Transcranial direct current stimulation combined with cognitive training for the treatment of Parkinson Disease: A randomized, placebo-controlled study

Accepted Manuscript Combined treatment is a useful approach in the management of mood and cognition in PD. transcranial Direct Current Stimulation combined with cognitive training for the treatment of Parkinson Disease: a randomized, placebo-controlled study Rosa Manenti, Maria Sofia Cotelli, Chiara Cobelli, Elena Gobbi, Michela Brambilla, Danila Rusich, Antonella Alberici, Alessandro Padovani, Barbara Borroni, Maria Cotelli PII:

S1935-861X(18)30250-X

DOI:

10.1016/j.brs.2018.07.046

Reference:

BRS 1281

To appear in:

Brain Stimulation

Received Date: 6 March 2018 Revised Date:

10 July 2018

Accepted Date: 16 July 2018

Please cite this article as: Manenti R, Cotelli MS, Cobelli C, Gobbi E, Brambilla M, Rusich D, Alberici A, Padovani A, Borroni B, Cotelli M, Combined treatment is a useful approach in the management of mood and cognition in PD. transcranial Direct Current Stimulation combined with cognitive training for the treatment of Parkinson Disease: a randomized, placebo-controlled study, Brain Stimulation (2018), doi: 10.1016/j.brs.2018.07.046. 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.

ACCEPTED MANUSCRIPT transcranial Direct Current Stimulation combined with cognitive training for the treatment of Parkinson Disease: a randomized, placebo-controlled study Rosa Manenti1 PhD, Maria Sofia Cotelli2 MD, Chiara Cobelli

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MSc, Elena Gobbi1 MSc, Michela

Brambilla1 PhD, Danila Rusich1 MSc, Antonella Alberici3 MD, Alessandro Padovani3 MD PhD,

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Barbara Borroni3 MD, and Maria Cotelli *1 PhD

Neuropsychology Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy

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Neurology Unit, Ospedale ValleCamonica, Esine, Brescia, Italy

Neurology Unit, Centre for Neurodegenerative Disorders, Department of Clinical and

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Experimental Sciences, University of Brescia, Brescia, Italy

Running Title: tDCS & cognitive training in Parkinson Disease

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Keywords: tDCS, Non-pharmacological treatment, Non-invasive brain stimulation, cognitive rehabilitation, PD.

Declarations of interest: none

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Financial disclosure: The authors have nothing to disclose.

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Funding sources: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

*Corresponding author Maria Cotelli PhD

IRCCS Centro San Giovanni di Dio Fatebenefratelli, Via Pilastroni, 4, 25125 Brescia, Italy Email: [email protected]; Tel. +39 030 3501593; Fax +39 030 3501592

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ACCEPTED MANUSCRIPT ABSTRACT Background: A number of non-motor symptoms occurs in Parkinson Disease (PD), cognitive decline and mood disturbances representing the most prevalent. Recent studies reported that cognitive training could potentially help to attenuate cognitive

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deficits in patients with PD and several researches demonstrated a beneficial effect of active transcranial Direct Current Stimulation (tDCS) over the left dorsolateral prefrontal cortex (anode over left dorsolateral prefrontal cortex, cathode over right supraorbital area) on cognitive deficits

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and mood disturbances.

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Objective: To investigate the effects of active tDCS combined with computerized cognitive training on cognition and mood disturbances in PD patients.

Methods: Twenty-two patients with PD were assigned to either active tDCS plus computerized cognitive training (CCT) or sham tDCS plus CCT groups. Each patient underwent two weeks’

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treatment of daily application of tDCS for 25 minutes during CCT focalized on functions related with prefrontal cortex. Each patient was evaluated at baseline, after treatment and at 3-month follow-up.

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Results: A significant reduction of depressive symptoms was observed in the active tDCS group

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from baseline to post- treatment assessment and from baseline to 3-month follow up. An improvement in cognitive performances, referring more specifically to language, attentional and executive functions, was observed in both groups post- treatment and at follow-up. However, phonemic verbal fluency showed significant greater changes from baseline in the active tDCS group. Conclusions: We concluded that cognitive training along with active tDCS is a useful combined approach in the management of mood and cognitive dysfunctions in PD.

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ACCEPTED MANUSCRIPT Introduction Parkinson disease (PD), one of the most common age-related brain disorders, is defined primarily as a movement disorder, with the typical symptoms being resting tremor, rigidity, bradykinesia and postural instability [1-4]. However, a number of non-motor symptoms occurs over disease

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course, cognitive decline and mood disturbances representing the most prevalent [5].

A higher cumulative risk of dementia and depressive symptoms has been largely demonstrated in PD patients as compared to the general population [6]. Different pharmacological approaches

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have been proposed for the treatment of cognitive decline and behavioral disorders, even though

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it has been recently argued for a beneficial effect of non-invasive treatment such as cognitive programs in patients with PD [7, 8]. In this regard, a meta-analysis reported that cognitive training could potentially help to attenuate cognitive deficits [8] and it has been demonstrated that cognitive rehabilitation was able to restore both cognitive performances and resting-state

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functional connectivity in PD patients [7].

Along with cognitive training, transcranial direct current stimulation (tDCS) gained much attention in the scientific community, in particular because this technique is non-invasive, easy to perform

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and free from side effects [9]. The use of tDCS stemmed on the fact that it might promote neural

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plasticity [10, 11] and some studies demonstrated a beneficial effect of anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC) on either cognitive deficits or mood disturbances in PD [12, 13].

