD
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Mean
---
50
6.5
44.5
0.68
-0.09
27.9
4.9
31
0.15
-0.32
---
---
7.4
---
---
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7.4
Note
STN DBS, subthalamic nucleus deep brain stimulation PD group; Clinical control, wait-listed PD group; M, masculine; F, feminine, LED, levodopa equivalent dose; UPDRS-III - Unified
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Parkinson’s Disease Rating Scale motor part, MedOFF – without antiparkinsonian medication, MedON – after antiparkinsonian medication, StimON – deep brain stimulation turned on.
Page 18 of 23
Table
Table 2. General cognitive ability and clinical scales scores at baseline and at second assessment
STN DBS (n=10)
BDI STAI –Total STAI-S STAI-T
28.5 (1.4) 6.3 (3.8)
29.3 (1.2) 7.7 (6)
2nd assessment
Mean (SD)
Mean (SD)
28.4 (1.4)
28.5 (0.8)
7.3 (6.1)
40.2 (21.6)
38.3 (19.9)
43.6 (18.6)
17.1 (12.4)
12.3 (9.7)
18.4 (12.1)
23.1 (11)
26 (12.4)
25.2 (10)
U
p
r
47
0.42
-0.05
8.6 (5.8)
47.5
0.85
-0.04
48.6 (21.4)
40.5
0.47
-0.16
22.5 (11.8)
46.5
0.79
-0.06
43.5
0.62
-0.11
26.1 (11.3)
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Note
Preoperative v. 1st assessment
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MMSE
Mean (SD)
1st assessment
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Mean (SD)
Postoperative
Mann-Whitney U test
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Preoperative
Clinical control (n=10)
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Clinical Scale
STN DBS, subthalamic nucleus deep brain stimulation PD group; Clinical control, wait-listed
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PD group; BDI, Beck Depression Inventory; MMSE, Mini Mental State Examination; STAI – Total, State and Trait Anxiety Inventory - Total score; STAI-S, State and Trait Anxiety
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Inventory, State Subscale; STAI-T, State and Trait Anxiety Inventory, Trait Subscale
Page 19 of 23
Table
Table 3. Results on the various measures of memory and executive functions in the two groups
STN DBS (n=10) Preoperative
Postoperative
Mean (SD)
Mean (SD)
Clinical control (n=10) 1st assessment Mean (SD)
2nd assessment
Mann-Whitney U test Preoperative v. 1st assessment
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Tasks
Mean (SD)
U
p
r
4.6 (0.8)
41
0.43
-0.17
6 (0.8)
43.5 0 .61
-0.11
4.6 (0.7)
4.8 (0.9)
4.4 (0.7)
DSF
6.1 (0.9)
6.4 (0.7)
5.8 (1)
DSB
4.3 (0.6)
4 (1)
3.7 (1.4)
4.1 (1.2)
27.5
0.08
- 0.39
2-back hit %
75 (25.5)
74 (28.3)
63.3 (29.1)
81.25 (19.6)
33.5
0.34
-0.23
3-back hit %
59 (27.6)
60 (24.9)
52.2 (17.8)
52.5 (29.6)
30
0.21
-0.30
TMT-A (sec)
55.6 (19.8)
58 (40.9)
66.3 (38.9)
67.7 (35.3)
46
0.76
-0.07
TMT-B (sec)
128.8 (56.1)
128.6 (90.6)
201.6 (154.1)
213.8 (197.5)
39.5
0.43
-0.18
Difference TrailB-TrailA
73.2 (55.2)
70.6 (54.1)
135.3 (134.4)
146.1 (177.6)
40.5
0.47
-0.16
Stroop Task CNC (RT)*
1409.3 (496.6)
1290.5 (333.9)
1193.5 (310.2)
1225.7 (312.2)
32
0.29
-0.24
Stroop Task CC (RT)
1300.9 (399.3)
1241.7 (257)
1321.6 (283.3)
1259.9 (383.1)
41
0.74
-0.07
Stroop Task IC (RT)
1600.2 (415.2)
1716.5 (425.8)
1688.1 (500.8)
2198.1 (1964)
40
0.68
-0.09
Stroop Task II (RT)
299.2 (290.8)
474.8 (334.4)
366.4 (318.4)
938.1 (1759.5)
41
0.77
-0.07
Phonological fluency
12.3 (3.7)
11.6 (3.1)
12.4 (5)
12.5 (5.7)
48
0.88
-0.03
Semantic fluency
