Nonmotor Symptoms of Parkinson’s...

Parkinson’s Disease

Nonmotor Symptoms of Parkinson’s Disease

Guest Editors: Shey‑Lin Wu, Rajka M. Liscic, SangYun Kim, Sandro Sorbi, and Yuan‑Han Yang

Parkinson’s Disease


Guest Editors: Shey-Lin Wu, Rajka M. Liscic, SangYun Kim,Sandro Sorbi, and Yuan-Han Yang

Copyright © 2017 Hindawi Publishing Corporation. All rights reserved.

This is a special issue published in “Parkinson’s Disease.” All articles are open access articles distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is prop-erly cited.

Editorial Board

Jan Aasly, NorwayC. Alves da Costa, FranceIvan Bodis-Wollner, USACarlo Colosimo, ItalyTed Dawson, USA

Francisco Grandas, SpainPeter Hagell, SwedenNobutaka Hattori, JapanMarjan Jahanshahi, UKElan D. Louis, USA

Maral M. Mouradian, USAAntonio Pisani, ItalyFabrizio Stocchi, ItalyEng King Tan, SingaporeHélio Teive, Brazil

Contents

Nonmotor Symptoms of Parkinson’s DiseaseShey-Lin Wu, Rajka M. Liscic, SangYun Kim, Sandro Sorbi, and Yuan-Han YangVolume 2017, Article ID 4382518, 2 pages

Meta-Analysis of the Relationship between Deep Brain Stimulation in Patients with Parkinson’s Diseaseand Performance in Evaluation Tests for Executive Brain FunctionsA. M. Martínez-Martínez, O. M. Aguilar, and C. A. Acevedo-TrianaVolume 2017, Article ID 9641392, 16 pages

Stigma Experienced by Parkinson’s Disease Patients: A Descriptive Review of Qualitative StudiesMarina Maffoni, Anna Giardini, Antonia Pierobon,Davide Ferrazzoli, and Giuseppe FrazzittaVolume 2017, Article ID 7203259, 7 pages

Parkinson’s Disease and Cognitive ImpairmentYang Yang, Bei-sha Tang, and Ji-feng GuoVolume 2016, Article ID 6734678, 8 pages

Event-Related Potentials in Parkinson’s Disease Patients with Visual HallucinationYang-Pei Chang, Yuan-Han Yang, Chiou-Lian Lai, and Li-Min LiouVolume 2016, Article ID 1863508, 7 pages

Gastrointestinal Dysfunctions in Parkinson’s Disease: Symptoms and TreatmentsAndrée-Anne Poirier, Benoit Aubé, Mélissa Côté, Nicolas Morin, Thérèse Di Paolo, and Denis SouletVolume 2016, Article ID 6762528, 23 pages

Aerobic Exercise Preserves Olfaction Function in Individuals with Parkinson’s DiseaseAnson B. Rosenfeldt, Tanujit Dey, and Jay L. AlbertsVolume 2016, Article ID 9725089, 6 pages

Cognitive Training in Parkinson’s Disease: A Review of Studies from 2000 to 2014Daniel Glizer and Penny A. MacDonaldVolume 2016, Article ID 9291713, 19 pages

EditorialNonmotor Symptoms of Parkinson’s Disease

Shey-LinWu,1 Rajka M. Liscic,2,3 SangYun Kim,4 Sandro Sorbi,5 and Yuan-Han Yang6,7,8

1Department of Neurology, Changhua Christian Hospital, Changhua, Taiwan2Department of Neurology, RHON Kliniken, Lehrkrankenhaus Philipps Universitat, Marburg, Germany3Department of Anatomy and Neuroscience, School of Medicine, University of Osijek, Osijek, Croatia4Neurocognitive Behavior Center, Seoul National University Bundang Hospital, Seongnam, Republic of Korea5Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence and IRCCS Don Gnocchi Firenze,Florence, Italy6Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan7Department of Master’s Program in Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University,Kaohsiung, Taiwan8Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan

Correspondence should be addressed to Yuan-Han Yang; [email protected]

Received 14 February 2017; Accepted 16 February 2017; Published 2 March 2017

Copyright © 2017 Shey-Lin Wu et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

The classical clinical features of the Parkinson’s disease (PD)are the motor disorders, in which parkinsonism is definedby the presence of bradykinesia plus at least one additionalmotor sign, rest tremor, rigidity, or impaired postural reflexes,the well-known clinical criteria [1]. However in the recentdecades, scientists and physicians have received a lot of atten-tion of the relevance and frequency of nonmotor symptoms(NMS) independently or dependently along with the motorsymptoms [2, 3]. In PD, in general, in its different stages ofdisease it could be found that overall 98.6% of the PD patientshave reported the presence of one or several NMS [4].Those reported NMS might include olfactory dysfunction,neuropsychiatric manifestations as depression or cognitiveimpairments, sleep disorders as rapid eyemovement behaviordisorder, autonomic dysfunctions as gastrointestinal disor-ders, postural hypotension or urinary disorders, and fatiguepain.

Among NMS, cognitive impairment is one of the mostcommon and significant aspects of PD.The cognitive deficitssuch as executive deficit or visuospatial disturbances couldseriously affect the quality of life, reduce life expectancy,prolong the duration of hospitalization, or therefore increaseburdens of caregiver [5, 6]. The pathophysiology of cognitivedeficits in PD is complex perhaps due to its complexity andvariability from patient to patient. Furthermore, the treat-ment of cognitive impairment including pharmacotherapy

and nonpharmacotherapy (e.g., cognitive training) is stillwith the limited evidence [7, 8].

Gastrointestinal dysfunction might occur at all stages ofPD, often preceding the onset of central motor symptom.Evidence for abnormal 𝛼-synuclein throughout the entericnervous system is growing [9]. Different gastrointestinalsymptoms, such as dental problem, drooling, dysphagia,gastroparesis, gastroesophageal reflux, constipation, difficultdefecation, or loss of weight, are frequent events in allthe stages of Parkinson’s disease. The treatment of thesesymptoms is still variable and inconclusive.

In addition to pharmacotherapy, deep brain stimulation(DBS) is a powerful surgical treatment for many aspectsof Parkinson disease but lacks consensus inasmuch as theimpact of the DBS procedure on executive brain functions[10].

People with PD may experience felt stigma, such asshame, embarrassment, and disgrace, and enacted stigmawhen encountering responses of others, such as staring, ques-tioning, and avoiding, to their visible features of movementand communication difficulties [11]. The qualitative researchmay allow a better understanding of a subjective symptomsuch as stigma in parkinsonian patients from an interculturaland a social point of view.

In order to reach such purposes, this special issue willmainly focus on nonmotor symptoms of PD with its content

HindawiParkinson’s DiseaseVolume 2017, Article ID 4382518, 2 pageshttp://dx.doi.org/10.1155/2017/4382518

http://dx.doi.org/10.1155/2017/4382518

2 Parkinson’s Disease

including above-mentioned topics. We sincerely hope thatthis special issue will provide interesting new data as well ascomprehensive up-to-date reviews for all readers.

Shey-Lin WuRajka M. LiscicSangYun KimSandro Sorbi

Yuan-Han Yang

References

[1] A. J. Hughes, S. E. Daniel, Y. Ben-Shlomo, and A. J. Lees, “Theaccuracy of diagnosis of parkinsonian syndromes in a specialistmovement disorder service,” Brain, vol. 125, no. 4, pp. 861–870,2002.

[2] A. Schrag, M. Jahanshahi, and N. Quinn, “What contributes toquality of life in patients with Parkinson’s disease?” Journal ofNeurology Neurosurgery and Psychiatry, vol. 69, no. 3, pp. 308–312, 2000.

[3] K. R. Chaudhuri, D. G. Healy, and A. H. V. Schapira, “Non-motor symptoms of Parkinson’s disease: diagnosis andmanage-ment,” Lancet Neurology, vol. 5, no. 3, pp. 235–245, 2006.

[4] M. B. Stern, A. Lang, and W. Poewe, “Toward a redefinition ofParkinson’s disease,”Movement Disorders, vol. 27, no. 1, pp. 54–60, 2012.

[5] T. C. Buter, A. Van Den Hout, F. E. Matthews, J. P. Larsen, C.Brayne, and D. Aarsland, “Dementia and survival in Parkinsondisease: a 12-year population study,” Neurology, vol. 70, no. 13,pp. 1017–1022, 2008.

[6] M. A. Hely, W. G. J. Reid, M. A. Adena, G. M. Halliday, and J. G.L.Morris, “The sydneymulticenter study of Parkinson’s disease:the inevitability of dementia at 20 years,” Movement Disorders,vol. 23, no. 6, pp. 837–844, 2008.

[7] A. Petrelli, S. Kaesberg, M. T. Barbe et al., “Effects of cognitivetraining in Parkinson’s disease: a randomized controlled trial,”Parkinsonism and Related Disorders, vol. 20, no. 11, pp. 1196–1202, 2014.

[8] E. Mamikonyan, S. X. Xie, E. Melvin, and D.Weintraub, “Rivas-tigmine for mild cognitive impairment in Parkinson disease: aplacebo-controlled study,” Movement Disorders, vol. 30, no. 7,pp. 912–918, 2015.

[9] M. G. Cersosimo, G. B. Raina, C. Pecci et al., “Gastrointestinalmanifestations in Parkinson’s disease: prevalence and occur-rence before motor symptoms,” Journal of Neurology, vol. 260,no. 5, pp. 1332–1338, 2013.

[10] C. E. Morrison, J. C. Borod, M. F. Brin et al., “A Program forNeuropsychological Investigation of Deep Brain Stimulation(PNIDBS) in movement disorder patients: development, feasi-bility, and preliminary data,” Neuropsychiatry, Neuropsychologyand Behavioral Neurology, vol. 13, no. 3, pp. 204–219, 2000.

[11] D. Rao, S.W. Choi, D. Victorson et al., “Measuring stigma acrossneurological conditions: the development of the stigma scale forchronic illness (SSCI),”Quality of Life Research, vol. 18, no. 5, pp.585–595, 2009.

Review ArticleMeta-Analysis of the Relationship between Deep BrainStimulation in Patients with Parkinson’s Disease andPerformance in Evaluation Tests for Executive Brain Functions

A. M. Martínez-Martínez,1 O. M. Aguilar,2 and C. A. Acevedo-Triana1

1Department of Psychology, Pontificia Universidad Javeriana, Bogota, Colombia2Department of Brain Repair and Rehabilitation, University College London, London, UK

Correspondence should be addressed to C. A. Acevedo-Triana; [email protected]

Received 25 August 2016; Accepted 11 October 2016; Published 8 February 2017

Academic Editor: Rajka M. Liscic

Copyright © 2017 A. M. Martınez-Martınez et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Parkinson’s disease (PD) is a neurodegenerative condition, which compromises the motor functions and causes the alteration ofsome executive brain functions.The presence of changes in cognitive symptoms in PD could be due to the procedure of deep brainstimulation (DBS). We searched in several databases for studies that compared performance in executive function tests before andafter the DBS procedure in PE and then performed a meta-analysis. After the initial search, there were 15 articles that specificallyevaluated the functions of verbal fluency, working memory, cognitive flexibility, abstract thinking, and inhibition. It was found thatthere were differences in the evaluation of the cognitive functions in terms of the protocols, which generated heterogeneity in theresults of the meta-analysis. Likewise, a tendency to diminish functions like verbal fluency and inhibition was found, being thisconsistent with similar studies. In the other functions evaluated, no difference was found between pre- and postsurgery scores.Monitoring of this type of function is recommended after the procedure.

1. Introduction

Parkinson’s disease (PD) is a common, progressive and incur-able neurodegenerative disease with an unknown etiology,whose main symptoms include motor alterations such asshaking, an abnormal increase in muscle tone, bradykine-sia, postural instability, impaired balance and walking, andemotional inexpressiveness [1–6]. In postmortem studies ofpatients with PD, these clinical features have been directlyrelated to the reduction of dopamine neurons in the cortical-thalamus-striated loop [1, 4–7], mitochondrial alterations[4], and the presence of clusters of 𝛼-synuclein presynapticprotein, known as Lewy bodies [4, 7, 8].

From a neurological perspective, the symptoms of PDhave been considered to be the result of alterations in thecommunication between the direct/indirect motor controlpathways of the basal ganglia. According to this “classic”model, this deficiency in communication is given by a reduc-tion in the dopaminergic transmission which in turn resultsin the diminished inhibition of the indirect pathway, the

excitation of the direct pathway, and the excessive activationin the discharge of internal globus pallidus (GPi) and aninhibition of the thalamic cortical motor system [9, 10].Given the model’s limitations in explaining PD systems otherthan the motor ones, it is recognized that the Cortico-BasalGanglia-Thalamus loop is implied in eye movement controlfunctions (the oculomotor circuit) [11], memory and spatialorientation (dorsolateral prefrontal circuit) [10], behavioraladjustment and control, and the reward and punishmentsystem (lateral orbitofrontal circuit) [9].

It has been suggested that cognitive [9], emotional [12],and behavioral [13] alterations can be generated in theBG-cortex communication. In this same sense, although ithas not been a characteristic present in all the reports, asignificant metabolic reduction has been found in patientswith Parkinson’s disease, predominantly in areas of parietaland medial frontal association [5].

Among the nonmotor clinical symptoms there is a broadspectrum of alterations at cognitive [1, 9, 14], emotional,mood [15], behavioral [16, 17], and psychiatric levels [17,

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18]. In some cases, the cognitive deficit is comparable toexecutive alterations similar to patients with lesions in thefrontal lobe, given the reduction of dopaminergic activityin the frontostriatal circuits, but without being considered a“frontal lobe syndrome,” leading to episodic alterations andvisuospatial and verbal fluency dysfunctions [9, 19]. Previousstudies have reported on the appearance of alterations in tasksthat assess executive brain functions, such as verbal fluency[20], Trail Making Test (TMT-B), Wisconsin Card SortingTest (WCST), Stroop [19],Theory ofMind [21, 22], and timingdeficits [23].

The treatments reported for PD include dopamine antag-onist pharmacological treatments [2, 3, 24], physical ther-apy [25, 26], genetic therapy [24], transcranial magneticstimulation [15, 27, 28], injury to the subthalamic nucleus[29], and high frequency deep brain stimulation (DBS) [30–37]. The latter has been proven to reduce the severity ofmotor symptoms, to reduce pharmacological treatment sig-nificantly, and to improve patients’ quality of life [1, 31, 32, 35,36, 38–40]. DBS has been reported in subcortical structuressuch as the subthalamic nucleus (STN), the internal globuspallidus (GPi), the pedunculopontine nucleus (PPN), andprelemniscal radiation [35, 36, 41–45]. Stimulator frequencydepends on the patient’s clinical aspects and the location ofthe electrodes [31, 42].

In the assessment of nonmotor symptoms (disturbedsleep patterns, salivation, mood, cognitive, and executivefunction), it has been reported that theDBS procedure fostersa number of changes. In DBS of the STN, Bickel et al. [29]found that general performance remained constant in frontalexecutive function tests [16, 23]. In bilateral DBS of the STN,significant improvement has been reported in the learning ofverbal information and visuoconstructive skills when thereis increased stimulator amplitude [38, 46]. Inasmuch as theDBS of the PPN, improvements have been reported in termsof tasks related to working memory (MT) [23, 47]. It has alsobeen reported that STN-DBS is involved in the generation ofimpulse control disorders but that this is not a maintainedeffect [48].

Some studies have identified metabolic changes associ-ated with execution of tasks, reporting that there is an activityreduction network in PD that includes the supplementarymotor area (preSMA), precuneus, the inferior parietal lobe,and the left prefrontal cortex, as well as an increase in thecerebellar vermis and the dentate nucleus, probably dueto the cerebellum-BG connections [5, 49]. Changes in thestructures of this area can be seen in tasks that involvecognitive performance which may suggest that alterationsin the network play a role in other cognitive functions[50].

A central aspect of this study is the DBS procedure andits impact on nonmotor symptoms in PD [40]. Thus, a meta-analysis of 28 studies was carried out of studies by Parsonset al. [51]. The authors analyzed the cognitive consequencesof STN-DBS, concluding that the procedure presents a smalleffect on all the cognitive domains assessed, except on verbalfluency, shedding light on a lower statistically significantperformance in phonetic and semantic verbal fluency testsafter DBS.

Given the lack of consensus inasmuch as the impact of theDBS procedure on executive brain functions specifically, theaimof this studywas to identify changes in the executive brainfunctions tests after DBS in six months or more, reported inthe last ten years. To do this, we used studies that showedresults for before and after DBS and analyzed these usingmeta-analysis.

2. Method

2.1. Study Selection. An information search was carried outin the Scopus databases using the following key words:“deep AND brain AND stimulation AND Parkinson ANDexecutive AND functions.” The search yielded 126 articlesthat covered the 2005–2015 period.Using the same keywords,the Pubmed database yielded 39 results; the Web of Science(WOS) database, 104 results; the Sage journals database, 142results; the Taylor Francis Online database, 125 results; theWiley Online Library, 1362 results; the Embase database,149 results; and Proquest, 3295 results. Finally, using thePsychNET database, the search initially gave no results; thusit was modified using the words “Parkinson AND DBS,”yielding 6 results. This gave a total of 5348 records in 9databases.The results were subsequently grouped by year andtypes of journal articles.

The cleaning process was undertaken in two phases.The first was a selection of articles published in sciencejournals, excluding reviews, meta-analyses, and case studies.The results for this first phase are shown in Figure 1.

2.2. Study Inclusion Criteria. The studies were selected con-sidering the following recommendations: (a) types of design;(b) types of intervention; (c) participant characteristics; (d)statistical data; and (e) the tests used [52]. All the reportedstudies were written in English and dated between 2005and 2015. The inclusion criteria for this meta-analysis werethe following: (a) pre- and postsurgery testing of stimulatorimplantation; (b) for the target, the subthalamic nucleus,globus pallidus, and other structures related to movement;(c) sociodemographic variables were not taken into accountfor participant characteristics (age, how long the patient hashad the disease, educational level, and type of medication);(d) studies that reported means, standard deviations, 𝑡-tests,significance levels; and (e) only those studies that reportedsome kind of test that assessed executive brain functions(working memory, verbal fluency, cognitive flexibility, plan-ning, inhibition, and abstract thinking) and processing speed.Figure 1 outlines the search procedure. Nonadditional studieswere identified by contacting clinical experts and searchingbibliographies in local repositories.

2.3. Codification of the Studies. The studies were codifiedindependently by 4 researchers and the codified informationwas subsequently corroborated.The following characteristicswere taken into account for the codification: (a) identificationof the study by the first author’s surname and the year ofpublication; (b) the number of participants; (c) the studydesign (before and after surgery; only after surgery; casesand controls; and correlational); (d) location of implanted

Parkinson’s Disease 3

Literature search

Databases: Scopus = 126, Pubmed = 39, Web ofScience = 104, Sage journal = 142, Taylor FrancisOnline = 125, Wiley Online = 1362, Embase = 149,

Proquest = 3295, and PsychNET = 6

Search results combined (n = 5348)

Articles screened on basis of titleand abstract

Included (n = 462)

Included (n = 50)

Manuscript review and applicationof inclusion criteria

Workingmemory

Verbalfluency

Cognitiveflexibility

Planning Inhibition Abstractthinking

Excluded (n = 4886)

Meta-analysis and reviews studiesCase studiesWithout neuropsychological evaluationScience journals

Excluded (n = 412)

No pre- and postsurgery testingStimulator outside of the subthalamicnucleus, globus pallidus, and otherstructures related to movementStudies that nonreported means,standard deviations, t-tests, andsignificance levelsOnly those studies that reported somekind of test that assessed executivebrain functions

Figure 1: Flow diagram of study selection. Adapted from Liberati et al. [53].

deep brain stimulation (subthalamus; globus pallidus; andother); (e) parameter related to the stimulator (pulse, fre-quency, voltage, and electrode type); (f) schooling (secondaryeducation, university education, graduate studies, none, andnot reported); (g) age (under 50, 51–60, 61–70, over 70,and not reported); (h) time of suffering from PD symptomsbefore brain stimulation surgery (short, less than 5 years;medium, 6–10 years; late, more than 10 years; and notreported); (i) sex (men, women, mixed, and not reported);(j) socioeconomic status (reported, not reported); (k) type ofmedication; (l) results values associated with the executivebrain functions tests undertaken (Table 1); and (m) timebefore assessment after the stimulator implantation surgery.When the informationwas codified for themeta-analysis, thetime after stimulator implantation variable was not taken asa homogenization criterion for the studies. That is, for thosethat presented more than one posterior measurement, themeasurement closest to 12 months after the surgery was used.

The executive brain functions considered in the studyanalysis include verbal fluency, cognitive flexibility, work-ing memory, processing speed, behavioral inhibition, andplanning (Table 2). Following Parsons et al. [51], the verbalfluency assessment tasks were separated due to the reportedsystematic reduction of the verbal fluency function in patients

with PD with DBS and the difference (category or letters) interms of task processing.

2.4. Statistical Analysis. The mean scores of the tests under-taken were calculated and Hedges’s 𝑔 values and standarderror (SE) for each study are reported together with 95%confidence intervals (CIs). It was assumed that if value 𝐼2was below 50% of heterogeneity, a meta-analysis with a fixedeffects model would be applied; otherwise, a random effectsmodel would be used [57].

To assess the publication bias, a funnel plot was used foreach of the meta-analyses [58]. The meta-analysis and funnelplot were carried out using the ComprehensiveMeta-analysis2.0 software. 𝑝 < 0.05 value was considered to have statisticalsignificance.

3. Results

Once the search was refined, 5348 studies were analyzed(Figure 1). Figure 1 shows the results of the initial search.

3.1. Descriptive. The descriptive results are shown in Table 2which outlines the studies, number of patients, age, time


Table1:Dem

ograph

icandclinicalaspectsof

patie

ntsinstu

dies

andfre

quency

ofneurop

scyhologicaltests

.

Stud

y𝑁

Cou

ntry

Design

Target

Age

Education

(years)

Onset

Parkinson

disease

Hoehn

&Yahr

stage

Timeto

poste

valua-

tionin

mon

ths

Pulse

Frequency

Voltage

Electro

des

Verb

fluency-sem

antic

Takehiko-Yam

anakae

tal.

(2012)

30Japan

Pre-po

stST

N61,1(9,1)

12,5(4,5)

11,5(5,7)

—1,12

90𝜇s

130H

z2,4

Mon

opolar

Daniels(2012)

60Germany

Pre-po

st+

control

STN

60,2(7,9)

—13,8(6,3)

2,29

(0,72)

660𝜇s

130H

z—

—

Caste

llietal.[54]

19Ita

lyPre-po

stST

N62,1(4,2)

—14,7(5)

—17

Right6

1,6(6,9),

left61,6(6,9)

Right3,2(0,4),

left3,2(0,5)

Mon

opolar

bilateral

Zang

aglia

etal.(2009)

65Ita

lyPre-po

st+

control

STN

58,84(7,70)

7,31(3,21)

11,84(5,07)

2,34

(0,43)

1,6,12,24,

36Semim

icroele

ctrode

Tang

(2015)

27Ch

ina

Pre-po

stST

N6,12

——

—Bilateral

Rothlin

d(2015)

164

USA

Pre-po

st+

control

STN+GPi

62,3(8,9)

14,8(3)

12,8(5,5)

3,3(0,9)

6—

——

Bilateral

Hou

venagh

el(2015)

26France

Pre-po

st+

control

STN

55,8(6,2)

10,1(2,4)

11,7(4)

1,8(0,8)

3—

——

Bilateral

Tram

ontana

(2015)

30USA

Pre-po

st+

control

STN+

medicine

60(7)

—2,2(1,4)

26y12

——

—Bilateral

Verb

fluency-pho

nemic

Takehiko-Yam

anaka(

2012)

30Japan

Pre-po

stST

N61,1(9,1)

12,5(4,5)

11,5(5,7)

—1,12

90𝜇s

130H

z2,4V

Mon

opolar

Merolae

tal.,(2011)

20Ita

lyPre-po

st+

control

STN+OTH

ER66

,5(2,5)

—16,4(4,3)

—14

——

——

Danielsetal.,2010

60Germany

Pre-po

st+

control

STN

60,2(7,9)

—13,8(6,3)

2,29

(0,72)

660𝜇s

130H

z—

—

Caste

llietal.,[54]

19Ita

lyPre-po

stST

N62,1(4,2)

—14,7(5)

—17

Right6

1,6(6,9),

left61,6(6,9)

Right3,2(0,4),

left3,2(0,5)

Mon

opolar

bilateral

LeJeun

eetal.[55]

13France

Pre-po

st+

control

STN

57(7,8)

—10,9(2,2)

——

64,6

R135,3H

z,L136,5H

zRight2,3Vy,left

2,4V

Quadripolar

Saez-Zea,etal.(2012)

9Spain

Pre-po

stST

N54

(14)

—12

(2)

3—

——

—Ca

stelli

etal.,(2010)

27Ita

lyPre-po

stST

N60,6(6,7)

8(4,1)

15,3(5,1)

—1

——

——

Rothlin

d(2015)

164

USA

Pre-po

st+

control

STN+GPi

62,3(8,9)

14,8(3)

12,8(5,5)

3,3(0,9)

6—

——

Bilateral

Hou

venagh

el(2015)

26France

Pre-po

st+

control

STN

55,8(6,2)

10,1(2,4)

11,7(4)

1,8(0,8)

3—

——

Bilateral

Tram

ontana

(2015)

30USA

Pre-po

st+

control

STN+

medicine

60(7)

—2,2(1,4)

26y12

——

—Bilateral


Table1:Con

tinued.

Stud

y𝑁

Cou

ntry

Design

Target

Age

Education

(years)

Onset

Parkinson

disease

Hoehn

&Yahr

stage

Timeto

poste

valua-

tionin

mon

ths

Pulse

Frequency

Voltage

Electro

des

Wisc

onsin

Card

SortingTest(W

CST)

Zang

aglia

(200

9)32

Italy

Pre-po

st+

control

STN

58,84(7,70)

7,31(3,21)

11,84(5,07)

2,34

(0,43)

1,6,12,24,

36Semim

icroele

ctrode

Fraraccio,(2008)

15Ca

nada

On-off

STN

58,1(7,46)

11,3(3,97)

13,6(4,39

)—

19Left:

94,0,right:

94,0

Left:

185H

z,rig

ht:185

Hz

Left:

2,8,rig

ht:2,8

Quadripolar

Williamse

tal.(2011)

19USA

Post

STN

62,1(10,3)

13,6(1,71)

10,1(6,24)

1,5–3,0

24—

——

—

Rothlin

d(2015)

164

USA

Pre-po

st+

control

STN+GPi

62,3(8,9)

14,8(3)

12,8(5,5)

3,3(0,9)

6—

——

Bilateral

Tram

ontana

(2015)

30USA

Pre-po

st+

control

STN+

medicine

60(7)

—2,2(1,4)

26y12

——

—Bilateral

Nels

onMod

ified

WSC

T

Caste

llietal.[54]

19Ita

lyPre-po

stST

N62,1(4,2)

—14,7(5)

—17

Right6

1,6(6,9),

left61,6(6,9)

right

3,2(0,4),

left3,2(0,5)

Mon

opolar

bilateral

Caste

lli,(2010)

27Ita

lyPre-po

stST

N60,6(6,7)

8(4,1)

15,3(5,1)

—1

——

——

Fasano

(2010)

20Ita

lyPre-po

stST

N56,9(7,2)

—13,7(4,8)

35,8

60𝜇s

130H

z—

—Le

juene,(2010)

13France

Pre-po

stST

N57

(7,8)

—10,9(2,2)

—3

2,7(±0,5)

68,7(±13,9)

38,1(±17,1)

Quadripolar

LeJeun

eetal.,[55]

13France

Pre-po

st+

control

STN

57(7,8)

—10,9(2,2)

——

64,6

R135,3H

z,L136,5H

zRight2,3V,

left

2,4V

Quadripolar

Hou

venagh

el(2015)

26France

Pre-po

st+

control

STN

55,8(6,2)

10,1(2,4)

11,7(4)

1,8(0,8)

3—

——

Bilateral

TrailM

akingTest(TMT-B)

Takehiko-Yam

anaka(

2012)

30Japan

Pre-po

stST

N61,1(9,1)

12,5(4,5)

11,5(5,7)

—1,12

90𝜇s

130H

z2,4V

Mon

opolar

Merola(

2011)

20Ita

lyPre-po

st+

control

STN+OTH

ER66

,5(2,5)

—16,4(4,3)

—14

——

——

Williams(2011)

19USA

Post

STN

62,1(10,3)

13,6(1,71)

10,1(6,24)

1,5–3,0

24—

——

—

Caste

llietal.[54]

19Ita

lyPre-po

stST

N62,1(4,2)

—14,7(5)

—17

Right6

1,6(6,9),

left61,6(6,9)

Right3,2(0,4),

left3,2(0,5)

Mon

opolar

bilateral

Lejuene,(2010)

13France

Pre-po

stST

N57

(7,8)

—10,9(2,2)

—3

2,7(±0,5)

68,7(±13,9)

38,1(±17,1)

Quadripolar

LeJeun

eetal.[55]

13France

Pre-po

st+

control

STN

57(7,8)

—10,9(2,2)

——

64,6

R135,3H

z,L136,5H

zRight2,3Vy,left

2,4V

Quadripolar


Table1:Con

tinued.

Stud

y𝑁

Cou

ntry

Design

Target

Age

Education

(years)

Onset

Parkinson

disease

Hoehn

&Yahr

stage

Timeto

poste

valua-

tionin

mon

ths

Pulse

Frequency

Voltage

Electro

des

Caste

lli,(2010)

27Ita

lyPre-po

stST

N60,6(6,7)

8(4,1)

15,3(5,1)

—1

——

——

Smedingetal.(2005)

20Netherla

nds

Pre-po

st+

control

STN+GP

59,2(8,6)

10,7(1,9)

12(3–50)

2,5(1,0–5,0)

6,12

——

——

Rothlin

d(2015)

164

USA

Pre-po

st+

control

STN+GPi

62,3(8,9)

14,8(3)

12,8(5,5)

3,3(0,9)

6—

——

Bilateral

Hou

venagh

el(2015)

26France

Pre-po

st+

control

STN

55,8(6,2)

10,1(2,4)

11,7(4)

1,8(0,8)

3—

——

Bilateral

PanTestFo

rward

Takehiko-Yam

anaka(

2012)

30Japan

Pre-po

stST

N61,1(9,1)

12,5(4,5)

11,5(5,7)

—1,12

90𝜇s

130H

z2,4V

Mon

opolar

CorsiSpan

Backward

Smeding,(2005)

20Netherla

nds

Pre-po

st+

control

STN

59,2(8,6)

10,7(1,9)

12(3–50)

2,5(1,0–5,0)

6,12

——

——

Fasano

(2010)

20Ita

lyPre-po

stST

N56,9(7,2)

—13,7(4,8)

35,8

60𝜇s

130H

z—

—

Caste

llietal.[54]

19Ita

lyPre-po

stST

N62,1(4,2)

—14,7(5)

—17

Right6

1,6(6,9),

left61,6(6,9)

right

3,2(0,4),

left3,2(0,5)

Mon

opolar

bilateral

Caste

lli,(2010)

27Ita

lyPre-po

stST

N60,6(6,7)

8(4,1)

15,3(5,1)

—1

——

——

Backwarddigits

Takehiko-Yam

anaka(

2012)

30Japan

Pre-po

stST

N61,1(9,1)

12,5(4,5)

11,5(5,7)

—1,12

90𝜇s

130H

z2,4V

Mon

opolar

Daniels(2010)

60Germany

Pre-po

st+

control

STN

60,2(7,9)

—13,8(6,3)

2,29

(0,72)

—60𝜇s

130H

zAd

juste

dfore

ach

one

Bilateral

Fasano

(2010)

20Ita

lyPre-po

stST

N56,9(7,2)

—13,7(4,8)

35,8

60𝜇s

130H

z—

—

Fraraccio,(2008)

15Ca

nada

On-off

STN

58,1(7,46)

11,3(3,97)

13,6(4,39

)—

19Left:

94,0,right:

94,0

Left:

185H

z,rig

ht:185

Hz

Left:

2,8,rig

ht:2,8

Quadripolar

Witt

etal.[56]

60Germany

Pre-po

st+

control

STN

60,2(7,9)

—13,8(6,3)

3,62

(0,85)

6—

——

—

Rothlin

d,etal.(2007)

29USA

On-off

STN+GP

61,4(10,11)

15,2(3,21)

12,9(4,3)

3,3(0,45)

——

——

—

Zang

aglia

(200

9)32

Italy

Pre-po

st+

control

STN

58,84(7,70)

7,31(3,21)

11,84(5,07)

2,34

(0,43)

1,6,12,24,

36Semim

icroele

ctrode

Rothlin

d(2015)

164

USA

Pre-po

st+

control

STN+GPi

62,3(8,9)

14,8(3)

12,8(5,5)

3,3(0,9)

6—

——

Bilateral

Tang

(2015)

27Ch

ina

Pre-po

stST

N6,12

——

—Bilateral

TrailM

akingTest(TMT-A)

Takehiko-Yam

anaka(

2012)

30Japan

Pre-po

stST

N61,1(9,1)

12,5(4,5)

11,5(5,7)

—1,12

90𝜇s

130H

z2,4V

Mon

opolar

Smeding,(2005)

20Netherla

nds

Pre-po

st+

Con

trol

STN+GP

59,2(8,6)

10,7(1,9)

12(3–50)

2,5(1,0–5,0)

6,12

——

——

Williams(2011)

19USA

Post

STN

62,1(10,3)

13,6(1,71)

10,1(6,24)

1,5–3,0

24—

——

—Stroop

Williams(2011)

19USA

Post

STN

62,1(10,3)

13,6(1,71)

10,1(6,24)

1,5–3,0

24—

——

—

Daniels(2010)

60Germany

Pre-po

st+

control

STN

60,2(7,9)

—13,8(6,3)

2,29

(0,72)

—60𝜇s

130H

zAd

juste

dfore

ach

one

Bilateral

Smeding,(2005)

20Netherla

nds

Pre-po

st+

control

STN+GP

59,2(8,6)

10,7(1,9)

12(3–50)

2,5(1,0–5,0)

6,1

——

——

Moreines,(2014)

17Pre-po

stOTH

12

—91𝜇s

130H

z—

—


Table1:Con

tinued.

Stud

y𝑁

Cou

ntry

Design

Target

Age

Education

(years)

Onset

Parkinson

disease

Hoehn

&Yahr

stage

Timeto

poste

valua-

tionin

mon

ths

Pulse

Frequency

Voltage

Electro

des

Fraraccio,(2008)

15Ca

nada

On-off

STN

58,1(7,46)

11,3(3,97)

13,6(4,39

)—

19Left:

94,0,right:

94,0

Left:

185H

z,rig

ht:185

Hz

Left:

2,8,rig

ht:2,8

Quadripolar

LeJeun

eetal.[55]

13France

Pre-po

st+

Con

trol

STN

57(7,8)

—10,9(2,2)

——

64,6

R135,3H

z,L136,5H

zRight2,3Vy,left

2,4V

Quadripolar

Rothlin

d,(2007)

29USA

On-off

STN+GP

61,4(10,11)

15,2(3,21)

12,9(4,3)

3,3(0,45)

——

——

—Le

juene,(2010)

13France

Pre-po

stST

N57

(7,8)

—10,9(2,2)

—3

2,7(±0,5)

68,7(±13,9)

38,1(±17,1)

Quadripolar

Witt

etal.[56]

60Germany

Pre-po

st+

Con

trol

STN

60,2(7,9)

—13,8(6,3)

3,62

(0,85)

6—

——

—

Rothlin

d(2015)

164

USA

Pre-po

st+

control

STN+GPi

62,3(8,9)

14,8(3)

12,8(5,5)

3,3(0,9)

6—

——

Bilateral

Hou

venagh

el(2015)

26France

Pre-po

st+

control

STN

55,8(6,2)

10,1(2,4)

11,7(4)

1,8(0,8)

3—

——

Bilateral

Tram

ontana

(2015)

30USA

Pre-po

st+

control

STN+

medicam

60(7)

—2,2(1,4)

26,12

——

—Bilateral

Planificatio

n

Zang

aglia

(200

9)65

Italy

Pre-po

st+

control

STN

58,84(7,70)

7,31(3,21)

11,84(5,07)

2,34

(0,43)

1,6,12,24,

36Semim

icroele

ctrode

Caste

lli,(2010)

27Ita

lyPre-po

stST

N60,6(6,7)

8(4,1)

15,3(5,1)

—1

——

——

Fasano

(2010)

20Ita

lyPre-po

stST

N56,9(7,2)

—13,7(4,8)

35,8

60𝜇s

130H

z—

—

Caste

llietal.[54]

19Ita

lyPre-po

stST

N62,1(4,2)

—14,7(5)

—17

Right6

1,6(6,9),

left61,6(6,9)

Right3,2(0,4),

left3,2(0,5)

Mon

opolar

bilateral


Table 2

Neuropsychological test 𝑘 𝑁 Age Years PD DBS Heterogeneity𝑄 𝑝 (𝑄) 𝐼2

Verbal fluency-semantic 4 141 60,56 12,96 STNVerbal fluency-Phonetic 7 178 60,21 13,51 STN 19,769 0,032 49,41WSCT 2 51 60,47 10,97 STNWSCT-Nelson 5 92 58,72 13,1 STN 34,759 0,021 42,46Trail Making Test-B 8 161 60,91 12,45 STN 5,26 0,511 0,000Corsi Span Backward 4 86 59,86 14,56 STNDigit Span Test 7 246 59,22 13.06 STN-GPi 3,088 0,686 0,000Trail Making Test-A 3 69 61,6 10,8 STN 0,581 0,748 0,000Stroop 9 246 65,2 12,18 STN-Cingulate (1)-GPi (1) 102,7 0,001 77,6Planning 4 98 59,61 13.85 STNNote: 𝑘, number of studies; 𝑁, number of patients, DBS (deep brain stimulation); 𝑄, heterogeneity intradomain; 𝑝(𝑄) 𝑝 value of 𝑄 statistic; 𝐼2, percent ofheterogeneity from difference.