Therefore, the main purpose of the present study was to investigate whether the application of active tDCS to the left DLPFC (anode over left dorsolateral prefrontal cortex, cathode over right supraorbital area) combined with computerized cognitive training would result in cognitive and mood improvement in patients with PD. Specifically, PD patients underwent a computerized cognitive training focused on executive abilities, using Posit Science BrainHQ (http://brainhq.com)

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ACCEPTED MANUSCRIPT during the application of active or sham tDCS over the left DLPFC (5 days/week over 2 weeks). Previous studies stated that Posit Science BrainHQ program fulfilled the gold standard for clinical trials [14-17]. We had two major hypotheses. First, we hypothesized that active tDCS combined with

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computerized cognitive training would improve mood disturbances more than sham tDCS combined with computerized cognitive training, measured by changes in the Beck Depression scores (Beck Depression Inventory-II, BDI-II) after treatment and at 3-month follow-up. Moreover,

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we hypothesized that active tDCS combined with computerized cognitive training would

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ameliorate cognitive performances related to prefrontal cortex, namely language, attention and executive functions more than computerized cognitive training alone. Such a prediction comes from previous works in individuals with mild to moderate PD [18-22]. Our secondary aim was to assess and compare the effects of active vs. sham tDCS combined with computerized cognitive

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training on other clinical and neuropsychological scales. Finally, we aimed to assessing long-term

Methods

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effects of multiple sessions of active tDCS over the left DLPFC combined to cognitive training.

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Recruitment and tDCS treatment protocol have been conducted at the IRCCS Centro San Giovanni di Dio Fatebenefratelli of Brescia from July 1, 2016 to September 30, 2017 (see Figure 1).

Study design This is a double-blind, randomized, placebo-controlled study. The patient and the examiner were blinded to the type of stimulation. Patients were randomized into two groups: a) active tDCS

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ACCEPTED MANUSCRIPT (AtDCS) over the left DLPFC plus computerized cognitive training (CCT) or b) sham tDCS (StDCS) over the left DLPFC plus CCT. The treatment group assigned to each patient was obtained by stratified randomization according to Parkinson’s Disease Cognitive Rating Scale (PD-CRS), Mini Mental Parkinson (MMP) and age. Stratified randomization is achieved by generating a separate

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block for each combination of covariates and participants are assigned to the appropriate block of covariates by a researcher blinded to the study aims. Details of the allocated group were given on cards contained in sequentially numbered, opaque and sealed envelopes.

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The study protocol was executed with no significant changes from the beginning.

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The study was approved by the local ethics committee (IRCCS Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy) and was conducted in accordance with the Declaration of Helsinki and reported according to CONSORT guideline [23, 24]. The trial was not registered. All participants were made fully aware of the aims of the research and written informed

Participants

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consent was obtained from all of them.

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Twenty-two patients fulfilling the UK Parkinson’s Disease Society Brain Bank clinical diagnostic

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criteria for PD were recruited [4, 25]. At the time of recruitment all patients were being treated with levodopa and/or dopamine agonists and they received stable therapy throughout the duration of the study. Patients were always tested in the on phase.

PD patients were classified according to the cut-off scores of the PD-CRS total score [PD-Mild Cognitive Impairment - PD-MCI: score= 65-81, PD-Dementia - PD-D: score ≤ 64 and PD-Normal Cognition - PD-NC: score ≥ 82 [26]].

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ACCEPTED MANUSCRIPT Stringent exclusion criteria were applied, as it follows: a) other neurological and psychiatric disorders; b) history of traumatic brain injury; c) clinically known hearing or vision impairment or a past history of alcohol abuse; d) clinical presentations suggestive of atypical parkinsonism, such as Dementia with Lewy Bodies, Corticobasal Syndrome, Progressive Supranuclear Palsy,

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Multiple System Atrophy or Vascular Parkinsonism, according to current clinical criteria; e) diagnosis of PD-Dementia [26] or MMP <25 [27, 28]; f) any contraindication to tDCS [9]; g) all patients were on stable pharmacological therapy for at least six months prior to enter the study

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and have been not engaged in cognitive training protocols within the year before the

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enrollment and during all the duration of the present study (from baseline to 3-month followup assessment).

Intervention

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All participants underwent to 25 minutes of CCT during tDCS treatment (either AtDCS or StDCS) five times weekly from Monday through Friday, for a total of 2 weeks with weekends off (10 sessions in total), in a 1:1 ratio (see Figure 2). Each patient underwent an extensive clinical,

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neuropsychological and behavioral evaluation, divided into two sessions. The assessment was

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administrated before the treatment (baseline), after two weeks’ treatment (post-treatment) and three months after treatment (follow-up visit). All assessments were performed by trained and blinded psychologists.

Clinical, Neuropsychological and Behavioral Assessment A comprehensive neuropsychological assessment based on the previously published recommendations was used [28, 29]. The cognitive tests battery included tests for assessing global cognitive abilities (PD-CRS [30-32]) and tests for cognitive domains (memory, language and

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ACCEPTED MANUSCRIPT attentional and executive functions). In addition, we used MMP as a brief screening test for global cognition [25, 27, 33, 34]. PD-CRS has undergone an extensive and rigorous validation process, and is applicable to all stages of PD both for routine clinical practice and for data collection in clinical trials. Moreover, PD-CRS is considered a PD-specific instrument for primary and secondary

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outcome measures, and it is rated as “recommended” by the International Parkinson and Movement Disorder Society [35-37]. A recent review [28] concluded that three scales, the Montreal Cognitive Assessment, the Mattis Dementia Rating Scale Second Edition and the

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Parkinson’s Disease-Cognitive Rating Scale, were classified as “recommended”. In particular, the

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PD-CRS has been defined useful for all types of studies, including screening, prevalence, correlation studies and treatment trials [28]. MMP was classified “recommended with caveats” because of limited evaluation of cognitive functions such as visuospatial functions, constructional praxis and executive abilities. The MMP has been described as suitable for screening and

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epidemiological studies in PD, but not for treatment trials because responsiveness has not been properly tested [28].

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The neuropsychological tests battery included measures used to assess different cognitive

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domains such as memory (Rey Auditory Verbal Learning Test, immediate and delayed recall, Digit Span Forward and Backward), language (phonemic and semantic verbal fluency, objects and actions picture naming of International Picture Naming Project, IPNP [38]), attention and executive functions (Trail Making Test, Test of Attentional Performance [39], Stroop Test, Frontal Assessment Battery - FAB). Depressive symptoms were assessed by Beck Depression Inventory-II (BDI-II). Clinical evaluation included the Parkinson’s Disease Quality of Life Questionnaire-39 (PDQ-39), the Barratt Impulsivity Scale (BIS-11), the Apathy Evaluation Scale and the REM Sleep Behavior

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ACCEPTED MANUSCRIPT Disorders Screening Questionnaire (RBDSQ) [40-43], the Unified Parkinson’s Disease Rating Scale (UPDRS-III) and the Hoehn & Yahr Scale [44].