17.4 (4.2)
14.9 (4.4)
17.2 (4.2)
17.5 (4.1)
46
0.76
-0.07
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Note
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CBTT
*In the Stroop Task the RT data represent median scores; STN DBS, subthalamic nucleus deep brain stimulation PD group; Clinical control, wait-listed PD group; DSF, Digit Span Forward Task; DSB, Digit Span Backward Task; CBTT, Corsi Block-Tapping Task; TMT-A, Trail Making Test A version; TMT-B, Trail Making Test B version; RT, reaction time; Stroop Task CNC, Stroop Color Word Interference Test colour naming condition, Stroop Task, CC, Stroop Color Word Interference Test congruent condition; Stroop Task IC, Stroop Color
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Word Interference Test incongruent condition; Stroop Task II, Stroop Color Word
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Interference Test inhibition index (Stroop Task IC RT – Stroop Task CNC RT)
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Table
Table 4. Change scores on neuropsychological tasks
Tasks
STN DBS (n=10) Mean (SD)
Clinical Control (n=10)
Mann-Whitney U test
Mean (SD)
U
p
r
0.8 (0.7)
0.1 (1.7)
27
0.07
-0.40
CBTT change score
0.2 (0.9)
0.2 (0.6)
48
0.87
-0.04
DSF change score
0.3 (0.6)
0.2 (0.9)
44.5
0.65
-0.10
DSB change score
-0.3 (0.6)
0.4 (0.9)
28.5
0.09
-0.38
2-back hit % change score
-1 (15.2)
14.2 (28.7)
18
0.09
-0.42
3-back hit % change score
1 (35.4)
7.1 (24.9)
29
0.55
-0.14
TMT-A change score (sec)
2.4 (41.5)
1.4 (30.6)
45.5
0.73
-0.08
TMT-B change score (sec)
-0.2 (67.8)
12.2 (86.4)
40
0.45
-0.17
Difference TrailB-TrailA change score (sec)
-2.6 (53.6)
10.8 (97.5)
35.5
0.27
-0.25
Stroop Task CNC change score (RT)**
-118.7 (558.4)
32.2 (108.4)
33
0.33
-0.22
Stroop Task CC change score (RT)
-59.2 (508.6)
-61.72 (231.1)
38
0.57
-0.13
Stroop Task IC change score (RT)
116.3 (446.3)
510 (1670.2)
44
0.94
-0.02
Stroop Task II change score (RT)
175.6 (374.7)
571.72 (1639.2)
40
0.68
-0.09
-0.7 (3.1)
0.1 (2.9)
44.5
0.68
-0.09
-2.5 (2.9)
3 (1.53)
21.5
0.03*
-0.49
Note
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Semantic fluency change score
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Phonological fluency change score
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MMSE change scores
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**In the Stroop Task the RT data represent median scores; STN DBS, subthalamic nucleus deep brain stimulation PD group; Clinical control, wait-listed PD group; MMSE, Mini Mental State Examination; DSF, Digit Span Forward Task; DSB, Digit Span Backward Task; CBTT, Corsi Block-Tapping Task; TMT-A, Trail Making Test A version; TMT-B, Trail Making Test B version; RT, reaction time; Stroop Task CNC, Stroop Color Word Interference Test colour naming condition, Stroop Task, CC, Stroop Color Word Interference Test congruent condition; Stroop Task IC, Stroop Color Word Interference Test incongruent condition; Stroop Task II, Stroop Color Word Interference Test inhibition index (Stroop Task IC RT–
Page 22 of 23
Stroop Task CNC RT). Positive change scores indicate improvement in case of memory and
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ed
M
an
us
cr
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fluency tasks and decline in case of the Trail Making and Stroop Tasks. *p < .05.