0.4

0.3

0.2

0.1

0.0

Stan

dard

erro

r

1.00.5−0.5 0.0 1.5 2.0−1.0−1.5−2.0Hedges’s g

Hedges’s gFunnel plot of standard error by

Figure 2: Funnel plot for standard error in publications of verbal fluency.

of illness, schooling, PD alteration scores, and other valuesreported for the studies.

3.2. Meta-Analysis. For this study, a fixed effects model wasused due to two conditions. First, the conditions of theparticipants and characteristics of the disease are similaramong the studies and with this a population effect size istheoretically assumed [52, 59]. On the other hand, giventhat it was previously assumed that the percentage of hetero-geneity exceeded 50% measured by coefficient 𝐼2, a randomeffects model was used [57]. It is important to signal thatonly one study has results of GPi stimulation (Rothlind,2015) and because of this the results and figures were notseparate.

3.3. Verbal Fluency. Figure 2 outlines the funnel plot of theSE for studies of verbal fluency and there is no bias in thestudies reported [58]. In this category, we obtained 21 studiesthat were clustered depending on the evaluation modality(semantic or phonetic), Hedges’s 𝑔was used to determine thesize of the effect, obtaining a medium effect size (Hedges’s 𝑔= −0.266; SE = 0.036; CI −0.337 to −0.195), which showedheterogeneity (𝑄(20) = 42,911; 𝑝 = 0.002) within an averagepercentage (𝐼2 = 53,39%), which, when in excess of 50%, ledto the application of a random model [60]. The results alsoshowed a significant reduction in performance in the test afterthe DBS procedure (𝑍 value = −5,607; 𝑝 < 0.001) (Figure 3).

3.4. Cognitive Flexibility. This functionwas assessed based onthe Wisconsin Shorting Card Test (WSCT) and Trail MakingTest (TMT) in its B and B-A versions. Figure 4 shows thefunnel plot used for the SE in WSCT; the figure shows threepoints outside the projection in the upper threshold, but theseare shown as equivalents to the points on the lower threshold.Themeta-analysis obtained 27 results in which theWisconsinShorting Card Test (WSCT) in its different versions (NelsonorModified)was assessed, bearing inmind the different typesof scores (errors, perseverations, or categories). A small effectsize was found (Hedges’s 𝑔 = 0.064; SE = 0.053; CI −0.04to 0.167), showing heterogeneity (𝑄(26) = 44,94; 𝑝 = 0.012)within an average percentage (𝐼2 = 42,14%), but withoutexceeding 50% [43, 60]. There seems to be no significantchange in the test scores after the DBS procedure (𝑍 value= 1,656; 𝑝 = 0.098) (Figure 5).

Using the Trail Making Test (TMT-A), 6 results wereobtained; Figure 6 shows the funnel plot for the SE of thetest, and no biases are observed. The studies in the meta-analysis reveal no differences in terms of execution (𝑍 value= −0.328; 𝑝 = 0.743), the effect detected was small (Hedges’s𝑔 = −0.02; SE = 0.061; CI −0.14 to 0.1), and the results showedhomogeneity (𝑄(5) = 3,202;𝑝 = 0.669) within the 0%value (𝐼2= 0%) (Figure 7). With respect to the other tests for the samefunction such as version B of the TMT, 10 of the results founddid not reveal an important change between the applications(𝑍 value = 0.912; 𝑝 = 0.362), the effect detected was small


Standarderror

Study name Subgroupwithin study

Statistics for each study

Lower limit Upper limitVariance

Rothlind et al., 2015 (STN) PhoneticRothlind et al., 2015 (GPi) PhoneticTramontana et al., 2015 PhoneticHouvenaghel et al., 2015 PhoneticTakehiko. Y et al. 2012 Phonetic

PhoneticMerola et al. 2011 PhoneticLe Jeune et al., 2008 Phonetic 0.689Daniels et al. 2012 PhoneticCastelli et al., 2010 PhoneticCastelli et al. 2007 PhoneticRothlind et al., 2015 (STN) SemanticRothlind et al., 2015 (GPi)

Semantic

0.677Tramontana et al., 2015

Semantic

Houvenaghel et al., 2015Semantic

Semantic

SemanticSemantic

SemanticSemantic

Takehiko. Y et al. 2012Daniels et al. 2012Zangaglia, R., et al. 2009Bergamasco et al 2007Tang et al, 2015 (STN)Tang et al, 2015 Semantic

0.00 1.00 2.00

Desfavorable Favorable

Z value p value

−0.216 −0.432 −0.001 −1.966

−1.660

−0.677−2.092−2.831

−2.744−3.309

−2.336−1.091−3.309−1.966

−0.933−0.681

−0.532

−3.309−2.179

−2.771 −2.771 −7.328

−1.897

−0.035−0.180

−0.340

−0.049

−0.001

−0.265−0.029

−0.164−0.164−0.195

−0.351

−0.310

0.143−0.294−1.070

−1.857−1.327

−1.372

−1.036−0.538−0.685−0.550−0.954−0.954−0.337

−0.146−0.717−0.505

−0.991−0.659

−0.333−0.560−0.576

−0.432

−0.076−0.553−0.585−0.302−1.083−0.8340.181−0.305−0.206−0.862−0.216

−0.231−0.130−0.651−0.283−0.337−0.117−0.559−0.559−0.266

0.077

0.0120.0120.0700.0430.0330.1560.0630.0690.0170.0360.0680.0120.0130.0610.0360.0390.0170.0320.0490.0410.0410.001

0.1100.1120.2640.2070.1820.3950.2520.2620.1300.1890.2600.1100.1140.2480.1910.1970.1300.1780.2210.2020.2020.036

0.055

0.694

0.164

0.3000.2550.244

0.0110.315

0.0010.0490.4990.3510.4960.0010.0290.0580.5950.0060.0060.000

0.0490.4990.0360.0050.0970.0060.0010.4910.0190.275

−1.00−2.00

S aez-Zea C. et al., 2012

Hedges’s gHedges’s g and 95% CI

Figure 3: Meta-analysis of verbal fluency comparing before and after DBS surgery. Verbal fluency was separated in phonetic and semanticparts. STN = subthalamic nucleus; GPi = internal globus pallidus.

0.4

0.3

0.2

0.1

0.0

Stan

dard

erro

r

1.00.5−0.5 0.0 1.5 2.0−1.0−1.5−2.0Hedges’s g


Figure 4: Funnel plot for standard error in publications of cognitive flexibility (WSCT).

(Hedges’s 𝑔 = −0.02; SE = 0.053; CI −0.056 to 0.153), and theresults showed homogeneity (𝑄(9) = 6,973; 𝑝 = 0.64) at a verylow percentage (𝐼2 = 0%) (Figure 9). Figure 8 presents thefunnel plot for the SE of the TMT-B. Finally, for the TMT-B-Aversion (5 results) the funnel plot is presented in Figure 10 andno differences were found between applications before andafter the DBS procedure (𝑍 value = −0.404; 𝑝 = 0.686). Theeffect detected was small (Hedges’s 𝑔 = −0.04; SE = 0.099; CI−0.234 to 0.154), and the results showed homogeneity (𝑄(4) =2,251; 𝑝 = 0.69) at a very low percentage (𝐼2 = 0%) (Figure 11).

3.5. Abstract Thinking. Figure 12 shows the funnel plot andno bias among the studies was observed. In this category, 6studies were obtained, and no changes in test performancewere observed after the DBS procedure (𝑍 value = 0.722;𝑝 = 0.471) (Figure 13). A small effect size was obtained(Hedges’s 𝑔 = 0.058; SE = 0.080; CI −0.099 to 0.215), and theresult showed homogeneity (𝑄(5) = 3,088; 𝑝 = 0.686) withina low percentage (𝐼2 = 0%).

3.6. Working Memory. Figure 14 shows the funnel plot andno bias among the studies is observed. In this category, 22

results were obtained, and no changes in test performancewere observed after the DBS procedure (𝑍 value = −1,533;𝑝 = 0.125) (Figure 15). A small effect size was obtained(Hedges’s 𝑔 = −0.051; SE = 0.033; CI −0.115 to 0.014), and theresult showed homogeneity (𝑄(21) = 13,682; 𝑝 = 0.883) at alow percentage (𝐼2 = 0%).

3.7. Inhibition. Figure 16 shows the funnel plot for inhibition;a number of scores outside the lower and upper thresholdswere obtained suggesting a bias in the studies. However,when visual criteria were applied, the bias does not presentitself fully, and there are a number of points close to theupper threshold. What does result from this analysis is a highdegree of heterogeneity between the studies (𝑄(40) = 88,95;𝑝 < 0.001) corresponding to over 89% of the variabilityamong them (𝐼2 = 55,03%). In this category, 41 results wereobtained.

Given this heterogeneity, a random model meta-analysiswas applied and a change in the execution of the test wasobserved as it significantly reduced after the DBS procedure(Z value = −0.406; 𝑝 < 0.001) (Figure 17). A small effectsize was found (Hedges’s 𝑔 = −0.211; SE = 0.039; CI −0.268to −0.135).


1.000.00 2.00−1.00−2.00


Standarderror



Lower limit Upper limitVariance Z value p value

MWCSTMWCSTMWCSTMWCSTMWCSTMWCSTMWCSTMWCSTWSCTWSCTWSCTWSCTWSCTWSCTWSCTWSCTWSCT

WSCT NelsonWSCT NelsonWSCT NelsonWSCT NelsonWSCT NelsonWSCT NelsonWSCT NelsonWSCT NelsonWSCT NelsonWSCT Nelson

Houvenaghel et al., 2015, CATHouvenaghel et al., 2015, E

Tramontana et al., 2015, ETramontana et al., 2015, EP

Le Jeune et al., 2010, CAT

Le Jeune et al., 2010, CAT

Le Jeune et al., 2010, E

Le Jeune et al., 2010, P

Le Jeune et al., 2010, E

Fasano et al., 2010, CAT

Fasano et al., 2010, E

Le Jeune et al., 2010, PFasano et al., 2010, P

Williams et al., 2011, E

Williams et al., 2011, P

Fraraccio et al., 2008, EP

Fraraccio et al., 2008, CATFraraccio et al., 2008, NPE

Zangaglia, R., et al. 2009, E

Rothlind et al., 2015 (STN), PRothlind et al., 2015 (GPi) E

Castelli et al., 2010, CATCastelli et al. 2007, CAT

Castelli et al., 2010, ECastelli et al. 2007, E

Castelli et al., 2010, PCastelli et al. 2007, P

0.4940.4940.4940.0090.4940.0090.4960.4960.4960.1150.3520.4990.4990.5930.0460.5050.1250.4940.4960.4910.4940.4960.0090.4940.4960.0090.115

0.229

0.2760.5710.2761.0760.5711.0760.5050.5050.4570.0870.7380.2910.2940.612

0.6660.1120.2820.4960.3330.2820.4961.3860.2820.4961.3860.087

0.167

0.2160.2160.2160.2360.2160.2360.1910.1910.1730.2270.2560.1100.1120.2450.2620.2540.2630.2210.1880.2620.2210.1880.3030.2210.1880.3030.227

0.053

0.0470.0470.0470.0560.0470.0560.0360.0360.0300.0520.0650.0120.0120.0600.0690.0640.0690.0490.0350.0690.0490.0350.0920.0490.0350.0920.052

0.003

0.148

0.6140.1480.6140.1300.1300.118

0.2380.0750.0760.131

0.169

0.128

0.1280.793

0.1280.793

0.064

−0.010

−0.148

−0.148

−0.359

−0.524

−0.403−0.151

−0.181−0.151

−0.151

−0.359

0.684

2.6070.6842.6070.6810.6810.680

0.9300.6770.6770.534

0.667

0.681

0.6812.620

0.6812.620

1.203

−0.684

−0.684

−1.578

−1.997

−1.534−0.684

−0.689−0.684

−0.684

−1.578

0.152

0.152

−0.571−0.276

−0.276

−0.244−0.244−0.222−0.804−0.263−0.141−0.143−0.350

−0.328−0.918−0.585−0.240−0.694−0.585

−0.585

−0.240

−0.040

−0.240

−0.804

0.200

0.200

−1.037

−0.571


Figure 5: Meta-analysis of WSCT comparing before and after DBS surgery. TheWisconsin Short Card Test had three versions. Version one:MWCST = modified WCST; version two: WSCT; and version three: WSCT Nelson version.

1.00.5−0.5 0.0 1.5 2.0−1.0−1.5−2.00.4

0.3

0.2

0.1

0.0

Stan

dard

erro

r

Hedges’s g


Figure 6: Funnel plot for standard error in publications of Trail Making Test (TMT-A).

1.000.00 2.00−1.00−2.00


TMT-A

TMT-ATMT-A

TMr-ATMT-ATMT-A

Standarderror




Rothlind et al., 2015 (STN)Rothlind et al., 2015 (GPi)Houvenaghel et al., 2015

Yamanaka et al., 2012Williams et al., 2011Smeding et al., 2005 (seconds)

0.496

0.283

0.575

0.499

0.499

0.496

0.743

0.228

0.677

0.302

0.139

0.294

1.074

0.677

0.244

0.100

0.032

0.050

0.046

0.012

0.012

0.036

0.004

0.179

0.223

0.216

0.108

0.112

0.240

0.076

0.191

0.061

−0.680

−0.561

−0.677

−0.328

−0.681

−0.471

−0.198

−0.543

−0.285

−0.143

−0.140

−0.505

−0.121

−0.121

−0.073

−0.020

−0.130


Figure 7: Meta-analysis of TMT-A comparing before and after DBS surgery.

4. Discussion

The results of this study were found to correspond to similarstudies in which there is a general reduction of executivebrain functions after the DBS procedure. This does not seemto have an impact on quality of life given the improvement

of motor symptoms [19, 51, 61]. It is worth highlighting thatthe study of EF has shown a reduction in tasks such asWCST,verbal fluency, and Stroop in patients with PD before the DBSprocedure. This could be explained by alterations in the BG-dorsolateral prefrontal cortex loop in relation to the reduction


1.00.5−0.5 0.0 1.5 2.0−1.0−1.5−2.00.4

0.3

0.2

0.1

0.0

Stan

dard

erro

rHedges’s g


Figure 8: Funnel plot for standard error in publications of Trail Making Test (TMT-B).

1.000.00 2.00−1.00−2.00


Standarderror




Castelli et al., 2010

Castelli et al., 2007

Yamanaka et al., 2012

Williams et al., 2011Merola et al., 2011

Smeding et al., 2005 (seconds)Smeding et al., 2005 (errors)

Rothlind et al., 2015 (STN)Rothlind et al., 2015 (GPi)

Houvenaghel et al., 2015

TMT-BTMT-BTMT-BTMT-BTMT-BTMT-BTMT-BTMT-BTMT-BTMT-B

0.596

0.496

0.348

0.343

0.494

0.808

0.066

0.499

0.499

0.496

0.362

0.466

0.228

0.629

0.647

0.585

0.369

0.028

0.294

0.291

0.505

0.153

0.035

0.032

0.047

0.049

0.049

0.046

0.050

0.012

0.012

0.036

0.003

0.187

0.179

0.217

0.222

0.221

0.215

0.224

0.112

0.110

0.191

0.053

0.099

0.211

0.151

0.076

0.075

0.130

0.049

0.204

−0.121

−0.052

−0.412

0.530

0.948

0.684

0.677

0.677

0.681

0.912

0.938

−0.680

−0.244

−1.837

−0.471

−0.268

−0.225

−0.282

−0.222

−0.473

−0.852

−0.141

−0.244

−0.143

−0.056


Figure 9: Meta-analysis of TMT-B comparing before and after DBS surgery.

1.00.5−0.5 0.0 1.5 2.0−1.0−1.5−2.00.4

0.3

0.2

0.1

0.0

Stan

dard

erro

r

Hedges’s g


Figure 10: Funnel plot for standard error in publications of Trail Making Test (TMT-AB).

Standarderror




1.000.00 2.00−1.00−2.00


TMT-B-ATMT-B-ATMT-B-ATMT-B-ATMT-B-AHouvenaghel et al., 2015

Le Jeune et al., 2008 (B-A)

Le Jeune et al., 2010 (B-A)Welter et al, 2015

Yamanaka et al., 20120.491

0.496

0.494

0.460

0.496

0.686

0.333

0.228

0.276

1.016

0.505 0.681

0.154

0.032

0.069

0.047

0.142

0.010

0.036

0.179

0.262

0.216

0.377

0.099

0.191

−0.689

−0.684

0.738

−0.404

−0.471

−0.694

−0.680

−0.571

−0.460

−0.244

−0.234

−0.181

−0.040

−0.121

−0.148

0.278

0.130


Figure 11: Meta-analysis of TMT-AB comparing before and after DBS surgery.


1.00.5−0.5 0.0 1.5 2.0−1.0−1.5−2.00.4

0.3

0.2

0.1

0.0

Stan

dard

erro

rHedges’s g

Figure 12: Funnel plot for standard error in publications of Raven Matrix.

1.000.00 2.00−1.00−2.00

Desfavorable

The thinking abstract function was evaluated with Raven Matrix in two versions: Progressive (RPM’47) and Colored.

Favorable

Standarderror

Study name

Fasano et al., 2010Castelli et al, 2007

Castelli et al., 2010 Raven’s Colored Progressive MatricesRaven’s Colored Progressive MatricesRaven’s Colored Progressive Matrices

Raven’s Progressive Matrices (RPM’47)Raven’s Progressive Matrices (RPM’47)Raven’s Progressive Matrices (RPM’47)

Subgroup within studyStatistics for each study

limit limitLower Upper

Z value p valueVariance

Zangaglia et al., 2009

Merola et al., 2011Yamanaka et al., 2012

−0.127

−0.127

0.127

−0.458

0.726

1.766

0.480

0.899

0.899

0.899

0.647

0.468

0.077

0.631

0.410

0.421

0.369

0.290

0.222

0.669

0.547

0.050

0.053

0.031

0.037

0.007

0.035

0.050

0.224

0.229

0.177

0.193

0.083

0.188

0.224

−0.028

−0.029

0.022

0.331

0.108

−0.088

0.060

−0.467

−0.479

−0.324

−0.036

−0.332

−0.102

−0.466

Hedges’s gHedges’s g

Figure 13: Meta-analysis of Raven Matrix comparing before and after DBS surgery.

1.00.5−0.5 0.0 1.5 2.0−1.0−1.5−2.00.4

0.3

0.2

0.1

0.0

Stan

dard

erro

r

Hedges’s g


Figure 14: Funnel plot for standard error in publications of Digit Span Test (DST).

of dopamine in the nigrostriatal and mesocortical pathways[10].

In general, the study of EF presents a difficulty in termsof the unification of concepts. It has been recognized that thelack of unity in the measurements and significance makesit difficult to establish the relationship with clinical aspectsand to explain the improvement or reduction of the functionstested [19]. Following Kudlicka et al. [19], the conclusionsare due to the performance in the tests presented withoutthis being an exhaustive analysis of EF. With this, it wasfound in a number of studies that the same test was used toassess various functions. The lack of representation of LatinAmerican individuals and the lack of studies carried out inLatin America are notable.

The meta-analysis studies and systematic reviews haveidentified important aspects of PD that could explain partof the emotional functioning, that is, a deficit of emotional

recognition which, although not reported in other clinicalstudies of PD, could help improve communication processesand mood alterations [62]. Such studies can also help usunderstand the possible relationship between structures suchas STN and the structures involved in emotional and cogni-tive processes [55] and, as such, better understand the diseaseas a whole.

In the case of the verbal fluency tests, a deterioration hasbeen reported for PD both with pharmacological treatmentand with DBS [54]. There is a change in verbal fluencyperformance with DBS, and this is coherent with other stud-ies and meta-analyses in which a reduction in performanceis reported [46, 51, 56]. This alteration has been relatedto the position of the electrodes on the STN in the lefthemisphere [63]. In neuroimaging studies of patients withPD, an associative-type reduction of the metabolic functionof the frontal and parietal areas has been found [5], and other


1.000.00 2.00−1.00−2.00


Standarderror



limit limitLower Upper

Variance Z value p value

ForwardForwardForwardForwardForwardForwardForwardForwardForwardForwardForwardForward

BackwardBackwardBackwardBackwardBackwardBackwardBackwardBackwardBackwardBackward

Fasano et al., 2010

Fasano et al., 2010

Tang et al, 2015, 12 months






Rothlind et al., 2007

Rothlind et al., 2007



Will et al, 2008

Will et al, 2008

Fraraccio et al., 2008

Williams et al., 2011Merola et al. 2011

Daniels et al., 2010

Daniels et al., 2010

Zangaglia et al., 2009

0.494

0.929

0.499

0.499

0.496

0.989

0.076

0.568

0.672

0.568

0.110

0.929

0.494

0.496

0.278

0.278

0.206

0.929

0.179

0.499

0.499

0.899

0.125

0.047

0.035

0.035

0.035

0.036

0.030

0.001

0.047

0.032

0.012

0.012

0.016

0.016

0.016

0.016

0.060

0.065

0.063

0.032

0.046

0.053

0.012

0.012

0.276

0.383

0.350

0.350

0.628

0.360

0.014

0.276

0.228

0.143

0.139

0.323

0.112

0.112

0.323

0.583

0.092

0.809

0.228

0.424

0.042

0.143

0.139

0.216

0.187

0.187

0.187

0.190

0.172

0.033

0.216

0.179

0.112

0.108

0.128

0.128

0.128

0.128

0.245

0.255

0.251

0.179

0.215

0.229

0.112

0.108

−0.148

−0.076

−0.073

0.073

0.104

0.073

−0.121

0.003

−0.408

−0.408

−0.017

−0.017

−0.148

−0.121

−0.139

−0.139

0.317

0.256

0.022

0.017

−0.076

−0.073

−0.051

−0.684

−0.677

−0.677

0.570

0.423

0.570

−0.680

0.014

−1.777

−1.598

−0.089

−0.089

−0.684

−0.680

−1.085

−1.085

1.264

1.345

0.127

0.089

−0.677

−0.677

−1.533−0.115

−0.316

−0.285

−0.294

−0.117

−0.383

−0.383

−0.175

−0.177

−0.376

−0.857

−0.418

−0.471

−0.285

−0.294

−0.350

−0.571

−0.177

−0.908

−0.390

−0.390

−0.471

−0.571


Figure 15: Meta-analysis of DST comparing before and after DBS surgery.

1.00.5−0.5 0.0 1.5 2.0−1.0−1.5−2.00.4

0.3

0.2

0.1

0.0

Stan

dard

erro

r

Hedges’s g


Figure 16: Funnel plot for standard error in publications of Stroop Test.

studies suggest that the striate nucleus may play a dissociablerole inmotor control and language cognitive processes, whichwould mean that different patterns of stimulation wouldaffect the structures of the basal ganglia and cortical regionsin different ways. This, in turn, explains why some patientsimprove in terms of their language articulation and at thesame time present a reduction in their verbal fluency afterDBS [51]. It has also been reported that the stimulationmay cause a decrease of activity in the temporal cortex andinferior frontal areas in the left hemisphere, which woulddecrease verbal fluency, especially of the phonological kind[64]. Nevertheless, it is necessary to highlight that thesehypotheses are still under study.

Inasmuch as heterogeneity, this can be explained based onthe variability in the rigorousness of the application and thestandardized test to assess it. Given that the reported hetero-geneity is close to 45%, it is proposed that the effect detectedcannot necessarily be attributed to the DBS procedure.

Inasmuch as cognitive flexibility, the tests assessed do notshow a significant change, despite being one of the functionswhich in other studies is reported as favorable [56]. Similarly,

the working memory function has been proposed as one ofthe aspects that becomes altered in PD.More alterations havebeen identified in the visuospatial modality than the verbalmodality [47, 65], and no significant changes are reported inthis study for after DBS.

Inasmuch as the Stroop, no clear effect was identifiedperhaps due to the high heterogeneity of the studies that maybe assumed as being derived from the alternative forms of thetest [56].

On the other hand, another type of meta-analysis in PDhas been carried out, linking the disease to different levels;for example, a genetic level which shows susceptibility to PDdepending on polymorphisms in monoamine oxidase genes(MAO) [66], with other diseases or effects of the transcranialmagnetic stimulation [15, 27].This sheds light on the fact thatthere is a variety of studies that attempt to explain specificaspects of PD, but, as yet, with no unity of analysis that allowsus to understand the diversity of the symptoms of patientswith PD.

One of the difficulties reported in establishing a STN-DBSeffect in systematic changes in the patients and that explains


1.000.00 2.00−1.00−2.00


Standard Lower Uppererror

Study nameStatistics for each study

limit limitVariance Z value p value

Rothlind et al., 2007 (Stroop word)

Rothlind et al., 2015 (GPi), word readingRothlind et al., 2015 (STN), word reading

Rothlind et al., 2015 (STN), colour word

Rothlind et al., 2015 (GPi), colour naming

Rothlind et al., 2015 (GPi), colour wordRothlind et al., 2015 (STN), colour naming

Rothlind et al., 2007 (Stroop colour)Rothlind et al., 2007 (Stroop colour-word)

Le Jeune et al., 2008

Le Jeune et al., 2010

Williams et al., 2011 (Stroop word)Williams et al., 2011 (Stroop colour-word)

Fraraccio et al., 2008 (colour naming (# in 45 s))Fraraccio et al., 2008 (word reading (# in 45 s))Fraraccio et al., 2008 (interference index (c/w) (# in 45 s)

Tramontana et al., 2015 (palabra)Tramontana et al., 2015 (colour)Tramontana et al., 2015 (colour-palabra)

Houvenaghel et al., 2015, colour

Houvenaghel et al., 2015, interference

Houvenaghel et al., 2015, wordHouvenaghel et al., 2015, colour-word

Smeding et al., 2005 (Stroop word seconds)Smeding et al., 2005 (Stroop colour seconds)Smeding et al., 2005 (Stroop colour word seconds)Smeding et al., 2005 (Stroop colour word errors)Daniels et al., 2010 (Stroop word seconds)Daniels et al., 2010 (Stroop colour seconds)

Wills et al., 2008 (Stroop 1 word reading time in black, seconds)Wills et al., 2008 (Stroop 1 word reading time in black, error rates)Wills et al., 2008 (Stroop 2 word reading time naming colour dots for simple colour naming)Wills et al., 2008 (Stroop 2 naming colour dots for simple colour naming, error rates)

Daniels et al., 2010 (Stroop interference condition/word reading)Daniels et al., 2010 (Stroop interference condition/colour naming)

Wills et al., 2008 (Stroop 3: interference condition reading words, seconds)Wills et al., 2008 (Stroop 3: interference condition reading words, error rates)Wills et al., 2008 (Stroop 4 interference condition, seconds)Wills et al., 2008 (Stroop 4 interference condition, error rates)Yamanaka et al., 2012, MST-AYamanaka et al., 2012, MST-B

−0.793

−0.448

−0.566

−0.537

−0.166

−0.423

−0.027

−0.516

−0.878

−0.915

−0.077

−0.076

−0.077

−0.223

−0.077

−0.060

−0.016

−1.011

−0.223

−0.130

−0.130

−0.130

−0.130

−0.105

0.314

−0.124

−0.272

−0.235

−0.255

−0.441

−0.305

−0.235

−0.255

−0.441

−0.067

−0.305

−0.113

−0.364

−0.490

−0.211

0.255

0.441

−1.386

−0.952

−1.086

−1.053

−0.600

−0.874

−0.448

−1.045

−1.468

−1.514

−0.300

−0.296

−0.300

−0.446

−0.300

−0.539

−0.494

−1.611

−0.446

−0.505

−0.505

−0.505

−0.505

−0.527

−0.118

−0.547

−0.701

−0.489

−0.509

−0.703

−0.560

−0.489

−0.509

−0.703

−0.317

−0.560

−0.363

−0.724

−0.860

−0.288

0.001

0.179

−0.200

−0.022

−0.287

−0.317

−0.001

−0.411

−0.001

−0.001

−0.179

−0.049

−0.047

0.057

0.268

0.028

0.393

0.013

0.146

0.144

0.146

0.146

0.419

0.463

0.244

0.244

0.244

0.244

0.317

0.746

0.298

0.157

0.018

−0.001

0.018

0.509

−0.179

0.703

−0.049

0.183

−0.003

−0.120

0.138

−0.135

0.303

0.301

0.305

0.114

0.306

0.114

0.130

0.134

0.130

0.265

0.257

0.263

0.221

0.230

0.215

0.270

0.114

0.112

0.114

0.114

0.244

0.244

0.191

0.191

0.191

0.191

0.215

0.220

0.216

0.219

0.129

0.130

0.129

0.130

0.134

0.134

0.130

0.128

0.184

0.189

0.128

0.039

0.092

0.091

0.093

0.013

0.094

0.013

0.017

0.018

0.017

0.070

0.066

0.069

0.049

0.053

0.046

0.073

0.013

0.013

0.013

0.013

0.060

0.060

0.036

0.036

0.036

0.036

0.046

0.049

0.046

0.048

0.017

0.017

0.017

0.017

0.018

0.018

0.017

0.016

0.034

0.036

0.016

0.002

0.009

0.004

0.003

0.049

0.001

0.049

0.049

0.001

0.019

0.033

0.082

0.041

0.454

0.066

0.899

0.056

0.499

0.499

0.499

0.499

0.807

0.949

0.496

0.496

0.496

0.496

0.625

0.154

0.565

0.214

0.069

0.049

0.069

0.049

0.001

0.001

0.019

0.598

0.048

0.009

0.378

0.000

−2.620

−1.739

−2.136

−2.042

−0.749

−1.839

−0.127

−1.912

−2.913

−2.998

−0.677

−0.677

−0.677

−1.966

−0.677

−0.245

−0.064

−3.303

−1.966

−0.681

−0.681

−0.681

−0.681

−0.488

1.425

−0.576

−1.244

−1.820

−1.968

−3.302

−2.336

−1.820

−1.968

−3.302

−0.527

−2.336

−0.882

−1.977

−2.597

−5.406

1.968

3.302


Figure 17: Meta-analysis of Stroop Test comparing before and after DBS surgery.

the variability of the effects, as well as the tasks, is the exactlocation of the electrodes. In this respect, it has been foundthat although the procedure is carried out in STN, the areaof location, the area of active stimulation, or the volume ofelectrode contact is not always homogeneous [6, 63, 67].

Another of the major difficulties in the systematic assess-ment of the changes realized by the DBS procedure is thelack of standardized tests to measure the functions [16].In this study, high variability was found in the versions ofsome of the tests which could be a factor that contributesto the heterogeneity. On the other hand, it has also beenproposed that the alterations presented in PD do not alwayscorrelate with the specific alterations related to the treatment(e.g., pharmacological). Thus, the alterations in the differentdomains and the lack of EF improvement afterDBS treatmentmay respond to a nonlinear model that involves different andcomplex circuits that are not necessarily modified by STN-DBS [68].

Finally, one of the important limitations to detecting ofthe effects of the procedure is the lack of control or placebogroups that would allow the identification of DBS [56].

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

This paper was made possible thanks to funding of Vicerrec-torıa de Investigacion of the Pontificia Universidad Javeriana

with ID Project: 00006578, titled “Effects of Deep BrainStimulation (DBS) on Performance of Executive FunctionTest in Patients with Parkinson’s Disease.”

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Review ArticleStigma Experienced by Parkinson’s Disease Patients:A Descriptive Review of Qualitative Studies

Marina Maffoni,1 Anna Giardini,1 Antonia Pierobon,1

Davide Ferrazzoli,2 and Giuseppe Frazzitta2

1Psychology Unit, Istituti Clinici Scientifici Maugeri, IRCCS Montescano (PV), Pavia, Italy2Parkinson’s Disease and Brain Injury Rehabilitation Department, Moriggia-Pelascini Hospital, Gravedona ed Uniti, Italy

Correspondence should be addressed to Anna Giardini; [email protected]

Received 23 September 2016; Revised 22 December 2016; Accepted 5 January 2017; Published 24 January 2017

Academic Editor: Shey-Lin Wu

Copyright © 2017 Marina Maffoni et al.This is an open access article distributed under the Creative CommonsAttribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Parkinson’s disease (PD) is a neurodegenerative disease characterized by motor and nonmotor symptoms. Both of them imply anegative impact onHealth-RelatedQuality of Life. A significant one is the stigma experienced by the parkinsonian patients and theircaregivers.Moreover, stigmamay affect everyday life and patient’s subjective and relational perception and it may lead to frustrationand isolation. Aim of the present work is to qualitatively describe the stigma of PD patients stemming from literature review, inorder to catch the subjective experience and the meaning of the stigma construct. Literature review was performed on PubMeddatabase and Google Scholar (keywords: Parkinson Disease, qualitative, stigma, social problem, isolation, discrimination) and wasrestricted to qualitative data: 14 articles were identified to be suitable to the aim of the present overview. Results are divided intofour core constructs: stigma arising from symptoms, stigma linked to relational and communication problems, social stigma arisingfrom sharing perceptions, and caregiver’s stigma. The principal relations to these constructs are deeply analyzed and describedsubjectively through patients’ and caregiver’s point of view.The qualitative researchmay allow a better understanding of a subjectivesymptom such as stigma in parkinsonian patients from an intercultural and a social point of view.

1. Introduction

At first blush, Parkinson’s disease (PD) is characterized bymotor symptoms. Indeed, the four cardinal features of thispathology are identified in the tremor at rest, rigidity, akinesia(or bradykinesia,) and postural instability [1]. Nevertheless,nonmotor symptoms are asmuch as relevant, even if invisibleor not immediately detectable, and they often imply a nega-tive impact onHealth-RelatedQuality of Life (HRQoL) [2, 3].A significant one is the stigma experienced by the parkinso-nian patients and their caregivers. In fact, this phenomenonhas not a secondary importance: stigma appears to providea determinant contribution to HRQoL in patients with PD[4]. Moreover, stigma may characterize everyday life with agloomy filter, marked by disability and isolation [5].

The general meaning of the word stigma is linked to acomplex experience concerning a devaluating, discriminant,and discomfort feeling. According to one of the first con-temporary conceptualizations of this construct, stigma is an

attribute implying a discredit of the subject who is considered“bad, or dangerous, or weak. She/he is thus reduced in ourminds from awhole and usual person to a tainted, discountedone” [6, p. 3]. A stigmatized person, that is a person withstigma, is someone who appears changed and different fromwhat is considered normal and accepted. As a consequence,the subject could be isolated and the social identity may bedeeply threatened and mined, too [7].