Computerized cognitive training (CCT) protocol

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BrainHQ (Posit Science) is a CCT system that can be adapt in difficulty during the training [14-17]. In addition, the system provides feedback on performances and detailed reports of the obtained results allowing a monitoring of the progress over time. Randomized clinical trials that have

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applied BrainHQ software in elderly healthy individuals showed effective long-term benefits in

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several cognitive domains and in behavioral and functional performances [14, 15, 17, 45]. In particular, the ACTIVE trial demonstrated that the intensive use of BrainHQ software was protective against quality of life’s decline (Ball et al., 2002).

Through BrainHQ software the user can create his individual cognitive training by choosing from

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29 exercises organized into 6 categories: attention, memory, brain speed, people skills, navigation and intelligence. The exercises adaptively progress in difficulty, beginning with relatively easy task forms and progressively advancing in the accuracy challenges. The progression of the exercise

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difficulty is governed by user’s performance during the training session: if a participant performs

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the task correctly, the difficulty level increases and if he performs the exercise incorrectly the difficulty level decreased.

In our study we selected ten exercises designed to enhance working memory, attention and executive functions, cognitive domains often impaired in PD patients [46]. In each training session a participant worked with five exercises, 5 minutes each (25 minutes in total for each session). Progresses were monitored using weekly electronic data upload.

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ACCEPTED MANUSCRIPT Patients were seated in front of a computer screen in a quiet room and the computer-based cognitive training was supervised by a trained neuropsychologist who was blinded to patients tDCS

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treatment (active or sham stimulation).

tDCS protocol

Patients underwent a daily session for two weeks of tDCS stimulation (AtDCS or StDCS) over the

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left DLPFC starting from the beginning of each CCT session. The stimulation was delivered by a

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battery-driven, constant current stimulator (BrainStim, EMS, Bologna, Italy) through a pair of saline-soaked sponge electrodes (7 cm×5 cm). The active electrode was placed on the left DLPFC, 8 cm frontally and 6 cm laterally with respect to the scalp vertex (over F3, according to the 10–20 EEG international system). The reference electrode was fixed on the right supraorbital area. A

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constant current of 2 mA was applied for 25 min (with a ramping period of 10 seconds at the beginning and at the end), lasting for the entire CCT session. The current density (0.06 mA/cm2) was maintained below safety limits (see Figure 2). In the sham stimulation, the tDCS montage was

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the same, but the current was turned off 10 seconds after the starting of the stimulation and was

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turned on for the last 10 seconds of the stimulation period, to make this condition indistinguishable from the experimental stimulation. StDCS or AtDCS were delivered after entering a number code to the device, leaving operator blinded to treatment assignment. In order to detect perceived sensations, we asked the participants to complete a questionnaire about the sensations experienced during tDCS, after the first and the last session. Since the scores reported in the AtDCS group were comparable with the scores in the StDCS group in both timings (first session: AtDCS mean=1.18, standard deviation [SD]=0.72; StDCS mean=1.09, SD=0.79, p=0.79; last session:

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ACCEPTED MANUSCRIPT AtDCS mean=1.00, SD 0.60; StDCS mean=1.27 SD=1.05, p= 0.49), there are no reasons to reject the double-blinded character of this study. No adverse effects were reported.

Outcomes

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Participants were assessed at baseline, post-treatment (2 weeks after baseline) and 3 months from baseline assessment.

The primary outcomes were the changes in BDI-II score and in the cognitive tasks’ scores related

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to prefrontal cortex, namely language, attentional and executive functions.

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The secondary outcomes included: 1) change in the Unified Parkinson’s Disease Rating Scale Part III, UPDRS III; 2) change in Parkinson’s Disease Quality of Life Questionnaire (PDQ-39); 3) change in the Barratt Impulsivity Scale- 11 (BIS-11); 4) change in the REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ); 5) change in the Apathy Evaluation Scale; 6) change in Rey Auditory

Statistical analysis

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Verbal Learning Test, immediate and delayed recall.

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The sample size was estimated for a power of 80% and a 2-tailed α level of 5% on the bases of a

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previous study on PD that demonstrated an effect of physical therapy plus active tDCS on PD-CRS values [13]. We obtained a total sample size of 18 and we considered an attrition rate of 20% increasing the targeted sample size from 18 to 22. Baseline characteristics were compared using Mann-Whitney test. Based on the previous literature [47], where repeated session of AtDCS were found to improve the performance of mood and frontal-executive neuropsychological tasks variables, a series of ANOVA models were carried out on the same variables (as dependent ones) in order to evaluate (and confirm) the efficacy of our treatment. In particular, ANOVA models for repeated measures were

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ACCEPTED MANUSCRIPT performed with the dichotomous group variable (2: AtDCS plus CCT vs. StDCS plus CCT) as between factor and time (3: baseline, post-treatment, 3-month follow-up) as within factor. It is worth nothing that our aim was not to consider the treatment effective as a consequence of a significant difference between the two groups in at least one variable among the clinical,

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neuropsychological and mood ones (in that case the tests should have been considered simultaneous and multiple comparison adjustments would be required) [48]. Conversely, we aimed at evaluate if each of target variables differed between groups and along time, through a

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series of independent experiments, each of them referring at one specific variable and domain

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under study [49].

First, we analyzed our primary outcomes using ANOVA models for repeated measures with BDI-II score and the scores obtained in cognitive tasks related to prefrontal cortex as dependent variables and group (2: AtDCS plus CCT vs. StDCS plus CCT) and time (3: baseline, post-treatment

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and 3-month follow-up) as independent variables.

Moreover, we added a further analysis to explore if the changes from baseline to post-treatment assessment or from baseline to 3-month follow-up assessment in the primary outcomes were

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different between the two experimental groups. We accordingly run ANOVA models for repeated

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measures with changes in the primary outcomes as dependent variables and group (2: AtDCS plus CCT vs. StDCS plus CCT) and time (2: from baseline to post-treatment and from baseline to 3month follow-up) as independent variables. In particular, the percentages of change from baseline (i.e. post-treatment minus baseline and follow-up minus baseline) were included in the analysis.

