The potential neuromodulatory impact of subthalamic nucleus deep brain stimulation on Parkinson’s disease progression

Journal of Clinical Neuroscience xxx (xxxx) xxx

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Clinical study

The potential neuromodulatory impact of subthalamic nucleus deep brain stimulation on Parkinson’s disease progression Stanislaw Szlufik a,⇑, Karolina Duszynska-Lysak a, Andrzej Przybyszewski b, Ilona Laskowska-Levy c,d, Agnieszka Drzewinska a, Justyna Dutkiewicz a, Tomasz Mandat e, Piotr Habela b, Dariusz Koziorowski a a

Department of Neurology, Faculty of Health Science, Medical University of Warsaw, Poland Faculty of Information Technology, Polish Japanese Academy of Information Technology, Poland Music Performance and Brain Laboratory, Department of Cognitive Psychology, University of Economics and Human Sciences, Warsaw, Poland d Psychotherapy Center, XIIIth Daily Department of Neurotic Disorders, Nowowiejski Hospital, Warsaw, Poland e Department of Neurosurgery, Maria Sklodowska Curie Memorial Oncology Center, Warsaw, Poland b c

a r t i c l e

i n f o

Article history: Received 26 September 2019 Accepted 30 December 2019 Available online xxxx Keywords: Parkinson’s disease Deep brain stimulation Neuroprotection Neuromodulatory DBS

a b s t r a c t Introduction: STN-DBS has been claimed to change progression symptoms in animal models of PD, but information is lacking about the possible neuromodulatory role of STN-DBS in humans. The aim of this prospective controlled study was to evaluate the long-term impact of STN-DBS on motor disabilities and cognitive impairment in PD patients in comparison to Best-Medical-Therapy (BMT) and Longterm-Post-Operative (POP) groups. Material and methods: Patients were divided into 3 groups: the BMT-group consisted of 20 patients treated only with pharmacotherapy, the DBS-group consisted of 20 PD patients who underwent bilateral STN-DBS (examined pre- and postoperatively) and the POP-group consisted of 14 long-term postoperative patients in median 30 month-time after DBS. UPDRS III scale was measured during 3 visits in 9 ± 2 months periods (V1, V2, V3) in total-OFF phase. Cognitive assessment was performed during each visit in total-ON phase. Results: The comparable UPDRS III OFF gain was observed in both BMT-group and POP-group evaluations (p < 0.05). UPDRS III OFF results in DBS-group revealed significant UPDRS III OFF increase in DV2-V1 assessment (p < 0.05) with no significant UPDRS III OFF alteration in DV3-V2 DBS-group evaluation (p > 0.05). Cognitive assessment revealed significant alterations between DBS-group and BMT-group in working memory, executive functions and learning abilities (p < 0.05). Conclusions: The impact of STN-DBS on UPDRS III OFF score and cognitive alterations suggest its neuromodulatory role, mainly during the first 9–18 months after surgery. Ó 2019 Published by Elsevier Ltd.

1. Introduction Deep brain stimulation (DBS) is an established treatment in Parkinson’s disease (PD), more often proposed to patients in an advanced stage of the disease. The procedure entails implantation of intracranial electrodes in specific brain structures, which is followed by chronic stimulation. Recently, subthalamic nucleus has become the most often chosen localization in PD patients, mainly due to its effect on most of motor symptoms [1,2] and on the reduction of daily levodopa dose [2]. The effect of STN-DBS on motor outcome in PD patients has been proven in randomized

⇑ Corresponding author at: Department of Neurology, Faculty of Health Science, Medical University of Warsaw, Kondratowicza 8, 03-242 Warsaw, Poland. E-mail address: [email protected] (S. Szlufik).

studies, though all of them compared the motor improvement and the amelioration in quality of life in advanced [3–5] and early stage of PD [6], none of them assessed the possible neuromodulatory impact of STN-DBS on the disease progression. The studies concerning the possible neuromodulative role on the disease progression in PD patients were related only to pharmacological treatment [7–9]. So far, the possible neuroprotective role of STN silencing has been investigated only in animal models using neurotoxin induced ablation [10], STN pharmacological inhibition [11], STN phenotypic shift [12], continuous STN DBS by implantable stimulation systems [13,14] and most recently using an adeno-associated virus (AAV) 1/2-driven human mutated A53T a-synuclein (aSyn)overexpressing PD rat model [15]. Except for Blandini et al. [11], all other studies showed a survival of tyrosine hydroxylase

https://doi.org/10.1016/j.jocn.2019.12.059 0967-5868/Ó 2019 Published by Elsevier Ltd.

