Inhibitory control is not lateralized in Parkinson's patients

Author’s Accepted Manuscript INHIBITory control is not lateralized IN PARKINSON'S PATIENTS G. Mirabella, M. Fragola, G. Giannini, N. Modugno, Daniel Lakens www.elsevier.com/locate/neuropsychologia

PII: DOI: Reference:

S0028-3932(17)30238-5 http://dx.doi.org/10.1016/j.neuropsychologia.2017.06.025 NSY6406

To appear in: Neuropsychologia Received date: 1 February 2017 Revised date: 16 June 2017 Accepted date: 21 June 2017 Cite this article as: G. Mirabella, M. Fragola, G. Giannini, N. Modugno and Daniel Lakens, INHIBITory control is not lateralized IN PARKINSON'S P A T I E N T S , Neuropsychologia, http://dx.doi.org/10.1016/j.neuropsychologia.2017.06.025 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Asymmetry of Parkinson's Disease and inhibitory control INHIBITORY CONTROL IS NOT LATERALIZED IN PARKINSON’S PATIENTS G. Mirabella1,2, M. Fragola1, G. Giannini1, N. Modugno1, and Daniel Lakens3 1

IRCCS Neuromed, Via Atinense 18, 86077 Pozzilli (IS), Italy

2

Department of Anatomy, Histology, Forensic Medicine & Orthopedics, University of Rome La

Sapienza, Piazzale Aldo Moro 5, 00185 Roma, Italy 3

School of Innovations Sciences, Eindhoven University of Technology, Den Dolech 1, 5600 MB,

Eindhoven, The Netherlands *

Corresponding author. Giovanni Mirabella, La Sapienza University, Piazzale Aldo Moro 5, 00185

Roma, Italy. Tel.: (+39) 06 4991 2312; fax (+39) 06 4991 0860. [email protected]

ABSTRACT Parkinson’s disease (PD) is often characterized by asymmetrical symptoms, which are more prominent on the side of the body contralateral to the most extensively affected brain hemisphere. Therefore, lateralized PD presents an opportunity to examine the effects of asymmetric subcortical dopamine deficiencies on cognitive functioning. As it has been hypothesized that inhibitory control relies upon a right-lateralized pathway, we tested whether left-dominant PD (LPD) patients suffered from a more severe deficit in this key executive function than right-dominant PD patients (RPD). To this end, via a countermanding task, we assessed both proactive and reactive inhibition in 20 LPD and 20 RPD patients, and in 20 age-matched healthy subjects. As expected, we found that PD patients were significantly more impaired in both forms of inhibitory control than healthy subjects. However, there were no differences either in reactive or proactive inhibition between LPD and RPD patients. All in all, these data support the idea that brain regions affected by PD play a fundamental role in subserving inhibitory function, but do not sustain the hypothesis according to which this executive function is predominantly or solely computed by the brain regions of the right hemisphere. 1

Asymmetry of Parkinson's Disease and inhibitory control

Keywords: Reaching arm movements; stop-signal task; Parkinson's Disease; symptoms asymmetry; reactive inhibition; proactive inhibition; Bayesian statistic

1. INTRODUCTION Action selection is at the root of behavioral flexibility and it relies on two key executive functions: (i) the ability to predict future outcomes of actions; and (ii) the ability to suppress preplanned action when they are unlikely to accomplish valuable results (see Mirabella, 2014; Mirabella and Lebedev, 2017). In fact, since the course of the events cannot be fully predicted, the computed value of the selected action might change during the temporal gap between the time when an action is chosen and the moment when motor output is about to be generated. In these instances, a quick change of the motor strategy is required to avoid catastrophic consequences. For instance, the sudden arrival of a car on the road we were about to cross requires us to suppress the pending action to avoid being hit. The neural underpinnings of action countermanding are still debated and controversial. A very influential hypothesis suggests that, in humans, voluntary inhibition of manual movements relies upon a right-lateralized frontal–basal ganglia–thalamic pathway (Aron et al., 2007). This network would comprise the inferior frontal gyrus (IFG), the pre-supplementary motor area (preSMA) and the subthalamic nucleus (STN) of the right hemisphere. Aron and colleagues (2007) suggested that these prefrontal areas would countermand planned movements through the right STN. However, other studies cast doubt on the existence of a right-lateralized network subserving inhibitory control, and instead suggest the two hemispheres cooperate (e.g. see Li et al., 2008; Mirabella et al., 2012; Mirabella et al., 2013). Hence, the aim of the present work was to assess the role of the right hemisphere in action countermanding.