Second, we analyzed our secondary outcomes using ANOVA models for repeated measures with UPDRS III, PDQ-39, BIS-11, RBDSQ Apathy Evaluation Scale and Rey Auditory Verbal Learning Test,

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ACCEPTED MANUSCRIPT immediate and delayed recall as dependent variables and group (2: AtDCS plus CCT vs. StDCS plus CCT) and time (3: baseline, post-treatment and 3-month follow-up) as independent variables. Post-hoc analysis via Fisher’s Least Significant Difference (LSD) tests was applied to evaluate pair-

comparisons were responsible for rejections in the ANOVA test.

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wise comparisons among levels of ANOVA significant factors, in order to discover which of the

Finally, we performed Pearson's correlation tests to evaluate whether significant changes on cognitive performances induced by the treatment were associated with changes on clinical scales

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and depressive symptoms.

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Statistical analyses were performed using Statistica software (version 10; www.statsoft.com). Statistical significance was set at p<0.05. Statistical power and Effect Sizes (Cohen’s d) were estimated using GPower 3.1 [50].

Participants

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RESULTS

All the 22 PD-MCI patients included in the study received 10 sessions of treatment and completed

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the final assessments. Follow-up evaluations ended in December 2017, when the last patient

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completed the last study visit.

The two groups did not differ in demographic and clinical features at baseline as shown in Table 1.

Primary Outcomes The primary outcomes were represented by the change in BDI-II score and by the change in the scores obtained in cognitive tasks related to prefrontal cortex, namely language, attentional and executive functions.

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ACCEPTED MANUSCRIPT ANOVA analysis with group and time as independent variables and depressive symptoms (BDI-II scores) as dependent variable revealed a significant interaction between group and time [F(2, 40)=3.87, p=0.029, η2 = 0.31, 1-β=0.99]. Post-hoc analysis showed a significant decrease of BDI-II scores in the AtDCS plus CCT group from baseline to post-treatment assessment (p=0.048, Cohen’s

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d=0.66, 1-β=0.51) and from baseline to 3-month follow-up (p=0.015, Cohen’s d=0.96, 1-β=0.82), indicating, exclusively in AtDCS plus CCT group, a reduction of depressive symptoms immediately after the treatment that could be maintained till the 3-month follow-up (Figure 3A and Table 2).

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ANOVA analyses with group and time as independent variables and scores obtained in cognitive

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tasks related to prefrontal cortex as dependent variables were applied to compare the effects of the treatments in the two experimental groups.

We observed a significant effect of time on the PD-CRS total [F(2, 40)=16.64, p=0.00006, η2 = 0.45, 1-β=0.99] and frontal-subcortical scores [F(2, 40)=18.05, p=0.000003, η2 = 0.47, 1-β=0.99],

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whereas no effects were observed for the cortical scores. Post-hoc comparisons highlighted that PD-CRS total score increased from baseline to post-treatment assessment (p=0.000001, Cohen’s d=0.61, 1-β=0.78) and from baseline to 3-month follow-up (p=0.004, Cohen’s d=0.33, 1-β=0.31),

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indicating an improvement immediately after the treatment that could be maintained till the 3-

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month follow-up. The same result was observed in regard to PD-CRS frontal-subcortical score, which increased from baseline to post-treatment assessment (p=0.000001, Cohen’s d=0.67, 1β=0.85) and from baseline to 3-month follow-up (p=0.002, Cohen’s d=0.36, 1-β=0.36). See Figure 4 A.

Moreover, significant main effect of time was observed for the phonemic [F(2, 40)=7.35, p=0.002, η2 = 0.27, 1-β=0.99] and semantic verbal [F(2, 40)=4.12, p=0.023, η2 = 0.017, 1-β=0.99] fluency. Regarding phonemic fluency, post-hoc comparison showed that the score increased from baseline to post-treatment assessment (p=0.0005, Cohen’s d=0.51, 1-β=0.62), but not from baseline to 3-

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ACCEPTED MANUSCRIPT month follow-up (p=0.17, Cohen’s d=0.19, 1-β=0.14). Regarding semantic fluency, there was a trend after intervention (p=0.075, Cohen’s d=0.27, 1-β=0.22), and a significant improvement from baseline to 3-month follow-up (p=0.007, Cohen’s d=0.44, 1-β=0.51). Significant effects were observed also for the actions naming abilities, whereas objects naming

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performance was unchanged. A significant main effect of time [F(2, 40)=6.34, p=0.004, η2 = 0.24, 1-β=0.99] was observed, with an increase from baseline to post-treatment assessment (p=0.003, Cohen’s d=0.47, 1-β=0.56) and from baseline to 3-month follow-up (p=0.004, Cohen’s d=0.23, 1-

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β=0.18).

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Finally, significant main effect of time was observed for the response flexibility task of the Test of Attentional Performance [F(2, 40)=8.51, p=0.0008, η2 = 0.30, 1-β=0.99] and for Stroop test [F(2, 40)=8.35, p=0.0009, η2 = 0.29, 1-β=0.99]. Post-hoc comparison showed that reaction times decreased from baseline to post-treatment assessment (flexibility task: p=0.0002, Cohen’s d=0.53,

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1-β=0.67; stroop test: p=0.009, Cohen’s d=0.34, 1-β=0.34) and from baseline to 3-month follow-up (flexibility task: p=0.031, Cohen’s d=0.37, 1-β=0.38; stroop test: p=0.0003, Cohen’s d=0.64, 1-

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β=0.82).

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Comparison of the changes from baseline on primary outcomes in the two groups ANOVA analyses with group (AtDCS and StDCS) and time (from baseline to post-treatment and from baseline to 3-month follow-up) as independent variables and percentage changes from baseline on primary outcomes as dependent variable were applied to compare the effects of the two treatments. Regarding depressive symptoms assessment, significant main effect of group [F(1, 20)=5.46, p=0.030, η2 = 0.21, 1-β=0.99] was observed on BDI-II scores that showed a greater decrease, indicating a greater reduction of depressive symptoms, irrespective to time in AtDCS plus CCT as

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ACCEPTED MANUSCRIPT compared to StDCS plus CCT (AtDCS plus CCT: post-treatment -22.6% SD 7.4, follow-up -28.5% SD 5.6; StDCS plus CCT: post-treatment -4.5% SD 2.9, follow-up +16.2% SD 7.7). See Figure 3B.