Please cite this article as: S. Szlufik, K. Duszynska-Lysak, A. Przybyszewski et al., The potential neuromodulatory impact of subthalamic nucleus deep brain stimulation on Parkinson’s disease progression, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.059

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S. Szlufik et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx

(TH)-positive cells in the substantia nigra compacta (SNc) [10,12– 15]. Spieles-Engemann et al. [16] also showed the BDNF upregulation in the nigrostriatal system suggesting that this therapy may exert effects on plasticity in the basal ganglia circuitry what, besides playing a role in the symptomatic effects of STN-DBS, may also support its neuroprotective effect in an animal model of the disease. The beneficial effects of STN-DBS on motor symptoms in PD have been frequently proven [3–6], but STN-DBS can be also accompanied by cognitive deterioration, mainly in frontal cognitive functions [17,18]. Though there are also studies [19,20] with no significant differences in cognitive decline after DBS surgery. The origin of cognitive impairment in STN-DBS patients remains not fully understood. Some authors propose that it can be related to the regional neuroinflammation [21] which has been shown in animal models to be most intensified during the first 6–12 months after electrode implantation [22], but some others suggest that impaired learning and visuospatial function can be associated with progressive neurodegeneration in PD [23,24]. The aim of this study was to evaluate the short-term and longterm postoperative impact of STN-DBS on PD patients’ motor disabilities and cognitive impairment in order to estimate its possible neuromodulatory effect on Parkinson’s disease progression, in comparison to a pharmacological group.

Whereas BMT and DBS patients were examined only prospectively, POP group was examined prospectively three times (V1, V2, V3) and compared to V0 which was assessed retrospectively. The demographic data of study patients is presented in Table 1. The study was approved by the Ethics Committee of Medical University of Warsaw. The experiments were conducted in accordance with the ethical standards of the Declaration of Helsinki. 2.2. Motor evaluation The neurological examination and UPDRS scale in total-OFF phase was performed 12 h after stopping levodopa or 24 h after stopping other antiparkinsonian drugs in the BMT group and in preoperative assessment in the DBS group. The neurological evaluation and UDPRS scale during postoperative assessment was performed 30 min after switching off both the stimulators (left and right) and after stopping levodopa for 12 h and 24 h after stopping other antiparkinsonian treatment stopping. The neurological examination and UPDRS scale evaluation was performed by the same investigator, who was a neurologist experienced in movement disorders. 2.3. Neuropsychological examination

2. Material and methods 2.1. Study design Patients were enrolled to this study if they were clinically diagnosed as idiopathic Parkinson’s disease and fulfilled UK Parkinson’s Disease Society (UKPDS) Brain Bank criteria. All of the study patients also had to meet the CAPSIT-PD criteria [25] in order to have the qualification criteria for bilateral STN DBS implantation. All patients were examined during 3 visits (V1, V2, V3) in 9 ± 2month periods. The UPDRS scale was evaluated in total-OFF phase. Cognitive evaluation was always performed in total-ON phase. The patients were divided into 3 groups: 1) BMT (Best Medical Therapy) group: 20 patients (56.7 mean age, 11 females, 9 males) treated only pharmacologically through the whole time of observation. The BMT group is a control group intended to assess Parkinson’s disease progression in patients treated with pharmacotherapy. 2) DBS (bilateral Deep Brain Stimulation) group: 20 patients (51.1 mean age, 8 females, 12 males) who were assessed once preoperatively and twice postoperatively after STNDBS. The DBS group has been constructed to estimate a possible short-term (18-month-period) neuromodulatory effect of STN-DBS on progression of Parkinson’s disease. 3) POP (Postoperative) group: 14 patients (51.4 mean age, 7 females, 7 males) in median 30-month time of first assessment after STN-DBS. The POP group has been created in order to estimate a possible long-term (>30-month-time) neuromodulatory effect of STN-DBS on disease progression.