When stigma is present in PD, it originates from the inter-face of the patient with the outside world [4]. That is, it is notonly an individual construct but rather a social one. Indeed, itis a sort ofmark underlining the deviant nature of the stigma-tized subject from the perspective of those who are the stig-matizers [8]. Indeed, despite different theories, approaches,and models developed over the years [9–11], there is always asocial component to consider when speaking about stigma.Therefore, stigma is a complex phenomenon due to theinteraction between a context and a subject who receives adevaluating mark [7].


http://dx.doi.org/10.1155/2017/7203259


Scales and tools have been developed in order to betterdescribe and quantify stigma in chronic illnesses, such as PD([12, 13]; for a review, [14]). Nevertheless, being a personalexperience, stigma is difficult to be objectively described.Thecore meaning of this construct could be better defined bycollecting the subjective point of view of PD patients [15].

Aim of the present work is to qualitatively describethe stigma of PD patients stemming from literature review,focusing on qualitative international research.

2. Method

The authors applied a research strategy to sum up a descrip-tive overview of the complex andmotley experience of stigmain PD linked both to disabling physical conditions and tosocial, relational, and communicative obstacles. The reviewwas restricted to qualitative published articles in order tocatch the subjective experience and meaning of the stigmaconstruct.

Literature review was performed on PubMed databaseand Google Scholar (keywords: Parkinson Disease, qualita-tive, stigma, social problem, isolation, discrimination) andwas not limited to any country neither to any period of time.26 papers were identified. The authors read all materials inorder to identify where the experience of a devaluating anddiscriminant feeling linked to the PD effectively emergedand/or was exhaustively discussed. The authors excludedpapers in which stigma was an introductive or very marginal,not informative theme. Duplicates were also deleted. Anotherexclusion criterion adopted was the focus on quantitativereports. Consensus was reached by a vis-a-vis discussion andfollowed by email discussions. An article was included in thestudy only when a general consensus was provided.

After that procedure, 6 articles were selected. Subse-quently, other 8 additional qualitative studies were selectedfrom references to chosen articles, according to the samemethodology previously adopted.At the endof the process, 14articles were identified to be suitable to the aim of the presentoverview.

In order to understand and identify the stigma experi-ence, two authors (MM, AG) read the selected 14 articles andtook notes of each aspect linked to the construct, discussingonline and trying to reach an agreement. In order to reacha consensus among all authors, an iterative process of con-tinuous analysis of data was applied. First, an initial or opencoding procedure was carried on, afterwards MM and AGextrapolated the meaningful issues, and AP, DF, and GF readthe articles verifying the coherence among the extrapolatedkey words and reported themes. All emerging issues wereconsidered in the review, considering that even the lessquoted experience could contribute to better understandingof the complex stigma phenomenon. All authors contributedto conceptualize stigma experience, critically organizing theemerging themes into major categories. Memos, diagrams,and maps were used as tools enabling data sharing and toreach a consensus.

Results are presented in a descriptive/narrative way,describing the thematic issues linked to stigma experience;in order to simplify comprehension, the results and the iden-tified categories are also presented in a table and graphicallysummed up.

3. Results

As for other chronic and progressive disabling diseases, PDdrove patients to experience stigma day after day. Frompatients’ point of view, stigma appears as a complex constructwith multiple undesirable facets. This emerged from theplethora of expressions linked to stigma used by patientsaddressing PD: shame, disgrace, embarrassment, feeling dis-honorable, and feeling awkward, terrible, or horrible, and soon [5, 16, 17, 23, 24, 28].

In Table 1, the 14 articles included in our descriptivereview are described. In order to organize data that emergedfrom literature review, results were divided into paragraphsaccording to identified key words; results are quantitativelydescribed in Table 2 and represented as a whole in Figure 1.

3.1. Stigma Arising from Symptoms. Elements and conditionsdetermining stigma are different. One of the main causesidentified by patients of this phenomenon aremotor, physical,and visible symptoms [5, 16, 18–20]. It is not casual thatancient Greeks coined the term stigma referring to “bodilysigns designed to expose something unusual and bad” [6, p.1]. Indeed, symptoms are impossible to hide and become aclear and concrete statement of the subjective perception of acapricious disease that speaks bymeans of the body [17, 21]. Inthe selected article, the perception of stigma emerges directlylinked to PD symptoms and theirmanifestation in public [18].In this regard, Israeli women describe their visible body as atraitor, since it unscrupulously reveals PD to the public [16].That is, body becomes a servant of PD acting by means of itsvisible symptoms. In this regard, Hermanns’s ethnographicapproach reveals that the observable traits of disturbancessuch as drooling, balance difficulties, shaking problems, andother similar symptoms are additional challenges for thepatient [5]. PD disrupts the experience of an autonomousand integrated human being due to the exterior signs of theillness condition [22]. Moreover, the deteriorated body imageprovokes feelings of shame and embarrassment leading toisolation [19, 20].

Nevertheless, stigma is not only linked to the changingexterior image of PD patient but also to the progressiveloss of functionality. The contribution of PD to the stigmaexperience is double: an undesirable self-image and a lossof autonomy and self-efficacy. Indeed, when asking to freelytell their life history with PD thorough in-depth interviews,subjects describe their symptoms as a matter of shamebecause of the physical dependence and the need for helpto do even the simplest tasks [16, 23, 25]. Stigma may arisefrom the consciousness of the awkwardness and inability toperform not only usual work activities but also simple motoractions [24]. An impoverishment of physical functionalityconducts to a reduction of activity and social engagementlinked to stigma perception [18].


Table1:Stud

ycharacteris

ticso

fthe

14articlesincludedin

theq

ualitativer

eview.

Stud

yLo

catio

nof

patie

nts’

recruitm

ent

Num

bero

fparticipants

Qualitativem

etho

dsStud

yaim

Nijh

of,1995

Amste

rdam

,The

Netherla

nds

23PD

pts

(10F;13

M)

In-depth

interviewsw

ithqu

alitativ

eanalysis

ofcontent

ToexploreP

Dsubjectiv

einterpretations

Posenetal.,2000

TelA

viv,Israel

15PD

pts(F)

Sessions

ofpsycho

educationalw

ork-grou

p(M

acKe

nzieandLivesle

y,1983)

Todescrib

ethe

PDexperie

nceinafem

ale

work-grou

p

Sunviss

onandEk

man,2001

Sweden

11PD

pts

(nogend

erdetails)

Interviewsd

uringap

eriodof

2yearsa

ndph

enom

enologicaldataanalysis

Toelu

cidateenvironm

entalinfl

uences

onlived

PDexperie

nces

VanDer

Brug

genand

Widdersho

ven,

2004

/4no

vels

Existentia

l-pheno

menologicalanalysisof

narrativem

aterialsof

PDpatie

nts

Tocatchthem

eaning

ofbeingaP

Dpatie

nt

Bram

leyandEa

toug

h,2005

Nottin

gham

,UK

1PDpts(F)

(singlec

ases

tudy)

Semi-structuredinterviews

analyzed

usinginterpretativ

eph

enom

enologicalanalysis(IPA

)To

catchthes

ubjectiveP

Ddaily

experie

nce

Miller

etal.,2006

(a)

Sund

erland

,UK

37PD

pts

(14F;23

M)

In-depth

interviewsw

ithqu

alitativ

eanalysis

ofcontent

Tostu

dychangesincommun

icationim

pacton

daily

PDpatie

nts’lives

Miller

etal.,2006

(b)

Sund

erland

,UK

37PD

pts

(14F;23

M)

In-depth

interviewsw

ithqu

alitativ

eanalysis

ofcontent

Toestablish

ifandho

wchangesinsw

allowing

impacton

daily

PDpatie

nts’lives

Mshanae

tal.,2011

Mwanza,Tanzania

28PD

pts,28

caregivers,4

health

workers,2

tradition

alhealers

(nogend

erdetails)

In-depth

interviewsa

ndfocusg

roup

sTo

detectho

wPD

isperceivedandtre

ated

ina

ruralA

frican

popu

latio

n

Chiong

-Riveroetal.,2011

USA

48PD

pts

(26F;22

M)

15caregivers

(13F

;2M)

Focusg

roup

sand

one-on

-one

interviews

TocollectHealth

-Related

Qualityof

Life

consequences

ofParkinson’s

diseasefrom

the

patie

nt’sandcaregivers’perspectiv

e

Hermanns,2013

Texas,USA

14PD

pts

(7F;7M

)

Ethn

ograph

icapproach

usinginterviewdata,

participanto

bservatio

ns,and

fieldwork(2-year

expo

sure)

Todiscussthe

visib

leandinvisib

lestigm

a

Soleim

anietal.,2014

Iran

10PD

pts

(3F;7M

)Semistructured,face-to-fa

ceinterviewsa

ndcontentanalysis

approach

Toexplorethe

effectsof

PDon

peop

le’ssocial

interactions

Soun

dyetal.,2014

/37

qualitativ

earticles

(review)

Metaethno

graphy

Tosummarizea

ndto

synthesiz

equalitative

studies

concerning

theP

Dexperie

ncea

ndperceptio

n

Giardinietal.,2016

Mon

tescano(PV),

Italy

27PD

pts

(14F;13M)

Semi-structuredinterviewsw

ithPD

patie

nts

analyzed

usingtheG

roun

dedTh

eory

metho

dology

Toqu

alitativ

elydescrib

ethe

rehabilitation

experie

nceo

fPDinpatie

nts

Soleim

anietal.,2016

Iran

17PD

pts

(7F;10M)

Semistructured,face-to-fa

ceinterviewsa

ndcontentanalysis

approach

Toexplorethe

prim

aryconcerns

and

perceptio

nsof

daily

PDpatie

nts’lives

Legend

:PD=Parkinson’s

disease;Pts=

patie

nts;F=female;M

=male.


Parkinson's disease (PD) experienceis linked to

Symptoms

Embarrassingvisible physical

symptoms

Progressive lossof functionalityand autonomy

Oral language(dysphonia,dysarthria)

Body language(facial mask)

Perceptions exchange

Beliefs on physical and mental status

(frail, not more ableto do usual tasks)

PD as illnessfor old

people only

Not beingunderstoodand takenseriously

Caregivers

Being afamily’sburden

Embarrassment andwithdrawal due to their

lover’s condition

Social withdrawal, stigmatization, and health-related worsening

The others towardsthe patient

Patient towardsthe others

Relational andcommunication

problems

StigmaDevaluating, discriminant and

discomfort feeling

Figure 1: Stigma’s core constructs in Parkinson’s disease.

Table 2: Thematic issues related to stigma experience identified in the reviewed articles.

Thematic issues Reference number of each reviewedarticle

Symptoms [5, 16–22]

[5, 16, 18, 23–25]Embarrassing visible physical symptomsProgressive loss of functionality and autonomy

Relational and communication problems [5, 19, 26, 27]

[5, 24]Oral language (dysphonia, dysarthria)Body language (facial mask)

Perceptions exchangeThe others towards the patient [5, 16, 21, 23, 24, 26]

[5, 16, 28]Beliefs on physical and mental statusPD as an illness for old people only

Patient towards the others [5, 26, 27],

[5, 16, 18, 24–26]Not being understood and taken seriouslyBeing a family burden

Caregivers[24, 25, 28]Embarrassment and withdrawal due to their lover’s

condition


3.2. Stigma Linked to Relational and Communication Prob-lems. Stigma experience arises also from the hindrances tocommunication and relational life imposed progressively byPD. Indeed, the relationship with the others becomes com-plex and contradictory since the PD patient has to find theright balance between contact and distance [21].

First of all, relations and communications are a matterof complaint; patients state to be frequently mislabelled, forexample, as drunkard [5]. Moreover, the delayed thinkingprocess and the difficulty to convey beliefs easily may causea subjective experience of frustration and isolation, sincethe others take their own decisions without waiting for thepatient’s feedback [26]. Communication changes may havean impact on the patients’ and their caregivers’ life; subjectsattribute to voice and articulation changes many disablingimpacts: formulation problems and attention difficulties andsubjective feelings of frustration and neglecting linked towithdrawal [27]. Indeed, all these issues conduct the PDpatient to remain confined at home, where she/he feelsnormal and more comfortable since they can bypass thecomparison with the outside society [5, 19].

However, communication is not only a matter of speak-ing. Human beings communicate by means of gesture andbody language too. In this regard, face is a sensitive topic toPD patients. Indeed, one of the most visible and undesirablefeatures is the typical rigid and unexpressive face of PDpatients, the facial mask. Patients describe other people’sdifficulty to decipher theirmute expression and this conditioninexorably causes isolation of the stigmatized person, whoperceives a progressive sense of alienation and disconnectionfrom the others [5, 24].

3.3. Social StigmaArising fromPerceptions Exchanges. Stigmais a complex matter of feeling and perceptions; the interfacebetween inside and outside is determinant. This meansthat the contribution of patients and caregivers is equallyimportant and the starting point of a stigmatizing perceptionis usually shared without clear boundaries.

3.3.1. The Others’ Perceptions towards the PD Patient. Takinginto account the others’ point of view, Hermanns highlightsthat a PD patient notices to be seen as frail by the others [5].Moreover, subjects describe a perceived sense of unease anduncomfortable feelings of individuals that are in front of theirphysical problems and that cannot escape from their sight[24]. Indeed, it is the response of the others that is a matterof shame [23]. When the disease proceeds and disabilityincreases, the patient has to struggle with the experience ofmarginalization and isolation due to the forced abandonmentof work and responsibilities [21].

As to symptoms (i.e., hallucinations), patients may avoidtelling their family members, since they worry they couldperceive them as cognitively impaired or not being reliableanymore [26]. Indeed, a group of women highlights thedifference when speaking of functional aspects that are moresocially accepted than of mental and degenerative issues: PDis linked to a diffused and stigmatizing belief of being adisease characterized by a cognitive impairment transform-ing patient into an insane [16].

Another main reason of social stigmatization is linked tocommon belief that PD is a disease only for old people; thisprejudicemay be strong in society, including familymembers[5, 16]. Interestingly, from a qualitative research conductedwithin a rural zone of Tanzania, PD is called “old age illness”in Swahili language due to the common prejudice of the agerange in which PD may appear [28].

3.3.2. The PD Patient’ Perceptions towards the Others. Fromthe patient’s perspective, stigma may be linked to patient’smetaperceptions of the other people’s beliefs towards PD [18].Patients frequently complain to be misunderstood or evennot to be understood and be taken seriously from the outsidenormal society [5]. A reason of misunderstanding may stemfrom the fluctuating nature of PD symptoms that leads familymembers and formal caregivers to believe she/he is pretend-ing [26]. Moreover, some interviewed PD patients complainnot to receive the right time to express themselves by theothers who replace them in discussions or decisions, withoutfully understanding their communication difficulties [27].

Stigma arises also from the patient’s perception to be aburden for caregivers, also due to the uncertain progressionof the disease [5, 16, 18, 24, 26]. Subjects may report feelingsof guilt and selfishness towards their caregivers due to theincreasingly demanding request of special attention in thedaily chores [25]. Moreover, PD patients experience a stigmafeeling due to the change or loss of their social roles: they arenot the providers of their families and they are often forcedto leave their workplace [24].

3.4. Caregiver’s Stigma. Stigma not only is an experience ofthe patients but rather may be also a feeling characterizingthe family caregivers. PD is something unwanted that marksall the family, leading to difficulties also in public settingsand to undesirable feeling of shame and pity [24]. In thisregard, Mshana et al. show that, in rural communities ofTanzania, there is a trend to stigmatize the entire PD patient’sfamily because of the dishonorable condition experienced[28]. Indeed, the PD patient’s family members may be totallyabsorbed by taking care of the ill family member, since theyare not able any more to take part in social and working lifeof their community. Equally, also in a European context, thepatient’s families have been frequently led to a forced with-drawal, in particular during meal time when it becomes dif-ficult to invite guests [25] or at least dealing with the embar-rassing and visible symptoms of their ill family member [24].

4. Clinical Implications

Being in contact with the patient and discovering her/hisexperience and inner psychological needs may guide healthcare professionals and caregivers to take care of the ill personin a more fitted and tailored manner. In fact, by understand-ing a disease as a whole, from a holistic point of view, onecould provide clues to be more effective in patient’s manage-ment. The capricious and unpredictable nature of this pro-gressive neurological disorder makes the comprehension ofa patient’s experience and psychosocial correlates even more


fundamental. Stereotypes, misunderstandings, shame, isola-tion, discriminations, and stigmatization are a silent, partlyvisible, and partly invisible phenomenon, which is necessaryto be considered [5]. Indeed, stigma has an importantnegative effect on the illness progress and management: itmay contribute to avoiding or interrupting treatment, as wellas to manifesting depressive symptoms [29, 30]. Althoughdedicated to mental illness and presenting still controver-sial results, specific psychotherapeutic approaches to stigmaseem to be effective, enhancing skills to deal with self-stigma through self-esteem, empowerment, and help-seekingbehavior enhancement [31, 32]. Further studies on patientswith chronic diseases intended to implement a focusedintervention on stigma, may be deserved, adapting protocolsand outcome measures on this specific population.

Moreover, stigma has an intrinsic complexity that deservesto be better understood [30]; there is an important need toreach and educate who is foreign to being chronically ill andas an outsider nurtures the stigma phenomenon. By dissemi-nating information and by educating the others, starting fromthe informal caregivers, we could treat properly this sourceof sufferance, in line with the WHO ICF model, where dis-ability stems from the interaction of a health condition withpersonal and environmental factors [33].

Finally, the choice of a holistic and multidisciplinarytreatment of all symptoms of PD appears of great importanceto guarantee a satisfying health management of the patient[17, 34]. The need to focus on nonmotor symptoms in PD,which stigma belongs to, moves a step forward to a tailoredpatient-centered medicine, enabling the health professionalsto see the patient as a person, living in an everyday life.

5. Conclusions

The social consideration and attitude towards a diseaseare important, since they contribute in determining theenvironment in which the patient has to live and interact in[5, 35]. Indeed, disability stems from the interaction betweenthe individual and the environment [36]. Stigma is a complexphenomenon well attested and in need of comprehension inthe context of chronic diseases and PD is not an exception[37]. Even if stigma could be a silent and invisible phenome-non [5], it may have direct relevant impact on HRQoL [4].

Our focus on qualitative approaches could contribute tosustain a subjective insight into patient’s experience [15]. Infact, patients are the most trustworthy witnesses of theirlives.They are the main protagonists of their changing illnessexperience: day after day, they live on with their body andcontinuously come to terms with the PD [5, 17].

Stemming from our review stigma could be consideredas a nonmotor symptom as relevant as the other ones. In fact,stigma is not only a feeling of shame and embarrassment aris-ing from a self-perception of inadequacy due to loss of auton-omy and visible symptoms but also an experience related tothe attitudes and beliefs of the social context towards the PDpatientwho is stigmatized and forced towithdrawal.That is, itis the negative or positive response of the outside world thatmay do the difference. Indeed, according to the recent ICFconceptualization, disability is not only a state linked to

personal limitations and impairments but also a conditioninterconnected with the environment and the interface withit [36, 38].

To date, what PD patients and their caregivers seem toexperience is a mark [8], a shameful sign of different needsand impaired behaviors. Indeed, PD manifestations breaksocial rules and all what is normally attended by a healthysocial community [23]. Further qualitative studies on thistopic are needed in order to better understand a subjectivesymptom as stigma in parkinsonian patients from an inter-cultural and a social point of view.

Competing Interests

The authors declare that there are no competing interests intheir submitted paper.

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Review ArticleParkinson’s Disease and Cognitive Impairment

Yang Yang,1,2 Bei-sha Tang,1,2,3,4 and Ji-feng Guo1,2,3,4

1Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China2Key Laboratory of Hunan Province in Neurodegenerative Disorders, Central South University, Changsha, Hunan 410008, China3State Key Laboratory of Medical Genetics, Changsha, Hunan 410008, China4Neurodegenerative Disorders Research Center, Central South University, Changsha, Hunan 410008, China

Correspondence should be addressed to Ji-feng Guo; [email protected]

Received 15 September 2016; Accepted 14 November 2016

Academic Editor: Yuan-Han Yang

Copyright © 2016 Yang Yang et al. This is an open access article distributed under the Creative Commons Attribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Parkinson’s disease (PD) is a progressive neurodegenerative disease primarily characterized by the hallmarks of motor symptoms,such as tremor, bradykinesia, rigidity, and postural instability. However, through clinical investigations in patients and experimentalfindings in animal models of Parkinson’s disease for years, it is now well recognized that Parkinson’s disease is more than justa motor-deficit disorder. The majority of Parkinson’s disease patients suffer from nonmotor disabilities, for instance, cognitiveimpairment, autonomic dysfunction, sensory dysfunction, and sleep disorder. So far, anti-PD prescriptions and surgical treatmentshave been mainly focusing on motor dysfunctions, leaving cognitive impairment a marginal clinical field. Within the nonmotorsymptoms, cognitive impairment is one of the most common and significant aspects of Parkinson’s disease, and cognitive deficitssuch as dysexecutive syndrome and visuospatial disturbances could seriously affect the quality of life, reduce life expectancy, prolongthe duration of hospitalization, and therefore increase burdens of caregiver and medical costs. In this review, we have done aretrospective study of the recent related researches on epidemiology, clinical manifestation and diagnosis, genetics, and potentialtreatment of cognitive deficits in Parkinson’s disease, aiming to provide a summary of cognitive impairment in Parkinson’s diseaseand make it easy for clinicians to tackle this challenging issue in their future practice.

1. Introduction

In developed countries, nearly one out of 100 people olderthan 60 years old are affected by Parkinson’s disease [1].Cognitive impairment in Parkinson’s disease, characterizedby predominant executive deficits, visuospatial dysfunction,and relatively unaffected memory, ranges from Parkinson’sdisease mild cognitive impairment (PD-MCI) to Parkinson’sdisease dementia (PDD), the former of which could onlybe detected by various means of comprehensive neuropsy-chological observations and normally does not affect thepatients’ daily operations whereas the latter hits more thanone area of cognition and is severe enough to impair socialor working functions.Moreover, longitudinal studies of long-term clinical investigations suggested that the majority of PDor PD-MCI patients develop dementia as disease deterioratesinto the late stage [2–4], and Parkinson’s disease dementia isa critically influential factor for the reduced life expectancyin patients with Parkinson’s disease [5]. Movement disorder

has long been addressed to be burdensome in Parkinson’sdisease and the development of relatively effective restorationof dopamine by pharmaceutical treatment also contributes tothe success of management of motor symptoms, leaving thetreatment of nonmotor deficits an unmet clinical need. Fur-thermore, the aggravation of cognitive disturbances mightalso be strongly predicted by neuropsychological testing inthe early stage of disease with or without timely medicaltreatment [5–8].

In this review, we illustrate the demographic and clinicalsymptoms potentially assessed as risk factors for nonmotordeficits in Parkinson’s disease and discuss the underlyingmechanisms of these symptoms with evidence from geneticstudies, with primary focus on the clinical manifestationsand diagnosis supported by neuropsychology research, neu-roimaging, pharmacology, andmolecular genetics. At last, weprobe into the clinical pharmacological and nonpharmaco-logical management for Parkinson’s disease patients in thelight of its heterogeneous nature.


http://dx.doi.org/10.1155/2016/6734678


2. Epidemiology

PD is one of the most common neurodegenerative disorders,whose incidence is secondonly toAlzheimer disease. Accord-ing to a 5-year follow-up study by Broeders and a NorwegianParkWest study by Pedersen, 25% to 50% of patients withParkinson disease develop PD-MCI or PDD or progressfrom PD-MCI to PDD within 5 years of diagnosis [9, 10].Studies that followed patients prospectively diagnosed PDwith normal cognition and discovered the incidence of cog-nitive impairment are few till now. However, according to theavailable evidence, the progression of cognitive impairmentwas very common and comparatively quick. For instance, onestudy exhibited that the cumulative incidence of developingcognitive impairment was 8.5% within 1-year follow-up andup to 47.4% within 6-year follow-up [11]. In other studies,the incidence of cognitive impairments in PD patients variedfrom 48% to 60% by 12–15 years of retrospective follow-up[12, 13]. In addition, the community-based studies indicatedthat 20–35% of PD population would develop PD-MCI andup to 10% would develop PDD per year [14, 15]. Nonetheless,it is difficult to compare the results of all studies mentionedabove, due to differences in sample sizes and statisticalmethods used. Furthermore, one designed study also clarifiedthat the onset of dementia in PDpatients is approximately 70-year-old no matter when the onset of PD is [16].

Not only does the incidence of cognitive impairmentin PD patients vary, but also the risk factors for PD-MCIand PDD vary. Pigott et al. claimed that increased baselineHoehn&Yahr Scale score andUnified PDRating Scalemotorscore, and decreased baseline Dementia Rating Scale (DRS-2) scores are powerful predictors of early cognitive deficits[17]. It is widely accepted that DRS-2 might be effective andadequate for predicting cognitive disturbance and could beused as a reference method to test comprehensive cognitivefunction [16, 18].

3. Etiology

In this part, we mainly focus on the genetics of PD. 18 PD-specific chromosomal loci are named PARK and numberedchronologically, nine of which have been identified andconfirmed by linkage analysis or exome sequencing [19–33]. Eight of these loci were identified by linkage analysis,functional candidate gene approach or GWAS studies, andare deemed as susceptibility loci as risk factors [34–39]. Andstill one of them is supposed to be erroneous locus foundto be identical with PARK1 [40]. Within the nine confirmeddisease-causing genes, SNCA, LRRK, and VPS35 exhibitan autosomal dominant hereditary pattern while other sixgenes, Parkin, PINK1, DJ-1, ATP13A2, PLA2G6, and FBX07,display an autosomal recessive hereditary pattern. Besides,some other genes, such as GIGYF2, were reported to besusceptible to PD with specific variants in different ethnicpopulations [41]. The mutated genes involved in PD causebrain dysfunction through various molecular mechanisms,including disturbance of presynaptic vesicle recycling anddopamine transmission, toxicity from aggregation of mutantproteins, degeneration of dopaminergic axon in substantia

nigra, instability ormislocation of certain kinases, overactiva-tion of ubiquitin kinase activities, and decreased efficienciesof ubiquitin degradation pathways [42–52]. Although only10–15% of PD cases are familial and studies related to thepathogenic mechanisms on the confirmed disease-causinggenes or susceptible loci of PD are far from being complete,the discovery of PD-related genes is a critical step for us tounravel the mysteries behind neurodegeneration in PD. Upto date, there is limited research specifically dedicated to thestudy of the relationship between the genetic classificationsof PD and molecular mechanisms of cognitive impairmentin PD. However, some negative results indicated some dis-tinctive genetic features of cognitive decline in PD could bedifferentiated from other neurodegenerative disorders withcognitive disturbances [53, 54]. Furthermore, the filamentousLewy body formation could be observed in early onset ofPDD carrying SNCA mutations and Dementia with Lewybodies (DLB) [42, 55], and the aggregation of 𝛼-synucleincould be detected in substantia nigra as well as cortex inidiopathic PD patients, which suggests that the accumula-tion of 𝛼-synuclein could be the presynaptic dysfunctionattributed to neuronal toxicity caused by various genetic ornongenetic risk factors. It is also found that the frequencyof glucocerebrosidase mutations is increased in postmortemsamples from PD patients who had positive 𝛼-synucleininclusions [56, 57], and the BDNF (Met/Met) homozygotesdemonstrate dramatically worse cognitive impairment in PDpatients compared to noncarriers [58].

4. Clinical Characteristics and Diagnosis

There is dramatic heterogeneity in clinical definition andcorrelation of cognitive impairment in PD, ranging frommildcognitive impairment to dementia [18, 59, 60]. It has been along time that the definition and characteristics of PD-MCIand PDD exist as a controversial issue, until the MovementDisorder Society (MDS) took the initiative to conduct aTask Force to systematically review the most representativeliteratures. They evaluated the incidences and characteristicsof PD-MCI, as well as its relationship with dementia and itsinclination of progressing to dementia [61]. For PD-MCI, theMovement Disorder Society (MDS) finally selected a totalof 8 articles (6 cross-sectional studies and 2 longitudinalstudies) from 1156 articles (874 for Parkinson & cognitiveimpairment and 172 for Parkinson &MCI) [18, 59, 62–67], inwhich the study design, population studied, methodology forstatistical analysis, and criteria for PD-MCI/PDD definitionvary considerably. On the other hand, publications related toPDD are much more available than those to PD-MCI. TheMDS also reviewed the previous publications of dementiain PD excluding the cases of Dementia with Lewy Bodies(DLB) in terms of the “1-year rule,” characterized the clinicalmanifestations, and used these results to illustrate the criteriaof probable and possible PDD based on the consensus fromexperts [68].

The criteria of both PD-MCI and PDD are defined byclinical, cognitive, and functional aspects. As more time andeffort have been devoted to the study of PDD, the criteria for


PDDwere established first, which also profoundly influencedthe proposed criteria for PD-MCI [68, 69]. Similar to thepracticality of diagnosis in PDD criteria, a two-level opera-tional schema on the thorough basis of neuropsychologicaltesting is also applied in PD-MCI criteria [69]. Level I isa practical set which could be utilized easily by physiciansand needs no neuropsychological testing from neurologicalor psychological experts, whereas Level II is documented inmuch more detail and is more favorable for researchers toconduct longitudinal studies.

In a brief assessment of Level I, clinical diagnosis of PDbased on Queen’s Square Brain Bank criteria for PD mustbe established for both PD-MCI and PDD [70, 71]. For PD-MCI, cognitive capability is declined slowly which might bedescribed by caregivers or patients or observed by cliniciansfrom testing results. On the other hand, cognitive impairmentcaused by the clinical manifestations of parkinsonism otherthan idiopathic PD, other primary possibilities for cognitivedisturbances, and other PD-associated comorbid circum-stances that could significantly influence the outcome ofcognitive testing should be excluded from PD-MCI [68].Themost important point to differentiate PDD from DLB is thatPD symptoms should develop prior to the onset of dementia,which could be obtained by clinicians, gathered from thepatient him/herself, informant or follow-up records/pastmedical history [69]. As PD-MCI is a prestage of PDDand progresses to PDD in most cases, the cognitive deficitsscaled by a global cognitive ability test or at least two ofneuropsychological tests for the five cognitive domains (toerase the limitation of a single neuropsychological test) inPD-MCI should be subtle on complex functional task and notbe sufficient to interfere significantly with functional inde-pendence [68]. However, the cognitive impairment, whichcan be examined by global cognitive ability tests (e.g., MMSEbelow 26 [72]) and by at least two of the neuropsychologicaltests (months reversed [73] or seven backward [72], lexicalfluency or clock drawing [74], MMSE pentagons [72], and3-word recall [72]), is supposed to be severe enough toimpair daily living activities, which could be assessed by alist of simple tasks. And the cognitive impairment should beassessed without administration of antiparkinsonian drugsand not be attributed to other categories of abnormalitiessuch as autonomic or motor symptoms caused by PDD [69].

Once the diagnosis of cognitive impairment, includingPD-MCI or PDD, is established, specifying the subtypes ofcognitive deficiency and evaluating the severity of disease arequite beneficial for research, clinical practicing and monitor-ing, and even standardized pharmacological interventions.For PD-MCI diagnosis by Level II criteria, at least two ofneuropsychological tests examining each of the five cognitivedomains are recommended byMDS. Performance of patientsbetween 1 and 2 standard deviations (SD) below individualvariation adjustment showing predominant impairment orpremorbid levels may be demonstrated in PD-MCI. Butpatients within 1 SD below normalization tested by a serialof neuropsychological measurements or who reported sig-nificantly cognitive decline over time are also accredited todiagnose PD-MCI [75]. For PD-MCI subtyping, to differ-entiate PD-MCI as single or multiple domains, at least two

neuropsychological tests in each cognitive domain should beconducted. Impaired performance of two tests in the sameone cognitive domain without impairment in other cognitivedomains demonstrates the single-domain subtype. On theother hand, impaired performance of at least one test inno less than two cognitive domains indicates the multiple-domain type [76–91]. However, for PDD Level II testing,assessments of severity using quantitative measurementsdo not have upper limit scores in diagnosis. The goal ofLevel II testing, for one thing, is to confirm the uncertainPDD diagnosis when the clinical manifestations of cognitiveimpairment are not obvious or relatively confused. It alsoserves to depict the individual characteristic of PDD andas an indicator of pharmacological responsiveness. In PDD,there are five cognitive domains involved in Level II testing:global cognitive efficiency, executive functions, memory,instrumental functions, and neuropsychiatric functions, inwhich executive functions and memory are classified assubcorticofrontal functions and instrumental functions arebelieved to be cortically mediated [92].

5. Treatment

Abnormal activities of various subtypes of neurons have beeninvolved in the cognitive impairment of PD, including thedysregulation of dopaminergic, cholinergic, and probablyglutamatergic or noradrenergic neurons [93, 94].

Cholinesterase inhibitors, such as rivastigmine, havebeen proved beneficial to the improvement of global cogni-tion and clinical manifestations as well as neuropsychiatrictesting (especially for attention and executive functioningamelioration) by several large-scale multicenter randomizedplacebo-controlled trials [95–98]. However, Donepezil, also acholinesterase inhibitor, was not effective for global cognitiveimprovement or other neuropsychiatric symptoms in PD-MCI or PDD in a large randomized controlled study [99, 100],although its beneficial effect was reported in some smallplacebo-controlled studies [99].

Partial NMDA-receptor antagonist has been used as atherapeutic option to treat PD patients with cognitive defectsin several placebo-controlled trails [101–104]. However, theresults of studies were not consistent or notable; only onetrial showed statistical differences in the improvement ofglobal cognition [102], whereas most of trials suggested nopharmacological effects of partial NMDA-receptor antago-nist on neuropsychiatric symptoms or improvement of dailylife [105].

Atomoxetine, a noradrenergic reuptake inhibitor, andclozapine, an inhibitor of serotonin and dopamine recep-tors, as well as second-generation tricyclic antidepressant(TCA) nortriptyline and pramipexole, have been shown tobe beneficial for the regulation of attention, psychosis, anddepression, respectively, by evidence from several placebo-controlled trials [93, 106, 107].

Dysexecutive profile, which is known as the most pre-dominant component of cognitive deficits in PD-MCI andPDD, has been substantiated to be improved with levodopatreatment [6, 93]. Levodopa was found to act on some


aspects of cognition such as flexibility and working memorywithout beneficial changes of other functions like visuospatialrecognition, verbal ability, or associative learning [6, 93]. Forpatients with nondopaminergic antiparkinsonian adminis-tration, antagonists of the NMDA-type glutamate receptor,amantadine, for instance, could slow down the progressivetransition from PD-MCI to PDD, via increasing dopaminerelease and blocking dopamine reuptake [108].

Subthalamic deep brain stimulation, which is commonlyconducted on PD patients with motor complications that areresistant to antiparkinsonian medication, was claimed to beharmful for semantic and verbal fluency as well as executiveprofiles by a meta-analysis [109]. In the meantime, thisinvasive procedure, with the possibility of causing damageto the vital brain regions in charge of advanced cognitivefunctions, has been related to significant exacerbation ofdysexecutive profile that is not observed in most desirablepharmacological treatments [110].

Neuroprotective agents aiming to interrupt 𝛼-synucleinaggregation or to restore neuronal integrity are currentlynot available, whereas some cognitive interventions that arehelpful in Alzheimer’s disease have been identified to havepositive results in the early stage of randomized clinicalstudies [111, 112].

While deep brain stimulation (DBS) is effective for themotor deficits of Parkinson’s disease (PD) that is well doc-umented, cognitive and psychiatric benefits and side effectsfrom the subthalamic nucleus (STN) and globus pallidusinterna (GPi) DBS for PD are increasingly recognized. Onone hand, it has been reported that DBS could significantlyimprove immediate verbal memory and reduce anxietysymptoms [113]; on the other hand, it is also investigatedthat certain types of impaired domain such as attentionimpairment predicted more detrimental results after DBS[114]. Therefore, the improvements of cognitive symptomsfrom DBS require further studies and warrant the precisecognitive tests that stratify the relative risks and benefits ofsurgery.

6. Conclusion

Cognitive impairment in PD, as in other neurodegenerativediseases, demonstrates the common role of neurodegenera-tion as well as the PD-featured damage in certain advancedcognitive brain regions accompanied with characterized clin-ical manifestations. The treatments for cognitive deficits inPD remain limited and inadequate since the disturbances ofneuronal network involved in the process are still obscureand elusive. As the population ages, the increasing burdenfor both patients and caregivers from PD-MCI and PDDmakes it urgent to approach to the pathogenic mechanismsand therapeutic targets of cognitive deficits in PD, as wellas to research and develop novel pharmacological treatmentsand other interventions that could potentially be used in PDcognitive impairment.

Competing Interests

The authors declare that they have no competing interests.