With respect to neuropsychological assessment, we observed a significant effect of time on the

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PD-CRS total [F(1,20)=5.87, p=0.025, η2 = 0.23, 1-β=0.99] and frontal subcortical scores [F(1,20)=6.35, p=0.020, η2 = 0.24, 1-β=0.99], suggesting a reduction of the improvement from post-treatment to follow-up (total score: AtDCS plus CCT: post-treatment +12.7% SD 1.5, follow-up

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+8.1% SD 1.4; StDCS plus CCT: post-treatment +8.6% SD 1.2, follow-up +3.8% SD 1.4; frontal

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subcortical score: AtDCS plus CCT: post-treatment +17.0% SD 2.8, follow-up +10.8% SD 2.6; StDCS plus CCT: post-treatment +19.7% SD 2.6, follow-up +11.4% SD 2.6).

Interestingly, significant main effects of time [F(1, 20)=7.14, p=0.015, η2 = 0.26, 1-β=0.99] and group [F(1, 20)=4.43, p=0.048, η2 = 0.19, 1-β=0.99] were observed for the phonemic verbal

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fluency, suggesting a general reduction of the improvement from post-treatment to follow-up and a significantly greater improvement induced by AtDCS plus CCT vs. StDCS plus CCT. Interestingly, with respect to changes from baseline to post-treatment, both groups show an improvement in

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phonemic verbal fluency score (AtDCS plus CCT: +18.7% SD 2.0; StDCS plus CCT: +10.4% SD 2.6),

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whereas, regarding the changes from baseline to 3-month follow-up, AtDCS plus CCT group obtained an improvement but StDCS plus CCT group showed a worsening (AtDCS plus CCT: +14.4% SD 3.0; StDCS plus CCT: follow-up -5.8% SD 2.8). No significant effects on the changes of the other primary outcomes were detected. See Figure 4B for details. Finally, we examined the effects of levodopa dose on active tDCS effects, but we did not find any significant effect of this predictor. In particular, Levodopa Equivalent Daily Dose (LEDD) did not significantly correlate with any significant percentage of change from baseline to post-treatment

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ACCEPTED MANUSCRIPT induced by active tDCS (PD-CRS total score: r=-0.14; PD-CRS subcortical score: r=-0.27; Verbal Phonemic Fluency: r=-0.25; Verbal Semantic Fluency: -0.40; Action Naming: r=-0.04; Stroop Test : r=0.24; Flexibility Task: r=-0.17). Moreover, including LEDD in the ANOVA analyses on percentage of changes from baseline, this predictor did not reach the significance and did not change the

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reported results [e.g. Phonemic Fluency: LEDD Levodopa dose: F(1,19)=2.81, p=0.11; tDCS group:

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F(1,19)=6.36, p=0.02)].

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Secondary outcomes

The secondary outcomes included: 1) change in the Unified Parkinson’s Disease Rating Scale Part III, UPDRS III; 2) change in Parkinson’s Disease Quality of Life Questionnaire (PDQ-39); 3) change in the Barratt Impulsivity Scale- 11 (BIS-11); 4) change in the REM Sleep Behavior Disorder Screening

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Questionnaire (RBDSQ); 5) change in the Apathy Evaluation Scale; 6) Rey Auditory Verbal Learning Test, immediate and delayed recall.

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No significant effects on the neuropsychological tests unrelated to prefrontal cortex were

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detected. No significant changes were found in UPDRS-III, PDQ-39, BIS-11, Apathy Evalutation Scale, RBDSQ and Rey Auditory Verbal Learning Test, immediate and delayed recall. See Table 2 for details.

Correlation analysis Finally, Pearson correlation coefficients between the significant changes in cognitive tests related to prefrontal cortex and the reduction of depressive symptoms (BDI-II score) induced by the

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ACCEPTED MANUSCRIPT treatment were estimated. This analysis did not show any significant correlation, suggesting that

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effects on mood and on cognition seem to be independent.

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ACCEPTED MANUSCRIPT DISCUSSION Common non-motor symptoms in PD are cognitive dysfunctions and mood disorders, which are associated to a poorer disease prognosis [1, 51-53]. Here, we examined whether tDCS along with computerized cognitive training was able to improve cognitive and mood symptoms in a selected

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cohort of patients with PD. We hypothesized that AtDCS on left DLPFC plus CCT may lead to an additional improvement in frontal abilities and mood as compared to StDCS plus CCT training. To address this question, we compared the effects of active or sham tDCS (anode over left

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dorsolateral prefrontal cortex, cathode over right supraorbital area) plus CCT focusing on

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executive functions in cognitive tasks related to prefrontal cortex, namely language, attentional and executive functions and depressive disturbances. Another important aim of the present study was to verify whether the benefits recorded immediately post-treatment would persist over the next three months.

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Overall, the results of our study show a significant additional effect of active tDCS over the left DLPFC on cognitive performances (as measured by changes from baseline in phonemic verbal fluency) and mood disturbances. Interestingly, these gains were maintained over the 3-month

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follow-up period.

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In regards to cognition, results of our study showed a significant improvement in PD-CRS, phonemic verbal fluency, semantic verbal fluency, action naming, Stroop test and flexibility task induced by computerized cognitive training, focused on executive functions irrespective of the tDCS protocol. In our study, we applied in both groups a combination of behavioral interventions that have been shown to induce executive functions’ improvement in patients with PD [8] inducing a cognitive improvement in both groups. With respect to global cognitive abilities scales, we obtained an increased PD-CRS total score in both groups after the treatment with a long-term effect at 3-month follow-up. Interestingly,

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ACCEPTED MANUSCRIPT previous study on a Spanish PD population reported that a change of 10-13 points on the PD-CRS total score is indicative of a clinically significant change [32] and in AtDCS plus CCT group we observed an improvement on the PD-CRS total score of 10 points immediately after treatment and 5.6 points at 3-month follow-up, whereas in StDCS plus CCT group we recorded an improvement

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of 6.4 points immediately after treatment and 3 points at 3-month follow-up.