Cognitive evaluation was performed by neuropsychologists experienced in assessment of patients with dementia and other neurodegenerative disorders. The battery of neuropsychological tests evaluated multiple broad domains of neuropsychological functioning: attention and working memory (WAIS-R digit span, Trial Making Test), executive functions (Tower of London test, verbal fluency tests: phonemic and category), language (Boston Naming Test-short version, WAIS-R similarities), memory (CVLT) and visuospatial functions (Benton’s Judgment of Line Orientation test, CLOX) – all tests are cataloged in Table 2. In order to minimize the effect of repeated exposure to the same tests, alternate forms of selected learning and memory tasks were administered. 2.4. Surgical intervention Study patients from the DBS-group and the POP-group underwent bilateral STN DBS under local anesthesia. Preoperative fusion of 1,5T MRI and stereotactic contrast-CT was performed with the use of Stereotactic Planning Software (Brainlab) to calculate the coordinates of STN using direct and indirect methods. Then, microrecording (MER) and macrostimulation were conducted using LeadpointÒ(Medtronic) followed by macrostimulation evaluated by a neurophysiologist and a movement disorders neurologist. If motor adverse effects appeared below 2 V from the M path and visual sensations appeared below 2 V from both paths at +2 bilaterally, microelectrodes were replaced by permanent electrodes (3389-28, Medtronic, Minneapolis, MN) bilaterally. A lateral control X-ray was performed to confirm the location of the electrode to be identical to the microelectrode, then the elec-

Table 1 Study population – demographics.

Gender Mean age Mean time of onset Mean symptoms’ duration time Mean LEDD Mean time of dyskinesia Mean OFF time

BMT group

DBS group

POP group

11 F, 9 M 56.7 ± 15.4 years 46.3 ± 15.1 years 10.4 ± 4.9 years 1254.0 ± 511.6 mg 1.8 ± 2.6 h/day 2.7 ± 1.3 h/day

8 F, 12 M 51.1 ± 15.3 years 39.7 ± 13.3 years 11.3 ± 3.9 years 1379.5 ± 510.0 mg 4.9 ± 2.9 h/day 4.6 ± 3.2 h/day

6 F, 7 M 51.4 ± 8.7 years 40.9 ± 8.3 years 10.5 ± 3.5 years 1273.2 ± 464.3 mg 5.9 ± 2.6 h/day 4.4 ± 1.8 h/day

Please cite this article as: S. Szlufik, K. Duszynska-Lysak, A. Przybyszewski et al., The potential neuromodulatory impact of subthalamic nucleus deep brain stimulation on Parkinson’s disease progression, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.059

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S. Szlufik et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx Table 2 Cognitive assessment in BMT, DBS and POP group (V1-V3). * means p < 0.05. BMT group

*

DBS group

POP group

D Visit:

D V2-V1

D V3-V2

D V2-V1

D V3-V2

D V2-V1

D V3-V2

D MMSE: D CLOX 1: D CLOX 2: D CVLT Immediate Recall Trial 1–5 Sum D CVLT short delay free recall D CVLT long delay free recall D CVLT long delay recognition D Benton JLO D WAIS-R Information D WAIS-R Similarities D WAIS-R Digit Span D Verbal Fluency Test – ‘K’ words D Verbal Fluency Test – ‘Animals’ D Verbal Fluency Test – ‘Sharp subjects’ D Boston Naming Test D Trial Making Test A D Trial Making Test B D Beck Depression Inventory D Tower of London – sum of movements D Tower of London – correct movements D Tower of London – time of execution D Tower of London – time of initiation

0.93* *na *na 1.68

0.58* 0.17 0.78* 1.97

0.65* *na *na 4.7*

0.25 0.91* 0.38* 0.5

0.14 *na *na 0.14

0.43* 0.29 0.14 3.29*

0.3

2.2*

0.75*

0.21

0.29 0.22 0.47 1.11* 2.05* 0.09 0.71 0.62 0.29 0.85* 4.16 8.64 1.25 1.97 2.8* 51.9* 10.26*

2.2* 0.05 *na 1.66* 0.09 1.3* 2.65* 1.95* 1.1* *na 5.34 0.88 3.05* *na *na *na *na

1.5* 0.45 1.91* 1.5* 1.1* 0.05 0.2 1.95* 1.3* 0.25 7.05* 9.35 0.8 5.98* 0.32 31.33* 7.53*

0.86 0.21 *na 1.0* 0.91 0.14 0 0.43 0.42 *na 1.57 9.21 0.62 *na *na *na *na

0.41 0.46 0.36 *na 0.51 2.35* 0.31 0.49 0.12 0.33 *na 2.9 15.91 3.07* *na *na *na *na

1.07* 0.43 0.64 1.65* 0.5 0.35 0.64* 1.29 1.21* 0.29 2.22* 7.14* 22.07* 1.64 1.82 1.04 58.06* 1.91

na = too small group to be statistically analysed.