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Research ArticleEvent-Related Potentials in Parkinson’s Disease Patients withVisual Hallucination

Yang-Pei Chang,1 Yuan-Han Yang,1,2 Chiou-Lian Lai,2,3 and Li-Min Liou2,3

1Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan2Department of Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan3Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan

Correspondence should be addressed to Chiou-Lian Lai; [email protected]

Received 22 September 2016; Accepted 9 November 2016

Academic Editor: Jan Aasly

Copyright © 2016 Yang-Pei Chang et al.This is an open access article distributed under theCreative CommonsAttribution License,which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Using neuropsychological investigation and visual event-related potentials (ERPs), we aimed to compare the ERPs and cognitivefunction of nondemented Parkinson’s disease (PD) patients with and without visual hallucinations (VHs) and of control subjects.We recruited 12 PD patients with VHs (PD-H), 23 PD patients without VHs (PD-NH), and 18 age-matched controls. All subjectsunderwent comprehensive neuropsychological assessment and visual ERPs measurement. A visual odd-ball paradigm with twodifferent fixed interstimulus intervals (ISI) (1600ms and 5000ms) elicited visual ERPs. The frontal test battery was used to assessattention, visual-spatial function, verbal fluency, memory, higher executive function, and motor programming.The PD-H patientshad significant cognitive dysfunction in several domains, compared to the PD-NH patients and controls.Themean P3 latency withISI of 1600ms in PD-H patients was significantly longer than that in controls. Logistic regression disclosed UPDRS-on score andP3 latency as significant predictors of VH. Our findings suggest that nondemented PD-H patients have worse cognitive functionand P3 measurements. The development of VHs in nondemented PD patients might be implicated in executive dysfunction withaltered visual information processing.

1. Introduction

Visual hallucinations (VHs) and cognitive impairment,which are nonmotor symptoms of Parkinson’s disease (PD),have been an intriguing issue in recent years [1]. It is crucialto screen mild cognitive impairment and dementia in PDpatients because dementia may cause nursing home place-ment, increased burden for health care and caregiver, andhigher mortality [2]. In the mid-stage of PD, VHs act as aclinical predictor of dementia [3, 4] and correlate with diseaseprogression and decline in Mini-Mental State Examination(MMSE) scores [5, 6]. Recent hypotheses suggest that thedevelopment of VHs in PD may result from an imbalance ofexternal and internal inputs and impaired reality monitoring,while cognitive impairment may play a role in reality mon-itoring [7, 8]. Cognitive correlation of VHs in PD patientsis evident [9–12]. A one-year neuropsychological follow-upstudy reported that nondemented PD patients with VHshave faster decline of complex visual function and multiple

cognitive domains than patients without VHs [13]. Previousstudies have also reported worse attention and visuospa-tial function in PD patients with VHs [14, 15]. However,another 4-year longitudinal observatory study showed thatVHs may be more associated with longer disease duration,increased functional impairment, and premorbid psychiatryillness rather than cognitive impairment [16]. Accumulatingevidence has demonstrated that cognitive dysfunction maycontribute to the occurrence of VH symptoms of PD patientsin nondemented PD patients with VHs regardless of theside effect of dopaminergic medication [17, 18]. Indeed,recent study using functional MRI technique suggests desyn-chronization between aberrant frontal circuit and posteriorcortical areas during active visual hallucinations [19].

Event-related potential (ERP) is a developed sensitive andnoninvasive tool to detect cognitive dysfunction in patientswith mild cognitive impairment and dementia [20–22]. Earlycomponents of ERP (N1 and P2) are considered exogenoussensory components that have been associated with attention


http://dx.doi.org/10.1155/2016/1863508


and sensory processing. The N2 component reflects an earlydetection of cognitive ability, such as target discrimination.P3 is a positive shift when a subject detects an informativetask-relevant stimulus [23, 24]. While some studies havesupported the correlation between ERP abnormality andcognitive impairment in PD patients with dementia, the roleof ERP in nondemented PDpatients is not confirmed [25–31].One study found visual cognitive impairment and prolongedvisual P3 latency especially in patients with PDdementia withhallucinations [32].

Since ERP may be a sensitive tool in the detection ofcognitive impairment in PD in the absence of clinicaldementia and VH is a potentially premonitory symptom ofdementia in PD patients, it may be interesting to explore theERP abnormality in nondemented PD patient with VHs. Inthe literature, few studies focused on the topic. We aim toassess the visual ERP and neuropsychological assessmentsin nondemented PD patients with (PD-H) and without VH(PD-NH) and healthy controls and find the linkage.

2. Materials and Methods

2.1. Participants. This study was conducted at the KaohsiungMedical University Hospital (KMUH), a tertiary referralcenter in Southern Taiwan. The KMUH institution reviewboard approved all procedures and written informed consentwas obtained from study participants. The control subjectswere recruited from volunteer in nearby community college.All PD participants had a presumptive clinical diagnosis ofPD according to UKPD Brain Bank criteria. Individuals wereinquired carefully and were assigned to groups according towhether they had experienced VHs in the past one year. Nopatient in the population sampled had a clinical diagnosis ofeither Alzheimer’s disease or Lewy body dementia. Patientswere excluded if Mini-Mental State Examination (MMSE)is less than 25. Patients with eye disease or migraine orother conditions like concurrent stroke, delirium, delusions,multiple sclerosis, and psychiatric illness or those underneuroleptics treatment were all excluded. Duration of illnessand medication were recorded and stage of illness wasscored according to the Hoehn and Yahr scale and UnitedParkinson’s Disease Rating Scale (UPDRS) during “on” state.PD patients take neuropsychological assessment and event-related potential during “on” state after regular oral medica-tions.

2.2. Neuropsychological Assessment. The neuropsychologicalassessment focusing on frontal lobe function [21] includesMini-Mental State Examination (MMSE), Digit Span (Wech-sler Adult Intelligence Scale-Revision (WAIS-R)), Digit Sym-bol (WAIS-R), Stroop Test, and Trail Making Tests (parts Aand B) to assess attention and concentration; Block Design(WAIS-R) and Rey-Osterrieth Complex Figure Test-Copyto evaluate visuoconstructional ability; word list generation(Controlled Oral Word Association; Category Fluency Test)to assess semantic verbal fluency; word list learning-recalland Rey-Osterrieth Complex Figure Test-Recall to evaluatememory; Wisconsin Card Sorting Test-Modified (WCST),

Design Fluency (Five-Point Test), and Similarity (WAIS-R)to assess higher executive function; Luria’s Hand Sequence toevaluate motor programming function.

2.3. Event-Related Potentials Measurements. A visual “odd-ball” stimulus paradigm (NeuroStim, NeuroScan, Inc.) wasused to elicit visual event-related potentials, and an electroen-cephalograph (EEG) was recorded using Ag/AgCl electrodesplaced at 5 scalp locations (FPz, Fz, Cz, Pz, and Oz),based on the 10–20 system. All were referenced to linkedearlobes. The electrode impedance was kept below 5 kΩ. TheEEG was amplified (band pass, 0.01–40Hz) by a SynAmpsamplifier (NeuroScan, Inc.), and continuous EEG recordswere kept for further offline analysis at a sampling rate of256Hz. The averaging epoch was 1024ms, including 200msof prestimulus baseline [21, 22].

The subjects sat in a comfortable chair in a sound-attenuated room with dim lighting 100 cm in front of a 19-inch LCD computer screen. Stimuli were presented in thecentral of the screen. The stimuli consisted of two neutralpictures from the NeuroScan template on a dark ground.The participants were asked to centrally fixate throughout therecording. We adopted a visual odd-ball task, with a targetstimulus and a nontarget stimulus.Mistrials including eyeballmovement artifacts were excluded from the offline analysis.

Stimuli were presented randomly with the probabilityof 20% target stimulus and 80% nontarget stimuli. In eachblock a total of 250 stimuli (50 targets, 200 nontargets)were presented for 100ms and interstimulus interval (ISI)of 1600ms and 5000ms. The experiment consisted of 4blocks (2 blocks with ISI of 1600ms and 2 blocks with ISIof 5000ms). Participants performed a brief training sessionto ensure they were able to detect the target accurately.During the examination, participants were asked to pressthe button as quickly as possible when they saw the target.Reaction time was measured relative to target onset forcorrect trials, while accuracy was measured as the percentageof correct responses out of all responses to the target stimulus.Individual trials with eye blink artifacts (more than 250𝜇Vofpeak-to-peak amplitude), target trials for which the reactiontime (RT) was more than 1.4 s, and nontarget trials witha response were all excluded from the averaging. SeparateERP averages were made for each trial type. For amplitudesanalysis, the mean potential during the 200ms period pre-ceding the stimulus onset served as baseline. The N1, P2,N2, and P3 components at Pz recording were assessed forhighest amplitude distribution. The latencies windows wereN1 component as the maximum negativity between 75 and160ms, P2 component as the maximum positivity between170 and 260ms, N2 component as the maximum negativitybetween 190 and 360ms, and P3 component as themaximumpositivity between 250 and 500ms.

2.4. Statistics. We performed statistical analysis with SPSS12.0 package, and 𝑝 < 0.05 was set to be statistically signifi-cant. We used two-tailed t-test for analyzing continuous dataof disease characteristic of PD patients. We used analysis of


Table 1: Characteristics in PD-H, PD-NH, and controls.

PD-H PD-NH Controls p𝑛 = 12 𝑛 = 23 𝑛 = 18

Age1, years 67.79 ± 7.93 66.36 ± 9.68 68.29 ± 6.83 0.753Women1, n (%) 5 (36) 7 (28) 10 (59) 0.107Education1, y 9.27 ± 6.65 10.88 ± 4.16 12.16 ± 3.32 0.245Disease duration2, y 11.73 ± 6.41 6.20 ± 4.86 n/a 0.007Duration of levodopa2, y 8.44 ± 5.78 3.04 ± 3.57 n/a 0.004H&Y2 2.65 ± 0.89 1.52 ± 0.65 n/a <0.001MMSE1 (score) 27.73 ± 2.20 27.58 ± 1.36 28.41 ± 1.37 0.472HDI1 (score) 5.00 ± 4.67 4.125 ± 4.11∗ 0.25 ± 0.79 <0.001UPDRS-III motor2 (score) 27.92 ± 13.00 14.20 ± 8.42 n/a <0.001Levodopa-equivalent dose 863.8 ± 390.6 311.2 ± 160.5 n/a 0.08PD-H: PD patients with visual hallucinations; PD-NH: PD patients without visual hallucinations; H&Y: Hoehn and Yahr stage; HDI: Hamilton depressionindex; UPDRS: Unified Parkinson’s Disease Rating Scale; n/a: not available.p: p value, 𝑝 < 0.05; by 1ANOVA 2t-test.

covariate (ANCOVA) to determine the differences of neu-ropsychological test between groups after adjusting diseaseduration, duration of levodopa use, Hoehn and Yahr stage,Hamilton depression index, and the scores of UPDRS-III. ForP3 latency and amplitude, we used ANCOVA to determinethe significant difference after adjusting age, gender, diseaseduration, duration of levodopa use, and Hoehn and Yahrstage with Tukey method used for post hoc analysis. One-way repeated measures analysis of variance (ANOVA) wasused to explore the effect of ISI on P3 latency and amplitude.Pearson correlation coefficient was calculated to explore therelationship between neuropsychological function and N1,P2, N2, and P3 latency and amplitude at Pz recording. ERPcomponents at Fz and Cz recordings were not analyzedbecause of artifacts. For our intent in analyzing the predictiverisk factors of VH, logistic regression with the existence orabsence of VHs as dependent variable was performed infour different models with different confounding factors. Toclarify the role ofUPDRS-on score in the development of VH,we adjusted age and gender in model 1, while we adjustedage, gender, and three cognitive domains in model 3. Tofurther observe the role of P3 latency in the development ofVH, age and gender and UPDRS-on score were adjusted inmodel 2, while age and gender, UPDRS-on score, and threecognitive domains were adjusted in model 4. The chosencognitive domains (Trail Making Tests, R-O copy, or LuriaHand Sequence) were significantly different between PD-H and PD-NH patients. According to WAIS-III Chineseversion, the cut-off values of three cognitive domains werechosen and were transformed to dichotomy dummy variablefor logistic regression.

3. Results

3.1. Demographic Data. Twelve PD-H patients, twenty-threePD-NH patients, and eighteen healthy control subjects wererecruited in this study (Table 1). The mean age, educationlevel, and MMSE did not differ significantly between thesethree groups, while there were significant differences between

the PD patients with and without visual hallucinations withregard to disease duration, duration of levodopa use, Hoehnand Yahr stage, and the scores of UPDRS-III. We also foundsignificant difference in Hamilton depression index in PD-Hor PD-NH patients when comparing with normal controls.

3.2. Neuropsychological Assessment. The data of neuropsy-chological investigations in all participants are shown inTable 2. There were multiple domains of frontal dysfunctionin PD patients, especially in PD-H patients. The PD-Hpatients performed significantly worse than normal controlsat Trail Making Test, R-O copy, Wisconsin Card SortingTest, and Luria Hand Sequence. Moreover, when comparingPD-H patients to PD-NH patients, significantly lower scoreswere found in the former group at Trail Making Test, R-O copy, Wisconsin Card Sorting Test, and Luria’s HandSequence. When comparing to normal controls, PD-NHpatients performed significantly worse in Wisconsin CardSorting Test.

3.3. Visual ERPData. For the highest amplitude distribution,the N1, P2, N2, and P3 components with two different ISIat Pz are outlined in Table 3. There was no significantdifference between PD-H patients, PD-NH patients, andcontrols, regardless of different ISI (1600ms and 5000ms).However, the mean latency of P3 with ISI of 1600ms in PD-Hpatients revealed significant prolongationwhen comparingwith that in controls. The mean reaction time and error rateof PD-H patients, PD-NH patients, and controls revealed nosignificant difference.

We also assessed the effect of ISI on P3 latencies, P3amplitude, and reaction time at Pz (Table 3) using one-way repeated measure ANOVA in PD-H patients, PD-NHpatients, and controls. P3 latency was significantly prolongedat 5000ms ISI compared to 1600ms ISI in PD-NH patientsand control (control, 𝐹 = 19.289, 𝑝 = 0.003; PD-NH,𝐹 = 5.391, 𝑝 = 0.04), while PD-H patients did notshow significant difference (𝐹 = 0.025, 𝑝 = 0.879). P3amplitude showed unremarkable difference in three groups


Table 2: Comparison of frontal test battery in PD patients and controls.

Demographic data PD-H PD-NH Controls pmean ± SD 𝑛 = 12 𝑛 = 23 𝑛 = 18

AttentionStroop Test (errors) 7.92 ± 9.09 7.33 ± 8.45 3.41 ± 5.19 0.151TMT-A (s) 122.21 ± 87.47ab 70.84 ± 41.47 52.76 ± 30.27 0.018TMT-B (s) 241.21 ± 121.73 134.00 ± 106.8 124.76 ± 84.81 0.264Digit Span 15.64 ± 4.24 15.88 ± 2.76 17.27 ± 4.54 0.198

Visual-constructional abilityBlock Design (score) 7.21 ± 4.16 12.08 ± 4.05 11.50 ± 3.78 0.255R–O-copy (score) 25.93 ± 10.17ab 32.08 ± 6.55 33.47 ± 1.91 <0.001

Verbal fluencyWord list generation 41.00 ± 14.81 44.21 ± 11.29 46.47 ± 8.68 0.122

MemoryWordlist learning recall (number) 17.21 ± 3.66 19.19 ± 3.76 22.29 ± 1.45 0.301R–O-recall (score) 7.71 ± 6.76 11.96 ± 9.19 13.00 ± 8.32 0.549

Higher executive functionSimilarities (score) 9.29 ± 6.08 10.12 ± 7.11 13.53 ± 4.58 0.760Five-Point Test (correct number) 2.79 ± 2.46 4.57 ± 2.92 5.35 ± 2.52 0.485WCST-category (number) 5.21 ± 2.12 6.00 ± 1.71 6.24 ± 2.31 0.697WCST-PN/total errors (%) 63.00 ± 32.91b 72.80 ± 31.40c 25.29 ± 20.95 0.027

Motor programmingLuria’s Hand Sequence (score) 1.29 ± 1.07ab 2.23 ± 1.14 2.12 ± 0.68 0.019

PD-H: PD patients with visual hallucinations; PD-NH: PD patients without visual hallucinations; TMT: Trail Making Test; R–O Complex Figure Test: Rey-Osterrieth Complex Figure Test; WCST: Wisconsin Card Sorting Test.p: p value, by one-way analysis of covariance (ANCOVA) with age, gender, and education as covariates.Post hoc analysis with Tukey method (aPD-H versus PD-NH, bPD-H versus controls, and cPD-NH versus controls).

when comparing 1600ms ISI to 5000ms ISI (PD-H, 𝐹 =0.324, 𝑝 = 0.585; PD-NH, 𝐹 = 2.987, 𝑝 = 0.112; control,𝐹 = 1.031, 𝑝 = 0.344). Reaction time was significantlyprolonged at 5000ms ISI compared to 1600ms ISI in PD-NHand PD-H patients (PD-NH, 𝐹 = 0.359, 𝑝 < 0.001; PD-H, 𝐹 = 13.059, 𝑝 = 0.005), while there was no significantdifference in controls (𝐹 = 2.831, 𝑝 = 0.111).

3.4. The Correlations of Frontal Function and ERPs in PD-H Patients. The domains of frontal function in PD-Hpatients were analyzed for their correlation with mea-sures of N1, P2, N2, and P3 at Pz lead. Pearson’s r val-ues of correlation between P3 latency, P3 amplitude, andneuropsychological scores are shown in supplementaryTable 1 (in Supplementary Material available online athttp://dx.doi.org/10.1155/2016/1863508). For higher execu-tive function (Similarities, Wisconsin Card Sorting Test),attention (Trail Making Test-type B, Digit Span), visuo-constructional ability (Digit Span, Rey-Osterrieth ComplexFigure copy test), verbal fluency (word list generation), andmemory (Rey-Osterrieth Complex Figure recall test), therewere significant correlations for P3. However, other earliercomponents of N1, P2, and N2 correlations with cognitivemeasures were not significantly evident (data not shown).

Supplementary Table 2 summarizes the odds ratio ofbinary logistic regression for UPDRS-on score and P3 latency

in different models. Overall, the results showed that increaseof UPDRS-on scores in PD patients was associated withsignificantly increased risk of VH in four different models.After adjusting age, gender, and UPDRS-on scores, model2 disclosed that one millisecond increase of P3 latency inPD patients was in line with 6% (𝑝 = 0.046) higher riskof having VH. By contrast, model 3 showed that therewas nonsignificant trend where poor performance of TrailMaking Tests, R-O copy, or Luria Hand Sequence was morelikely to have VH.

4. Discussion

Our study showed that nondemented PD patients with VHshad worse cognitive function than those without VHs andage-matched controls. In addition to UPDRS scores, thelatency of visual P3 was associated with VH after statis-tically adjusting the possible confounding factors and alsocorrelated with cognitive impairment in PD patients. Inaccordance with previous studies using neuropsychologicalassessment or functional MRI [15–18, 33, 34], our findingsuggests that frontal dysfunction may play a role in thedevelopment of VH in nondemented PD patients.

The term of P300 is composed ofmainly two distinct sub-components, P3a and P3b. Although the precise functionalorigin of P300 induced by visual stimuli is controversial,


Table 3: Comparisons of latencies and amplitude at Pz in visual ERPs of PD-H, PD-NH, and controls.

PD-H PD-NH Controls p𝑛 = 12 𝑛 = 23 𝑛 = 18

Amplitude, uVISI = 1600msN1 −0.59 ± 3.19 −2.48 ± 4.75 −2.57 ± 5.18 0.479P2 7.05 ± 3.81 10.87 ± 6.75 7.18 ± 5.73 0.164N2 −0.07 ± 5.42 0.95 ± 7.77 −1.33 ± 6.04 0.388P3 12.19 ± 4.74 14.14 ± 9.76 11.62 ± 7.86 0.934

ISI = 5000msN1 −1.44 ± 3.42 −2.02 ± 1.81 −2.26 ± 4.25 0.351P2 6.40 ± 3.40 5.83 ± 3.81 6.18 ± 4.89 0.831N2 −1.57 ± 5.08 −1.24 ± 4.39 −1.48 ± 4.32 0.836P3 11.18 ± 5.21 12.38 ± 8.33 13.34 ± 6.50 0.831

Latency, msISI = 1600msN1 140.29 ± 13.03 139.43 ± 21.83 133.73 ± 15.34 0.585P2 183.67 ± 15.40 185.57 ± 22.67 176.60 ± 8.09 0.643N2 277.11 ± 33.45 262.85 ± 18.26 263.92 ± 18.67 0.288P3 396.44 ± 28.19a 366.57 ± 21.58 359.89 ± 27.89 0.005

ISI = 5000msN1 152.86 ± 22.68 131.17 ± 20.25 135.63 ± 13.19 0.594P2 215.14 ± 26.02 191.13 ± 29.20 197.11 ± 18.28 0.391N2 282.75 ± 34.45 278.00 ± 22.94 265.17 ± 22.41 0.498P3 397.38 ± 18.78 395.89± 28.29b 404.44 ± 39.88b 0.827

RT, msISI = 1600ms 434.39 ± 71.49 395.65 ± 77.05 382.70 ± 52.97 0.145ISI = 5000ms 480.81± 88.60b 450.64 ± 94.03b 421.29 ± 121.03b 0.321

Error rateISI = 1600ms 0.03 ± 0.02 0.04 ± 0.05 0.19 ± 0.02 0.178ISI = 5000ms 0.03 ± 0.04 0.02 ± 0.02 0.02 ± 0.02 0.552

PD-H: PD patients with visual hallucinations; PD-NH: PD patients without visual hallucinations; RT: reaction time. Values are expressed as mean ± SD.p: p value, by one-way analysis of covariance (ANCOVA) with age, gender as covariate for between-group comparison and by one-way repeated measuresanalysis of variance (ANOVA) for within-group comparison.a𝑝 < 0.05, PD-H versus control, Tukey method for post hoc analysis,b𝑝 < 0.05, ISI = 5000ms versus 1600ms, by paired t-test.

visual P3b represents parietal cortical distribution reflectingthe top-down allocation of attention resources to relevantstimuli [35–37]. As wemeasured our visual P3 latency as P3b,our P3 latency may reflect the top-down attribution of visualprocessing.

In the present study, P3 latency with ISI of 1600ms inPD-H patients was significantly longer than control andassociated with VH after adjustment of confounding factors.As P3 latency of ERPs increases in line with cognitive declinein Lewy body dementia patients and demented PD patientswithVHs [29, 32, 38], our finding implies that visual cognitivefunctions are particularly impaired in nondemented PDpatients with visual hallucinations. It is accepted that VHsin PD could be related to central cholinergic dysfunction inpedunculopontine nucleus [33, 39]. On the basis of indirectpharmacological evidence, P3 ERPs in Alzheimer’s diseasecould reflect central cholinergic function [40, 41]. Hence, a

possible explanation for our findings might be that nonde-mented PD patients with VHs might have more dysfunctionover the frontobasal cholinergic pathways. In addition, visualERP of fixed ISI with 1600ms might be an auxiliary tool todetect cognitive dysfunction in nondemented PD.

There are several theoretical models implicated in thedevelopment of VHs in PD, and integrative approach maybe needed to explore sensory, attention, and cognitive deficits[42]. Functional MRI during active VHs showed desynchro-nization between frontal and posterior cortical areas involvedin visual processing [19], while Shine et al. suggest thatdecreased attentional network activity and increased primaryvisual system connectivity with default mode network maycontribute to the development ofVHs [43].Our PD-Hpatientalso showed significant deficits in tests about attention,visuoconstructional ability, executive function, and motorprogramming when comparing to PD-NH patients and


control. However, latencies and amplitude of N1 ERP or P2ERP, which may be more correlated with attentional networkin brain, did not show significant differences between groups.

There were several limitations in our study. First, wecollect PD patients from university-based hospital and thecollection bias cannot be completely excluded. Secondly,visual ERP may be affected by excessive eyelid blinkingrelated to blepharospasm, which is common in PD [44].We did not exclude PD patients with blepharospasm in thisstudy but the eyeball movement artifacts are excluded fromthe analysis. Thirdly, neuropsychological assessment may beaffected by poor attention or decreased motor function inPD patients. We arranged the assessment in the morningand patients receive regular medications before the exam, butpoor attention or motor fluctuation may still happen duringthe time-consuming tests.

5. Conclusion

We found that P3 ERPs measurements may be associatedwith visual hallucination and cognitive impairment in nonde-mented PD patients. Further longitudinal follow-up may beneeded to confirmwhether P3 ERPmeasurements and visualhallucinations might predict the development of dementia inPD patients

Competing Interests

The authors declare that they have no competing interests.

Acknowledgments

This study was supported by grants from Kaohsiung Med-ical University Hospital (KMUH97-7G30 and KMUH-IRB-980169).The authors are grateful for contributions from Pro-fessor Pang-Ying Shih. Professor Pang-Ying Shih passed awayon September 1, 2013.

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Review ArticleGastrointestinal Dysfunctions in Parkinson’s Disease:Symptoms and Treatments

Andrée-Anne Poirier,1,2 Benoit Aubé,1 Mélissa Côté,1,3 Nicolas Morin,4

Thérèse Di Paolo,1,2 and Denis Soulet1,2,3

1Axe Neurosciences, Centre de Recherche du CHU de Quebec (Pavillon CHUL), Quebec City, QC, Canada2Faculty of Pharmacy, Laval University, Quebec City, QC, Canada3Department of Psychiatry and Neuroscience, Faculty of Medicine, Laval University, Quebec City, QC, Canada4Faculty of Medicine, Laval University, Quebec City, QC, Canada

Correspondence should be addressed to Denis Soulet; [email protected]

Received 15 August 2016; Accepted 16 October 2016

Academic Editor: Shey-Lin Wu

Copyright © 2016 Andree-Anne Poirier et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

A diagnosis of Parkinson’s disease is classically established after themanifestation ofmotor symptoms such as rigidity, bradykinesia,and tremor. However, a growing body of evidence supports the hypothesis that nonmotor symptoms, especially gastrointestinaldysfunctions, could be considered as early biomarkers since they are ubiquitously found among confirmed patients and occurmuch earlier than their motor manifestations. According to Braak’s hypothesis, the disease is postulated to originate in theintestine and then spread to the brain via the vagus nerve, a phenomenon that would involve other neuronal types than thewell-established dopaminergic population. It has therefore been proposed that peripheral nondopaminergic impairments mightprecede the alteration of dopaminergic neurons in the central nervous system and, ultimately, the emergence of motor symptoms.Considering the growing interest in the gut-brain axis in Parkinson’s disease, this review aims at providing a comprehensive pictureof themultiple gastrointestinal features of the disease, alongwith the therapeutic approaches used to reduce their burden.Moreover,we highlight the importance of gastrointestinal symptoms with respect to the patients’ responses towards medical treatments anddiscuss the various possible adverse interactions that can potentially occur, which are still poorly understood.

1. The Importance of Nonmotor Symptomsin Parkinson’s Disease

In the early 19th century (1817), with the publication ofAn Essay on the Shaking Palsy [1], Dr. James Parkinsonwas the first to provide a clear clinical description of thedisease that now bears his name [2, 3]. There are currentlyfour motor features characterizing this neurological disorder,namely, muscle rigidity, tremor at rest, bradykinesia, andpostural instability [3, 4]. However, a definitive diagnosisof Parkinson’s disease (PD) is difficult to establish and canbe obtained only postmortem by the demonstration of thepresence of Lewy bodies [3]. Therefore, clinicians currentlyrely not only on motor symptoms manifestations but also ona positive response to levodopa (L-DOPA) treatment [4].

Progressive alterations of dopaminergic (DAergic) neu-rons in the nigrostriatal pathway are at the core of theabovementionedmotor symptoms, resulting in a dysfunctionof the somatomotor system. The extent of dopamine (DA)loss in the substantia nigra is already about 50–70% whenthe first motor symptoms emerge, and although PD is aprogressive neurological disorder, DAergic deterioration isusually very slow and varies from one person to another[4]. An early diagnosis of the disease based on the UnifiedParkinson’s Disease Rating Scale (UPDRS) has a favorablelong-term impact on the quality of life of patients [3].

Over the course of PD progression, motor impairmentsare generally preceded by nonmotor symptoms (NMS) suchas depression, olfactory deficit, sleep behavior disorder, andconstipation, sometimes by up to ten years [5–8]. In his essay,


http://dx.doi.org/10.1155/2016/6762528


James Parkinson had mentioned some of these nonmotorfeatures, namely, constipation, sleep disorders, dysphagia,drooling (sialorrhea), bladder dysfunction, and a slight stateof confusion [1]. Nowadays, NMS are increasingly associatedwith PD, although they have not yet received extensiveattention [6]. Indeed, patients report less than 40% of theirnonmotor problems to healthcare professionals, either outof embarrassment or because these symptoms are seen ascommonplace and inconsequential events [8]. To compoundthis problem, only a few NMS are recorded in medicalfiles and are associated as such with PD, although thoseproblems have been shown to result from the disease itselfrather than being unremarkable manifestations of normalaging [9–12]. Therefore, these NMS, which are very oftenoverlooked and are poorly investigated and treated, can havea major negative impact on the clinical care and quality oflife of PD patients [6, 13–15]. Patients also often indicate thattheir NMS are more difficult to manage than their motorproblems and may sometimes result in their hospitalizationand institutionalization [6, 15, 16]. In addition, it has beendemonstrated that attenuating NMS greatly improves thequality of life of patients, particularly those who positivelyrespond to a DAergic therapy [15, 17]. Thus, the recentlydeveloped awareness on the detection of the different NMSearly in the course of PD has led to amore critical appraisal ofits etiology, the identification of risk factors, and the currentadvances in neuroprotective and therapeutic biomarkers ofPD [5, 6, 18–20]. In light of these lines of evidence, PD canno longer be viewed solely as a complex disorder of motorfunctions, but rather as a progressive condition involvingbothmotor and nonmotor features [5, 15, 21]. Some investiga-tors have even proposed that PD could be divided into threephases, namely, preclinical, premotor (corresponding to theNMS), andmotor phases [6, 20]. In some patients, nonmotorproblems can be reminiscent of complications resulting frompharmacological and surgical interventions for the treatmentofmotor symptoms [16]. NMS can also bemore predominantin the “off” medication state and some might be alleviatedby DAergic therapy or, on the contrary, be exacerbated bythe latter [8]. Furthermore, the high costs associated withmedical care and the aging population strongly stress theneed to expand our knowledge base on all aspects of PD[13]. The various effects of which NMS are comprised andtheir highly divergent patterns of progression between PDpatients further raise the challenge imposed by NMS in themanagement of PD [15].

About a decade ago, Dr. Braak et al. proposed theintriguing hypothesis that PD might result from an infectionspreading first by intestinal and olfactory mucosae [22, 23].This proposal followed the first description of Lewy bodiesin the dorsal vagal nucleus by Friederick Lewy in the early20th century [6, 15]. Based on Lewy bodies distributionin PD postmortem patients, Braak et al. also suggested sixneuropathological stages, corresponding to disease evolution[23]. As such, the first signs of Lewy pathology appearin projection neurons of the dorsal motor nucleus of thevagus nerve at the early stage of PD [23]. Despite itspotential interest, this hypothesis is not widely accepted,mainly because of the paucity of patients studied and the lack

of associated clinical data [24]. However, the manifestationof NMS, preceding motor diagnosis, closely correspondsto the progression of Lewy pathology, supporting Braak’shypothesis [8]. Some studies have further suggested that thepathological process leading to PD could be initiated in theenteric nervous system (ENS) before spreading to the centralnervous system (CNS) via autonomous connections such asthrough the vagus nerve [25, 26]. In connectionwith the latterobservation, a recent study has demonstrated that differentforms of human alpha-synuclein (𝛼-syn), the major proteincomponent in Lewy bodies, injected in the intestine of micecan propagate to the brain via the vagus nerve and reach thedorsal motor nucleus in the brainstem, supporting Braak’shypothesis [27].

There are several different approaches to categorize thenonmotor features encountered in PD, but they have usuallybeen separated into five major classes, namely, cognitiveimpairment, neuropsychiatric disorders, autonomic dysfunc-tion, sleep disturbances, and other NMS [4–7]. Confusionand dementia are the most commonly reported cogni-tive impairments, whereas neuropsychiatric disorders ratheroccur as hallucinations, anxiety, depression, and impulse con-trol disorders. Importantly, PD medication can potentiallyexacerbate some of the latter problems [13]. For example, theeffects of DA agonists on the mesolimbic pathway could beresponsible for impulse control disorders such as compulsivegambling, compulsive shopping, and hypersexuality [7, 28].In addition, an injury to the autonomic nervous system canbe observed in various peripheral NMS such as orthostatichypotension, functional bladder disorder, excessive sweating,erectile dysfunction, and gastrointestinal (GI) symptomssuch as constipation, drooling, dysphagia, and nausea [4,6, 13, 16, 26, 28]. Other nonmotor features that are stillpoorly categorized include pain, fatigue, unexplained weightchanges, and visual as well as olfactory disturbances. To betteridentify these elements, Chaudhuri et al. developed the Non-Motor Symptoms Scale, which allows for a more accuratemeasurement of the frequency and severity of NMS andallows determining the impact of treatment on these symp-toms [15, 29]. In addition, the Non-Motor Questionnaire, theScales for Outcomes in Parkinson’s Disease, and a revisedversion of the UPDRS (sponsored by theMovement DisorderSociety) also contribute to the establishment of standardizedand reliable means to assess NMS in PD [8, 30].

2. GI Manifestations in Autonomic Disorders

Early PD, when left untreated, is often accompanied by auto-nomic nervous system impairments among which GI symp-toms represent the most common NMS [31]. Indeed, severalstudies relying on nonmotor rating scales have underscoredthe particular significance of GI symptoms in assessing thequality of life and have shown that thesemanifestations occurin 60% to 80% of patients [13, 16, 32, 33]. GI disorders areamong the most common causes of emergency admissionand often result in severe complications such as malnutri-tion (15% of PD patients), pulmonary aspiration (2.4% ofPD patients), megacolon (mostly asymptomatic; incidence


unknown), intestinal obstruction (rarely reported; incidenceunknown), and even intestinal perforation (a few casesreported; incidence unknown) [34–38]. Moreover, older age,DAergic medication, and higher disease severity are usuallyassociated with these nonmotor features [28]. Hence, GIsymptoms reflect disturbances of GI tractmotility at all levels.

There are twomajor neural influences that regulate theGItract, namely, the extrinsic pathway, which is associated withthe vagus nerve, and the ENS, a component of the autonomicnervous system [39]. Due to its capacity to operate inde-pendently of the CNS and its 100 million neurons, the ENSis often considered as the second brain of the human body[39–41]. The ENS contains the myenteric and submucosalplexi, which are responsible for controlling smooth muscleactivity in the GI tract [40, 41]. The latter intestinal function,which is regulated by the ENS, requires the involvement ofseveral types of neurotransmitters such as DA, serotonin,acetylcholine, vasoactive intestinal peptide (VIP), substanceP, and nitric oxide synthase (NOS) [42]. Although the ENShas the ability to function independently of external stimuli,it also closely interacts with the vagal system [39, 41].

2.1. Constipation. Constipation is one of the initial NMSrelated to PD pathophysiology, affecting about 50–80% ofpatients. It often occurs early in the course of the disease andmay precede the appearance of motor symptoms by severalyears [6, 13, 28, 31, 43, 44]. Constipation is usually defined asfewer than three bowel movements per week and straining topass stools [45]. Although constipation is mainly consideredas a delay of the GI transit, some evidence suggests that itcan also be ascribed to a paradoxical contraction of voluntarysphincters during defecation, resulting in difficulties withrectal expulsion. In the early stages of PD, decreased GImotility has been associated with neuronal loss in the myen-teric and submucosal plexi and inclusions of Lewy bodiesin the dorsal motor nucleus of the vagus, underscoring theirpotential role in slowing down intestinal peristalsis [7, 28, 32].In addition to its association with autonomic alterations and,in some cases, urologic impairment, constipation is linked toa 2.7- to 4.5-fold increase in the risk of suffering from PD[15, 43, 46]. Constipation may also be accompanied by otherGI features that can affect intestinal transit. For instance, pain,nausea, bloating, vomiting, and distension are all symptomsof paralytic ileus, inducing complete obstruction of thegut and affecting about 7% of parkinsonians. Anismus, theabnormal contraction of the external anal sphincter andpuborectalis muscle during attempted defecation, is anotherproblem that can occur in synergy with constipation inapproximately 65% of PD patients, which is more frequentlyobserved during “off” periods [16, 28, 47]. Other intestinalcomplications such as megacolon (mostly asymptomatic),pseudoobstruction, sigmoid volvulus, and bowel perforationmay also arise in severe conditions, although their exactincidence is still currently unknown [32, 37, 38, 48].