We observed a significant additional effect of AtDCS on phonemic verbal fluency in PD, since the combined treatment ameliorated phonemic verbal fluency more than cognitive training alone and

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this greater effect remained after three months. In particular, we found a worsening in phonemic

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verbal fluency performance at the 3-month follow-up, as compared to baseline in patients that received sham tDCS plus CCT, whereas an improvement was observed after active tDCS plus CCT. Deficit in verbal fluency represents one of the most frequently cognitive change in PD and occurs from the initial stages of the disease, probably because language and executive functions are

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involved [54-60]. Moreover, deficits in phonemic verbal fluency have been attributed to the frontal lobe dysfunctions that characterize PD [56, 61]. The greater enhancement in phonemic fluency performance for AtDCS vs. StDCS plus CCT group

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reported in the present study is consistent with the body of literature showing that prefrontal

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stimulation improves verbal fluency in healthy individuals [62-64] and in patients with PD [20]. With respect to mood, several lines of evidence suggested that left DLPFC might be critical for mood and increasing its activity might result in an enhancement [e.g., 65]. Here, an improvement in mood was recorded exclusively in the group that received the combined treatment, suggesting that the effect on mood would represent an add-on effect of tDCS. Interestingly, these gains were maintained over 3 months.

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ACCEPTED MANUSCRIPT Concerning the impact of tDCS on mood, our finding is consistent with previous studies on PD that showed beneficial effects of active tDCS applied over DLPFC [12, 13] and with researches on depressed patients that described improvement on mood induced by active tDCS applied over the left DLPFC [47, 65-75]. The rationale for applying tDCS over the left prefrontal cortex for the

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treatment of depression was drawn by the hypothesis of mood dysregulation as the result of an imbalance between prefrontal and limbic regions [76]. More specifically, hypometabolism of the left DLPFC was associated with reduced cognitive control of emotion, as confirmed by

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neuroimaging studies [77-81]. Moreover, recent studies have shown that tDCS over prefrontal

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cortex also largely influences deeper brain structures [82-84].

In addition, our results are in line with literature data that demonstrated cognitive interventions as effective in PD patients [8, 21, 85, 86].

As far as the combined treatment effects on cognition, our data are in line with previous report of

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multi-day sessions of cognitive training and tDCS in PD [18] and expand findings of single-session brain stimulation studies on cognition in PD [19, 20]. In a crossover study, a single session of active tDCS over the left DLPFC improved performance in a working memory task [19]. In another

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crossover study, a single session of active tDCS improved verbal fluency more significantly when

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the stimulation was applied to the left DLPFC than to the left temporo-parietal cortex [20]. In the literature, there are only two studies [13, 18] based on repeated sessions of tDCS delivered during a training (physical or cognitive) in PD patients. In a sham-controlled study with a parallelarm design, 10 sessions of active tDCS over the DLPFC contralateral to the most affected body side during a physical therapy program was found to increase global cognitive performance and verbal fluency only in the active tDCS arm group, while effects on motor abilities and on depressive symptoms were similarly observed in both groups [13]. These improvements lasted at least for 3 months. In a placebo-controlled design with PD–MCI patients Biundo et al. [18] reported that 16

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ACCEPTED MANUSCRIPT daily sessions of active tDCS over the left DLPFC applied during a computerized cognitive training increased performance in an executive task at the 3-month follow-up, without any significant change at post-treatment assessment [18]. Moreover, in a placebo-controlled study aimed to assess the effects of tDCS over left or right

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DLPFC without any training in PD patients, Doruk and coworkers [12] have shown that tDCS protocol over either left or right DLPFC led to increased performance in executive functions and ameliorated depressive symptoms in PD.

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The mechanisms underlying the effects of tDCS have not been understood yet but may involve

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changes in the neuromodulation of different neurotransmitters [11, 87]. tDCS modifies the synaptic microenvironment by changing the synaptic strength dependent on NMDA receptors and modulating GABAergic activity; it also interferes with brain excitability through modulation of intracortical and corticospinal neurons and it leads to transient changes in the density of protein

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channels localized below the stimulating electrode [11, 87, 88]. Interestingly, neurotransmitters, in particular dopamine, seem to induce a non-linear, dosage-dependent effect on the plasticity promoted by tDCS [10, 87, 89].

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Moreover, regarding the putative mechanism underlying the improvement induced by repeated

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sessions of active tDCS, it has been suggested that facilitation processes could be a mechanism thought to take place in the hours or days after tDCS [90-92]. This approach is supported by data obtained in healthy participants by Reis and collaborators [93], that applied active tDCS over the primary motor cortex on acquisition and retention of a motor skill-learning task in young individuals over the course of 5 days, suggesting that the relative increase of later performance in the active tDCS condition was selectively due to enhanced offline effects under active tDCS compared with sham.

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ACCEPTED MANUSCRIPT We acknowledge that this study has some limitations. First, given that our sample size was relatively small, findings reported here should be reproduced in larger cohorts before firm conclusions can be drawn. Second, we are not able to disentangle the separate impact of cognitive training and brain stimulation due to the lack of a control group with active or sham stimulation

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without cognitive training. Moreover, the inclusion of a control group receiving only cognitive treatment is required to identify the amount of contribution of the cognitive training alone and in combination with tDCS treatments. Third, as we did not vary the stimulation target, we cannot

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conclude for specificity of the left dorsolateral tDCS for the observed effects. Fourth, the lack of a

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longer follow-up would be required to evaluate the trajectories of changes. Fifth, in the present study an intergroup variability in some cognitive performances at baseline could be seen. For example, the group that received active tDCS had a slightly better, even if not significantly different, performance on PD-CRS scores than the group of patients that received sham tDCS. The

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adoption of a crossover design would avoid problems of comparability of the groups with regard to confounding variables. Finally, further studies would allow to check for learning effects due to the repetition of the assessments in multiple time visits. However, several factors suggest that

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cognitive improvements observed in our study cannot be solely accounted for by task practice

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effects: it seems unlikely that the magnitude of improvement found in this study is solely due to a task practice effect and we show the lack of any tDCS effects on memory tasks, suggesting the specificity of the results. We acknowledge that these are preliminary findings, and present data cannot entirely rule out the practice effect, therefore future studies should use parallel versions of the same neuropsychological assessments to evaluate cognitive performance during pre- and post-treatment visits.