Page 23 of 23
S0304-3940(17)30247-1 http://dx.doi.org/doi:10.1016/j.neulet.2017.03.026 NSL 32714
To appear in:
Neuroscience Letters
Received date: Revised date: Accepted date:
13-1-2017 2-3-2017 15-3-2017
´ Sz˝oll˝osi, A. ´ Please cite this article as: G. Demeter, I. Val´alik, P. Pajkossy, A. Luk´acs, F. Kem´eny, M. Racsm´any, The effect of deep brain stimulation of the subthalamic nucleus on executive functions: impaired verbal fluency and intact updating, planning and conflict resolution in Parkinson’s disease, Neuroscience Letters (2017), http://dx.doi.org/10.1016/j.neulet.2017.03.026 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
*Highlights
Highlights The effect of bilateral STN DBS on executive functions was tested in PD
The focus was on three different executive functions known to be involved in PD
Results were compared to a DBS wait-listed PD control group
Impaired fluency and intact updating, planning and conflict resolution was found
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*Manuscript
Running title: DBS effect on cognitive functions in PD The effect of deep brain stimulation of the subthalamic nucleus on executive functions: impaired verbal fluency and intact updating, planning and conflict resolution in
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Parkinson’s disease
Gyula Demetera,b, István Valálikc, Péter Pajkossya,b, Ágnes Szőllősib, Ágnes Lukácsb, Ferenc
Frontostriatal System Research Group, Hungarian Academy of Sciences, Budapest, Hungary
b
Department of Cognitive Science, Budapest University of Technology and Economics,
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a
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Keményd & Mihály Racsmánya,b
Budapest, Hungary
Department of Neurosurgery, St. John's Hospital, Budapest, Hungary Institute for Psychology, University of Graz, Graz, Austria
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Corresponding author
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Gyula Demeter
Department of Cognitive Science Budapest University of Technology and Economics Egry József utca 1 1111 Budapest, Hungary [email protected]
Page 2 of 23
Abstract
Although the improvement of motor symptoms in Parkinson’s disease (PD) after Deep Brain Stimulation (DBS) of the subthalamic nucleus (STN) is well documented, there are open
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questions regarding its impact on cognitive functions. The aim of the present study was to assess the effect of bilateral DBS of the STN on executive functions in PD patients using a
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DBS wait-listed PD control group. Ten PD patients with DBS implantation (DBS group) and
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ten PD wait-listed patients (Clinical control group) participated in the study. Neuropsychological tasks were used to assess general mental ability and various executive
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functions. Each task was administered twice to each participant: before and after surgery (with the stimulators on) in the DBS group and with a matched delay between the two task
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administration points in the control group. There was no significant difference between the DBS and the control groups’ performance in tasks measuring the updating of verbal, spatial or
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visual information (Digit span, Corsi and N-back tasks), planning and shifting (Trail Making B), and conflict resolution (Stroop task). However, the DBS group showed a significant
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decline on the semantic verbal fluency task after surgery compared to the control group, which is in line with findings of previous studies. Our results provide support for the relative cognitive safety of the STN DBS using a wait-listed PD control group. Differential effects of
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the STN DBS on frontostriatal networks are discussed.
Keywords: Deep Brain Stimulation; Parkinson’s disease; executive functions; verbal fluency
2 Page 3 of 23
Introduction
In Parkinson’s disease (PD), beside the motor symptoms, several cognitive domains are also affected: in 20 to 40% of patients in the early stage of the disease mild cognitive impairment
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(MCI) is also present [1]. Based on previous studies it seems that the central cognitive deficit in PD is related to executive dysfunction [2].
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One interesting possibility to gain further data regarding the nature of executive dysfunctions
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in PD focuses on the differential effect of Deep Brain Stimulation (DBS) on specific executive functions. In the past decades DBS became a widely used and accepted procedure
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in the symptomatic treatment of PD [3].
DBS of the subthalamic nucleus (STN) in PD is associated with a clear motor benefit, and
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with minimal or no changes in cognitive functions [4,5]. There are studies reporting declines in certain executive [6-8] and memory tasks after STN DBS [4,8-10], studies reporting
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improvement on certain executive [4,6,10] and memory tasks [11] and studies reporting no change in specific tasks measuring these cognitive domains [7,12-14]. One of the most
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systematically reported decline is in verbal fluency tasks after STN DBS surgery [6,9,14] with this pattern of performance deteriorating further in the long term [8,15]. Our aim in this study was twofold. First, we hoped to gather further evidence regarding the
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effect of STN DBS on the three main executive components (updating, conflict resolution and planning) [16], within one experimental study. Second, we wanted to overcome the methodological problems faced in the majority of previous studies regarding the use of a relevant clinical control group. In general, we can find two main approaches in the literature regarding control groups in the study of DBS effects on cognitive outcomes: a) those comparing the performance of PD patients after DBS with the stimulators switched on either to the preoperative or to the postoperative state without DBS stimulation [4,6,10,13], and b)
3 Page 4 of 23
those comparing the performance of PD patients after DBS with the stimulators turned on to the performance of a clinical control group with PD diagnosis, but without a planned DBS intervention [7,17]. To overcome some of these methodological problems (e.g. deterioration of cognitive
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functions with time in PD, differences in symptoms, medication dosage, applied treatment methods across patients, etc.) we designed a study with a so called wait-listed PD control
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group. In this group, PD patients with DBS indication were investigated twice during the
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period between their referral to DBS and surgery. This way we could control cognitive changes related to both (a) cognitive deterioration over time and (b) different patient
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populations, and thus this design enables us to focus more closely on possible changes related to the DBS procedure in itself. In sum, the aim of the present study was to asses the effect of
Participants
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Materials and methods
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using a DBS wait-listed PD control group.