2.2. Drooling. Also known as sialorrhea, drooling is themost common NMS of PD and is generally predominantlyobserved in the late stages of the disease and during the “off”

state medication [5, 49, 50]. Affecting 70 to 80% of parkin-sonians, sialorrhea corresponds to an exaggerated increase ofsaliva production and/or retention in the mouth cavity, withoccasional overflow into the pharynx [13, 32, 49–51].The sub-mandibular, sublingual, and parotid glands are the three pairsof salivary glands responsible for most of the approximately1.5 liters of saliva secreted daily and are controlled by theautonomic nervous system, mainly under parasympatheticcholinergic innervations [52, 53]. Sialorrhea may result fromthree phenomena, namely, abnormal production of saliva,impairment of salivary clearance, and/or inability tomaintainsaliva in the mouth [51]. Furthermore, excessive salivaryproduction may sometimes lead to serious complications,including saliva-induced asphyxiation and aspiration pneu-monia [31, 45]. Different scales, such as Drooling Severityand Frequency Scales, Drooling Rating Scale, and SialorrheaClinical Scale for PD, have been proposed to assess sialorrheaaccording to standard criteria [52, 54, 55]. However, droolingis rarely due to overproduction of saliva but is rather morecommon due to dysphagia, which itself is essentially amanifestation of bradykinesia [50, 56]. Indeed, in most PDpatients, decreased salivary production is in fact observed[51, 56, 57]. Studies have shown that patients do not produceexcessive amounts of saliva but rather have a more limitedability to swallow properly which, when associated with a for-ward head posture, might contribute to the onset of drooling[32, 49, 58]. In general, the inability to control oral secretionscan affect eating and speech and cause social embarrassment[59]. Somepatients even consider sialorrhea as theirworst PDsymptom [32].Different factors can influence sialorrhea, suchas male gender [60], aging [61], severity and duration of PD[62], hallucinations [59], orthostatic hypotension, dysphagia,dysarthria, UPDRS scores, and the use of antidepressants [51,63]. Furthermore, the peripheral autonomic nervous systemand the dorsal motor nucleus of the vagus nerve have beenimplicated in drooling, and Lewy bodies have been found inthe submandibular salivary glands in some studies [5, 64].

2.3. Dysphagia. Dysphagia, a feature of PD pathophysiology,is defined as a difficulty in swallowing food, liquids, orpills due to an impaired function of the medullary center[65, 66]. Dysphagia can result from muscular coordina-tion dysfunctions in at least one of the three phases ofdeglutition: oral, pharyngeal, and oesophageal [67]. Themain cause of swallowing difficulties, that is, a dysfunctionof the oropharyngeal phase (found in about one-third ofPD patients [68]), often results from motor symptoms ofbradykinesia and a reduced motor control of the tongue.Thus, these motor features contribute to the pathophysio-logical development of dysphagia and, by extension, mightalso play a role in the onset of sialorrhea in PD [51].Various abnormalities in the oropharyngeal phase, such as adelayed swallowing reflex, laryngeal movement deficits, andvallecular and piriform sinus residues, have been reported[66, 69]. In the oesophageal phase, complete aperistalsis,simultaneous oesophageal spasms, slower oesophageal tran-sit, and deficit in sphincter relaxation and pressure havebeen the predominantly observed abnormalities [67, 70].


Interestingly, this involuntary component of deglutition isunder autonomic control, and Lewy bodies have been iden-tified in the oesophageal myenteric plexus [66, 67]. Thesefindings suggest that swallowing impairment could partlyresult from direct damage to the ENS. Moreover, in viewof the various aforementioned abnormalities, dysphagia isclearly linked to an increased risk of mortality by causingand/or exacerbating other PD-related complications such asaspiration pneumonia (estimated to account for 70% of themortality rates among PD patients [36]), choking, malnutri-tion, unexplainedweight loss, and dehydration [13, 66, 69, 71].Unfortunately, the degree of dysphagia cannot be predictedby PD progression because it has no direct connection withthe clinical severity of the disease as evaluated by motorcriteria [31, 70]. Moreover, data from various studies suggestthat up to about 50% of parkinsonians might suffer fromdeglutition problems, which, as with drooling, occur mainlyduring the late stages of the disease [66, 71, 72].

2.4. Nausea, Vomiting, and Gastroparesis. Nausea and vomit-ing (which are experienced by approximately 20% of patients[45]) are related, most of the time, to antiparkinsonianmedications for motor symptoms, rather than occurringas intrinsic features of PD [6, 7, 28]. Indeed, these sideeffects generally appear following the initiation of DAer-gic treatments [28]. However, nausea may likely occur inuntreated parkinsonian patients as well, and such casesmightbe explained by underlying gastroparesis [73]. Also knownas delayed gastric emptying, gastroparesis corresponds todecreased stomach motility, which may eventually affectgut transit. In addition to nausea, chronic gastroparesisis characterized by early satiety, a sensation of fullness,weight loss, and abdominal pain and bloating [74]. Thisphenomenon could well be related to the degeneration ofautonomic neurons in the myenteric plexus and brainstem[45]. Moreover, intestinal absorption of L-DOPA and othermedications might be slowed by such protracted gastricretention, thus reducing the effectiveness of treatment andpreventing the improvement of motor symptoms [75]. PD-associated gastroparesis deserves proper medical attention asits observed prevalence approaches 90% of patients [76].

2.5. Pathophysiology. Recently, several clinical and post-mortem studies exploring Lewy bodies expression and/or thepresence of neurodegeneration in the enteric nervous systemof parkinsonian patients have been conducted in order tobetter understand the etiopathogenesis of PD (see Table 1).

2.5.1. Lewy Bodies. The pathophysiological mechanismsunderlying GI dysfunctions are likely to be multifaceted,reflecting not only the involvement of the intrinsic inner-vation of the gut, but also extrinsic inputs because of thepresence of Lewy pathology in the dorsal motor nucleus ofthe vagus, sacral parasympathetic nuclei, and sympatheticganglia [77–79]. The occurrence of Lewy pathology in thegut of PD patients was first reported in an autopsy survey inwhich Qualman et al. found myenteric Lewy bodies in thecolon of one patient and in the esophagus of another [80].

A subsequent clinical study demonstrated the presence ofLewy bodies in the colon of one PD subject [81]. Theseprimary observations led Wakabayashi et al. to perform asystematic assessment of Lewy pathology in the ENS ofseveral PD patients [82]. Lewy bodies were found in the GItract of seven patients and were distributed widely from theupper esophagus to the rectum. In a follow-up study, the sameteam reported that most Lewy bodies observed within theGI tract of the three patients were located in VIP+ neuronsand to a lesser extent in neurons immunoreactive for tyrosinehydroxylase (TH) [83]. Therefore, this suggests potentialinterplay between these neurons and cholinergic neurons ofthe vagus nerve contributing to the spread of 𝛼-syn to theCNS. It was also mentioned that few Lewy bodies were foundin neurons that were negative for either VIP or TH. To date,these have been the only studies suggesting that a specificsubset of enteric neurons could bear Lewy pathology [83].No further reports regarding GI Lewy pathology in patientswith PDwere published, until 2006 when Braak et al. broughtthis topic to the forefront [84]. In this postmortem study,they investigated the gastric myenteric and submucosal plexifrom five individuals with Lewy body disease. Clinical datademonstrated that three out of the five patients with Lewybody pathology displayed motor symptoms reminiscent ofPD while the other two patients were reported to be freeof such symptoms. However, Lewy pathology was presentin both the myenteric and the submucosal plexi of all fivepatients. This led Braak and colleagues to postulate that thepathology initiates in the ENS before progressing to theCNS [84]. Despite being a potentially important finding, thishypothesis has not been widely accepted, mainly because ofthe paucity of patients studied and the lack of associatedclinical data [24]. More recently, a comprehensive survey onthe occurrence of Lewy pathology in the peripheral nervoussystem, and especially in the ENS, has been published bythe Arizona Parkinson’s Disease Consortium [79]. One ofthe most striking results of this study was the identificationof Lewy inclusions in the esophagus of 14 out of 15 PDpatients, suggesting that enteric pathology is present in thevast majority of PD cases [79]. Other recent studies havealso observed 𝛼-syn positive staining in GI tissues collectedbefore patient’s diagnosis [85] and in the vast majority ofparkinsonian patients’ colon tissues [86, 87].

The abovementioned data on the ENS in PDpatients werecollected either at autopsy or using colectomy specimens.To extend this work by analyzing enteric neuropathologyin living patients, Lebouvier et al. took advantage of anovel colonic biopsy technique [88, 89]. Twenty-nine patientswith an established PD diagnosis were enrolled togetherwith 10 healthy subjects who had undergone colonoscopyfor colorectal cancer screening. Biopsies from 21 out ofthe 29 patients with PD (72%) showed Lewy neurites intheir submucosal plexus, whereas no Lewy pathology wasobserved in any of the controls [89]. Chronic constipationwas more frequent in patients with than without Lewyneurites, suggesting a pathogenic role for these inclusions.However, Lebouvier et al. did not consider the myentericplexus, which is directly involved in the control of bowelmotility [89]. These findings are in line with other reports


Table1:GIp

hysio

pathologic

manifestations

inPD

.Sum

maryof

clinicalstudies

exploringLewybo

dies

expressio

nand/or

presence

ofneurod

egenerationin

enteric

nervou

ssyste

mof

parkinsonian

patie

nts.

Stud

ies

GIp

art

Plexi

Dise

ases

tage

ordu

ratio

nSymptom

s(num

bero

fPDpatie

nts)

GIp

atho

logicalobservatio

ns(num

bero

fPDpatie

nts)

Qualm

anetal.,

1984

[80]

Esop

hagusa

ndcolon

Myenteric

Unk

nown

Lewybo

dies

(2/3)

Kupsky

etal.,1987

[81]

Colon

Myenteric

Unk

nown

Megacolon

(1/1)

Lewybo

dies

(1/1)

Wakabayashi

etal.,

1988

[82]

Upp

eresop

hagustothe

rectum

Myentericand

subm

ucosal

From

lessthan

1yearto27

years

IntraneuriticLewybo

dies

inmyentericneuron

sof

thee

soph

agus

(7/7),sto

mach(2/7),du

odenum

(2/7),jejunu

m(1/7),colon(1/7),andrectum

(1/7)

IntraneuriticLewybo

dies

insubm

ucosalneuron

sof

thejeju

num

(1/7),colon(2/7),andrectum

(1/7)

Intracytop

lasm

icLewybo

dies

inmyenteric

neuron

softhe

esop

hagus(1/7

)

Wakabayashi

etal.,

1990

[83]

Upp

eresop

hagustothe

rectum

Myentericand

subm

ucosal

8years,27

years,andun

know

n

Alm

ostallneuron

scon

tainingLewybo

dies

were

TH+or

VIP+(3/3)

Noapparent

lossof

TH+andVIP+neuron

scell

bodies

andprocess

Sing

aram

etal.,

1995

[99]

Ascend

ingcolon

Myentericand

subm

ucosal

Long

standing

severe

disease

(>20

yearsfor

8patie

nts)

Megacolon

(9/11

)Colon

cancer

(1/11

)Neededmanualevacuation

(7/11

)

DecreaseinDAe

rgicneuron

snum

ber(9/11)

Lewybo

dies

inmyentericneuron

s(11/11

)∗𝑀𝑜𝑠𝑡𝑙𝑦observed

inVI

PandTH

+neurons

DecreaseinDAconcentration

NodifferenceinTH+,V

IP+,and

totaln

eurons

number

Braaketal.,2006

[84]

Distalesop

hagusa

ndsto

mach

Myentericand

subm

ucosal

Stage2

tosta

ge5

IntraneuronalL

ewybo

dies

(5/5)

Lebo

uviere

tal.,

2008

[102]

Ascend

ingcolon

Subm

ucosal

>5years

Con

stipatio

nLewyneurites(4/5)

NodifferenceinTH+andtotaln

eurons

number

Beachetal.,2010

[79]

Upp

eresop

hagustothe

rectum

,sub

mandibu

lar

gland,liver,pancreas,and

gallb

ladd

er

Myentericand

subm

ucosal

Morethan80%in

stage

3or

4Lewybo

dies

inclu

sions

(11/1

7)∗14/15

patientsfor

onlyesophagusa

ndsubm

andibu

larg

land

Lebo

uviere

tal.,

2010

[89]

Ascend

inganddescending

colon

Subm

ucosal

Group

1:≤6years(9patie

nts)

Group

2:7–12

years(10

patie

nts)

Group

3:≥13

years(10

patie

nts)

Chronicc

onstipatio

n∗𝑀𝑜𝑟𝑒fre

quenta

mong

patientsw

ithLewy

neurites

Lewyneurites(21/29)

∗𝐺𝑟𝑜𝑢𝑝

1=7;Gr

oup2=5;Gr

oup3=9

∗𝑃𝑟𝑜𝑝𝑜𝑟𝑡𝑖𝑜𝑛

ofpatientsw

ithLewy

pathologyd

idnot

correla

tewith

diseasep

rogressio

nbutp

ositively

correla

tedwith

age

∗60%we

refoun

din

TH+neurons

Decreaseintotaln

eurons

number


Table1:Con

tinued.

Stud

ies

GIp

art

Plexi

Dise

ases

tage

ordu

ratio

nSymptom

s(num

bero

fPDpatie

nts)

GIp

atho

logicalobservatio

ns(num

bero

fPDpatie

nts)

Ann

erinoetal.,

2012

[92]

Stom

ach,du

odenum

,ileum

,transversec

olon

,andrectum

Myenteric

From

4to

22years

Lewybo

dies

(12/13)

Lewyneurites(13/13

)∗<3%

werefoun

din

TH+neurons

∗𝑁𝑜correla

tionwith

ageo

rdise

asep

rogressio

nNodifferenceinTH+,V

IP+,N

OS+,and

total

neuron

snum

ber

Poucletetal.,2012

[90]

Ascend

inganddescending

colonandrectum

Subm

ucosal

From

1to24

years

Lewyneuritesinascend

ingcolon(17/26),in

descending

colon(11/2

6),and

inrectum

(6/26)

Poucletetal.,2012

[91]

Descend

ingcolon

Subm

ucosal

From

3to

15years

Lewyneurites(4/9)

Shanno

netal.,

2012

[86]

Sigm

oidcolon

Subm

ucosal

From

6mon

thsto8years

Mild

disabilities

𝛼-syn

positives

taining(9/9)

Goldetal.,2013

[87]

Colon

Myentericand

subm

ucosal

Unk

nown

𝛼-syn

positives

taining(10/10)

∗𝐻𝑖𝑔ℎ𝑒𝑟

prevalence

andgradeo

f𝛼-sy

ndetecta

bility

than

controls

Hilton

etal.,2014

[85]

Esop

hagus,sto

mach,sm

all

intestine,colon,

andgall

bladder

Subm

ucosal

From

8yearsp

riortotheo

nsetof

motor

symptom

sto15

yearsa

fter

diagno

sis

Postu

ralhypotensio

n,constip

ation,

dysphagia,

urinaryincontinence,

impo

tence,no

cturia,and

droo

ling

𝛼-syn

positives

taining(7/62)

∗11%

in“postdiagnosis”

tissues,7%in

“upto5years

priortodiagnosis”tissues,17%in

“5–10yearsp

rior

todiagnosis”tissues,and0%

in“m

orethan10

years

beforediagnosis”tissues

∗𝑃𝑟𝑜𝑝𝑜𝑟𝑡𝑖𝑜𝑛𝑠ofpositiveb

iopsies

inboth

theu

pper

andthelow

erGI

tractwe

resim

ilar

Gelp

ietal.,2014

[93]

Distalesop

hagus,sto

mach,

ileum

,colon

,and

rectum

Myenteric

Averageo

f11.5

years

∗𝐴V𝑒𝑟𝑎𝑔𝑒of18

yearsfor

PDpatientsw

ithdementia

Dem

entia

(6/10

)Lewyneuritesa

ndLewybo

dies

inclu

sions

indistal

esop

hagus,sto

mach,andcolon(8/10

)

Corbille

etal.,2014

[103]

Ascend

inganddescending

colon

Subm

ucosal

From

1to24

years

NodifferenceinTH+andtotaln

eurons

number

Beachetal.,2016

[96]

Sigm

oidcolon

Myentericand

subm

ucosal

Averageo

f15.2years

𝛼-syn

positives

tainingin

thes

ubmucosal(5/5)a

ndmyenteric(4/5)p

lexi

∗:note.


on PD enteric pathology, which showed that, besides Lewybodies, Lewy neurites were also observed in the ENS ofpatients [79, 84, 90–93]. Using 𝛼-syn immunostaining, theauthors also demonstrated that approximately half of theLewy neurites observed in the submucosal plexus belongedto postganglionic neurons, thus supporting their extrinsicorigin [84]. The origin of the remaining Lewy neuritesremains to be determined, but it is possible that they couldoriginate both from submucosal and from myenteric neu-rons, which have been shown to project to the submucosalblood vessels [94]. This observation is in agreement withrecent studies showing 𝛼-syn immunolabeling in the submu-cosal perivascular regions [95, 96]. Depending on the typeof 𝛼-syn immunostained and the intestinal region studied,some discrepancies in the observation of Lewy bodies inGI biopsies or postmortem tissues are possible, especiallybecause 𝛼-syn is physiologically expressed by red blood cellsand vascular endothelial cells [96].

Interestingly, an animal model of PD recently developedprovides some clues on the role of ENS alterations in GIdysfunction. Transgenic 𝛼-syn SNCA, A53T, and A30P micedisplay aggregates within their enteric ganglia, which isassociated with a prolonged whole-gut total transit time andreduced colonic motility [97]. However, there is no evidenceof pathologic changes in the dorsalmotor nucleus of the vagusor autonomic cardiovascular dysfunction. These findingssuggest that ENS alterations in these mice are intrinsic inorigin, being caused by 𝛼-syn aggregation in enteric neuronsonly. It is possible in PD patients that at least some of the GIsymptoms could be caused by enteric neuropathy. It shouldbe pointed out, however, that studies on GI symptoms inPD have focused mainly on motility disorders and thereforethe role of the myenteric plexus and associated consequencesof Lewy pathology in the submucosal plexus have, to ourknowledge, not been addressed either in patients or inexperimental models of PD.

2.5.2. Neurodegeneration. Enteric neurons produce a sub-stantial amount of DA which regulates normal gut motility[67]. Interestingly, slowed GI transit and decreased gut con-traction in PD patients occur via altered DA-ENS circuitry,which normally promotes the peristaltic reflex [98]. PDpatients with severe constipation have been reported topresent lower levels of GI DA, suggesting that damage tothe enteric DAergic system might be an important factorunderlying GI dysfunction [99]. More recently, age-relatedloss of myenteric neurons has been associated with chronicconstipation, although studies are widely controversial [100,101]. Unfortunately, it is still not clear whether PD leads tothe loss of enteric neurons. Singaram et al. reported thatmost patients present DAergic neuronal loss in the colonicmyenteric and submucosal plexi, whereas other types ofneuronswere not affected based onTH immunostaining [99].Other teams also used thismarker on postmortem tissues andcolon biopsies, and none reported DAergic enteric neuronalloss [88, 92, 102, 103].

Systemic administration of the selective DAergic neu-ronal toxin 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine

(MPTP) leads to the loss of DAergic neurons in the intestinaltracts of mice [104, 105], but MPTP-treated monkeys werereported to display an increased number of neurons in theirmyenteric ganglia [106]. MPTP causes a transient increase ofstool frequency and colon relaxation lesions in mice [104],although this effect is inconsistent with the slow GI motilityof PD patients. Therefore, despite the fact that inhibitoryintestinal DAergic neurons could be impaired in PD, theseneurons are not the only neuropathological targets of thedisease [106–108]. Indeed, intestinal non-DAergic neuronscould also be impaired, but the discrepancy between datamakes it difficult to draw robust conclusions. Andersonet al. demonstrated that MPTP-treated mice presented nodifference in nitric oxidergic neurons [104]. Another studyshowed in a PD model induced by directional stereotaxicbrain injection of the neurotoxin 6-hydroxydopamine (6-OHDA) that rats exhibited slow colon motility accompaniedwith nitric oxidergic neuron loss in the myenteric plexus[109]. Other studies showed that a primate MPTP model ledto an increase in nitric oxidergic neurons [106]. Overall, mostof these studies have shown that GI cholinergic transmitterswere not significantly altered in PD [104, 106, 110].

According to these data, constipation in PD patientscannot be explained solely by a decrease in DA levels linkedto damage to neurons. Digestive tract motility would requiresophisticated synchronization from all neurotransmitters,not only DA. Moreover, the important variability betweenthe results pertaining to enteric neuronal loss refers to theneurodegenerative paradox. Even if DAergic neuronal deathis the histopathological hallmark of PD, it is one of themost difficult parameters to highlight in the ENS becauseof both the rarity of apoptosis in the neurodegenerativeprocess and the difficulty in counting neurons [111]. This hastogether led to numerous unanswered questions concerningneurodegenerative processes occurring in the ENS and theirimpact on GI impairments.

2.6. Other Outcomes of PD Therapies on GI Dysfunctions.Antiparkinsonianmedication considerably hampers the eval-uation of the potential correlation between GI dysfunctionsand the severity of PD symptoms. An individual stabilizedby drug therapy may indeed display a better overall con-dition than another patient with early PD, thus receivinga suboptimal treatment [37]. Moreover, in some situations,addressing motor symptoms only may affect GI featuresboth positively and negatively. Indeed, DAergic therapy mayimprove dysphagia and drooling but, on the other hand,might also worsen gastroparesis and reduce GI motility[69, 75, 112]. However, since nausea and vomiting are oftenside effects of various medications, they can limit the useof the latter and, as a result, preempt the benefit of suchmedications on motors symptoms [31]. Moreover, deep brainstimulation (DBS), which is widely used to treat motorsymptoms, has been shown to have a potential impact onthe manifestation of GI symptoms [113, 114]. According tosome studies, constipation and deglutition are significantlyimproved after surgery in the subthalamic nucleus [115–117].However, there is no consensus on the putative effect of DBS


Under investigation

¤

¤

MosaprideCisaprideErythromycinGastric pacemaker

Under investigation

∗

∗

∗

¤

¤

¤

Apomorphine injectionsDuodopaPrucaloprideCisaprideMosaprideTegaserodMisoprostolNeostigmineDomperidoneTrimebutineErythromycinNeurotrophin 3Botulinum toxin injectionsSacral nerve stimulationProbiotics/prebioticsBiofeedback therapyDeep brain stimulation

∗ Not available in the United States¤ Withdrawn from the market

Effective

∗

Small and frequent mealsTaking fluids during mealsWalking after mealsDomperidoneTrimethobenzamideAvoid fatsAvoid metoclopramide

Constipation

Under investigationIpratropium bromide sprayScopolamineBenztropineClonidineModafinilTropicamideRadiotherapyNeurectomySalivary gland excisionSalivary duct ligation or relocation

EffectiveChewing gum or sucking on hard candySpeech and position therapyBotulinum toxin A/B injectionsAtropine ophthalmic dropsGlycopyrrolateAvoid cholinesterase inhibitorsAvoid clozapine, yohimbine, and quetiapine

Nausea

Vomiting

Gastroparesis

EffectiveExerciseDietary fibersIncreased fluid uptakeMacrogolLactuloseMagnesium sulfateBisacodylSodium picosulfateDocusate sodiumPsylliumSenna acutifoliaLubiprostoneMethylnaltrexoneLinaclotideAvoid opioids, tricyclicantidepressants, antimuscarinics,and some antiparkinsonian drugs

DroolingDysphagia

Figure 1: Treatment options for gastrointestinal dysfunctions in Parkinson’s disease. Overview of the different pharmacological treatmentsor therapeutic approaches that are currently effective or under investigation to manage constipation (left panels), drooling/dysphagia (rightpanels), and nausea/vomiting/gastroparesis (bottom panels). Please note that some drug options are not available in the USA (∗) or had tobe withdrawn from the market due to unacceptable side effects (¤).

on GI manifestations, as shown by reports that the latterneurosurgery does not improve dysphagia and drooling [51,118, 119].

3. Therapeutic Approaches to GI Symptoms

Importantly, GI impairments can impact other symptoms,which further complicates the clinical management of PD.For instance, GI problems such as gastroparesis and delayedintestinal absorptionmight lead tomore erratic absorption ofL-DOPA, which is reflected by motor fluctuations [120]. Thelatter problem emphasizes the necessity for clinicians to exertdue vigilance during office visits of PD patients and regularly

ask specific questions regarding GI manifestations. Recentstudies have also provided evidence for symptomatic treat-ments of constipation and drooling, but, unfortunately, thecurrent armamentarium for dysphagia and nausea remainsquite limited [31]. In this regard, Figure 1 and Table 2 providea summary of GI symptoms as well as the current treatmentalternatives.

3.1. Constipation

3.1.1. Effective Treatments. To prevent constipation problemsin PD, therapies aimed at accelerating colonic transit may be


Table2:Eff

ectiv

etherapeutic

approaches.C

lassificatio

nandmechanism

sofa

ctionof

thevario

useffectiv

eop

tions

fortreatingGIs

ymptom

sexp

erienced

byPD

patie

nts,depend

ingon

efficacy

andsid

eeffects.

GIsym

ptom

sClassifi

catio

nTh

erapeutic

approaches

Mechanism

sofaction

Dosage

(adu

lt)Effi

cacy

(on

patie

nts)

Side

effects

(%of

patie

nts)

Com

ments

Stud

ies

Constip

ation

(1)Us

ewith

caution

Tricyclic

antid

epressants

Anticho

linergics

idee

ffects

[15,52]

Antim

uscarin

ics

Anticho

linergics

idee

ffects

[15,52]

Opioids

Anticho

linergics

idee

ffects

[15,52]

(2)N

onpharmac

ologica

loptions

Exercise

Intestinalstim

ulationby

movem

ents,

increased

fluids,andmuscularm

ass

[6,16,32]

Dietary

fibers

[6,16,32]

Increasedflu

idup

take

[6,16,32]

(3)L

axatives

Macrogol

(polyethyleneg

lycol)

Passes

throug

htheg

utwith

outb

eing

absorbed

anddigeste

dby

enzymes,

causingretentionof

water

intheintestin

altube

Oral:17g(∼1

tablespo

on)d

issolved

in240m

Lof

water

orjuiceo

nced

aily

Abdo

minalbloatin

g,cram

ping

,diarrhea,

flatulence,andnausea

Dono

tuse

for>

1-2weeks

[121,189]

Lactulose

Passes

throug

htheg

utwith

outb

eing

absorbed

anddigeste

dby

enzymes,

causingretentionof

water

intheintestin

altube

Oralorrectal:10

to20

g,daily

Abdo

minaldiscom

fortand

diste

ntion,

belch

ing,

cram

ping

,diarrhea

(excessiv

edose),flatulence,

nausea,and

vomiting

[190]

Magnesiu

msulfate

Blocks

perip

heralm

uscular

contractions

and

neurotransmission

Oral:2–4level

teaspo

onso

fgranu

les

dissolvedin

240m

Lof

water;m

ayrepeat

in6hours

Hypermagnesemia,

flushing,hypo

tension,

and

vasodilatation

Dono

texceed2do

ses

perd

ay[19

1]

Bisacodyl

Stim

ulates

enteric

nerves

tocausec

olon

iccontractions

Oralorrectal:

5–15mgas

single

dose

<1%

:abd

ominalmild

cram

ps,m

etabolicacidosis

oralkalosis

,hypocalcemia,

nausea,rectalirritatio

n,vertigo,andvomiting

[124]

Sodium

picosulfate

Stim

ulates

peris

talsisa

ndprom

otes

water

and

electro

lytesa

ccum

ulation

inthec

olon

Oral:150m

Lin

the

eveningbefore

the

colono

scop

y,follo

wed

byas

econ

ddo

se∼5ho

ursb

efore

thep

rocedu

re

Hypermagnesemia(12%

),hypo

kalemia(7%),

increasedserum

creatin

ine

(5%),hypo

chloremia(4%),

hypo

natre

mia(4%),

headache

(3%),nausea

(3%),andvomiting

(1%)

Mainlyused

for

colono

scop

yprocedure

[124]


Table2:Con

tinued.

GIsym

ptom

sClassifi

catio

nTh

erapeutic

approaches

Mechanism

sofaction

Dosage

(adu

lt)Effi

cacy

(on

patie

nts)

Side

effects

(%of

patie

nts)

Com

ments

Stud

ies

Docusates

odium

(alone

orin

combinatio

nwith

psylliu

m)

Unclear;m

ayinhibitfl

uids

absorptio

nor

stimulate

secretionin

jejunu

m

Oral:50

to360m

g,once

daily

orin

divideddo

ses

Throatirr

itatio

n(1to10%)

[192]

Senn

aacutifolia

Redu

cesfl

uidabsorptio

nfro

mthefaecesa

ndinflu

encesfl

uidsecretions

bythec

olon

Long

-term

useisn

otrecommended

[126]

(4)O

ther

pharmacologica

loptio

ns

Lubiprostone

IntestinalClC-

2chlorid

echannelactivator

Oral:24𝜇gtwice

daily

64%

Interm

ittentloo

sesto

ols

(48%

),nausea

(29%

),diarrhea

(12%

),abdo

minal

pain

(8%),flatulence(6%

),dizziness(3%

),and

vomiting

(3%)

[126,

127]

Methylnaltre

xone

𝜇-O

pioidantagonist

Subcutaneous:12m

g,once

daily

60%

Abdo

minalpain

(45%

),flatulence(33%),diarrhea

(30%

),andnausea

(24%

)

Disc

ontin

ueall

laxativ

espriortouse;if

respon

seisno

toptim

alaft

er3days,laxative

therapymay

bereinitiated

[128]

Linaclo

tide

Guanylatecycla

seCagon

istOral:145𝜇

g,once

daily

Abdo

minalcram

ping

(4%),

discom

fort(4%),and

diarrhea

(4%)

Con

traind

icated

inpediatric

patie

nts(<6

yearso

fage)

[129,

130,193]

Droolinga

nddysphagia

(1)Us

ewith

caution

Cholinesterase

inhibitors

[51]

Clozapine

Serotoninantagonist

Dem

onstr

ated

effectiv

enessa

gainst

dyskinesias

[51,161,

194]

Yohimbine

Presyn

aptic𝛼2-adrenergic

blocking

agent

[51,162]

Quetia

pine

D2receptors(mesolim

bic

pathway)a

nd5H

T2A

(fron

talcortex)

antagonist

Dem

onstr

ated

effectiv

enessa

gainst

dyskinesias

[51,195]

(2)N

onpharma-

cologicaloptions

Chew

inggum

orsuckingon

hard

cand

y5tim

esim

proved

[158]

Speech

andpo

sition

therapy

Self-motivationisan

impo

rtantfactorto

obtain

apositive

outcom

e

[159,

160]


Table2:Con

tinued.

GIsym

ptom

sClassifi

catio

nTh

erapeutic

approaches

Mechanism

sofaction

Dosage

(adu

lt)Effi

cacy

(on

patie

nts)

Side

effects

(%of

patie

nts)

Com

ments

Stud

ies

(3)P

harm

acologi-

caloptions

Botulin

umtoxinA/B

injections

(parotid

andsubm

andibu

lar

glands)

Inhibitsthec

holin

ergic

parasympatheticand

postg

anglionics

ympathetic

activ

ity

Atoxin:

500un

itsdivided

amon

gaffected

glands

Atoxin:

dryn

esso

fmou

thandmild

transitorysw

allowing

difficulties

(6%)

Prod

uced

byClostridium

botulin

umbacterium

[163,165,

166,168]

Btoxin:

1,000

units

into

each

parotid

glandand250

units

into

each

subm

andibu

larg

land

Btoxin:

dryn

esso

fmou

th(40%

),worsenedgait(25%

),diarrhea

(15%),neck

pain

(15%),andmild

transitory

swallowingdifficulties

(16%)

[50,163,

167]

Atropine

ophthalm

icdrop

s(sublingual

administratio

n)Anticho

linergicthatb

locks

muscarin

icreceptor

M3

1dropof

1%atropine

solutio

n,twice

daily

for1

week

Hallucinatio

ns(29%

)and

delirium

(14%)

Lack

ofclinical

evidence

fortreatments

lasting

longer

than

afewweeks

Use

with

cautionin

the

elderly;increased

risk

fora

nticho

linergic

effects,

confusion,

and

hallu

cinatio

ns

[170]

Glycopyrrolate

Anticho

linergicthatb

locks

muscarin

icreceptor

M3

Oral:1m

g3tim

es,

daily

95to100%

Dry

mou

th(52%

),urinary

retention(13%

),visio

nprob

lems(13%),

constip

ation(13%

),and

nausea

(4%)

[171,172,

174,175]

Nausea,

vomiting

and

gastroparesis

(1)Us

ewith

caution

High-fatfoo

ds[31]

Metoclopram

ide

Dop

aminea

ntagon

ist

Con

traind

icated

forP

Dpatie

ntsb

ecause

itworsens

motor

symptom

sbyblocking

dopaminer

eceptorsin

theC

NS

[31]

(2)N

onpharma-

cologicaloptions

Smalland

frequ

ent

meals

[31]

Drin

king

durin

gmeals

[31]

Walking

after

meals

[31]


Table2:Con

tinued.

GIsym

ptom

sClassifi

catio

nTh

erapeutic

approaches

Mechanism

sofaction

Dosage

(adu

lt)Effi

cacy

(on

patie

nts)

Side

effects

(%of

patie

nts)

Com

ments

Stud

ies

(3)P

harm

acologi-

caloptions

Dom

perid

one

Dop

aminea

ntagon

ist

Oral:initiatingat

10mg

3tim

es,daily

(maxim

um:

30mg/day)

100%

Xerosto

mia(2%)a

ndheadache

(1%)

Doesn

otreadily

cross

theB

BB∗𝑈𝑠𝑒

thelow

esteffective

doseforthe

shortest

duratio

nnecessa

ry∗𝑁𝑜𝑡

availableinthe

UnitedStates

[149,196,

197]

Trim

etho

benzam

ide

Unclear;m

ostlikely

involves

thec

hemoreceptor

triggerz

one(throug

hwhich

emeticim

pulse

sare

transportedto

thev

omiting

center)

Oral:300m

g;intram

uscular:

200m

g,3or

4tim

esdaily

20%

Dizziness,headache,

blurredvisio

n,anddiarrhea

May

masktoxicityof

otherd

rugs

orcond

ition

s[19

8]

∗:note.


effective. Increasing the levels of daily activity and introduc-ing dietary changes are the first options to consider. Patientsshould be encouraged to maximize dietary fibers (cereals,bran, citrus fruits, etc.), as well as ensure adequate fluidintake to avoid dehydration [6, 15, 16, 32]. Nevertheless, anexhaustive pharmaceutical evaluation of the drug treatmentsalready prescribed to patients is important before introducingadditional measures. Indeed, the dosage of medicationsknown to increase constipation symptoms should be opti-mized as much as possible. Some antiparkinsonian drugs aswell as opioids, tricyclic antidepressants, and antimuscarinicsare recurrent sources of severe constipation, likely due totheir anticholinergic effects [15, 52]. Other available optionsto increase the frequency of bowel movements and improvestool consistency are (i) osmotic laxatives such as macrogol(polyethylene glycol), lactulose, and magnesium sulfate, (ii)stimulant laxatives such as bisacodyl and sodium picosulfate,and (iii) stool softeners [28, 30, 121–123]. The safety profileassociated with the long-term use of osmotic agents makesthem the preferred group of laxatives. Macrogol, which isavailable in the USA and is recommended by the Ameri-can Academy of Neurology and the Movement DisordersSociety, is considered to be an effective and safe osmoticlaxative for PD patients [15, 32, 121]. Bisacodyl and sodiumpicosulfate, which both act by stimulating colonic smoothmuscle contractions as well as electrolyte andwater secretion,may represent additional alternatives to treat constipation[124]. Moreover, stool softeners such as docusate sodiummay be used alone or in combination with psyllium husksto increase stool volume and, therefore, peristalsis reflex [6,7, 125]. By increasing intestinal fluid secretion, lubiprostone,an intestinal ClC-2 chloride channel activator, also improvesconstipation issues (64% of PD patients) [7, 28, 52, 126].Themost common adverse events observedwere intermittentloose stools (48% of PD patients), nausea (29%), diarrhea(12%), abdominal pain (8%), flatulence (6%), dizziness (3%),and vomiting (3%) [52, 126, 127]. Methylnaltrexone (𝜇-opioid antagonist) is another medicinal agent approved inthe USA and indicated for the treatment of opioid-inducedconstipation, with approximately 60% of patients havingreported beneficial intestinal effects [28, 128]. In 2008, aclinical trial led by Portenoy et al. showed that adverse effectsexperienced by patients taking methylnaltrexone are mostlyabdominal pain (45%), flatulence (33%), diarrhea (30%),and nausea (24%) [128]. Linaclotide, a guanylate cyclase Cagonist, has also recently been approved by the Food andDrugAdministration (FDA) as a treatment for irritable bowelsyndrome and chronic constipation. Abdominal cramping,discomfort, and diarrhea are the adverse events commonlyreported by patients for linaclotide (about 4%) [52, 129, 130].Finally, several other studies have also demonstrated theeffectiveness of the Senna acutifolia plant, but the long-termuse of this well-known laxative is not recommended [122].