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ACCEPTED MANUSCRIPT Despite these limitations, the benefits induced by the combined treatment on cognition and mood are quite encouraging and should pave the way for future studies aiming at the identification of the optimal parameters for a combined treatment protocol. Although further controlled studies are needed to demonstrate the efficacy of cognitive training

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and stimulation interventions, the current pilot study highlights that a computerized cognitive treatment might be useful in enhancing cognition functioning in PD patients and that active tDCS effects may have add-on effects if applied during a cognitive training protocol. Furthermore, only

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the combined treatment induced a significant improvement on mood symptoms.

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Further research is needed to define long-term effects and impact on functional activities of this

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type of treatment.

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ACCEPTED MANUSCRIPT Tables

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Table 1. Demographic and clinical features of the sample at baseline grouped according randomized treatment procedure. StDCS plus AtDCS plus Computerized Computerized Cognitive Cognitive Training Training (N=11) (N=11) pMean (SD) Mean (SD) value* Age (years) 63.8 (7.1) 65.5 (6.4) 0.58 Education (years) 11.8 (4.7) 9.5 (4) 0.24 Gender (males/females) 7/4 5/6 0.42 Levodopa equivalent daily dose (mg) 559.8 (306.5) 618.6 (304.4) 0.67 Age of onset (years) 55.8 (6.2) 59.5 (7.2) 0.29 Disease duration (years) 7.6 (3.4) 6.2 (3.9) 0.34 Cumulative Illness Rating Scale – severity 1.4 (0.2) 1.7 (0.3) 0.10 Cumulative Illness Rating Scale – comorbidity 2.3 (1.7) 3.3 (1.8) 0.24 Unified Parkinson’s Disease Rating Scale, UPDRS III 22.7 (7.8) 26 (10.3) 0.53 Hoehn & Yahr 1.9 (0.5) 1.6 (0.8) 0.49

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StDCS: Sham tDCS; AtDCS: Active tDCS. Raw scores are reported. Standard deviation between brackets. Cut-off scores according to Italian normative data are reported. p-value*: Mann-Whitney tests between groups at the baseline

24

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Table 2. Effects of the randomized treatment procedure on clinical, depressive and cognitive assessment in the sample groups. StDCS plus Computerized Cognitive Training (n=11)

Clinical scales Unified Parkinson’s Disease Rating Scale Part III, UPDRS III Hoehn & Yahr Parkinson’s Disease Quality of Life Questionnaire (PDQ-39) Barratt Impulsivity Scale- 11 (BIS-11)

22.7 (7.8) 1.9 (0.5) 22.1 (13.6) 60.4 (9.6)

Post-treatment

Baseline

24.7 (8.5) 1.9 (0.5) 23.2 (14.9) 56.5 (7.8)

22.4 (6.3) 1.9 (0.5) 22.8 (17.9) 58.7 (12.9)

26 (10.3) 1.6 (0.8) 23.9 (12) 59.3 (6.7)

p-value

3-Month Follow-up

time

24.5 (9.4) 1.6 (0.8) 25.1 (13.4) 61.7 (8.9)

24.5 (9.7) 1.6 (0.8) 19.7 (11.2) 56.3 (12.2)

0.666 0.900 0.358 0.327

0.630 0.271 0.557 0.892

0.441 0.982 0.369 0.072

Post-treatment

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Baseline

AtDCS plus Computerized Cognitive Training (n=11)

3-Month Follow-up

group

time x group

Cut-off

52-71

4.8 (2.7)

5 (2)

6 (2.9)

3.3 (2.2)

3.6 (2.5)

3.7 (2.1)

0.216

0.079

0.592

<5

Apathy Evaluation Scale Depressive symptoms scale Beck Depression Inventory-II (BDI-II) Cognitive assessment Global cognitive abilities Mini Mental Parkinson (MMP) Parkinson’s disease-cognitive rating scale (PD-CRS) PD-CRS Total Score ( maximum=134) PD-CRS Cortical Score ( maximum=30) PD-CRS Frontal Subcortical Score ( maximum=104) Memory Rey Auditory Verbal Learning Test, immediate recall Rey Auditory Verbal Learning Test, delayed recall Language Verbal Fluency, phonemic Verbal Fluency, semantic Naming Objects of IPNP (%) Naming Actions of IPNP (%) Attentional and Executive Functions Frontal Assessment Battery (FAB) Stroop test interference effect on time (seconds) Stroop test interference effect on errors Trail Making Test, part A (seconds) Trail Making Test, part B (seconds) Digit Span (Forward) Digit Span (Backward) Test of Attentional Performance (TEA) Go/NoGo (time, milliseconds) Go/NoGo (correct responses, maximum=30) Working Memory (time, milliseconds) Working Memory (correct responses, maximum=15) Response Flexibility (time, milliseconds) Response Flexibility (correct responses, maximum=100)

10.2 (9.5)

11(10.9)

12.6 (11.8)

11.1 (10.6)

10 (6)

7.4 (6.4)

0.921

0.642

0.174

< 39

11.8 (7.5)

11.6 (7.7)

14 (13.3)

10.1 (3.9)

7.6 (4.5)*

6.8 (3.8)*

0.003

0.367

0.007

< 14

27.9 (2.5)

27.5 (3.7)

28.3 (2.4)

27.7 (3.5)

29.1 (1.8)

29.4 (1.9)

0.272

0.419

0.363

≥ 22.85

76.6 (15.2) 27.3 (4.1) 49.4 (15.3)

83 (15.9)* 25.9 (2.6) 57.1 (13.7)*

35.7 (11) 6.7 (3.8)

33 (14.3) 6.1 (3.8)

31.2 (10.4) 39 (7.7) 89 (8.6) 65.8 (14.9)

35.1 (14.3)* 39.7 (10.2)^ 85.7 (13.9) 70.7 (15.7)*

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81.9 (13.3) 26.6 (1.9) 55.3 (12.1)