trode was locked (Stimlock, Medtronic) at the burr-holes and the scalp wounds were closed. After removal of the stereotactic frame, the next step, conducted under general anesthesia, was connection of internal pulse generators (Activa SC, Medtronic, Minnneapolis, MN) to the electrodes. After 4 weeks, the stimulators were switched on and tuned in order to start the stimulation without adverse effects. If the stimulation effect was balanced and stable, pharmacotherapy was reduced. 2.5. Statistical analysis A linear mixed model analysis was implemented through use of LME4 (version 1.1) with intercepts for subjects included as random effects. Pairwise interactions between each fixed factor were included in the model. Tukey contrasts (from lsmeans package, version 2.25) were used to compare results between timepoints and treatments. All calculations were performed in statistical computing software R (version 3.3). P values < 0.05 were considered significant. 3. Results 3.1. Impact of STN-DBS on motor functioning BMT, DBS and POP group patients were evaluated in UPDRS III score in total OFF phase in order to estimate the possible impact of STN DBS on Parkinson’s disease motor progression. The results of UPDRS III OFF score showed the statistically significantly constant progression of the disease in the BMT group (DV2-V1 – 4.7pts, DV3-V2 – 4.65pts, p < 0.05), whereas the inter-visit UPDRS III score gain analysis in the DBS group revealed a definite UPDRS III OFF gain enhancement in the first postoperative period (DV2V1 – 8.8pts, p < 0.001) with subsequent inhibition of the UPDRS III OFF score gain in the next 9 months (DV3-V2 – 2.2pts, p > 0.05). In the POP group, there were no DV2-V1 or DV3-V2 UPDRS III gain variabilities (p > 0.05), but interestingly, there was also no statistically significant increase in UPDRS III score gain in

Fig. 1A. UPDRS III [points] in total-OFF phase in BMT, DBS and POP group (V1-V3). * means p < 0.05 (BMT DV2-V1, BMT DV3-V2, DBS DV2-V1).

DV2-V1 and DV3-V2 evaluation (3.5 and 4.2 pts respectively, p > 0.05) (Fig. 1A). The mixed model analysis of UPDRS total OFF score was performed in order to estimate Parkinson’s disease progression in all aspects of patients daily living and motor outcome. It showed statistically significant differences among visits in the BMT, DBS and POP groups (p < 0.05). The continuous linear gain of UPDRS total OFF score was observed in consecutive evaluations of the BMT group (DV2-V1 – 6.45 pts, DV3-V2 – 5.7 pts, p < 0.05), but neither in the DBS group (DV2-V1 – 3.15 pts, DV3-V2 – 3.6 pts, p > 0.05) nor in the POP groups (DV2-V1 – 5.2 pts, DV3-V2 – 6.0 pts, p > 0.05) assessment, though the long-term DBS evaluation (POP group) clearly showed a smaller long-term rather than shortterm impact of DBS on UPDRS TOTAL gain enhancement (p < 0.05) (Fig. 1B). 3.2. Impact of STN-DBS on cognitive impairment The mixed model analysis was also performed in order to estimate the possible influence of STN-DBS on cognitive deterioration

Please cite this article as: S. Szlufik, K. Duszynska-Lysak, A. Przybyszewski et al., The potential neuromodulatory impact of subthalamic nucleus deep brain stimulation on Parkinson’s disease progression, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.059

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Fig. 1B. UPDRS Total [points] in total-OFF phase in BMT, DBS and POP group (V1V3) * means p < 0.05 (BMT DV2-V1, BMT DV3-V2).