3.1.2. Treatments under Investigation. Treating constipationremains an active research area and various studies haveassessed the impact and clinical relevance of options that

could help relieve the discomfort and adverse effects associ-ated with this GI problem encountered in PD. For example,subcutaneous injections of apomorphine have translated topositive effects on intestinal motility (improvement of thedefecatory mechanisms and anorectal dysfunction [6, 32,131, 132]) and UPDRS motor scores (in about 70% of PDpatients [133]), although adverse effects such as orthostatichypotension (in 50% of patients), nausea, and drowsiness(in 75% of patients) may occur following administrationof this DA agonist [8, 134]. It is also recommended thatpatients use an antiemetic as a pretreatment before receivinginjections in order to avoid the unpleasant effect of nausea[31]. Therefore, due to these various secondary effects, thelong-term use of apomorphine appears to be inadvisable [32].Intrajejunal infusion of L-DOPA/carbidopa (or duodopa) hasalso proved beneficial relatively to constipation problems(in approximately 70% of PD patients) [135, 136]. Moreover,a body of research has been heavily focused on differentligands (agonists or antagonists) of the 5-HT4 serotoninreceptors. These receptors, which are located partly in thesmooth musculature and cholinergic nerves of the GI tract,are, among others, capable of increasing gastric and colonicmotility by facilitating acetylcholine release [137–139], thusmaking them an attractive target for treating constipation.The main 5-HT4 agonists studied to date are prucalopride,cisapride, mosapride, and tegaserod [137, 140–142]. Unfortu-nately, although these agonists were found to be effective inthe treatment of constipation in PD patients, those prokineticagents have been removed from the US market or havenot been approved by the FDA due to possible adversecardiovascular effects (less than 1% of patients) [141, 143–145].Other medicinal agents are also under investigation, suchas misoprostol (a prostaglandin E1 analogue; 55% efficacy)[32, 146], neostigmine (an acetylcholinesterase inhibitor;50% efficacy) [7, 147], and domperidone (a DA antagonist;about 35% efficacy) [148]. However, even if the promotilityagent domperidone could be potentially effective, due toits absence of permeation through the blood-brain barrier(BBB) [149], there is insufficient evidence to recommend itsutilization for constipation, as in the case of trimebutine (anenkephalinergic agonist) and erythromycin (the well-knownmacrolide antibiotic) [143]. In recent years, the NGF receptoragonist neurotrophin 3 has also been studied to improveGI motility dysfunction in PD. Although its mechanism ofaction with respect to GI motility remains unknown, thisneurotrophic factor was found to be effective in treatingconstipation (in about 20% of patients) [52, 150]. In a clinicaltrial conducted by Pfeiffer et al., a reduced colonic transittime, an increase in stool frequency, and shortening ofthe intervals without stool were observed [151]. However,abdominal cramps and diarrhea were noted in three patients,who were forced to reduce neurotrophin 3 dosage (300𝜇g/kgthree times weekly) [151]. Injections of botulinum toxin(BTX), a neurotoxin produced by the Clostridium botulinumbacterium that inhibits acetylcholine release, have also beenproposed to help reduce constipation burden in PD [51, 152].However, not only are such injections technically challenging,including ultrasound guidance, but also there is insufficientevidence that this method offers an effective treatment [30,


153, 154]. For example, Albanese et al. reported a beneficialclinical effect of BTX injections on constipation, but only ina single patient [153]. In another clinical study, Cadeddu etal. observed an improvement of constipation symptoms in 10out of 18 patients after two months of BTX treatment [154].However, the authors mentioned that repeated injectionscould be necessary to maintain this clinical improvementsince the effects of the toxin wear off within three monthsof administration. Nonpharmacological strategies have alsobeen put forward to treat constipation, such as sacral nervestimulation (with 57% efficacy) [28, 155], synbiotic yogurt(i.e., probiotic- and prebiotic-enriched yogurt) [7, 16, 52],biofeedback therapy (79% efficacy) [52], and DBS (about25% efficacy after two years of treatment, a percentage thatmight however be influenced by the postoperative reductionin DAergic therapy and an improvement in motor fluctu-ations) [116, 117]. Milk fermented with the probiotic strainLactobacillus casei Shirota has also been suggested to dampenconstipation problems by modulating the host immuneresponse, enhancing mucosal function, suppressing growthof pathogenic bacteria, and blocking epithelial attachmentby pathogens, resulting in an improvement in 70 constipatedadults [156, 157]. A decrease in abdominal pain, bloating, andsensation of incomplete emptying is also observed in patientsusing probiotics [52].

3.2. Drooling and Dysphagia

3.2.1. Effective Treatments. For patients with mild symptomsof drooling and/or dysphagia, chewing gum or sucking onhard candy may be effective in ameliorating swallowing (anapproximately 5-fold improvement) and thus reduce drooling[13, 67, 152, 158]. Speech and position therapies can alsoprove efficient for easing these GI symptoms (with 60 to 90%efficacy) [159]. These therapies consist basically in trainingto learn voluntary airway protection techniques throughadequate swallowing methods and improved head postures.Marks et al. investigated such techniques and observed thatself-motivation was an important factor in obtaining a posi-tive outcome [160]. It is strongly recommended to consider allthese nonpharmacological options first to improve droolingand dysphagia symptoms before changing over to drug-based solutions. However, such drug-free approaches mayonly provide temporary improvement and might not beeffective or suitable for all patients. Indeed, pharmacologicaltreatments are generally considered when more aggressiveintervention is required [31]. Itmust be emphasized that somecategories of medications used to treat other PD symptomsmay in fact aggravate drooling and dysphagia and should thusbe avoided as much as possible. Such medications includeacetylcholinesterase inhibitors, the antipsychotic quetiapine,and adrenergic receptor agonists such as clozapine andyohimbine [51, 161, 162]. The pharmacological treatmentmost often mentioned for drooling/dysphasia is undoubt-edly BTX injections. Local injections of this toxin in theparotid and submandibular glands inhibit the cholinergicparasympathetic and postganglionic sympathetic activity,thereby reducing saliva production [163]. This treatment,

which denervates the salivary glands, was shown to be effec-tive in reducing drooling severity and frequency (in about80 to 90% of patients) without compromising swallowing[50, 51, 164–167]. Unfortunately, published studies cannotbe easily compared due to the important disparity betweenthe methodologies employed. Indeed, there is no standardtechnique for the injection (gland, ultrasound guidance,etc.) and no compliance regarding the optimal dose to beadministered [51]. The sole guideline for achieving the besteffect using this therapeutic approach is to inject the toxinbilaterally and periodically [31, 163]. Dryness of the mouth(or xerostomia) is the common adverse effect observed withBTX [51]. Importantly, submandibular glands injections arerecommended only under the supervision of a specialist dueto potential side effects caused by spreading of the toxin tonearby structures and should be performed exclusively whentreatment of the parotid gland alone is insufficient [163].Among the several serotypes of BTX, only A and B have beenstudied and are commercially available [51]. In the majorityof these studies, no side effects were observed with BTX-A,although BTX-B injections inducedmild adverse events suchas dry mouth (in about 40% of patients), diarrhea (∼15%),neck pain (∼15%), and worsened gait (∼25%) [50, 168, 169].This suggests a preferential action of BTX-B on autonomicneurons and therefore might point to its higher effectivenesscompared to BTX-A [152]. However, in two different clinicaltrials, Lagalla et al. observed that some patients experiencedmild transitory swallowing difficulties 7 days after a BTX-Ainjection (in about 6% of patients) [166] and 10 days aftera BTX-B injection (∼16%) [167], but they recovered within10 to 14 days. In spite of these potential drawbacks, thesestudies, which are the only ones that have compared theA andB serotypes, failed to demonstrate a significant difference inthe effectiveness between both neurotoxins [166, 167]. Otherpharmacological alternatives to BTX in the treatment ofdrooling/dysphagia include anticholinergic drugs that blockmuscarinic receptors and particularly theM3 subtype. Never-theless, the currently available agents are not selective for M3receptors and might thus give rise to several undesirable sideeffects (e.g., confusion, hallucinations, drowsiness, urinaryretention, and constipation) [51]. Thus, some of these drugshave yet to be considered truly effective, which warrantfurther investigations. A few studies have claimed that thetwo anticholinergics, atropine and glycopyrrolate, are theonly potentially useful therapies available for improvingdrooling/dysphagia [51, 52, 123]. Despite being effective,atropine still causes a wide range of undesirable adverseeffects such as hallucinations (2/7 patients) and delirium (1/7patients; but this was confounded by a concomitant urinarytract infection) [170]. Since glycopyrrolate does not crossthe BBB, unlike atropine, it is therefore the preferred agentbecause it is less likely to cause adverse effects in the CNS[152, 171]. Between 95 and 100% of patients who completedclinical studies reported improvement in drooling/dysphagiawith glycopyrrolate [172–174]. As expected, the side effectsobserved occurred in the periphery and mostly includedxerostomia (in approximately 52% of patients), urinary reten-tion (13%), constipation (13%), vision problems (13%), and


nausea (∼4%) [171, 175]. While anticholinergics might be effi-cient for treating drooling/dysphagia, they do not representa suitable option for PD patients since other NMS can besubsequently worsened. Moreover, there is a lack of clinicalevidence for treatments lasting longer than a few weeks andthe long-term adverse effects of atropine and glycopyrrolatehave not been documented, thus leaving important safetyissues unresolved [51, 171]. All the pharmacological optionslisted above may thus be regarded as effective treatmentsfor drooling/dysphagia, but, considering their potential sideeffects, they should remain a secondary choice compared tononpharmacological therapies.

3.2.2. Treatments under Investigation. Other anticholinergictreatments such as ipratropium bromide spray, transdermalscopolamine, and benztropine have also been investigated fortreating drooling/dysphagia [123, 176–178]. However, previ-ous studies on the effectiveness of anticholinergic treatmentshad failed to conclude on the superiority of one drug overanother [179]. The ipratropium bromide spray (which hasinduced a significant effect on the UPDRS part 6 subscore[178]) is used sublingually as a bronchodilator and does notcross the BBB, thereby reducing systemic side effects [152].Unfortunately, there is insufficient data about its safety andefficacy to draw definite conclusions on its potential interestin drooling/dysphagia management [51, 123]. Adrenergicreceptors agonists have also been explored in this context.Clonidine, a selective 𝛼2-adrenergic receptor agonist, sig-nificantly improved the frequency at which patients had toclear their mouths [51, 52, 152]. The most common adverseevents observed with clonidine were diurnal somnolence(2/17 patients), dizziness (1/17), and dry mouth (1/17) [180].The 𝛼1-adrenergic agonist modafinil has also been reportedto exert rather beneficial effects on drooling/dysphagia inPD patients (6/6 patients), although this improvement wasmostly related to dysphagia rather than hypersalivation [51,181]. Moreover, Lloret et al. have investigated tropicamide, ashort-actingmuscarinic receptor antagonist, in the treatmentof drooling/dysphagia. So far, this treatment has shownpotential efficacy (33% average reduction in salivary volumefor 16 patients who completed the study) along with alack of noticeable side effects and no side effects, althoughthe data must still be considered as preliminary [182].Radiotherapy has also been suggested as a treatment fordrooling/dysphagia and studies in this context have shown asignificant improvement in symptoms (79% of patients), aneffect that could be maintained for at least one year [183].Common side effects were xerostomia (40% of patients) anda loss of taste (45%), which were mostly transient (25% and35%, resp.). Regrettably, the success of radiotherapy is largelycompromised by its potential to induce neoplasia [183, 184].Therefore, this treatment should only be considered whenall other options discussed above have proved ineffective.Finally, surgical options such as neurectomy, salivary glandexcision, salivary duct ligation or relocation, and DBS havealso been explored to ameliorate drooling/dysphagia [50,118, 184–187]. Neurectomy, that is, the surgical sectioningof the chorda tympani nerves, reduces salivary production

(improvement in 74% of patients) but might induce seri-ous complications such as hearing loss and a loss of taste[152, 188]. These invasive options (neurectomy and salivarygland/duct surgeries) can be realized individually or incombination (with>75% success) and possible adverse effectsinclude dental caries (10% of patients), cracked lips (10%),aspiration pneumonia, and xerostomia [152, 184–186]. Dueto their high risk of irreversible adverse effects, all theseinterventions are considered only when all other availableoptions have failed to bring about a positive outcome [32].DBS intervention has not been studied much to date in thecontext of drooling/dysphagia improvement, but, with thelimited information obtained so far, it seems unlikely thatDBS represents a useful option [51, 118].

3.3. Nausea, Vomiting, and Gastroparesis

3.3.1. Effective Treatments. Despite substantial progress inrecent research on constipation and drooling treatment, thearmamentarium of useful agents for other PD-associatedGI symptoms, such as nausea, vomiting, and gastroparesis,remains severely limited [31]. The effective antiemetic med-ications that have been investigated so far include domperi-done (100% efficacy) and trimethobenzamide (∼20% efficacy)[123, 198, 199]. Domperidone is a peripheral DA antagonistthat does not cross the BBB and has been reported to safelyimprove gastroparesis and associated GI symptoms in PDpatients [199]. This antiemetic agent is not available in theUSA but is prescribed in many other countries across theworld [13, 16]. Interestingly, metoclopramide, another DAreceptor antagonist often employed in gastroparesis treat-ment, is contraindicated for PD patients because it worsensmotor symptoms by blocking DA receptors in the CNS[31]. Finally, changes in the lifestyle of patients with nausea,vomiting, and gastroparesis symptoms are also strongly rec-ommended.Thus, having small and frequent meals, avoidinghigh-fat foods, drinking during meals, and walking aftermeals are the suggested options [31].

3.3.2. Treatments under Investigation. Other treatments havebeen considered to improve nausea, vomiting, and gastro-paresis in PD patients. Mosapride and cisapride, two mild5-HT4 serotonin receptor agonists that act as prokineticagents, have been shown to reduce gastroparesis symptomsin PD (3/5 and 8/12 patients, resp.) [200, 201]. However,due to their cardiotoxicity, these drugs have been removedfrom the US market [31]. Other potential options such aserythromycin and the implantation of a gastric pacemakermight be beneficial to correct gastroparesis, but they have notyet been specifically tested in PD patients [31]. Furthermore,electric stimulation, surgery, or application of BTX in thepyloric sphincter can be employed, albeit exclusively inextreme cases [16].

3.4. Possible Interactions of PD Treatment with GI Dysfunc-tions. As mentioned above, treatments for motor symptomsmay influence GI symptoms, but the opposite may also holdtrue [31]. These considerations hamper interpretations as


to whether symptoms observed in a given patient reflectthe disease per se or, on the contrary, are iatrogenic. Forinstance, L-DOPA is usually administered in combinationwith carbidopa, which is well known to exacerbate nausea[13]. In the periphery, carbidopa prevents the conversionof L-DOPA to DA, and as its half-life exceeds that of L-DOPA, one might theoretically expect residual effects ofcarbidopa outside the CNS [202]. This treatment might wellprevent the conversion of endogenous peripheral L-DOPAin addition to the exogenous L-DOPA that is concomitantlyadministrated. Such potentially protracted effects of thecombination therapy due to putative residual carbidopa couldresult in decreased DA production in the periphery, whichwould then affectNMS, includingGI features. It has also beenshown that carbidopa might influence DA concentrationsin the kidney [203]. Therefore, the potential impact ofcarbidopa on peripheral organs involved in NMS deservescareful evaluation. This concept may be of importance whenconsidering the administration of L-DOPA by intestinal gelinfusion, which may act directly on GI tract [202].

4. Discussion

Despite increased interest in the recent years in PD-associated NMS, there is still a paucity of knowledge on theGI features of PD. This is an unfortunate state of affairs sincethese features are more difficult to manage thanmotor symp-toms and are therefore of great concern for parkinsonianpatients. In addition to their adverse effects on quality of life,GI problems are even more relevant to the understanding ofthe etiology of PD, insofar as Braak's hypothesis holds true.Accordingly, by collecting more clinical data on peripheralsymptoms in putative cases of PD, an early diagnosis andbetter preventive action, aswell asmore efficientmanagementof this disorder at its critical initiation and developmentstages, might be possible. For the time being, such atherapeutic approach is still purely speculative since PD isdiagnosed solely following the recurrent manifestation ofmotor symptoms. Therefore, inasmuch as the importance ofthe ENS is further confirmed by future PD research, it mightbecome essential to target the earliest manifestations of thedisease in order to delay or even prevent neurodegenerationand thus the apparition of motor symptoms in PD patients.

This review summarizes the range of effective as wellas potential therapeutic approaches to the management ofGI symptoms in PD patients. Unfortunately, all existingtreatments for both motor and nonmotor symptoms arepurely symptomatic and result in merely temporary relief ofthese manifestations. Furthermore, it is very difficult to ade-quately treat GI symptoms because the exact target remainsoften unknown due to the lack of basic knowledge on thepathophysiology of the ENS component in the etiology of PD.Indeed, the main objective of current therapeutic research onPD is still oriented towards its management within the limitsof present knowledge, that is, mainly reducing the side effectsof medication, rather towards the further investigation of PDpathogenesis.

To date, several hypotheses have been proposed to under-stand the GI aspects in the physiopathology of PD. The mostpromising among these hypotheses include neurodegenera-tion, 𝛼-syn overexpression, inflammation, intestinal hyper-permeability, and microbiota disturbance as likely mecha-nisms involved in GI dysfunction [83, 84, 99, 204–208].Furthermore, some factors have been suggested to participatein the initiation of the PD process, namely, disruption ofthe lysosomal and proteasomal systems, abnormal autophagy,endoplasmic reticulum stress, mitochondrial dysfunction,and oxidative stress [209–215]. Unfortunately, none of thelatter putative factors could be confirmed as a PD biomarkerdue to the lack of an animal or cellular model that faithfullyreproduces all features of PD. In the current state of our basicknowledge onPDpathophysiology,more optimal therapeuticavenues might be obtained by targeting a subset of theseelements, given the fact that PD is clearly a multifactorialdisease. However, a better insight into the etiology andmechanisms of the disease is crucial in order to find moretargeted and effective treatments.

As summarized in the present review, there are nowseveral lines of evidence that clearly demonstrate that GIdysfunctions not only are painful symptomswhose treatmentconstantly challenges clinicians, but also are relevant to thevery process that causes PD, likely as reflections of processesthat are under control by the ENS.Thus, GI symptoms in PDdefinitely should deserve much closer attention and warrantmore detailed investigation in order to grasp the causativemechanisms at the core of this complex disease, which is anecessary prelude to the proper management of the disease’ssymptoms and, ultimately, to an actual curative strategy.Undoubtedly, further critical aspects of the mechanism lead-ing to PD remain to be discovered and should call for areassessment of the whole medical approach to this devastat-ing disorder. Thus, in view of the recent developments in PDresearch emphasized in the present coverage of the literature,the peripheral aspects of PD should remain a priority in orderto improve the therapeutic approaches to the disease, whichare clearly in need of major improvements.

Abbreviations

𝛼-syn: Alpha-synucleinBBB: Blood-brain barrierBTX: Botulinum toxinCNS: Central nervous systemDA: DopamineDAergic: DopaminergicDBS: Deep brain stimulationENS: Enteric nervous systemGI: GastrointestinalL-DOPA: Levodopa, L-3,4-dihydroxyphenylalanineNMS: Nonmotor symptomsNOS: Nitric oxide synthasePD: Parkinson’s diseaseUPDRS: Unified Parkinson’s Disease Rating ScaleVIP: Vasoactive intestinal peptide.


Competing Interests

The authors declare that there are no competing interestsregarding the publication of this paper.

Acknowledgments

The authors acknowledge the grant support of the CanadianInstitute of Health Research (Therese Di Paolo and DenisSoulet) and the Canadian Foundation for Innovation (DenisSoulet). Andree-Anne Poirier holds studentship awards fromthe Fonds de la Recherche du Quebec-Sante (FRQS), Parkin-son Quebec, Societe Parkinson Canada and La Fondationdu CHU de Quebec (Scholarship Didier-Mouginot). DenisSoulet holds a career award Chercheur-Boursier Junior 2from Fonds de la Recherche du Quebec-Sante (FRQS). Theauthors also wish to thank Dr. Jaclyn I. Wamsteeker Cusulin(Hoffmann-La Roche, Basel, Switzerland) and Dr. RichardPoulin (Centre de Recherche du CHU de Quebec, Quebec,Canada) for their critical reading of the manuscript.

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Research ArticleAerobic Exercise Preserves Olfaction Functionin Individuals with Parkinson’s Disease

Anson B. Rosenfeldt,1 Tanujit Dey,2 and Jay L. Alberts1,3,4

1Department of Biomedical Engineering, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44119, USA2Quantitative Health Sciences, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44119, USA3Center for Neurological Restoration, Cleveland Clinic, 9500 Euclid Ave., Cleveland, OH 44119, USA4Cleveland FES Center, L. Stokes Cleveland VA Medical Center, 10701 East Blvd, Cleveland, OH 44106, USA

Correspondence should be addressed to Jay L. Alberts; [email protected]

Received 2 September 2016; Accepted 24 October 2016


Copyright © 2016 Anson B. Rosenfeldt et al. This is an open access article distributed under the Creative Commons AttributionLicense, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properlycited.

Introduction. Based on anecdotal reports of improved olfaction following aerobic exercise, the aim of this study was to evaluatethe effects of an 8-week aerobic exercise program on olfaction function in individuals with Parkinson’s disease (PD). Methods.Thirty-eight participants with idiopathic PD were randomized to either an aerobic exercise group (𝑛 = 23) or a nonexercise controlgroup (𝑛 = 15). The aerobic exercise group completed a 60-minute cycling session three times per week for eight weeks while thenonexercise control group received no intervention. All participants completed the University of Pennsylvania Smell IdentificationTest (UPSIT) at baseline, end of treatment, and a four-week follow up. Results. Change in UPSIT scores between the exercise andnonexercise groups from baseline to EOT (𝑝 = 0.01) and from baseline to EOT+4 (𝑝 = 0.02) favored the aerobic exercise group.Individuals in the nonexercise group had worsening olfaction function over time, while the exercise group was spared from decline.Discussion. The difference in UPSIT scores suggested that aerobic exercise may be altering central nervous system pathways thatregulate the physiologic or cognitive processes controlling olfaction in individuals with PD. While these results provide promisingpreliminary evidence that exercise may modify the disease process, further systematic evaluation is necessary.

1. Introduction

The majority of individuals with Parkinson’s disease (PD)experience olfaction dysfunction [1, 2]. Hyposmia and anos-mia are associated with loss of enjoyment of food, difficultymanaging body weight, safety concerns (i.e., detecting gasand smoke), insecurities with body odor, and social isolation[3]. These factors lead to a decreased quality of life andincreased rates of depression when compared to individualswith normal sense of smell [4].

Although the exact mechanism for olfaction loss inParkinson’s disease is unknown, it is likely that olfactiondysfunction is due to changes in the central nervous system(CNS) and is not a result of damage to the peripheral olfactorysystem [5]. It has been proposed that olfaction dysfunctionin Parkinson’s disease evolves from Lewy bodies formed inthe olfactory bulb and progresses to brain stem nuclei such

as the locus coeruleus and substantia nigra and eventuallyto the cerebral cortex [6]. In addition, neurotransmitterssuch as acetylcholine, norepinephrine, serotonin, and, to alesser extent, dopamine, all of which are typically altered inParkinson’s disease, impact olfaction through various directand indirect pathways [7].

The clinical importance of hyposmia continues to evolve,and in individuals with PD olfaction testing can be used ata diagnostic tool [8] and is predictive of long-term cognitivedecline and postoperative delirium [9–11]. In a large cohortof de novo patients, it was reported that PD patients withhyposmia exhibit more severe motor symptoms and requiredgreater levodopa-equivalent at a 2.5-year followup comparedto those patients with normal olfactory function [12]. Thegrowing importance of olfaction as a diagnostic and predic-tive tool in individual with PD highlights the need for furtherexamination.


http://dx.doi.org/10.1155/2016/9725089


While hyposmia is not a target of PD treatment per se,antiparkinsonian medications have no effect on olfactiondysfunction [13, 14]. It has been proposed that deep brainstimulation (DBS) may indirectly affect olfaction; however,most large randomized DBS studies have not utilized anolfaction outcomemeasure, and the fewDBS studies that havereported an olfaction outcome have been conducted on rela-tively small sample sizes and have yielded conflicting results[15–18]. There is preliminary evidence that exercise mayhave a positive impact on olfaction. In an 8-week swimmingintervention in adult rats, synapsin and neurotrophic factorsin the olfactory bulb were greater in the exercise group thanthe nonexercise control group [19]. In a longitudinal study ofover 1800 older adults, those who exercised three times perweek were at a lower risk of developing olfaction dysfunctionover a 10-year follow-up period [20]. These studies providerationale to investigate the idea that exercise may facilitateneuroplasticity of the olfaction system.

Aerobic exercise, in animal models of Parkinsonism,has been shown to have neuroprotective and neurorestora-tive effects, likely through modulation of neurotrophic fac-tors that support angiogenesis and synaptogenesis, suppressoxidative stress, and enhance mitochondrial function [21].Recently, we have demonstrated that a specific mode of aer-obic exercise, forced exercise (FE), reduces motor symptomsas measured by blinded clinical assessments, improves upperextremity motor functioning and control, and produceschanges in cortical and subcortical functional connectivity[22–25]. In our preliminary study examining forced and vol-untary rate cycling, some participants with PD self-reportedimprovements in olfaction following aerobic exercise, thusleading to the hypothesis that aerobic exercise may befacilitating neuroplasticity within the olfactory system. Theaim of this project was to formally evaluate the effects of an8-week forced and voluntary aerobic exercise program onolfaction function in individuals with Parkinson’s disease.

2. Methods

2.1. Participants. Thirty-eight individuals with a diagnosisof idiopathic PD completed the informed consent processapproved by the Cleveland Clinic Institutional Review Board.Primary inclusion criteria were clinical diagnosis of idio-pathic PD by a neurologist, age between 30–75 years, andHoehn and Yahr stages II-III when off antiparkinsonianmedication. Primary exclusion criteria were existing car-diopulmonary disease or stroke, presence of dementia, andanymedical ormusculoskeletal contraindications to exercise.Participants completed a cardiopulmonary exercise (CPX)test on a stationary bicycle equipped with MedGraphicsCardiO2/CP system with Breeze software and a twelve-leadelectrocardiograph to screen for cardiac abnormalities thatmay warrant exclusion from the study.

2.2. OutcomeMeasure. TheUniversity of Pennsylvania SmellIdentification Test (UPSIT), a 40-item “scratch and sniff”test, has been established as a valid and reliable tool forindividuals with olfaction dysfunction and healthy controls

[26]. After scratching the scent area, the participant selects asmell from 4 options in a forced-choice paradigm. A higherscore (out of 40 points) indicates better odor identification.TheUPSIT is a self-administered test that is objectively scoredwith an answer key. Testing was completed at baseline, end oftreatment (EOT), and 4-week followup after end of treatment(EOT+4). In order to test participants in the off-medicationstate, subjects were asked to refrain from taking their PDmedications after 8 pm the night before.

A blinded rater completed theUnified Parkinson’s diseaseRating Scale (UPDRS) motor examination, a standardizedtest that assesses motor function in individuals with PD.

2.3. Experimental Design. Following baseline testing, indi-viduals were randomized into one of the following groups:(1) FE Cycling (FE), (2) Voluntary Exercise Cycling (VE),and (3) Nonexercise control group. Randomization wasperformed by having participants draw an envelope froma nonreplenished box. Of note, olfaction testing was addedto the study testing protocol of an ongoing aerobic exercisestudy due to subjects’ self-report of improved smell; thus thesample sizes were not evenly distributed.

2.4. Exercise Intervention. Participants in the VE and FEgroups attended exercise sessions in the Neural ControlLaboratory of the Cleveland Clinic, three times per week for atotal of eight weeks. Participants were asked to take their PDmedication as prescribed by their neurologist on the day ofeach exercise session. During exercise session, participants inthe VE groups performed a 10-minute warm-up, 40- minuteexercise set, and a 10-minute cool-down on a semirecumbentbike at a self-selected pace. Participants were encouraged tomaintain a target heart rate zone of 60–80% based on heartrate reserve (HRR) method using results from individualmaximal CPX test.

The FE group exercised for an identical period of timeand target heart rate zone on a semirecumbent stationaryexercise cycle custom engineered with amotor and accompa-nying control algorithm designed to augment the individual’storque production during pedaling, thus resulting in a steady,high-rate cadence. It is important to note that the FEapproach required active participation from the participantand that cycling was not passive. The motor assisted theindividual in achieving a pedaling rate 30% greater thantheir preferred voluntary rate as determined during CPXtesting, a percentage increase that resulted in global motorimprovements in our previous work with PD [22, 27]. Forboth exercise groups, cadence in revolutions per minute(rpm) and heart rate were recorded for each session.

The control group received no exercise intervention andwas asked to continue their current level of physical activity.

2.5. Statistical Analysis. Theprimary outcomewas the changein UPSIT scores from (1) baseline to EOT and (2) baseline toEOT+4. Shapiro-Wilk test was used to determine normalityof the variables considered in the study. A 3 × 3 analysis ofvariance (ANOVA) model was used to examine UPSIT scorechanges at three time points (baseline, EOT, and EOT+4) for


Table 1: Participant baseline demographics.

Nonexercise Exercise (VE + FE) 𝑝 value

Sample size 15 FE = 9VE = 14

Age, years (SD) 60.9 (7.2) 60.5 (7.4) 0.85Gender, male 8 16 0.33Disease duration,years (SD) 3.3 (3.1) 3.3 (2.1) 0.93

Baseline UPSIT,points (SD) 24.0 (7.3) 21.6 (8.2) 0.35

Baseline UPDRSmotorexamination,points (SD)

21.9 (5.5) 23.5 (9.9) 0.52

FE: forced exercise; SD: standard deviation; UPDRS: Unified Parkinson’sDiseaseRating Scale;UPSIT:University of Pennsylvania Smell IdentificationTest; VE: voluntary exercise.

three groups (FE, VE, and nonexercise) and the interactionbetween the time and group variables. A two-sample 𝑡-testwas performed to determine the influence of exercise perfor-mance variables, cadence andHRR, between the two exercisegroups. An analysis of covariance (ANCOVA) model wasused to determine the association between the UPSIT andthe exercise performance variables, HRR and cadence. Allhypothesis testing was completed at 5% level of significance.

3. Results

Using UPSIT score as the dependent variable in the ANOVAmodel, neither group (F2,105 = 0.09, 𝑝 = 0.91), time (F2,105= 0.30, 𝑝 = 0.74), nor the interaction between groupand time (F4,105 = 0.24, 𝑝 = 0.92) was significant. Whilea trend was present for the VE group to be exercisingat a greater intensity as measured by HRR, there was nosignificant difference between exercise intensity for the VEand FE groups with means of 57.9 and 48.9 percent of HRR,respectively (𝑝 = 0.06). Results from the ANCOVA, usingHRR as the dependent variable, revealed a nonsignificantinteraction effect between HRR and changes in UPSIT scoresbetween VE and FE (𝑝 = 0.48 at EOT; 𝑝 = 0.51 at EOT+4).There was a significant difference in cadence between the VEand FE groups, withmeans of 69.7 and 82.9 rpms, respectively(𝑝 < 0.01); however, an ANCOVA model, using cadence asthe dependent variable, revealed a nonsignificant interactionbetween cadence and change in UPSIT score between groups(𝑝 = 0.13 at EOT; 𝑝 = 0.59 at EOT+4). Due to the similaritiesin exercise performance variables, data were collapsed acrossexercise groups for comparison to the nonexercise controlgroup. Baseline demographics, provided in Table 1, weresimilar between the exercise and the nonexercise groups.

Table 2 and Figure 1 provide summary statistics for theexercise and control groups. A 𝑡-test indicated a significantdifference in UPSIT scores between exercise and nonexercisegroups from baseline to EOT (𝑝 = 0.01) and from baseline

Table 2: Summary statistics for change in UPSIT scores frombaseline to EOT and EOT+4.

Mean ofchange inUPSIT(points)

Standarddeviation(points)

Range(points) 𝑝 value

Baseline to EOTNonexercise (2.9) 2.3 (8.0)–0.0Exercise (0.5) 3.3 (10.0)–5.0 0.01

Baseline to EOT+4Nonexercise (2.7) 3.4 (10.0)–4.0Exercise 0.2 3.5 (7.0)–8.0 0.02

( ) indicates a score indicating a worsening in UPSIT score compared tobaseline. A positive number indicates an improvement in UPSIT score.EOT: end of treatment; EOT+4: end of treatment + 4 weeks; UPSIT:University of Pennsylvania Smell Identification Test.

Baseline to EOT Baseline to EOT+4

−6

−4

−2

0

2

4

Chan

ge in

UPS

IT sc

ore (

poin

ts)

NonexerciseExercise

∗ ∗

Figure 1:Mean change inUPSIT scores frombaseline to EOT.Therewas a significant difference (indicated with ∗) between the exerciseand nonexercise groups in change in UPSIT scores from baselineto EOT and EOT+4, respectively. A positive change in UPSIT scoreindicates improved odor identification.

to EOT+4 (𝑝 = 0.02). Figure 2 is a graphical depictionof the individual responses from each the groups frombaseline to EOT. At EOT, no participants in the nonexercisegroup demonstrated an improvement on the UPSIT witha mean decrease of 2.9 (2.3) points. In contrast, 12 outof 23 individuals in the exercise group demonstrated animprovement in UPSIT scores; overall there was a meandecrease of 0.5 (3.3) points. From baseline to EOT+4, thenonexercise group had a decrease of 2.7 (3.4) points in UPSITscore while the exercise group exhibited a slight improvementof 0.2 (3.5) points.

Therewas no relationship between responders (thosewhoimproved their UPSIT score) and nonresponders (those whostayed the same or got worse in their UPSIT score) and thedemographic variables listed in Table 1.


Nonexercise Exercise

0

10

20

30

40U

PSIT

scor

e

EOTBaseline EOTBaseline

Figure 2: UPSIT scores at baseline and EOT for individuals in theexercise and nonexercise groups. At EOT, no participants in thenonexercise group demonstrated an improvement in UPSIT score;in contrast, 12 out of 23 individuals in the exercise group displayedan improvement in UPSIT score. Of note, 2 sets of individualsin the exercise group and 1 set of individuals in the nonexercisegroup scored identically from baseline to EOT; thus the lines areoverlapping.

4. Discussion

Based on the UPSIT data, PD patients who did not exercisedemonstrated a worsening of olfaction throughout the 8-week study and 4-week follow-up period, while those partic-ipating in aerobic exercise were spared from further worsen-ing of olfaction function.The significant difference in UPSITscores between the exercise and nonexercise groups suggeststhat aerobic exercise may be altering neurophysiologicalpathways or neurotransmitter function that regulate thephysiologic or cognitive processes controlling olfaction [19,20]. While we are not able to determine the exact mechanismunderlying a sparring of olfaction, it is plausible, based onresults from animal exercise studies, that the physiologicalchanges (i.e., increased neurotrophins, neurotransmitters,and improved functional connectivity) and increases in cere-bral blood flow associatedwith intensive aerobic exercisemayhave facilitated function of the olfaction system centrally orimproved the higher level cognitive processes associated withodor detection [21, 28, 29]. While our previous imaging datasupports altered CNS patterns of activation in the primarymotor cortex, supplementary motor area, thalamus, globuspallidus, and putamen [24, 25], there is still much unknownabout the role that aerobic exercise plays in modifying thestructural and functional role of the CNS.