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bilateral STN DBS on executive functions with widely used cognitive tasks in PD patients
Patients were recruited from the St. John's Hospital, Budapest, Hungary and were assessed by
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a neurosurgeon (I.V.) and a neurologist (L.F.), both specialized in movement disorders. Only patients who met the UK Parkinson’s Disease Society Brain Bank clinical diagnostic criteria for PD were included. All patients were assessed first and then those who had surgical intervention during the 4-6 month period between the two assessment points were assigned to the experimental group. The remaining participants (with no surgical intervention) were assigned to the control group. Ten PD patients with bilateral DBS implantation (STN DBS group) and 10 PD wait-listed patients (Clinical control group) participated in the study.
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Parkinsonian motor symptoms were rated using the motor part III of the Unified Parkinson’s Disease Rating Scale (UPDRS) [18] by the same specialist at the first and at the second assessment points in both groups. Daily doses of medications were standardized by a formula for L-dopa-equivalent doses (LED). As inclusion criteria we used a cutoff score of > 24 on the
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Mini Mental State Examination (MMSE) [19] and a cutoff score of > 19 on the Beck Depression Inventory (BDI Hungarian version) [20]. Anxiety was assessed by the Spielberger
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State and Trait Anxiety Inventory (STAI Hungarian version) [21]. We did not include in the
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study those participants who had a lifetime history of alcohol or drug dependence and who met the criteria for any psychiatric or neurological diagnosis other than PD (see Table 1 for
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sample characteristics).
The research protocol was approved by the hospital’s ethical review board and it was carried
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out in accordance with the latest version of the Declaration of Helsinki. All patients were assured that participation in the study would not interfere with their clinical treatment and all
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patients received a detailed description of the study before they signed the informed consent
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forms.
- Table 1 about here -
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Experimental design and procedure
A mixed factorial design was used with group (STN DBS vs. Clinical control) as a betweensubjects factor and assessment points (1st vs. 2nd) as a within-subjects factor. Each patient in the DBS group was assessed twice with the same cognitive and neuropsychological task battery: before surgery on medication and after surgery on medication with the stimulators on. Patients in the control group were also assessed twice before the DBS surgery with the same
5 Page 6 of 23
task battery. We made an attempt to maintain a similar time interval between the two assessment points as in the DBS group and this time interval varied between 4 and 6 months. The position of the implanted electrodes was confirmed on the post-operative CT-scan, and the active contacts’ relationship to the STN was confirmed by fusion of the postoperative CT
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to the preoperative MRI data set on custom-developed Vister-3D planning software. The active contact was positioned 1-2 mm posterior, 10.8-12.0 mm lateral, and 1-2 mm below the
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mid-comissural point. Eight patients were treated with monopolar stimulation at 130 Hz with
Cognitive and neuropsychological assessment
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delivered through two pairs of contacts on both sides.
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60 or 90 μs pulse duration and 2.6-3.9 mA. In 2 patients interleaving bipolar stimulation was
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General mental ability was assessed by the MMSE [19]. Widely used neuropsychological tasks were used to assess executive functions, including the updating of verbal (Digit span
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forward and backward) [22], spatial (Corsi block-tapping task) [23] and visual (letter N-back task with two- and three-back conditions) [22] information. Conflict resolution was tested by
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the Stroop task [16], while planning and shifting were assessed by the Trail Making Test B [24]. The fluency of information processing was measured by phonemic and semantic verbal
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fluency tasks [25].
Statistical analysis
Due to technical problems, the results of one participant in the Clinical control group were not recorded in the Stroop test and in the N-back task. During data analysis, non-parametric statistical methods were used. A change score was determined for each participant and for each task by calculating the difference between scores obtained at the first and second
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assessment points. Then change scores were compared between the groups (STN DBS vs. Clinical control) by conducting a series of Mann-Whitney U Tests. For within-subject comparisons (1st vs. 2nd assessment point), a series of Wilcoxon signedrank tests was conducted in the two groups separately. For between-subjects comparisons
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(STN DBS vs. Clinical control), a series of Mann-Whitney U Tests was conducted for the two assessment points separately. A Spearman’s rank correlation was conducted between the
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Semantic fluency task change score and the time (in months) elapsed between the two
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assessment points and age.