91.9 (13.9)* 27.8 (1.8) 64.1 (12.5)*

87.5 (9)* 27.5 (1.3) 59.9 (8.4)*

<0.0001 0.937 <0.0001

0.240 0.270 0.273

0.386 0.100 0.919

-

33.1 (11.3) 5.6 (3.7)

36.9 (7.4) 7.5 (2.4)

37.3 (7.9) 7.6 (2.8)

36.7 (4.8) 6.3 (2.1)

0.610 0.060

0.467 0.449

0.562 0.613

> 28.52 > 4.68

30.2 (13.9) 41.3 (8.3)* 89.5 (26.4) 68.3 (22.6)*

32.1 (6.5) 37.2 (7.9) 88.7 (6) 70.4 (10.5)

38.1 (9.1)* 40.5 (7)^ 88.6 (6.2) 76.8 (24.2)*

36.7 (10.2) 41.1 (7.5)* 89.4 (26.3) 76.3 (7.3)*

0.002 0.024 0.137 0.004

0.468 0.900 0.832 0.261

0.107 0.689 0.406 0.689

> 16 > 24 -

15.7 (2.3) 31.4 (21.2)* 3.5 (3.4) 40 (12.6) 184.2 (130.6) 5.4 (0.9) 4.4 (1)

20.3 (12) 29.2 (14.2)* 2.4 (2.3) 41.5 (14.3) 238.9 (206.2) 5.7 (0.9) 3.8 (0.7)

15.5 (2.1) 28 (9.2) 1.6 (2.2) 52.6 (22.6) 164. 1 (96.4) 5.8 (0.8) 3.9 (0.9)

17.1 (0.7) 25.2 (8.6)* 1.8 (2.4) 53.2 (25.4) 161.5 (98.9) 5.6 (1) 4.5 (0.9)

16.5 (1.6) 21.6 (8)* 1.7 (2.6) 42.2 (15.5) 182.9 (148.6) 5.6 (0.8) 4.2 (0.8)

0.110 0.0009 0.503 0.061 0.514 0.458 0.142

0.957 0.309 0.216 0.638 0.628 0.417 0.722

0.193 0.448 0.581 0.183 0.737 0.147 0.496

> 13.4 < 36.92 < 4.24 < 94 < 283 > 4.25 > 2.64

529.4 (103.1) 27.7 (3.3) 772.8 (194.4) 10.4 (3.6) 1166.9 (151.8)* 69.6 (8.3)

512.3 (96.9) 28 (2.4) 801.5 (180.2) 10.7 (3.2) 1664.3 (395.8)* 75.4 (6.9)

537.8 (94.7) 28.3 (2.1) 785.7 (220.5) 11.7 (2) 1429 (142.7) 75.3 (5.1)

534.2 (98.4) 29 (0.7) 788.8 (223.9) 11.9 (2.1) 1189.9 (98.6)* 75.8 (6)

505.6 (86.1) 29 (0.7) 700.6 (118.8) 11.9 (1.8) 1213.9 (135)* 83.2 (5)

0.255 0.932 0.460 0.955 0.0008 0.063

0.897 0.346 0.619 0.237 0.818 0.427

0.723 0.208 0.293 0.897 0.203 0.850

-

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79.6 (17.4)* 25.9 (2.5) 53.7 (15.5)*

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15.6 (2.4) 38 (16.3) 3.4 (3.7) 54.2 (33.9) 210.2 (161.2) 5.2 (0.7) 4.1 (0.8)

520.4 (94.6) 28.5 (1.6) 801.8 (166.6) 11.5 (2.3) 1665.9 (334.4) 73.6 (8.4)

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REM Sleep Behavior Disorder Screening Questionnaire (RBDSQ)

StDCS: Sham tDCS; AtDCS: Active tDCS; IPNP: International Picture Naming Project. Raw scores are reported. Standard deviation between brackets. Cut-off scores according to Italian normative data are reported. Bold font and *: significant improvement when compared to baseline. ^=p<0.08

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ACCEPTED MANUSCRIPT Captions

Figure 1. Consort Flow Diagram.

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The flow diagram displays the progress of all participants through the study.

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Figure 2. Experimental procedure.

Experimental therapy protocol of transcranial direct current stimulation (tDCS) plus CCT.

B.

Current flow model of tDCS montage (anode over F3 and cathode over the right

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A.

supraorbital area), using two 7×5 sponge pads represented in coronal, sagittal and transverse views from the Male 1 model in the Soterix HD Targets software (Soterix Medical). Arrows

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represent direction of current flow.

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Figure 3. Effects of therapy protocol on depressive symptoms.

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The plot shows: (A) the score obtained in the Beck Depression Inventory after active (continuous line) or sham (dotted line) transcranial Direct Current Stimulation plus computerized cognitive training - CCT; (B) the percentage of changes in BDI-II score from baseline after active (light grey) or sham (dark grey) transcranial Direct Current Stimulation plus CCT. Error bars represent standard errors of the mean. Asterisks (*) indicate significant variations when compared with the baseline.

Figure 4. Effects of therapy protocol on neuropsychological tests.

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ACCEPTED MANUSCRIPT A.

The plot shows changes in Parkinson Disease Cognitive Rating Scale (PD-CRS) total score

after active (continuous line) or sham (dotted line) transcranial Direct Current Stimulation plus computerized cognitive training - CCT. On the y-axis the cut-off score between PD Mild Cognitive

B.

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Impairment (PD-MCI) and PD normal cognition (PD-NC) is represented.

The plot shows the mean cognitive performance changes (%) from baseline after Active

(light gray) or Sham (dark grey) tDCS plus CCT in Parkinson Disease Cognitive Rating Scale (PD-CRS)

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from Test of Attentional Performance (TEA).

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total and frontal subcortical scores, Verbal Fluency, Action naming, Stroop and Flexibility Task

Error bars represent standard errors of the mean. Asterisks (*) indicate significant variations when

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compared with the baseline.

27

ACCEPTED MANUSCRIPT

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Two weeks’ treatment of daily application of tDCS during CCT.

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Reduction of depressive symptoms in the active tDCS group after treatment and at FU.

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Improvement in cognition in both groups after the treatment and at follow-up.

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Greater changes from baseline in the active tDCS group in phonemic verbal fluency.

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Combined treatment is a useful approach in the management of mood and cognition in PD.