Although debated, olfaction function may worsen withdisease duration [30], which is consistent with the nonex-ercise group demonstrating a decline in UPSIT scores overtime. The wide range of change in UPSIT scores from theexercise group gives rise to the possibility that there is anindividualized neurophysiological response to exercise ([28,31, 32]). Individualized responses are reported with phar-macological interventions to PD, where some individualsexhibit a strong favorable response to levodopa therapy and

others experience modest benefits [33]. Since our previousresearch revealed acute bouts of FE that resulted in CNSchanges similar to those seen with Parkinson’s disease med-ications [24, 25], it is possible that, similar to medication,individuals experience varying responses to aerobic exercise.The genetic response to exercise continues to be evaluated;Bath and colleagues reported impaired odor discriminationassociated with brain derived neurotrophic factor (BDNF)val66met polymorphism in mice and propose a mechanismof decreased neurogenesis in the olfactory bulb as a resultof the polymorphism [34]. While we are unable to speculateif genetics played a role in our results, the role of geneticsin response to exercise in individuals with PD is an area forfuture study.

There are limitations to the current study. First, thesample was a relatively small group of individuals with mildto moderate Parkinson’s disease; thus the data should beinterpreted within this context. A larger scale (𝑁 = 100)clinical trial is currently testing a similar cycling protocolthat includes a variety of motor and nonmotor outcomes,including the UPSIT. Second, we did not screen for indi-viduals who may have had preexisting nasal disease orolfactory dysfunction. Third, although the UPSIT is a well-studied test, the minimal clinical important difference isunknown; thus we are not able to determine if a changein the score is meaningful to the participant. Additionally,although the UPSIT is an odor identification test that iseasily administered in a clinical setting, odor detection andthreshold are not measured by this test. Notably, there was nodifference in UPSIT scores between the FE and VE groups;thus it appears that the mode of cycling was less importantthan the aerobic nature of the exercise. In the future it willbe important to determine the relationship between mode,frequency, duration, and intensity of aerobic exercise andolfaction dysfunction in PD.

These findings, although preliminary, have potential toimpact quality of life in individuals with PD. Hyposmia isone of the top five symptoms in individuals diagnosed withPD ≤6 years in duration [35], and individuals with olfactorydysfunction are more likely to report difficulties with activi-ties of daily living and to rely on community resources [36]. Ameaningful implication of halting the progression of anosmiawith aerobic exercise is the potential that exercisemaymodifythe disease progression. The difference in UPSIT scoresexhibited by the exercise group supports previous findingsthat intensive aerobic exercise is linked to global changesin PD function [22, 23]. This work may have significantimplications regarding the relationship between exercise andbrain function and the potential to modify the course of thisprogressive neurological disorder through exercise.

5. Conclusion

In this study, individuals with PD who participated in 24 ses-sions of aerobic exercise maintained their olfaction functionas measured by the UPSIT, while individuals who did notexercise demonstrated a worsening in UPSIT scores. Whilethese results provide promising preliminary evidence that


exercise may modify the disease process, further systematictesting is needed.

Disclosure

Thecontent is solely the responsibility of the authors and doesnot necessarily represent the views of the funding sources.

Competing Interests

Jay L. Alberts has authored intellectual property associatedwith the algorithm used in the control of the forced-exercisecycle. The remaining authors declare no competing interests.

Acknowledgments

The authors would like to thank Amanda M. Penko and A.Elizabeth Jansen for their assistancewith subject recruitment,protocol implementation, and data collection.This study wasmade possible by support from the National Institute ofHealth under Award no. R21HD056316 and B6678RVAMeritReview and the Davis Phinney Foundation.

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Review ArticleCognitive Training in Parkinson’s Disease: A Review of Studiesfrom 2000 to 2014

Daniel Glizer1 and Penny A. MacDonald1,2

1MacDonald Lab, Brain and Mind Institute, University of Western Ontario, London, ON, Canada2Clinical Neurological Sciences, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada

Correspondence should be addressed to Daniel Glizer; [email protected]

Received 15 June 2016; Accepted 3 August 2016


Copyright © 2016 D. Glizer and P. A. MacDonald. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Cognitive deficits are prevalent among patients with Parkinson’s disease (PD), in both early and late stages of the disease. Thesedeficits are associated with lower quality of life, loss of independence, and institutionalization. To date, there is no effectivepharmacological treatment for the range of cognitive impairments presented in PD. Cognitive training (CT) has been exploredas an alternative approach to remediating cognition in PD. In this review we present a detailed summary of 13 studies of CT thathave been conducted between 2000 and 2014 and a critical examination of the evidence for the effectiveness and applicabilityof CT in PD. Although the evidence shows that CT leads to short-term, moderate improvements in some cognitive functions,methodological inconsistencies weaken these results. We discuss several key limitations of the literature to date, propose methodsof addressing these questions, and outline the future directions that studies of CT in PD should pursue. Studies need to providemore detail about the cognitive profile of participants, include larger sample sizes, be hypothesis driven, and be clearer about thetraining interventions and the outcome measures.

1. Introduction

Parkinson’s disease (PD) is a disorder characterized by degen-eration of dopamine-producing cells in the substantia nigra(SN) and to amuch lesser degree in the ventral tegmental area(VTA). This deficiency produces the cardinal motor symp-toms of tremor, rigidity, and bradykinesia [1]. Additionally,cognitive symptoms are now also recognized as an undis-putable feature of PD [2, 3].

The pathophysiology of cognitive deficits in PD is com-plex. It seems likely that at least some cognitive deficitsresult from striatal dopamine deficiency [4–6]. Dopaminer-gic drugs used to treat motor symptoms in PD have also beenimplicated in diverse cognitive deficits, proposed to be dueto an overdosing of the relatively spared VTA [7–12]. Inaddition to dopaminergic pathways, dysregulation in cholin-ergic [13, 14], serotoninergic [15, 16], and noradrenergic [17–19] pathways potentially contributes to cognitive deficits inPD. Alpha-synuclein-containing Lewy bodies deposited in

SN and cortex have also been strongly associated with thedevelopment of dementia in PD in early and especially at laterstages of the disease [20–22].

Although motor impairments are well addressed bydopaminergic medications and deep brain stimulation [23,24], cognitive symptoms, perhaps due to their complexityand variability from patient to patient, lack clearly effectivetherapies. Dopaminergic medications improve some cogni-tive functions but worsen others [7, 10, 23–26]. Further, theclinical significance of these effects has not been systemati-cally studied in placebo-controlled randomized trials. Finally,cholinesterase inhibitors improve cognition and quality of life(QOL; for review, see [27]) but these therapies are limitedto patients who are diagnosed with clinically significantdementia and not lesser cognitive impairment. Addition-ally, the effects on cognitive dysfunction are minimal, notsustained with advancing disease, or sufficient to producetrulymeaningful enhancements of function [28]. In sum, nei-ther dopaminergic treatments nor cholinesterase inhibitors


http://dx.doi.org/10.1155/2016/9291713


modify disease progression, being merely prescribed forsymptomatic relief. Investigating effective nonpharmacolog-ical treatment options for cognitive decline in lieu of orto enhance available pharmacological treatment in PD istherefore an important area of research.

To better understand what treatments might be useful forcognitive decline in PD, there is a need to better character-ize the cognitive impairments associated with this disease.Cognitive decline in PD includes impairments in diversefunctions and skills. To date, there is considerable evidence ofimpairments in executive functions such as workingmemory(WM), attention, reasoning, and planning even in early,nondemented PD patients [29–32]. Additionally, more basicperceptual visuospatial and verbal processes have been shownconsistently to be impaired in PD [32–35]. Impairments inmemory have also been documented [36].

Cognitive deficits are very prevalent in PD patients.Even at the time of PD diagnosis, approximately 30–50%of patients already exhibit symptoms consistent with mildcognitive impairment (MCI) or dementia [37] and from60 to 80% of cases develop into full dementia within 10years [38, 39]. Cognitive impairments are strongly related tolower QOL ratings and challenges in activities of daily livingin patients [40–43]. These deficits present challenges toeveryday functioning [41, 44] and are a major cause of lossof independence and institutionalization in PD [45]. Conse-quently, effective therapies for cognitive impairment in PDare an important but unmet need [23, 45]. Exploration andempirical testing of interventions to address cognitive declinein PD are imperative.

Over the last decade, nonpharmacological treatmentsthat aim to improve cognition have increasingly been a focusin healthy aging as well as in various clinical populationsother than PD. Cognitive training (CT), a nonpharmacologi-cal intervention, has generated significant interest and engen-dered a wealth of research. CT is an approach that broadlyencompasses the idea that repeated performance of cognitivetasks leads to strategy development or brain changes thatimprove cognitive functions either within a specific domainor in general.

In healthy populations, evidence suggests that CT canbenefit older adults through either restorative or protectivefactors [46–51], although other studies appear to find modestor no effects following CT [52, 53]. Thus, it remains to beseen whether a CT intervention can be developed that leadsto meaningful effects in a healthy population. A thoroughreview of this controversy, however, is beyond the scope ofthe current review, which will focus more on CT in PD.

CT in Clinical Populations. In contrast to studies in healthycontrols, in clinical populations, CT has shown much morepromising and consistent results. CT and attention traininghave been found to improve visuospatial and language abili-ties in patients with aphasia and neglect syndromes follow-ing traumatic brain injury (TBI; [54, 55]). Several reviewsand meta-analyses of TBI treatments concluded that CTapproaches have potential as remediation strategies afterstroke but noted that further research is warranted [56, 57]. Inconjunction with other approaches, CT has been successfully

employed in the treatment of disorders such as schizophrenia[58–60], Attention Deficit Hyperactivity Disorder (ADHD),and various addictions and mood disorders [61–64]. Finally,in at-risk populations, such as older adults susceptible toAlzheimer’s disease and dementia, various forms of CT showprotective effects and even improvements in select cognitivefunctions [49, 51, 65–67].

There have now been a number of studies investigatingthe effect ofCTon cognitive dysfunction in PD. In this review,we present and summarize each study individually, discussthe potential of CT as a therapy for cognitive impairment inPD, highlight knowledge gaps, and make recommendationsfor future studies. We will critically evaluate the design andmethods of studies of CT in PD. The ultimate goal of thisreview is to focus the research on CT in PD, to suggestguidelines for future studies, and to highlight common issuesthat are noted in the literature.

Literature Search. To identify all studies that investigatedCT to treat cognitive symptoms of PD, we conducted asearch in PubMed and PsycINFO using the following keyterms and combinations: cognit∗ train∗ AND Parkinson∗;memory train∗ AND Parkinson∗; attention train∗ ANDParkinson∗; cognit∗ rehabilitation AND Parkinson∗; mem-ory rehabilitation AND Parkinson∗; attention rehabilitationAND Parkinson∗; cognit∗ remediation AND Parkinson∗;memory remediation AND Parkinson∗; attention remedia-tion AND Parkinson∗. We selected for further inspectionstudies that included information on (1) the training group(s),(2) the training intervention, (3) the outcome measures, and(4) specifically used CT interventions, alone or in combina-tion with (an)other nonpharmacological therapy in PD. Wefound only 13 studies that met all of these criteria. In eachstudy, we examined whether (1) there was a control groupor comparison intervention, (2) training was multimodal,computerized, or pen and paper, (3) CT was combined withanother intervention, (4) CT was standardized or individ-ually tailored, and (5) QOL changes were assessed. Table 1lists the identified studies and categorizes them according todesign.

2. Results

2.1. Single Group, Uncontrolled Studies. In a small preliminarystudy of CT with inpatients, Sinforiani et al. [68] examinedthe effects of a rehabilitation program consisting of motorand cognitive training in patients with early stages of PDand mild cognitive decline but not dementia. They usedTraining Neuropsicologico (TNP; [82])—a computerized CTprogram aimed at improving attention, abstract reasoning,and visuospatial abilities. The PD patients (𝑁 = 20) whoenrolled in the program for 12 sessions showed significantimprovement on measures of verbal processing and verbalmemory as well as on one measure of abstract reasoning.These improvements remained when examined at a six-month follow-up. However, without a control group, it isimpossible to attribute improvement to CT specifically. Alter-natively, change in function could have owed to nonspecificeffects of being enrolled and followed in a study, to the


Table 1: Classification of studies of CT in PD according to design.

Single group, uncontrolledstudies

Waitlist-controlledstudies

Studies comparing CT tostandard treatments

Comparing different CTinterventions

Sinforiani et al., [68]Mohlman et al., [69]Disbrow et al., [70]

Nombela et al., [71]Naismith et al., [72]Edwards et al., [73]

Sammer et al., [74]Parıs et al., [75]

Pompeu et al., [76]Pena et al., [77]Cerasa et al., [78]

Reuter et al., [79]Petrelli et al., [80]

Zimmermann et al., [81]

passage of time, to fluctuations in clinical disease withregression to mean behaviour, or to decreased anxiety orstress of performing with repeated exposure to the setting.Additionally, participants were an inpatient group at arehabilitation centre, making them a special subset of thePD population. This scenario enhances the possibility thatimprovement represented regression to mean performance,with the passage of time of the inciting event or circumstanceleading to admission to a rehab setting and later testing.Other confounds exist due to the rehabilitation setting. Thegroup received motor rehabilitation in addition to the CTprogram so the influence of the two cannot be teased apart.Additionally, it is important to note that a majority of themeasures of cognition yielded no significant improvement,including measures of overall cognition (Mini-Mental StateExamination score,MMSE),WM (digit span, Corsi block), andmeasures of cognitive flexibility (Wisconsin Card Sorting Test,WCST), and the authors did not indicate if corrections formultiple comparisons were applied.

In another study, Mohlman et al. [69] examined theacceptability and feasibility of administering CT to patientswith PD. Participants (𝑁 = 16) completed neuropsychologi-cal tests and psychometric questionnaires before and aftertraining to assess changes in cognition and mood. The neu-ropsychological battery consisted of the digit span forwardand backward tasks, the Stroop Color Word Test, the TrailMaking Test (TMT), and the Controlled Oral Word Asso-ciation Test (COWAT). The psychometric tests included thePenn StateWorry Questionnaire, the Beck Anxiety Inventory(BAI), the trait scale of the State-Trait Anxiety Inventory(STAI), and theBeckDepression Inventory (BDI).During thetraining period, which lasted one month, with 90 minutes oftraining per week, participants came to the lab on universitycampus and performed the Attention Process Training (APT-II) Intervention, a computerized CT program. The modulesincluded in the APT-II focused on training sustained atten-tion, selective attention, alternating attention, and dividedattention. Participants also received daily homework assign-ments throughout the month. The main focus of the studywas to determine the acceptability and feasibility of the CTacross 4 dimensions: fatigue, effort, progress, and enjoyment.Findings indicated that participants showed good acceptanceand completion of the training program. In addition, allparticipants’ scores on the 4 neuropsychological tasks improvedfrom pre- to postintervention (though no statistics were pro-vided). As the main focus was on acceptability of the CT,the article did not include information about the cognitiveperformance of the group before or after training.

A study by Disbrow and colleagues [70] investigated theeffects of executive function and motor focused CT on per-formance of a similar motor sequence learning task, as wellas measures of cognitive flexibility, verbal fluency, and timedinstrumental activities of daily living (TIADL).They enrolled30 PD patients and 21 age matched controls. During pre-training, participants performed a motor sequence learningtask (which also served as the training task), the TMT, theDelis-Kaplan Executive Function Scale (D-KEFS), and theTimed-Up-and-Go Test (TUG). In the motor sequence task,participants had to press on a keypad the sequence ofnumbers corresponding to the sequence that was displayedon the screen (e.g., 1-3-4). Sequence length varied between 1and 4 digits and included two conditions, the Externally Cued(EC) condition, where feedback was displayed on the screenevery trial, and an Internally Represented (IR) condition,where feedback was not displayed on the screen every trial.Based on performance on the motor sequence task, PDpatients were split into two groups for further analyses, animpaired performance group (𝑁 = 14) and an unimpairedperformance group (𝑁 = 16). Outcome measures for themotor sequence learning task were time to initiate motorresponse, time to end sequence, and number of errors.During the training period, participants performed themotorsequence task for 10 sessions each taking 40minutes, over thecourse of about two weeks.

Results showed that training benefitted both the EC andthe IR conditions in all groups. Although after training theimpaired PD patients still had slower initiation and com-pletion times in the EC condition than the unimpaired PDpatients and controls, their performance in the IR conditionimproved after training and was not significantly differentfrom the other two groups. This indicates that the train-ing improved motor performance dependent on executivefunction, as required when participants internally representand plan a sequence but not a simpler version of motorperformance when feedback and digit sequence are shown.The previously impaired PD patients also made fewer errorsafter completing training, similar to the unimpaired PDgroup and the control group. Training did not have an effecton the D-KEFS, the TIADL, or the TUG. There was a maineffect on training on the TMT B minus A scores; however,the impaired PD patients still showed impaired performanceafter the training compared to the other two groups.

Overall, the results of this study suggest that patients withspecific impairments can particularly benefit from specialized,focused training. It is important to note that the training andoutcome tasks were nearly identical; thus, it is unclear whetherthe effects of this type of training transfer to other functions.


Improvement on the TMT suggests that there may be somedegree of transfer althoughno effectswere found onmeasuresof QOL and other motor tasks. Moreover, there was nowaitlist PD group so it is impossible to attribute improvementsolely to the training rather than repeated testing or thepassage of time.

2.2. Waitlist-Controlled Studies. In a study employing neu-roimaging to investigate CT, Nombela et al. [71] scannedparticipants using fMRI before and after training. Ten par-ticipants with PD and ten healthy age-matched controlscompleted a variation of the Stroop task at baseline and aftertraining. Half of the PD patients were enrolled in a trainingintervention (𝑁 = 5), and half served as the untrainedwaitlistcontrol group (𝑁 = 5). Training consisted of a series ofSudoku puzzles completed at home every day for the durationof six months, with weekly meetings with the researchers togo over the puzzles. During baseline assessment, participantscompleted an easy Sudoku puzzle, the modified Stroop task,and several questionnaires evaluating cognition and PDsymptoms (MMSE, Unified Parkinson’s Disease Rating Scale(UPDRS), Montgomery-Asberg Rating Scale). PD patientshad slower response times (RTs) on the Stroop task, moremissed trials, and poorer performance overall. They alsotook longer to complete the easy Sudoku puzzle compared tocontrols. Functional neuroimaging revealed more extensivebrain activation in patients than in controls and less activa-tion in the left precentral gyrus, left medial frontal gyrus,right precuneus, and the left inferior parietal gyrus. Afterthe six-month training period, the trained PD group hadfaster RTs on the Stroop task, more correct answers, andfewermissed trials than the untrained patients.Their RTs andcorrect and missed trials were also better than during theirbaseline assessment. Further, they completed the Sudokupuzzles more quickly than the untrained PD group.The brainactivation of the trained PD group during the Stroop task wasmore similar to that of the healthy control group. The resultsof this study suggest that daily performance of cognitiveexercises can improve performance on these exercises as wellas other related cognitive tasks, but the study is limited by asmall sample size and a very unusual and time consumingintervention. Additionally, the assignment to the traininggroup was not random but voluntary, leading possibly tofundamental differences between the training and untrainedgroups, with the former beingmore engaged and enthusiasticparticipants.

A study by Naismith et al. [72] combined psychoeduca-tion and CT and found that, compared to a waitlist controlgroup (𝑁 = 15), the treatment group (𝑁 = 35) improvedon measures of learning and memory retention. The CTintervention was based on the Neuropsychological Educa-tional Approach to Remediation (NEAR), was individual-ized to each participant, and comprised a wide array ofcommercially available computer-based programs dependingon the individual’s strengths and weaknesses. Participantscompleted 14 training sessions over two weeks in a lab group-setting. The primary outcome variable was episodic mem-ory measured through the Logical Memory subtest of the

Wechsler Memory Scale III (LOGMEM). Secondary meas-ures consisted of psychomotor speed and mental flexi-bility (TMT), verbal fluency (COWAT), general cognition(MMSE, National Adult Reading Test), and knowledge aboutPD assessed using a multiple choice questionnaire. Resultsrevealed that the CT group improved more than the waitlistgroup on LOGMEM (learning andmemory retention).Therewas no improvement on measures of psychomotor speed,mental flexibility, verbal fluency, or depressive symptoms.Theresults lend support to CT as a viable intervention to possiblyslow down memory decline in PD patients and improveperformance on some memory and learning tasks. Due tothe difficulty of administering such a comprehensive andindividually tailored intervention as well as the high degreeof variability in terms of the intervention between patients, itis difficult to assert whether these effects might generalize toPD patients broadly.

A randomized, waitlist-controlled study by Edwards andcolleagues [73] investigated the effect of a processing speedtraining intervention on useful field of view (UFOV), self-rated cognition, and depressive symptoms. One group ofPD patients received Speed of Processing Training (SOPT;𝑁 = 44), and a second group of PD patients served as awaitlist control (𝑁 = 43).The groups did not differ on anymotor, cognitive, or demographic measures at pretrain-ing. The training intervention consisted of a SOPT program(InSight, Posit Science, Inc., San Francisco, CA) whichincluded five exercises focusing on rapid processing of visualstimuli, selective attention, and visual working memory.Training was self-administered, computerized, and com-pleted at home. The intervention lasted for three months,with a recommended schedule of three sessions per week,each session taking an hour. Outcome measures were UFOV,the Cognitive Self-Report Questionnaire, and the Centre forEpidemiological Studies Depressive Symptoms Scale (CES-D). Analyses revealed that although both the SOPT andthe waitlist group showed significantly improved performanceon the UFOV task, the SOPT group improved significantlymore from pre- to posttraining than the waitlist group. Theother two measures, self-reported cognition and depressivesymptoms, did not show any changes. The results of this studyprovide evidence that SOPT, even when self-administeredand completed at home, can lead to improvement in similartasks, more than can be accounted for by test-retest effects.An important caveat the authors mention is that the effectsweremost strongly associated with factors accounting for lesssevere PD stage (e.g., age at onset, disease duration, and L-dopa equivalent dosage). Additionally, none of the patientshad symptoms consistent with MCI; thus it will be helpfulto conduct a similar study with MCI patients to evaluatewhether the SOPT program can benefit more severe stagesof PD or cognitive decline.

2.3. Studies Comparing CT to Standard Treatments. Sammeret al. [74] investigated the effectiveness of CT with inpatientsat a rehabilitation centre. Participants were divided into twogroups: one group (𝑁 = 12) received a treatment focusingon executive functions; the other group (𝑁 = 14) completed


a standard treatment comprised of occupational therapy,physiotherapy, and physical treatment sessions.The executivefunction intervention consisted of a range of both standard-ized and novel tasks training WM, abstract reasoning, prob-lem solving, visuospatial processing, and verbal processing.After 10 training sessions over the course of a 3-4-weekhospital stay, only the executive function treatment groupimproved on some measures of executive function and WM(Behavioural Assessment of the Dysexecutive Syndrome-ruleshift and 6-element subtests). However, there were othermeasures of WM and executive function (TMT and a face-name learning task) and a measure of attention, on whichneither group improved. There was also no change in ratingsof well-being or depression between the two groups. Theresults of this study provide some limited evidence that CTcan lead to enhancements of executive function. However, itis necessary to identify why some tasks of executive functionshowed improvement whereas other tasks of executive func-tion did not. With no corrections for multiple comparisons,it is possible to find statistically significant differences in asubset of many tasks due to chance alone, which cannot beruled out in this case.

In a randomized, controlled, experimenter-blinded studyof CT in patients with PD, Parıs and colleagues [75] comparedthe effects of an intensive individualized CT program (𝑁 =12) to a speech therapy intervention (𝑁 = 12). Each partici-pant in the CT group received individual training using aplatform of 28 tasks (i.e., SmartBrain computerized program)focusing on specific cognitive domains known to be impairedin PD patients such as memory, attention, WM, executivefunctions, visuospatial abilities, and psychomotor speed.They also trained on nonspecific tasks that tapped overallcognition including language, simple calculations, and cul-ture. Additionally, participants received homework exercisesto be completed outside the sessions. The speech therapyparticipants received group-sessions focusing on commu-nication difficulties as a result of PD. The interventionprogram for both CT and speech therapy groups consistedof 12 sessions over four weeks, each session lasting 45minutes. The CT group also received 20 weekly homeworkexercises to stimulate cognition. At a baseline assessment,participants completed a comprehensive battery of tasksmeasuring overall cognition (e.g., MMSE), attention andWM (e.g., digit span), information processing speed (e.g.,TMT), verbal and visual processing, learning, and executivefunctions (e.g., Tower of London (TOL), Stroop test), aswell as questionnaires assessing QOL and mood. Followingthe training period, the CT group showed significantly moreimprovement than the speech therapy group on measuresof attention, processing speed, memory, visuospatial abilities,executive function, and semantic and verbal fluency.There wasno difference between the groups onmeasures of QOL or mood.More importantly, although many outcome measures wereincluded, not all measures showed improvement, and therewas no indication that analyses were corrected for multiplecomparisons. Despite describing aspects of cognition that thetraining program focused on, the specifics of each trainingtask were not included in the manuscript, thwarting wide-spread implementation. These details are also needed to

determine how well the trained skills transferred to the out-come measures, and whether the training effect generalizedto similar or diverse tasks.

In a study examining the effects of a CT-like interventionon symptoms of PD and independent activities of daily livingmeasured by the UPDRS-II, Pompeu and colleagues [76]divided 32 PD patients into two groups. Both groups receivedan intervention consisting of 14 sessions of 30 minutes ofglobal physical exercises. The control group (𝑁 = 16) re-ceived additional 30minutes of balance exercises, whereas thetraining group (𝑁 = 16) received 30minutes of training usingWiiFit games. WiiFit games focus on motor performance(e.g., Torso twist, soccer heading, basic step, and speed run),though cognitive processes such as planning, decision mak-ing, and divided attention are invoked to perform the tasks.The main outcome measure, performance of activities of dailyliving as assessed by the self-report on the UPDRS-II, revealedno difference between the two groups before training, aftertraining, or at 60-day follow-up evaluations. Both groupsindicated improvement on theUPDRS-II, leading the authorsto conclude that training using the WiiFit games does notlead to any improvement over performance of general balanceexercises. However, the WiiFit games are designed primarilyto focus on motor performance rather than cognitive pro-cesses. It is likely that the chosenWiiFit games did not have aclear focus on any aspect of cognition per se and instead thecognitive training occurred as a by-product of performing themotor task. Although the authors claim that theWiiFit gamestrained cognition, the CT tasks and the cognitive evaluationswere a secondary measure and were not clearly defined.

Another study conducted by Pena et al. [77] compareda structured, pen and paper CT program to occupationalactivities. Outcome measures were processing speed (TMT-A, Salthouse Letter Comparison Test), verbal learning andmemory (Hopkins Verbal Learning Test), visual learningand memory (Brief Visual Memory Test), executive function(Stroop), and Theory of Mind (Happe test). The CT group(𝑁 = 22) received a standardized intervention (REHACOP,a Spanish cognitive rehabilitation program for psychosis)focused on improving attention, memory, language, verbalprocessing, executive function, and theory of mind, as wellas general cognition and functional disability ratings. Theoccupational therapy group (𝑁 = 22) performed activitiessuch as drawing, reading the newspaper, and arts and crafts.Both groups completed 39 sessions over 13 weeks, three perweek, with each session taking an hour. They found that,following training, the CT group showed more improvementthan the occupational therapy group on measures of processingspeed, visual memory, theory of mind, and functional dis-ability. This provides further evidence that structured CTis more beneficial than interventions not explicitly focusedon cognitive improvement. Also, the improvement on thefunctional disability scale suggests that CT might lead tobenefits that generalize to functional activities. However, thetraining program is quite a bit longer than those usuallystudied in CT so results are difficult to compare to otherstudies.

A study by Cerasa and colleagues [78] compared a com-puterized CT program designed to rehabilitate attention in


patients with multiple sclerosis (REHACOM) to a group per-forming a simple visuomotor coordination tapping task.Participants were also scanned using fMRI at resting statebefore and after training. Both the CT group (𝑁 = 8) and thePD control group (𝑁 = 7) completed 12, one-hour trainingsessions over six weeks. On the outcome measures, whichincluded a range of tasks assessing verbal memory, spa-tial memory, verbal fluency, information processing speed,visuospatial processing, mood, cognition, and QOL, the CTgroup improved more than the control group on two tests.In some cases improvement was found in only some testsbut not others from the same cognitive domain, or eventests that are similar to each other (e.g., digit span forwardimproved whereas digit span backward did not). There wasalso a difference in resting state brain activity in the leftdorsolateral prefrontal cortex within the left central executivenetwork between the CT and the PD control group. Overall,results from the study provide weak evidence that CT canlead to improvements in cognition and some changes in brainactivation. However, no differences between the groups werefound on most cognitive measures, and also on measures ofQOL and mood, so these effects do not seem to benefit dailyfunctioning.

2.4. Studies Comparing Different Forms of CT. Reuter et al.[79] conducted a large scale study of CT with inpatients andtheir caregivers, examining the effects of three interventionprograms on tests of memory, language, reasoning, attention,executive function, and visuospatial processing, measuredwith the Alzheimer Disease Assessment Scale-Cognition(ADAS-Cog) and the Scale for Outcomes in Parkinson’sDisease-Cognition (SCOPA-Cog) testing batteries. Measuresof general cognitive function (Parkinson NeuropsychometricDementia Assessment (PANDA) and MMSE), QOL, andactivities of daily living (Parkinson’s disease questionnaire(PDQ-39)) were also taken to assess the overall impact ofthe training programs on cognition. Patients completed thetraining while staying at a hospital for four weeks, for a totalof at least 14 training sessions, and were assessed before, after,and at six-month follow-up.

Group “A” (𝑁 = 71) completed an array of individu-ally tailored tasks focused generally on executive functions,memory, reasoning, WM, attention and concentration, andplanning (for a list of tasks please see Table 2). Group “B”(𝑁 = 75) received the same program as well as transfertraining that aimed to improve management of activities ofdaily living and increase self-confidence through the use ofstrategies such as mnemonics, decision making, handling ofmoney, reading comprehension, and other tasks that patientsidentified as challenging. Group “C” (𝑁 = 76) received theCT, the transfer training, and motor training, which con-sisted of games and tasks that focus on inhibitory control,coordination, speed, perception, orientation, WM, attention,and visuospatial abilities. The caregivers of participants fromeach group also received educational sessions pertaining tothe skills practiced with the patients.

All groups showed improvement on the outcome measures;however, GroupC, the group receiving all interventions, showed

significantly more improvement than Group A or B across allmeasures. Participants in each group also showed increases inrated QOL, with Group C reporting the most improvement.At the six-month follow-up, a larger proportion of partici-pants in Group C had retained their skills and improved per-formance compared to Groups A and B. The results strong-ly suggest that multimodal rehabilitation programs can leadto significant improvements across a variety of cognitivefunctions, and that carefully designed, individualized CTprograms can generalize to improvement on untrained butsimilar cognitive tasks. However, there are limitations to suchan approach. First, it is difficult to understand and clearlyattribute benefits to individual components of the interven-tion given that all groups received multiple componentsof active treatment. Such an intervention is very time andresource consuming, because training programs have tobe tailored to each participant and therefore widespreadapplication seems unfeasible. Additionally, it requires a sig-nificant time commitment from the patients who completethe training program, ranging from four hours per week witha trained professional for Group A, and upward of six hoursper week for participants in Groups B and C, which showedthe most change.

In a randomized controlled study Petrelli and colleagues[80] examined the effects of a structured and an unstructuredCT intervention relative to a waitlist control group on meas-ures of memory, attention, and executive functions, as wellas QOL and mood. One group received a structured CT pro-gram (𝑁 = 22) administered using theNeuroVitalis software.A second group received an unstructured CT program (𝑁 =22) administered using the MentallyFit program. Finally, athird group was a waitlist control (𝑁 = 21). Training sessionswere completed in a group setting led by a supervisor, andtraining lasted 12 sessions which took 90 minutes each. Atpre- and posttraining evaluations, participants completed acomprehensive battery of cognitive tests and neurologicalassessments. Primary outcome measures were performanceon the Brief Test of Attention (BTA), DemTect, a cognitivescreening tool, and Memo, a verbal processing test. Sec-ondary measures included visuoconstruction (Complex Fig-ure Test), depression scores (BDI), and QOL (PDQ-39).

When compared to the waitlist control, the group receiv-ing the structured CT program showed improvement inmeasures of WM and short term memory, whereas theunstructured CT group showed trends in improvement onverbal memory and fluency. The unstructured CT group alsoshowed a decrease in depression scores. The structured CTgroup showed significantly more improvement than eithergroup on WM measures, as well as a trend in verbal shorttermmemory.This study supports CT as an intervention thatcan improve performance on untrained measures of cogni-tion and suggests that a structured program leads to morebenefits than an unstructured one. The use of many outcomemeasures that overlap in domains and the fact that someWMtasks showed improvement whereas others did not, weakensthe conclusions drawn somewhat. Additionally, the traininginterventions included various tasks completed in groupsessions which reduces the specificity of the intervention and


Table2:Summaryof

studies

ofCT

inPD

.

Articleby

Participants

Descriptio

nof

training

interventio

nOutcomem

easures

Results

onou

tcom

emeasures

(#sig

nificant

differences/to

tal#

ofmeasures)

Descriptio

nof

setting

#weeks|#

sessions|se

ssionleng

th(m

inutes)|total

interventio

nleng

th(hou

rs)

Com

bined

interventio

nor

onlyCT

Standardized

interventio

nAssessedQOL

Sinforiani

etal.,2004

[68]

20PD

-MCI

MMSE∼25

Nodementia

H&Y1.5

TNPsoftw

are,focuso

nattention,

abstr

act

reason

ing,visuospatia

labilitie

s,different

levelof

complexity.

MMSE

Digitspan

Corsi’stest

COWAT

FAS

Babcock’s

story

Raven’s

matric

esWCS

TStroop

test

Pre-po

stim

provem

ent:

3/8

Babcok’ssto

ry;∗

COWAT

FAS;∗∗

Raven’s

matric

es∗

Com

puteriz

ed,hospital

program

6|12|60|12

CTandmotor

rehabilitation

Yes,TN

Psoftw

are.

No

Sammer

etal.,

2006

[74]

12PD

CT14

PDsta

ndard

treatment

MMSE∼27

Nodementia

H&Y2-3

CT-B

ADS(unu

sed

subtests)

;Raven’smatric

es;

picturea

rrangementtasks,

picturec

ompletiontasks,

blockdesig

n,ob

ject

assembly(fr

omWISC)

;shortstorie

s&discussio

ns;

pictures

prom

ptingsto

ries.

Standard

treatment,

occupatio

naltherapy,

physiotherapy,andph

ysical

treatment.

BADS,ruleshifting

BADS,six

elem

ents

CET,German

version

TMT,German

version

Face

namelearningtest

Attention

Wellbeingscale

Verbalintelligences

cale

Ham

ilton

Ratin

gScalefor

Depression

Pre-po

stim

provem

ent:

2/5

CTmorethansta

ndard

treatment,im

proved

onBA

DSruleshifting∗

CTandsta

ndard

treatmentgroup

s,im

proved

onBA

DSsix

elem

ents∗∗∗

Non

compu

teriz

ed,

hospita

lprogram

3-4|10|30|5

OnlyCT

inho

spita

lversus

stand

ard

treatment

Not

stand

ardized

interventio

n.Ad

ditio

nally,

task

difficulty

was

adjuste

daccordingto

each

participant’s

perfo

rmance

level.

Yes.

Nochange

(moo

dqu

estio

nnaire)

Nom

belaetal.,

2011[71]

5PD

CT5PD

untrained

10healthycontrols

MMSE

25-26

H&Y2.5

PDun

trained

&healthy

controls,

waitlist

CT,one

easy

levelSud

oku

puzzle(4×4grid,2×2

blocks)d

ailyforsixmon

ths.

Weeklymeetin

gs.

UPD

RSMMSE

Stroop

accuracy

Stroop

RTSudo

kuRT

Brainactiv

ation

PosttrainingPD

CTversus

PDun

trained:

Sudo

ku,fastersolving

time∗

Stroop,m

orec

orrect

answ

ers∗,few

ermissing

answ

ers∗∗∗,low

erRT∗∗.

PDCT

grou

pshow

edbrainactiv

ationpatte

rnmores

imilartocontrols.