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Results
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Characteristics of the STN DBS and Clinical control groups
The main results regarding the characteristics of the two groups are summarized in Table 1.
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The patients in the two groups did not differ significantly at baseline in the duration of illness, years of education, symptom severity, in daily L-dopa equivalent dose, but there was a
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significant difference in age: the clinical control group was older. Both groups had significantly lower UPDRS part III ratings on medication than off medication (STN DBS group: z = -2.81, p < 0.01, r = -0.89; Clinical control group: z = -2.81,
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p < 0.01, r = -0.89).
There was no significant difference between the two groups at baseline on self-reported depression as measured by the BDI, on the level of anxiety as measured by the STAI total scores and in general cognitive ability as measured by the MMSE (see Table 2 for details). The results on the memory and executive tasks are summarized in Table 3.
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Table 2 and Table 3 about here –
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The effect of STN DBS on motor and clinical scores The patients were assessed after DBS surgery with the stimulators turned on. STN DBS led to a significant decrease in the UPDRS motor scores with medication ON (z = -2.82, p < 0.01, r
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= 0.89) and in the medication OFF condition as well (z = -2.81, p < 0.01, r = 0.89). The mean daily LED was significantly (z = -2.7, p < 0.01, r = -0.85) reduced after surgery from
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606.7±250.2 mg to 129.1±295.7 mg, and complete elimination of dyskinesias was observed.
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According to our results STN DBS did not cause a significant change in self reported depressive (z = -0.06, p > 0.05, r = -0.02) and anxiety symptoms (z = -0.3, p > 0.05, r = -
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The effect of STN DBS on executive functions
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0.09).
To analyze the effect of surgical intervention on executive functions we calculated change
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scores for each task (the difference between the second assessment task scores and baseline scores) and we compared the change scores between the two groups. Mann-Whitney U test
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showed a significant difference only in the Semantic fluency task score (U = 21.5, p < .05, r = -.49) between the two groups. No other group differences were significant. The detailed
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results for all tasks are summarized in Table 4.
- Table 4 about here -
Due to the difference between the groups regarding time elapsed between the assessment points (U = 20, p < 0.05, r = -0.52), we calculated the Spearman’s correlation coefficients for the semantic fluency change score and the time elapsed for the whole sample (r = -0.35, p > 0.05) and for the STN DBS (r = -0.06, p > 0.05) and Clinical control groups (r = -0.26, p >
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0.05) separately. Due to the significant age differences between the two groups we conducted control analyses. We calculated the Spearman’s correlation coefficients for the semantic fluency change score and age for the whole sample (r = 0.09, p > 0.05) and for the STN DBS (r = -0.52 p > 0.05) and Clinical control groups (r = -0.21, p > 0.05) separately. None of the
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correlations were significant.
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Discussion
In accordance with main findings in the literature, we found evidence in support of the
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relative cognitive safety of STN DBS. We addressed the methodological problems we identified in the literature by using a wait-listed patient group as a clinical control group.
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There was no significant difference between the two groups at the baseline level according to the main motor symptoms assessed by the UPDRS motor scale, medication (L-dopa
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equivalent dose), main clinical symptoms - anxiety and depression - assessed by the STAI and BDI, respectively, and education. The clinical effect of DBS on the motor UPDRS score and
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on daily LED changes in the patients was consistent with previous reports [5]. Our findings suggest that STN DBS does not affect the main executive functions. The DBS group performed at the same level as the control group on tasks measuring updating of verbal
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(Digit span tasks), spatial (Corsi block tapping task) and visual (N-back task) information. Similarly, we found no significant difference between the two groups on the Stroop task (conflict resolution), on the Trail Making Test – B version (planning and shifting) either at baseline or in changes between the two assessment points (change scores). Taken together, our results based on comparisons with a wait-listed control group support previous findings that describe no substantial cognitive change after the surgical intervention [7,13,14] and contradict others arguing for beneficial effects of the STN DBS on memory and
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executive functions [4]. Contradictory findings are probably due to different factors. The differences in the sensitivity of the different tasks used to measure these cognitive functions can lead to conflicting results which could be further complicated by the presence of confounding variables such as the severity of the symptoms, the presence of different
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comorbid disorders and medication use. Our results from verbal fluency tasks are consistent with previous results on a postoperative
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decline in verbal fluency [6]. This decline seems to be unrelated to changes in psychomotor
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speed, given that most PD patients showed similar or improved performance on word-reading tasks [4].