2

Asymmetry of Parkinson's Disease and inhibitory control To this end, we exploited a unique feature of PD, namely the asymmetrical onset of its cardinal symptoms (rigidity, bradykinesia, resting tremor, and postural changes). In fact, in the largest majority of cases, motor symptoms develop unilaterally either on the left or the right side of the body (e.g. Toth et al., 2004; Uitti et al., 2005; see Verreyt et al., 2011 for a review). As the disease progresses, they spread to the other side and become bilateral. Nevertheless, the asymmetry usually persists throughout the entire span of disease progression as motor symptoms remain more severe on the side on which they initially emerged (Djaletti et al., 2006). The unilateral onset of PD has been associated with the asymmetric degeneration of dopaminergic cells in the substantia nigra pars compacta and the subsequent dysfunction of the dorsal striatal region contralateral to the predominantly affected side of the body (e.g. Huang et al. 2001; Marek et al., 1996). As the dorsal striatum projects to cortical motor areas, dopaminergic depletion affects their functioning, causing the emergence of the typical motor symptoms of PD (e.g. see Suppa et al., 2010; Wu et al. 2011). Hence, it follows that lateralized PD patients are an ideal population in which to test the hemispheric specialization of an executive function such as inhibitory control. Even though it is well known that Parkinson’s patients suffer from a specific deficit in inhibitory functions (Gauggel et al. 2004, Obeso 2011), to the best of our knowledge no previous studies have directly examined whether right-dominant PD (RPD) patients exhibit better inhibitory control than left-dominant PD (LPD patients). To assess whether or not this might be the case, we gave a reaching version of the countermanding task (e.g., see Mirabella et al., 2009) to Parkinson’s patients with left- and rightdominant PD. This paradigm probes a subject’s ability to control the production of arm movements by randomly intermixing trials in which speeded responses are required (no-stop trials) with trials in which movements have to be withheld because, unexpectedly, an imperative stop-signal is presented during the planning phase (stop trials). The countermanding task provides measures of both reactive and proactive inhibition. Reactive inhibition refers to the ability of a subject to react to the stop instruction, and it is measured by the stop-signal reaction time (SSRT). This variable cannot be measured, but it can be estimated by using the race model (Logan and Cowan 1984). In 3

Asymmetry of Parkinson's Disease and inhibitory control contrast, proactive inhibition refers to the ability of subjects to shape their response strategy in anticipation of known task demands driven by endogenous signals. In the case of the countermanding task, the endogenous signal is represented by the awareness of the fact that sometimes an imperative stop-signal could have been presented. Proactive control could be assessed by measuring reaction times (i.e. the time to initiate a response, RTs) and movement times (i.e. the time to execute the motor response, MTs) of no-stop trials. Previous research has shown that when a movement is produced in the context of the countermanding task, that is when the subject executes a no-stop trial, its RT is lengthened (e.g. Mirabella et al. 2006; Verbruggen and Logan 2009) and its MT is shortened compared to situations in which the same movement has to be performed in the context of a simple RT-task (go-only trial). This phenomenon has been called the ‘context effect’, and it represents an optimization of costs and benefits, because shorter RTs are compensated by longer MTs and vice versa (Mirabella et al. 2008, Mirabella et al. 2013). It is plausible that the awareness of the presence of a stop signal induces a lengthening of RTs on no-stop trials, which allows for a better coding of the target parameters. Conversely, the shorter RTs of go-only trials do not allow for a full specification of the movement plan which has to be completed during the movement phase. In other words, the length of MTs could reflect the different need for on-line planning during go-only and no-stop trials (Mirabella et al., 2008). We hypothesized that if the inhibitory function is predominantly or solely computed by the brain regions of the right hemisphere then LPD patients should be significantly more impaired than RPD patients as far as both reactive and proactive control are concerned.

2. MATERIALS AND METHODS 2.1 Subjects and clinical assessment From the outpatients of the Parkinson’s unit of the ’Istituto di ricovero e cura a carattere scientifico’ (IRCCS) Neuromed Hospital we selected 59 patients who were affected by idiopathic PD. All patients were under stable treatment with the administration of L-dopa and dopamine 4