Non

compu

teriz

ed,at

homew

ithweekly

meetin

gsto

discuss

progress,Sud

okutable

1/day,for

6mon

ths

Impo

ssibleto

calculate

totaltrainingtim

e

OnlyCT

No,Sudo

kuplus

weekly

meetin

gs,

muchlong

erdu

ratio

nthan

tradition

alCT

.

No

Moh

lman

etal.,2011[69]

16PD

MMSE

28Nodementia

AttentionProcessT

raining

II(A

PT-II),aud

ioCD

s,pen

andpaperw

orksheets,

respon

seclickers.

Training

susta

ined

attention,

dividedattention,

alternatingattention,

and

selectivea

ttention.

Acceptability

Feasibility

COWAT

Stroop

Digitspan

f&b

TMTB

Pre-po

stim

provem

ent.

Nosta

tistic

s

Com

puteriz

ed+daily

practic

e,in

lab,assisted

4|4|90|6

OnlyCT

butn

otassessing

effectiv

eness

Yes,APT

-II.

Not

repo

rted


Table2:Con

tinued.

Articleby

Participants

Descriptio

nof

training

interventio

nOutcomem

easures

Results

onou

tcom

emeasures

(#sig

nificant

differences/to

tal#

ofmeasures)

Descriptio

nof

setting

#weeks|#

sessions|se

ssionleng

th(m

inutes)|total

interventio

nleng

th(hou

rs)

Com

bined

interventio

nor

onlyCT

Standardized

interventio

nAssessedQOL

Parıs

etal.,

2011[75]

16PD

CT12

PDcontrol

Exclu

dedMMSE<23,

someM

CIin

both

grou

psH&Y2.37,2.25

PDCT

:Sm

artBrain

interventio

nas

wellasp

enandpaper

homew

ork.

Individu

alized

from

aplatform

of28

tasks

focusin

gon

attention,

WM,

executivefun

ction,

mem

ory,visuospatia

labilitie

s,psycho

motor

speed.Also

training

inlang

uage,calculatio

ns,and

cultu

re.

PDcontrol:

speech

therapy,focuso

nspeech

andcommun

ication

difficulties.

MMSE

ACE

AttentionandWM:

(i)WAIS

IIID

igitSpan

f&b

(ii)C

VLT

II-List

A1

Inform

ationprocessin

gspeed:

(i)SD

MT

(ii)T

MTA

(iii)Stroop,w

ordsubtest

Verbalmem

ory:

(i)CV

LT-II-Short-D

elayFree

Recall

(ii)C

VLT

-II-Lo

ng-D

elay

Free

Recall

(iii)Lo

gicalM

emorysubtestI

(iv)L

ogicalMem

orysubtestII

Learning:

(i)CV

LT-II-ListATo

tal

Visualmem

ory:

(i)RO

CFT-Im

mediateRe

call

(ii)R

OCF

T-Dela

yedRe

call

Visuoconstructiv

eabilities:

(i)RO

CFT-Cop

yVisuospatia

lAbilities:

(i)RB

ANS-Line

Orie

ntation

Verbalflu

ency:

(i)Ph

onem

ic-C

OWAT

FAS

(ii)S

emantic-C

OWAT

Animals

Executivefun

ctions:

(i)TM

T-B

(ii)T

OL-To

talM

oves

(iii)TO

L-To

talC

orrect

(iv)T

OL-Ru

lesV

iolations

(v)S

troop

Test-

Interfe

rence

PDQ-39

Moo

d,geria

tricdepressio

nscale

Cognitiv

ediffi

culties

inactiv

ities

ofdaily

living,

Cognitiv

eDeficitsScale

SmartBrain

grou

pim

proved

on10/23

measuresc

omparedto

PDcontrolgroup

.AttentionandWM

1/4:

digitspanforw

ard∗

Inform

ationprocessin

gspeed1/3

:Stro

opword∗∗∗

Visualmem

ory2

/4:

ROCF

T,im

mediate∗∗

anddelayed∗

Verbal1/2

:Semantic-Animals∗∗bu

tno

tPho

nemic-FAS

Executivefun

ctions

3/5:

TMT-B∗

,TOLTo

tal

Moves∗∗,and

Total

Correct∗∗

Com

puteriz

edand

noncom

puteriz

edplus

homew

orktasks,in

lab

andatho

me

4|12|45|9

Plus

homew

orkfor

unspecified

amou

ntof

time

OnlyCT

versus

speech

therapy

No,selectionof

tasksp

lus

SmartBrain,

individu

alized

fore

ach

participant.

Yes.

Nochange

onPD

Q39,on

measure

ofmoo

d,or

ofactiv

ities

ofdaily

living


Table2:Con

tinued.

Articleby

Participants

Descriptio

nof

training

interventio

nOutcomem

easures

Results

onou

tcom

emeasures

(#sig

nificant

differences/to

tal#

ofmeasures)

Descriptio

nof

setting

#weeks|#

sessions|se

ssionleng

th(m

inutes)|total

interventio

nleng

th(hou

rs)

Com

bined

interventio

nor

onlyCT

Standardized

interventio

nAssessedQOL

Pompeuetal.,

2012

[76]

16PD

General

balance

16PD

WiiF

itH&Y1-2

MOCA

22-im

paire

d

WiiF

itandcognition

(cognitio

nas

partof

the

game’s

requ

irements,

not

specifically

trained).G

ames

used:

Sing

leLegEx

tension,

Torso

Twist,TableTilt,

TiltCity,

Soccer

Heading

,Penguin

Slide,Rh

ythm

Parade,

Obstacle

Cou

rse,Ba

sicStep,

Basic

Run.

GeneralBa

lance:Similar

motor

requ

irementsas

the

Wiigames.

UPD

RS-II(activ

ities

ofindepend

entliving)

MOCA

Staticanddynamicbalance

measures

WiiF

itandgeneral

balancee

xercise

grou

psbo

thshow

edim

provem

entinUPD

RSII∗(in

depend

ent

activ

ities

ofdaily

living

scale)andMOCA

scores∗.N

odifference

betweengrou

psbefore,

after,ora

t60-day

follo

w-up.

Com

puteriz

ed-sessio

nsledby

aninstr

uctor

7|14|60|14

Com

binedwith

glob

alexercises.

Com

puteriz

edbu

tnot

cogn

itive

focused.

Yes,WiiF

itgames.

Yes.

Both

grou

psim

proved

onUPD

RSII-activities

ofindepend

ent

living

Reuter

etal.,

2012

[79]

71PD

CT(group

A)

75PD

CT+transfe

r(group

B)76

CT+transfe

r+motor

(group

C)MCI

inallgroup

s

CT-B

ADS(unu

sed

subtests)

;Raven’smatric

es;

picturea

rrangementtasks,

picturec

ompletiontasks,

blockdesig

n,ob

ject

assembly(fr

omWISC)

;shortstorie

s&discussio

ns;

pictures

prom

ptingsto

ries.

CT+tra

nsfer

:sam

eas

above+

daily

taskssuchas

groceryshop

ping

,tending

toav

egetablepatch,andso

forth.

CT+tra

nsfer

+motor:sam

eas

above+

games

andtasks

toenhanceinh

ibito

rycontrol,WM,coo

rdination,

andso

forth.

ADAS-

Cog

SCOPA

–Cog

BADS-

sixelem

ent

BADS–zoomap

BADS–instr

uctio

nPA

SAT

GoalA

ttainmentS

cale

PDQ–39

UPD

RS

Nodetailedsta

tistic

s,all

grou

psim

proved.Th

emoreinvolvedgrou

ps(group

sBandC)

improved

more.

Therew

asas

ignificant

grou

p×tim

einteraction,

suggestin

ggrou

pCim

proved

more

than

otherg

roup

son

ADAS-Cog∗∗∗and

SCOPA

-Cog∗∗∗

Com

puteriz

edand

noncom

puteriz

ed,

hospita

land

atho

me,at

least14sessions,4/w

eek,

60minutes,thenat

home,3/week,45

minutes

each.

Minim

um:

4|16|60|16

OnlyCT

versus

CT+transfe

rtraining

versus

CT+transfe

rtraining

+psycho

motor

training

No

Individu

alized

Yes.

Improvem

entin

ordero

fmagnitude

C>B>A

Disb

rowetal.,

2012

[70]

14PD

CTim

paire

d16

PDCT

unim

paire

d21

Con

trols

Two-phaseb

uttonpresstask,

amotor

sequ

ence

learning

task,partic

ipantshadto

pressn

umberedkeys

correspo

ndingto

the

numbersequences

hownon

screen.Sequencelength

varie

dbetween1and

4digits.

Motor

sequ

ence

learning

task

TIADL

TMT

D-K

EFS

TUG

Posttraining,the

impaire

dPD

grou

pshow

edsig

nificant

improvem

entintim

efor

sequ

ence

initiation,

time

forsequence

completion,

andnu

mber

oferrorsin

theinternally

representedcond

ition

ofthetask.

Com

puteriz

ed,adaptive

difficulty,com

pleted

atho

me

2|10|40|∼6.5

OnlyCT

Yes,bu

tadaptiv

edifficulty.

Yes.

Nochangesin

timetocomplete

instr

umental

activ

ities

ofdaily

living


Table2:Con

tinued.

Articleby

Participants

Descriptio

nof

training

interventio

nOutcomem

easures

Results

onou

tcom

emeasures

(#sig

nificant

differences/to

tal#

ofmeasures)

Descriptio

nof

setting

#weeks|#

sessions|se

ssionleng

th(m

inutes)|total

interventio

nleng

th(hou

rs)

Com

bined

interventio

nor

onlyCT

Standardized

interventio

nAssessedQOL

Naism

ithetal.,

2013

[72]

35PD

CT+

psycho

education

15PD

waitlist

MMSE

27

Neuropsychologica

lEd

ucationa

lApproachto

Remediatio

n(N

EAR),

individu

alized,com

puter

basedtraining

program

devisedaccordingto

their

testresults,usin

gam

ixof

commerciallyavailableC

Tinterventio

nsandsoftw

are

programs.

WechslerM

emoryScaleIII:

LOGMEM

I-Im

mediateLO

GMEM

II–

Delayed

TMTA

TMTB

COWAT

FAS

BDI

CT>waitlist

improvem

ento

n2/7

measures:

LOGMEM

I–Im

mediate∗

LOGMEM

II–

Delayed∗

Com

puteriz

ed,inlab

grou

psessions

7|14|12

0|28

CTcombined

with

psycho

education

No

Individu

alized

Yes

Noeffectson

depressio

nBD

I.

Edwards

etal.,

2013

[73]

44PD

Speedof

Processin

gTraining

(SOPT

)43

PDwaitlist

H&Y1–3

MMSE

28

SOPT

,self-administered,

compu

terb

ased

training

program

thatinclu

des5

exercisesa

imed

attraining

speedof

inform

ation

processin

g.Th

eexercise

sadaptindifficulty

according

toperfo

rmance.

UFO

VCognitiv

eSelf-Report

Question

naire

Depressives

ymptom

s(C

ES-D

)

SOPT>waitlist

improvem

ento

n1/3

measures:

UFO

V∗∗

Com

puteriz

ed,

self-administered,at

home

12|36|60|≥20

OnlyCT

Standardized

program

(InSight),

individu

ally

adaptiv

edifficulty

levels.

Yes

Noeffectson

depressio

nCE

S-D

Petre

llietal.,

2014

[80]

22PD

NeuroVitalis

(NV)

22PD

mentally

fit(M

F)21

PDwaitlist

H&Y1–3

Nodementia

MMSE

28

Structured:

Psycho

education,

grou

pgames,ind

ividualand

grou

ptasks,focusin

gon

attention,

mem

ory,and

executivefun

ctions.

Unstructured:

Group

conversatio

n,grou

pgames,ind

ividualand

grou

ptasks,focusin

gon

attention,

mem

ory,

executivefun

ctions,

lang

uage,and

creativ

ethinking

.Tasks

fore

ach

sessionchosen

atrand

om.

Dem

Tect

MMSE

BriefT

esto

fAtte

ntion

Mem

oCom

plex

figure-RO

CFTand

Taylor

COWAT

FAS

BDI

PDQ-39

NV>waitlistim

proved

on2/12:

Mem

o-Ve

rbalshortterm

attentionscore∗∗∗and

Dem

Tect,digitspan

reverse∗.

MF>waitlistim

proved

onBD

I∗.

NV>MFim

proved

onDem

Tect,digitspan

reverse∗∗.

Com

puteriz

ed,pen

and

papera

ndactiv

ities,in

labgrou

psessions

6|12|90|18

OnlyCT

NVgrou

psta

ndardized

interventio

n.MFun

stan-

dardized,

unstr

uctured.

Yes.

MFim

proved

onBD

Iscores.No

changesin

PDQ-39

Zimmermann

etal.2014[81]

19PD

CogniPlus

20PD

WiiF

itMMSE

29H&Y1-2

CogniPlus-fo

cused

attention;

N-Back;planning

andactio

n;respon

seinhibitio

n.WiiF

it-tenn

is,sw

ordp

lay,

archery,airspo

rts.

Tests

ofAttentional

Perfo

rmance-Alertness

Tests

ofAttentional

Perfo

rmance-W

MTM

TBlockdesig

ntest

CVLT

Nooveralltesto

fim

provem

entfor

each

grou

pseparately.

WiiF

itgrou

pim

proved

over

CogniPlus

grou

pon

1/5measures:Tests

ofAttentional

Perfo

rmance-Alertness∗.

Com

puteriz

ed,inlab

supervise

dby

assistant

4|12|40|8

OnlyCT

versus

pure

Wiisports

Yes,bo

thinterventio

ns.

No


Table2:Con

tinued.

Articleby

Participants

Descriptio

nof

training

interventio

nOutcomem

easures

Results

onou

tcom

emeasures

(#sig

nificant

differences/to

tal#

ofmeasures)

Descriptio

nof

setting

#weeks|#

sessions|se

ssionleng

th(m

inutes)|total

interventio

nleng

th(hou

rs)

Com

bined

interventio

nor

onlyCT

Standardized

interventio

nAssessedQOL

Pena

etal.,2014

[77]

22PD

REHAC

OP

22PD

occupatio

nal

therapy

MMSE

27

REHAC

OP,grou

psessions

inclu

ding

focuso

nattention,

mem

ory(visu

alandverbal,recalland

recogn

ition

),lang

uage

and

verbalprocessin

g,executive

functio

ns(plann

ingand

logicalreasoning

),social

cogn

ition

andTh

eory

ofMind.

Processin

gspeed:

TMTA

Salth

ouse

lette

rcom

paris

ontest

Verbalmem

ory:

Hop

kins

verballearning

test,

learning

andlong

term

recall

Visualmem

ory:

Briefvisu

almem

orytest,

learning

andlong

term

recall

Executivefun

ction:

Stroop

wordcolor,interfe

rence

scores

Theory

ofMind:

Happe

test

REHAC

OP>

occupatio

naltherapy

improved

on4/9

measures.

Processin

gspeed∗

Visualmem

ory∗

Theory

ofMind∗

Functio

nald

isability∗

Non

compu

teriz

ed,

psycho

logistledgrou

psessions

13|39|60|39

OnlyCT

Yes,

REHAC

OP

mod

ules.

Yes.

Functio

nal

disabilityscores

improved

inRE

HAC

OPgrou

pmorethan

occupatio

nal

therapygrou

p

Cerasae

tal.,

2014

[78]

8PD

RehaCom

7PD

coordinated

tapp

ingtask

RehaCom

,com

puter

assis

tedtraining

ofattention

andinform

ationprocessin

g.Tapp

ingtask,also

compu

teriz

ed,usin

gin-hou

sesoftw

are.

ROCF

TSelectiveR

eminding

Test

Judgem

entL

ineO

rientation

COWAT

SDMT

PASA

TDigitspan

f&b

Stroop

TMTA&B

RehaCom>control

tapp

inggrou

pim

proved

on2/20

measures.

Digitspan

forw

ard∗

SDMT∗∗

Com

puteriz

ed,group

sessions

with

weekly

meetin

gs6|12|60|12

OnlyCT

Yes,Re

haCom

training

.

Yes.

Nochangesin

PDQ-39scores

ormeasureso

fmoo

d

𝑃valueind

icators:

∗:<

0.05.

∗∗:<

0.01.

∗∗∗:<

0.001.


limits the accessibility and independent performance of theCT regimen.

In a controlled, randomized, participant-blinded study,Zimmermann and colleagues [81] compared the effects ofa structured CT program and an alternative, nonspecifictreatment intervention, on measures of attention, executivefunction, visuoconstruction, and episodic memory. The CTgroup (𝑁 = 19) performed a series of training tasks on thecomputer using the CogniPlus software. The alternativetreatment group (𝑁 = 20) played an interactive videogamewhich involved physical activity (WiiSports). Both traininginterventions ran for 12 sessions over the course of fourweeks, each session taking 40 minutes and supervised bya psychologist or trained student, who were not blinded togroup allocation. Neuropsychological assessment includedparts of the Tests of Attentional Performance battery (alert-ness, working memory), the TMT, the Block Design Testfrom the Wechsler Intelligence Scale for Adults, and theCalifornia Verbal Learning Test. The alternative treatmentgroup that completed training using the WiiSports gamesshowed significant improvement on the alertness portionof the Tests of Attention relative to the CT group and atrend level improvement on tests of visuoconstruction andepisodic memory. These results suggest that a nonspecifictraining intervention might be as effective as a CT interventionin improving attention. However, it is likely that theWiiSportstasks were more novel and engaging than the standardizedCT program delivered using CogniPlus, which could explainthe improvement in attention. Finally, as the authors note,there is increasing evidence that physical activity promotescognition [83, 84], potentially accounting for these findingsbecause performance of WiiSports games involves physicalactivity.

A summary of the studies discussed above is presentedin Table 2. Due to largely varied methodologies and relativelysmall sample sizes it remains unclear whether CT is effectiveas a wide-spread, cognitive intervention in PD. Reviews ofearlier CT studies noted similar limitations [85, 86]. Based onthe research published to date, there is insufficient informa-tion to determinewhich training programor schedule ismostlikely to promote improvements, what outcome measuresbest estimate the impact of CT, andwhich cognitive functionsbenefit most from training.

Due to lack of standardized training programs in thisfield, there was little consistency or convergence betweentraining tasks or outcome measures, making cross-experi-mental comparisons difficult and eliminating the opportunityfor true replication. Moreover, some studies found improve-ment across a wide array of tasks and cognitive skills, whereasothers found more modest and domain-specific effects. Evenwhen there was improvement on outcome measures, it wasseldom explained from a theoretical perspective by thecognitive elements thatwere targeted by the training regimen.Further, training did not often generalize to other untrainedaspects of cognition.

More recent studies of CT in PD used active controlgroups and compared different CT interventions to one an-other, as well as to alternative interventions such as psychoed-ucation, physiotherapy, skill transfer training, and video-

games [72, 76–81]. However, there is still crucial informationlacking that would enable predictions to the larger PD popu-lation or permit widespread and faithful application beyondthe study. Studies need to (1) be clear about exact details of theintervention applied to the training group, (2) include largersample sizes, (3) describe more fully the patient populationcharacteristics in case only subgroups are expected to benefit,and (4) examine effects on QOL and long term outcomes.Providing detailed information about the methodology andtask administration will enable comparisons of results acrossstudies.

It is clear that there is burgeoning interest in CT asan intervention in PD, yet due to lack of methodologicalconsistency even the positive results are difficult to evaluateacross studies. This problem appears to permeate all areasof research of CT, in healthy younger and older popula-tions, as well as in studies with clinical patients [57, 87].Several reviews still note that methodological limitations areholding the field back [66, 87, 88], and these need to beaddressed so thatCT can be examinedwith the scientific rigorand standardized protocol that many pharmaceutical andbehavioural interventions currently undergo. In effect, thereare no clear replications and consequently the legitimacy ofCT as a therapy for cognitive impairment in PD has not beenconclusively determined. This is in line with a recent meta-analysis suggesting that the evidence for CT in PD is notrobust and more research is needed [88]. In the discussionthat follows we examine several of these issues in more depthand provide suggestions for unifying the research in this field.

3. Discussion

3.1. Cognitive and Demographic Profile of Participants andImplications for CTEffects. If investigations of CT in PDhopeto address the ambiguity regarding training effects and theextent to which training can benefit individuals, there is aneed to consider the cognitive and demographic profile of thestudied sample. Demographic and clinical characterization ofparticipants in future studies should more clearly describethe groups under study as these patient features mightinteract with CT effects. This will also define the groupsto which findings might be applicable because PD patientscan vary vastly in their cognitive aptitudes depending uponstage of disease, and some interventions might be moresuitable to relatively unimpaired patients, whereas otherscould be particularly beneficial for patients showing moresevere decline. Therefore, studies need to clearly describe theseverity of disease and providemeasures indicating the extentof cognitive decline, both as an overall score and ideally as acomposite of different cognitive domains as recommended bythe MDS Task Force [89]. It is also necessary to consider theeffect different disease severity (as measured by the Hoehnand Yahr scale or the UPDRS) can have on the ability tocomplete the training intervention either autonomously orwith assistance, and how this might impact performance onoutcome measures.

Many studies of CT in PD exclude patients with demen-tia or MCI, enrolling only PD patients who are clinically


cognitively intact. Considering that baseline cognitive func-tion is a variable that will likely strongly impact CT effects,full characterization of PD patients included in studiesneeds to be disclosed. Finally, studies that explicitly contrastPD groups, formed on the basis of cognitive abilities, areneeded to directly investigate this issue though only onehas been conducted to date [70]. Of the studies reviewed,some included participants with MCI and others includedonly cognitively healthy patients (see Table 2). Since theeffects of CT are likely different for cognitively healthyversus cognitively impaired participants, it is impossible tomake conclusions about the effectiveness of CT when onestudy employs a cognitively healthy population and anotheremploys patients with MCI. The interpretation of the resultsis limited further when the participants are not thoroughlydefined in terms of their cognitive abilities or diseaseseverity.

3.2. Mechanisms Underlying CT. Over the last decade severalstudies found that CT can lead to functional and structuralbrain changes. Most commonly and reliably, fMRI studieshave shown improvement-correlated changes in activationin frontostriatal networks, the dorsolateral prefrontal cortex(dlPFC), medial PFC (mPFC), and the parietal cortex (PC)following CT [61, 71, 90–94]. Functional connectivity (FC)analyses have revealed increased connectivity following CTin areas of the PFC, PC, and the basal ganglia [95, 96]. Studieshave also observed functional changes using measures ofcerebral blood flow (CBF) in the Default Mode Network(DMN) and the External Attention System, as well as globally[96, 97].

Recently, Chapman and colleagues [97] observed bothfunctional and structural changes in healthy seniors follow-ing CT.The authors found increased global and regional CBFin the DMN and the central executive network as well asgreater connectivity in these regions, compared to a waitlistgroup. They also found differences suggesting changes inwhitematter integrity, which could be due to increased axonalmyelination.More support for structural changes comes fromMcNab and colleagues [98], who used Positron EmissionTomography (PET) and found changes in dopamine D1receptor density and binding potentials in the PFC and PCafter 14 hours (across five weeks) of training. These changeswere correlated with behavioural improvement inWM tasks.Finally, in nonhuman primates,WM training has been shownto lead to changes in neuronal firing patterns, leading tothe recruitment of more neurons but a less variable andcorrelated firing rate (for review, please see [99]).

These findings that CT leads to brain changes and poten-tially normalization of activation and connectivity patternsare intriguing and increasing the plausibility of CT as an effec-tive therapy (see review in [91]). However, more research isneeded to understand the nature of these changes.There is asof yet no consensus that these changes reflect actual restora-tive processes of impaired brain function/structure integrityin clinical populations. An alternative explnatio is thatbrain changes could reflect protection from cognitive declinegiven that these alterations occur in healthy older adults

performing CT who show less decline than a waitlist com-parison group [97, 100]. The changes in brain activation andstructure notwithstanding, at a behavioural level, CT likelyimparts consciously and/or unconsciously developing cogni-tive strategies that permit more effective task performance.One such example could be the use of mnemonics or othermemory aids, as well as chunking of items to reduce memoryload (e.g., as in [93]). Ultimately, whatever the mecha-nism, whether due to neural alterations or acquisition of new,more effective cognitive strategies, it remains unclearwhetherthese alterations are long lasting or temporary, and whetherthey correlate with improvement in daily tasks.

3.3. Selecting and Characterizing Outcome Measures of CT.Before CT can be established as a therapeutic or preventativemeasure of cognitive dysfunction in PD, it is necessary todemonstrate that completion of a CT program translatesinto improvements in untrained contexts and activities. Toevaluate the effectiveness of CT, there needs to be someindication that general skills or functions improve and thatthis improvement transfers to other untrained activities. Dis-cussing CT-mediated changes with reference to learning andtransfer of learning literatures (e.g., [91, 101, 102]), trainingon one task should, at a minimum, lead to improvementsin similar tasks that invoke the same cognitive processesor strategies. This is termed near transfer. An example ofnear transfer would be improvement on an N-back task,requiringWMmaintenance and updating, following trainingon a digit span task, also requiringWMmaintenance.Thoughthese are different tasks on the surface, both engage anddepend on WM processes. In this way, improvements inone task following training of the other presumably resultfrom general enhancement of WM processes. An ideal CTregimen, however, would not only produce near transfereffects but in fact optimize performance of very different tasksor skills, relying on quite disparate cognitive processes fromthose that were trained. This is referred to as far transfer.An example of far transfer would include practice on a digitspan task augmenting efficiency of designing amultistep planto achieve a goal in the Tower of Hanoi task. Far transfereffects potentially arise due to shared cognitive processesor strengthening of more general cognitive processing. CT-related improvements only on trained tasks that do nottranslate to benefits outside the specific experimental context,termed direct transfer or simply training effects, would betrivial, having little importance given the aim of addressingcognitive impairment in PD in the real world.That is, thoughtraining effects can have value in some scenarios where skilllearning is the focus, for example, in learning to fly a plane,these would be insufficient to merit investment of time orresources for the stated purpose of preventing or remedyingcognitive dysfunction in PD. Studies investigating CT effectsneed to state clearly the degree of transfer effects that theyhave achieved so their value can be understood.

Although there is some evidence of whatmight constitutefar transfer of skills in PD in some of the studies that werereviewed, these effects are difficult to ascertain because oftenmultiple tasks are included in training interventions without


explicit design to test far transfer. In part this relates to the factthat most studies use training paradigms that are unfocussed,incorporating tasks that trainmany cognitive domainswithina single regimen to increase the probability of a success-ful outcome. While pragmatic, this approach unfortunatelymakes it very difficult to identify the specific component(s) ofthe training intervention that promotes improvement. Futurestudies should employ the concepts of direct, near, and fartransfer explicitly in their hypotheses, choice of interventions,and corresponding outcome measures to investigate theseissues more clearly and provide a context for the results.

Ultimately, it is important to test whether CT leads to anyQOL changes. Studies that have found improvement on thesemeasures delivered CT either in a social group setting or inone-on-one sessions with an instructor (e.g., [69, 76, 77, 79]).In this way, the improvement was potentially confoundedby increased social contacts and a greater sense of involve-ment in a community rather than the specific CT regimen.Although from a practical perspective these improvementsare desirable regardless of the underlying cause, from theperspective of gaining theoretical understanding and forevolving recommendations regarding the most effectiveapproaches, the specific effect of a CT regimen on QOL andmood needs to be isolated from other nonspecific effects.To tease apart these influences, it would be necessary tocompare the same CT when self-administered versus whenit was delivered in a group, attending to QOL changes relatedto each intervention. Future studies must establish whetherCT specifically enhances QOL and performance of dailyactivities, as these are ultimately the changes that are mostimportant to patients with cognitive impairments. Subjectivebenefit in real life function is an important endpoint. Manystudies to date did not examine the effect of CT-derivedimprovements in PD on everyday QOL.

3.4. Description of Interventions. There is a significant lackof clarity, detail, and consistency regarding CT interventionsin PD. No gold-standard CT program has been developedto date; consequently many different CT interventions havebeen investigated. A variety of tasks tend to be used as partof any given CT regimen. In some studies, the interventioncomprised a developed standalone CT program, whereas inothers, the intervention consisted of a multitude of trainingtasks with no overarching theoretical basis for inclusion.Additionally, when including a task as an outcome mea-sure, it should be noted why this task is chosen and whatis the expected outcome (e.g., decrease in reaction time,higher accuracy, and fewer steps taken). Interventions andoutcome measures tend to be chosen due to convenienceand availability, and no true replications have been achieved.There is a dire need for consistency in the literature so thatresults of different studies can be synthesized and comparedin a more meaningful way. The design of future CT studiesshould be more programmatic and theoretically motivated.Ideally, the training regimen should consider known cogni-tive impairments in PD. The specificity of the target trainingregimen should be determined by comparing to a task or setof tasks that train cognitive skills that are not known to be

impaired in PD. Finally, outcomemeasures should be selectedto represent broad cognitive function to evaluate near andfar transfer effects. Following this more reasoned approach,the probability of deriving CT programs that are effective andimpactful seems increased.

A related issue is that some studies individually tailoredCT to each participant, whereas others used the same tasksand levels of difficulty for all participants. Although tailoredtraining in theory might be expected to lead to betteroutcomes, this has not been proven and therefore the time-consuming and costly nature of this approach is not empir-ically justified yet. To fully explore this, a study would needto directly compare a group receiving a tailored intervention(based on deficits in baseline performance) taken from abattery of standardized tasks, with another equivalent groupreceiving a random selection from the same battery of tasks. Ifthe patients that received the individualized training benefitmore from the intervention than the random training group,there will be merit in adjusting a training program for eachparticipant on an individual basis. We offer that until sucha study has been conducted, a middle ground would beselection of tasks and CT programs that take into accountthe cognitive profile of PD patients. That is, CT would betailored not to each individual, but to the PD population asa whole. It appears that recent studies do indeed employ suchan approach; however, there needs to be stronger theoreticalbacking for training task and outcome measure selectionas described in the preceding paragraph. Finally, studiesshould attempt to select tasks and programs that have parallelversions to control for test-retest effects between baseline andposttraining. Again, direct transfer or practice effects are oflittle value given the aim of rehabilitating cognition in PDoutside of the experimental context.

One of the challenges of CT programs is that theytend to be time-consuming and generally require the pres-ence of an administrator to lead the session, especiallyduring group sessions. This might limit the accessibilityand availability of the CT program for patients who liveremotely, mobilize with difficulty, or for other reasons areunable to attend the sessions. Some might simply preferthe convenience of in-home regimens. Computerized CTprograms have been developed with these notions in mindand allow participants to complete the program on a varietyof electronic devices, including home computers, laptops,and even tablets or phones. Computerized CT is potentiallymore convenient for some patients, allowing for more acces-sibility and conferring a feeling of autonomy. On the otherhand, some patients might feel daunted by the technologywhich could be a disadvantage. Studies of computerizedCT programs in healthy older adults and individuals withTBI, schizophrenia, and PD show that these computerizedprograms can be as effective as or even more effective thantraditional pen and paper programs [48, 50, 56, 67, 94, 103].It remains undetermined which approach is more effectivein PD, however, without head-to-head comparisons. This isan important empirical question that needs to be resolvedgiven the expense of one-on-one administration of someprograms. Once again, a direct comparison of the same CTdelivered by an administrator or in a pencil and paper version


versus a computerized format is necessary to address thisquestion. Until then, this remains a confounding factor withsome studies administering computerized CTwhereas othersspend face-to-face time with patients to provide training.

Finally, there has been no investigation of the appropriatelength of an individual training session or the number ofsessions that are needed to produce positive effects. Further,the question of whether promoted changes are enduringremains unanswered. The duration of training courses seemschosen for practical reasons (e.g., the duration of admissionto a rehabilitation center) or at random with virtually nojustification for the parameters that were chosen. Goingforward, investigating dose effects, by varying and comparingeffects of more or less intense and prolonged CT regimens,will be needed.

3.5. Replication andMultiple Comparisons. Despite themanycomparisons conducted in each CT study, there is seldom astatistical adjustment for multiple comparisons. This greatlyweakens our confidence in the results, as performing a largenumber of comparisons will inflate the chance of findingdifferences in pre-post intervention measures or across com-parison groups due to chance alone. This confidence wouldbe increased if on an a priori basis a chosen regimen waspredicted to improve some skills relative to others. Further,greater confidence would be inspired by similar effects of CTon outcome measures that gage the same cognitive domain.In our review, we often found inconsistent effects of CT onmeasures tapping into a common cognitive domain, thoughmore often studies were simply not designed to allow for thisconceptual replication. Most studies of CT train participantson a variety of popular and widely used tasks dividedbroadly into the areas ofWM, attention, reasoning, planning,visuospatial processing, and verbal processing. Some studiesfind improvement across a wide array of tasks and cognitiveskills, whereas others find more modest effects in only asubset of the outcome measures. In some studies, out of themany comparisons, only a few actually reveal any change orbenefit, raising concern for the possibility of a Type 1 error.

4. Conclusion

Patients with PD are at an increased risk of cognitive decline.MCI and dementia are significantly more prevalent in PDrelative to age-matched controls, and pharmacological treat-ments for these symptoms are modest at best. Consequently,developing alternative or adjunctive therapies is vital. To date,the small literature investigating CT in patients with PDsuggests that these interventions are promising, at least inthe immediate or short term for some cognitive domains.However, there remain many unanswered questions. Owingto a lack of consistency across studies in terms of partici-pants included, outcomemeasures and training interventionsselected, and modes of administration with few direct com-parisons across alternative groups, regimens, or methods ofadministration, the efficacy of CT and the expected impactin PD remains largely unknown.

Indeed, it remains unclear if any element(s) in a CTregimen render it effective. The literature is mostly silenton the dosage of intervention required to produce changesand whether any improvements are enduring. There is also avital need to address the generalizability of CT effects withinthe framework of transfer of learning. We highly recom-mend examining transfer of trained skills to practical andfunctional outcomes that are more similar to daily activities.Examination of QOL changes is also of utmost importancebecause ultimately the goal is for cognitive improvementsto lead to an increased functionality and QOL. Lastly, andmost importantly, to advance CT in PD literature, futurestudies need to provide clear and detailed justification andoperationalization of outcome measures and training tasks.Significant changes in outcome measures achieved by train-ing regimens that are rational, theoretically motivated, andhypothesis driven will inspire greatest confidence. Based onthe current literature, it is premature to make recommenda-tions for immediate and practical clinical application of CTin PD. This area of research remains in its initial stage butit is crucial that future investigations incorporate clear andappropriate controls, well-described and justified trainingand outcome tasks, and replications within and betweenstudies.

Abbreviations

ACE: Addenbrooke Cognitive ExaminationADAS-Cog: Alzheimer’s assessment scaleBADS: Behavioral assessment of the

dysexecutive syndromeBDI: Beck Depression InventoryCES-D: Centre for Epidemiological

Studies-Depression ScaleCET: Cognitive estimation testCOWAT: Controlled Oral Word Association

TestCT: Cognitive trainingCVLT: California Verbal Learning TestD-KEFS: Denis-Kaplan Executive Function

Scalef & b: Forward and backwardH&Y: Hoehn and Yahr ScaleMCI: Mild cognitive impairmentMF: Mentally fitMMSE: Mini-Mental State ExaminationMOCA: Montreal cognitive assessmentNV: NeuroVitalisPASAT: Paced auditory serial attention testPD: Parkinson’s diseasePDQ-39: Parkinson’s disease questionnaireRBANS: Repeatable battery for the assessment

of neuropsychological statusROCFT: Rey Osterrieth complex figure testRT: Reaction timeSCOPA-Cog: Scales for outcome of Parkinson’s

diseaseSDMT: Symbol digit modality test


SOPT: Speed of Processing TrainingTIADL: Timed instrumental activities of daily

livingTMT: Trail Making TestTNP: TrainingTOL: Tower of LondonTUG: Timed-Up-and-Go TestUFOV: Useful field of viewUPDRS: Unified Parkinson’s disease rating

scaleWAIS: Weschler adult intelligence scaleWCST: Wisconsin card sorting taskWISC: Wechsler intelligence scale-children’s

versionWM: Working memory.

Competing Interests

The authors declare that there is no conflict of interestsregarding the publication of this paper.

Acknowledgments

This work was supported by a Canada Graduate Scholarshipfrom the Canadian Institutes of Health Research awarded toDaniel Glizer and a CRC Tier 2 in Cognitive Neurosciencesand Neuroimaging CRC Grant no. 950-230372 awarded toPenny A. MacDonald.

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