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We found impaired semantic verbal fluency after STN DBS, and this impairment was not present in the clinical control group as the time passed by. This pattern of performance in the
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DBS group could be seen in the case of phonological fluency, but the difference did not reach statistical significance probably due to the small sample size. Verbal fluency is taken to be a
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measure of executive functions, and to provide an index of the ability to get controlled and flexible access of verbal information stored in memory [26]. The neural mechanisms
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underlying verbal fluency performance are not fully understood; imaging studies revealed the activation of the left inferior frontal gyrus during word generation [27] and plausible assumptions were also outlined regarding the role of STN in language functions [28].
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A possible explanation of the impaired verbal fluency performance after STN DBS could be that DBS intervention affects those cortico-basal ganglia circuits that play a crucial role in word retrieval processes [29]. This finding is also in line with the assumption that DBS affects the basal ganglia outflow to frontal areas [30], which leads to impaired performance on certain executive tasks, as well as in verbal fluency tasks. Alternatively, Schroeder et al. [31] argue that STN stimulation might reduce the activity in the temporal and inferior frontal areas contributing to the impaired verbal fluency performance.
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Further studies are needed to understand the role of STN in language processing and its connectivity with areas involved in linguistic, especially lexical processes. Previous studies described a reduction in self-reported symptoms of anxiety and depression after STN DBS [10] in PD, which the authors attributed to the high frequency stimulation on
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prefrontal-subcortical circuity, to the improvement in motor functioning or to the reduction in dopaminergic medication. We did not find evidence for the STN DBS beneficial effect on
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affective symptoms. There was no significant difference between the first and second
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assessment points in the DBS group in the level of anxiety as measured by the STAI and depression as measured by the BDI. One explanation could be that those patients who were in
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the moderate and severe range in terms of anxiety and depression measures were not included in our sample. Further studies are needed to clarify the complex relationship between self-
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reported affective states, motor symptoms and cognitive functions. By including a wait-listed surgical control group, our study represents an important step
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towards overcoming some of the methodological issues faced by DBS research with Parkinson’s patients. This initiative also has its difficulties and matching the DBS group to
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wait-listed patients is still far from the experimental ideal. The interpretation of the results must factor in the limitations mentioned above. The heterogeneity of the patient groups, the small sample size, and the lack of further follow-up
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could be among the limitations of our study, as of most DBS studies. Further studies or metaanalyses should clarify whether some of our non-significant nominal differences might signal a real population-based effect. Keeping this in mind, we believe that future studies with similar designs should focus on evaluating the clinical significance of the effect of the STN DBS in other cognitive domains and non-motor symptoms, together with assessing the changes in the quality of life of PD patients and possible relationships between these factors, contributing to a more comprehensive understanding of this procedure and its effects.
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Conclusions Our results provide further support for the relative cognitive safety of the STN DBS using a wait-listed PD control group. After the surgical intervention the only difference we found was
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impaired semantic verbal fluency performance in the STN DBS.
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Author contributions
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MR, GYD and ÁL designed the study and wrote the protocol; GYD collected, analyzed, interpreted the data and wrote the first and final draft of the manuscript; IV organized the
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study, discussed the data and commented the first and final draft of the manuscript; PP, ÁSZ, ÁL, FK discussed the data and commented the first and final draft of the manuscript; MR
M
discussed the data and revised the final draft of the manuscript. All authors have approved the
Acknowledgments
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final manuscript.
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This study was supported by a grant from the Hungarian National Academy of Sciences (KTIA_NAP_13-2-2014-0020 to Mihály Racsmány). Gyula Demeter was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences. The authors are
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grateful to Lehel Finta for neurological assessment of PD patients. We also thank Zsófia Budai, Gyöngyi Oláh and Annamária Tóth for their assistance in data collection.