of PD patients. The inter-visit analysis revealed a statistically significant deterioration in executive functions, particularly in verbal fluency tests in the short-term in the DBS group (p < 0.05), not observed in the BMT group (p > 0.05). Attention and working memory tests (WAIS-R, Trial Making Test) also revealed a significant deterioration, mainly in later postoperative observations (DV3-V2 in the DBS and POP groups). Efficacy of learning and memory processes (CVLT) significantly decreased in short-term evaluations of the DBS group (p < 0.05), but it’s minor deterioration was also observed in long-term postoperative observation – POP group DV3-V2 examination. Constructional abilities worsened in both the BMT and DBS groups (DV3-V2 in BMT and DBS group CLOX 2 evaluations). Language functioning did not significantly change during the observation time (p > 0.05). All patients were also examined using Beck Depression Inventory, which revealed significant improvement in DV2-V1 (first postoperative) DBSgroup evaluation (p < 0.05) with coexistent significant deterioration in DV2-V1 BMT group (p < 0.05) (Table 2). 4. Discussion The novelty of our assessment is the motor evaluation of PD DBS and BMT patients in UPDRS total OFF (DBS OFF/MED OFF) phase which was not performed in any of the previous randomized trials [3–6]. This assessment has been performed in order to estimate the potential neuromodulatory impact of STN DBS on motor symptoms’ progression, which has not been proven in humans yet. Our study consists of an early-DBS (DBS) group and a late-DBS (POP) group (which is STN-DBS postoperative group of patients in median 30 months after the surgery) in order to assess the possible neuromodulatory impact of DBS STN on short-term and longterm motor impairment in postoperative PD patients. Our results show definite deterioration in the first 9 months after DBS implantation with subsequent inhibition of motor progression in the next 9-month assessment, which was not observed either in the BMT group (continuous progression of the disease) or the late-DBS (POP) group. The analysis of the POP group revealed long-term continuous, but noticeably slower UPDRS III OFF worsening than in the BMT group, which also shows minor long-term impact of STN DBS on motor symptoms in PD patients, which has been also described by other authors [26–28]. The initial worsening after DBS surgery can occur secondarily to regional neuroinflammation after intracranial electrodes’ implantation, as was demonstrated in animal models [21,22]. Orlowski et al. [22] demonstrated a complex brain tissue reaction to neurostimulation with a strong neuroinflammatory response during the first 6 months after electrode implantation with a subsequent

minor response after 12 months from surgery. The second postDBS motor evaluation (18-month assessment) in our PD DBS patients showed a significant inhibition in UPDRS III OFF worsening, what is in accordance with the animal study [22] and can also be a result of decreased glutamatergic-induced neurotoxicity because of the functional inhibition of the STN [29,30]. We also performed a cognitive assessment of our patients in order to estimate the potential neuromodulatory impact of STNDBS on cognitive alterations in early-term and long-term postoperative periods. Our results indicated the role of STN-DBS procedure in deterioration in more cognitive domains than was previously thought, mainly in verbal fluency and working memory, but also in learning ability and recall new information after a delay. These functions worsened in the short-term DBS group in the first postoperative evaluation, but some of them (learning, working memory) were also worsening in the long-term observation of the late-DBS (POP) group. These results are in agreement with the majority of previous studies in DBS patients [17,18] which revealed executive functions’, working memory and verbal fluency postoperative decline, the mostly significant in semantic and phonemic fluency tests. Our findings also correspond to findings from an animal study by Hirshler et al. [21] who demonstrated that sustained memory deficits observed in postoperative animals can be triggered by intense and widespread neuroinflammation in cortical regions after electrode implantation [21]. Therefore, the cognitive assessment in STN-DBS patients may also demonstrate the neuromodulatory impact of STN-DBS on Parkinson’s disease progression. 5. Conclusions Our study, for the first time, emphasizes the neuromodulatory effect of STN-DBS on the motor and non-motor outcome in Parkinson’s disease patients. The UPDRS-III and UPDRS-Total examination in total-OFF phase in 3 consecutive measurements show a clear worsening of UPDRS III/Total OFF score in the first postoperative months in the DBS group, with significant improvement in the subsequent early-term and minor long-term impact of STN-DBS. A similar pattern of decline was observed in short-term postoperative cognitive evaluation, but there was a perceived long-term influence of STN-DBS on cognitive functioning as well. The main limitations of this study are the number of patients in study groups and 30-minute DBS-OFF time before motor examination – future studies should consider higher population and longer total-OFF time. Nevertheless, our results are in accordance with previous animal studies showing the presence of a local inflammatory response not only subcortically, but also in cortical regions, and presenting the most visible neuroinflammatory tissue response during the first 6–12 months after stimulator placement. Therefore, taking into consideration the results of animal studies along with our results indicates the neuromodulatory impact of STN-DBS on Parkinson’s disease progression. 6. Contributions SS and DK contributed conception and design of the study; SS, KD-L, AP, IL-L, AD, JD, TM and PH organized the database; SS and DK performed the statistical analysis; SS, AP and DK wrote the first draft of the manuscript; All authors contributed to manuscript revision, read and approved the submitted version. Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Please cite this article as: S. Szlufik, K. Duszynska-Lysak, A. Przybyszewski et al., The potential neuromodulatory impact of subthalamic nucleus deep brain stimulation on Parkinson’s disease progression, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.059

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Please cite this article as: S. Szlufik, K. Duszynska-Lysak, A. Przybyszewski et al., The potential neuromodulatory impact of subthalamic nucleus deep brain stimulation on Parkinson’s disease progression, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.12.059