Conflicts of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
12 Page 13 of 23
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Table
Table 1. Sample characteristics
STN DBS
Clinical control
(n=10)
(n=10)
Characteristics
Mann-Whitney U test
SD
Age (years)
54.8
5.9
64.2
10
Education (years)
13.5
2.4
13.2
3.5
4/6
5/5
8.6
2.5
8.1
Hoehn & Yahr stage
3.6
0.5
3.8
606.7
250.2
Postop daily LED (mg)
129.1
295.7
UPDRS-III score MedOFF
48.2
10.4
UPDRS-III score MedON
23.7
10.9
UPDRS-III score MedOFF StimON
18.5
UPDRS-III score MedON StimON
17.8
821.1
M
16
0.01
46.5
0.78
r -0.57 -0.06
46
0.76
-0.07
0.4
40
0.34
-0.21
33
0.2
-0.29
389.6
---
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Daily LED (mg)
p
3.8
us
Disease duration (years)
U
---
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Sex (M/F)
Mean SD
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Mean
---
50
6.5
44.5
0.68
-0.09
27.9
4.9
31
0.15
-0.32
---
---
7.4
---
---
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ed
7.4
Note
STN DBS, subthalamic nucleus deep brain stimulation PD group; Clinical control, wait-listed PD group; M, masculine; F, feminine, LED, levodopa equivalent dose; UPDRS-III - Unified
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Parkinson’s Disease Rating Scale motor part, MedOFF – without antiparkinsonian medication, MedON – after antiparkinsonian medication, StimON – deep brain stimulation turned on.
Page 18 of 23
Table
Table 2. General cognitive ability and clinical scales scores at baseline and at second assessment
STN DBS (n=10)
BDI STAI –Total STAI-S STAI-T
28.5 (1.4) 6.3 (3.8)
29.3 (1.2) 7.7 (6)
2nd assessment
Mean (SD)
Mean (SD)
28.4 (1.4)
28.5 (0.8)
7.3 (6.1)
40.2 (21.6)
38.3 (19.9)
43.6 (18.6)
17.1 (12.4)
12.3 (9.7)
18.4 (12.1)
23.1 (11)
26 (12.4)
25.2 (10)
U
p
r
47
0.42
-0.05
8.6 (5.8)
47.5
0.85
-0.04
48.6 (21.4)
40.5
0.47
-0.16
22.5 (11.8)
46.5
0.79
-0.06
43.5
0.62
-0.11
26.1 (11.3)
M
Note
Preoperative v. 1st assessment
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MMSE
Mean (SD)
1st assessment
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Mean (SD)
Postoperative
Mann-Whitney U test
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Preoperative
Clinical control (n=10)
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Clinical Scale
STN DBS, subthalamic nucleus deep brain stimulation PD group; Clinical control, wait-listed
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PD group; BDI, Beck Depression Inventory; MMSE, Mini Mental State Examination; STAI – Total, State and Trait Anxiety Inventory - Total score; STAI-S, State and Trait Anxiety
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Inventory, State Subscale; STAI-T, State and Trait Anxiety Inventory, Trait Subscale
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Table
Table 3. Results on the various measures of memory and executive functions in the two groups
STN DBS (n=10) Preoperative
Postoperative
Mean (SD)
Mean (SD)
Clinical control (n=10) 1st assessment Mean (SD)
2nd assessment
Mann-Whitney U test Preoperative v. 1st assessment
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Tasks
Mean (SD)
U
p
r
4.6 (0.8)
41
0.43
-0.17
6 (0.8)
43.5 0 .61
-0.11
4.6 (0.7)
4.8 (0.9)
4.4 (0.7)
DSF
6.1 (0.9)
6.4 (0.7)
5.8 (1)
DSB
4.3 (0.6)
4 (1)
3.7 (1.4)
4.1 (1.2)
27.5
0.08
- 0.39
2-back hit %
75 (25.5)
74 (28.3)
63.3 (29.1)
81.25 (19.6)
33.5
0.34
-0.23
3-back hit %
59 (27.6)
60 (24.9)
52.2 (17.8)
52.5 (29.6)
30
0.21
-0.30
TMT-A (sec)
55.6 (19.8)
58 (40.9)
66.3 (38.9)
67.7 (35.3)
46
0.76
-0.07
TMT-B (sec)
128.8 (56.1)
128.6 (90.6)
201.6 (154.1)
213.8 (197.5)
39.5
0.43
-0.18
Difference TrailB-TrailA
73.2 (55.2)
70.6 (54.1)
135.3 (134.4)
146.1 (177.6)
40.5
0.47
-0.16
Stroop Task CNC (RT)*
1409.3 (496.6)
1290.5 (333.9)
1193.5 (310.2)
1225.7 (312.2)
32
0.29
-0.24
Stroop Task CC (RT)
1300.9 (399.3)
1241.7 (257)
1321.6 (283.3)
1259.9 (383.1)
41
0.74
-0.07
Stroop Task IC (RT)
1600.2 (415.2)
1716.5 (425.8)
1688.1 (500.8)
2198.1 (1964)
40
0.68
-0.09
Stroop Task II (RT)
299.2 (290.8)
474.8 (334.4)
366.4 (318.4)
938.1 (1759.5)
41
0.77
-0.07
Phonological fluency
12.3 (3.7)
11.6 (3.1)
12.4 (5)
12.5 (5.7)
48
0.88
-0.03
Semantic fluency
17.4 (4.2)
14.9 (4.4)
17.2 (4.2)
17.5 (4.1)
46
0.76
-0.07
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ed
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Note
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CBTT
*In the Stroop Task the RT data represent median scores; STN DBS, subthalamic nucleus deep brain stimulation PD group; Clinical control, wait-listed PD group; DSF, Digit Span Forward Task; DSB, Digit Span Backward Task; CBTT, Corsi Block-Tapping Task; TMT-A, Trail Making Test A version; TMT-B, Trail Making Test B version; RT, reaction time; Stroop Task CNC, Stroop Color Word Interference Test colour naming condition, Stroop Task, CC, Stroop Color Word Interference Test congruent condition; Stroop Task IC, Stroop Color
Page 20 of 23
Word Interference Test incongruent condition; Stroop Task II, Stroop Color Word
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M
an
us
cr
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Interference Test inhibition index (Stroop Task IC RT – Stroop Task CNC RT)
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Table
Table 4. Change scores on neuropsychological tasks
Tasks
STN DBS (n=10) Mean (SD)
Clinical Control (n=10)
Mann-Whitney U test
Mean (SD)
U
p
r
0.8 (0.7)
0.1 (1.7)
27
0.07
-0.40
CBTT change score
0.2 (0.9)
0.2 (0.6)
48
0.87
-0.04
DSF change score
0.3 (0.6)
0.2 (0.9)
44.5
0.65
-0.10
DSB change score
-0.3 (0.6)
0.4 (0.9)
28.5
0.09
-0.38
2-back hit % change score
-1 (15.2)
14.2 (28.7)
18
0.09
-0.42
3-back hit % change score
1 (35.4)
7.1 (24.9)
29
0.55
-0.14
TMT-A change score (sec)
2.4 (41.5)
1.4 (30.6)
45.5
0.73
-0.08
TMT-B change score (sec)
-0.2 (67.8)
12.2 (86.4)
40
0.45
-0.17
Difference TrailB-TrailA change score (sec)
-2.6 (53.6)
10.8 (97.5)
35.5
0.27
-0.25
Stroop Task CNC change score (RT)**
-118.7 (558.4)
32.2 (108.4)
33
0.33
-0.22
Stroop Task CC change score (RT)
-59.2 (508.6)
-61.72 (231.1)
38
0.57
-0.13
Stroop Task IC change score (RT)
116.3 (446.3)
510 (1670.2)
44
0.94
-0.02
Stroop Task II change score (RT)
175.6 (374.7)
571.72 (1639.2)
40
0.68
-0.09
-0.7 (3.1)
0.1 (2.9)
44.5
0.68
-0.09
-2.5 (2.9)
3 (1.53)
21.5
0.03*
-0.49
Note
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M
ed
Semantic fluency change score
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Phonological fluency change score
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MMSE change scores
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**In the Stroop Task the RT data represent median scores; STN DBS, subthalamic nucleus deep brain stimulation PD group; Clinical control, wait-listed PD group; MMSE, Mini Mental State Examination; DSF, Digit Span Forward Task; DSB, Digit Span Backward Task; CBTT, Corsi Block-Tapping Task; TMT-A, Trail Making Test A version; TMT-B, Trail Making Test B version; RT, reaction time; Stroop Task CNC, Stroop Color Word Interference Test colour naming condition, Stroop Task, CC, Stroop Color Word Interference Test congruent condition; Stroop Task IC, Stroop Color Word Interference Test incongruent condition; Stroop Task II, Stroop Color Word Interference Test inhibition index (Stroop Task IC RT–
Page 22 of 23
Stroop Task CNC RT). Positive change scores indicate improvement in case of memory and
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M
an
us
cr
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fluency tasks and decline in case of the Trail Making and Stroop Tasks. *p < .05.
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