Asymmetry of Parkinson's Disease and inhibitory control agonists. Patients did not present severe sensory deficits or any other neurological disease besides PD, as assessed by a standard neurological examination, and they were all right-handed as assessed by the Edinburgh handedness inventory. We excluded patients with overt signs of dementia (minimental state examination, MMSE >24) and/or severe tremor. Patients’ motor symptoms were rated by a neurologist (N.M.) using the Unified Parkinson’s Disease Rating Scale part 3 (UPDRS3). Severity of left- and right-sided symptoms were calculated as the sum of the motor examination scores of UPDRS3 evaluating the Parkinsonian symptoms on the left and right extremities (e.g. see Huber et al. 1992). The prevalence of left- and right-sided symptoms were expressed as an asymmetry index (AI), applying the following formula: AI= (Rscore - Lscore) /(Rscore+ Lscore) where Rscore and Lscore represent the severity of motor symptoms of the respective sides measured by the sum of the UPDRS motor scores. Therefore, negative AI values represent more severe motor symptoms on the left side whereas positive values indicate more severe motor symptoms on the right side. The dominant side of the onset of PD was classified as either right or left based on the congruency between (i) medical reports about onset disease, (ii) the sign of the AI and (iii) the magnitude of the absolute value of AI, which had to be 0.3. Thus, for instance, a patient was classified as RPD when his medical record indicated a right onset and an AI value larger than 0.3. To ensure a homogeneous population we included only patients whose Hoehn and Yahr scores (indicating the stage of PD disease) ranged between 2 and 3. We ended up having 20 right- and 20 left-onset patients. Importantly, patients were matched for the severity of the disease. In fact, neither the L-dopa equivalents [t(38)=-1.5; p=0.14], nor the Hoehn & Yahr scores [t-test t(38)=-0.58, p=0.57], nor the UPDRS 3 [t-test t(38)=-1.61; p=0.11], nor the years since diagnosis [t-test t(38)=0.06, p=0.95], nor the absolute values of the AI [t(38)=-0.63; p=0.57], nor the score of the MMSE [t(38)=-0.4; p=0.69] were significantly different (see Tables 1 and 2 for a summary of all clinical data). As it has been shown that, at least when the countermanding task was employed, 5

Asymmetry of Parkinson's Disease and inhibitory control dopaminergic medications do not influence inhibitory control in PD (e.g., Claassen et al., 2015; George et al., 2013; Obeso et al., 2011), patients were allowed to take their habitual doses of Levodopa medication (levodopa, dopamine agonists, anticholinergic drugs, or a combination of levodopa and an anticholinergic drug) at the time of testing. At this time just one left-onset patient exhibited some of the typical symptoms of impulse control disorder (Voon et al., 2006), but since his behavioral performance was not different from the average performance by the other patients in the sample he was included in the data analysis. Finally, to have a baseline measure of inhibitory control we compared both reactive and proactive parameters in 20 right-handed healthy subjects (10 females, 10 males; age range 52-69, mean ± SD, 61±5.7 years; years of education 11.15±3.7) with normal or corrected-to-normal vision, without history of neurological diseases. The average age of control subjects and their education were not statistically significant from that of the two groups of PD patients (one-way ANOVA on age, F[2,57]= 1.02; p=0.37; one-way ANOVA on education, F[2,57]= 0.01; p=0.91).

Table 1. Clinical data of PD patients with right-dominant disease participating in the experiment. For each patient sex, age, years since diagnosis, L-dopa equivalents/kg, Hoehn & Yahr scores (indicating the stage of PD disease) after the assumption of the habitual dose of Levodopa medication (ON therapy), UPDRS-3 in ON therapy, the asymmetry index, the MMSE, and the years of education (see text for further details) are given.

1 2 3 4 5 6 7 8 9

Sex

Age

Years since diagnosis

L-DOPA eq/Kg

Hoehn& Yahr

UPDRS 3 (ON therapy)

Asymmetry index

MMSE

Years of education

M M F M F M M F M

66 71 61 70 61 72 45 56 63

8 7 7 7 8 12 8 6 12

580 453 680 750 605 1263 830 410 1300

2.5 2 2 2 2 3 2 2 3

22 12 20 19.5 12 16 19 18 16

0.33 0.60 0.69 0.32 0.38 0.38 0.75 0.48 0.46

30 28 27 30 25 30 29 25 29

18 13 13 12 8 13 12 5 13

6

Asymmetry of Parkinson's Disease and inhibitory control 10 11 12 13 14 15 16 17 18 19 20

M F M M F M M F M F M

52 71 74 63 58 61 47 58 55 50 74

9 5 5 5 12 4 7 12 7 10 6

680 350 685 300 825 300 675 750 500 450 400

2 2 2.5 2 3 2 2.5 2 2 2 2

17 11 16 10 26 12 21 20 16 20 18

0.71 0.33 0.41 0.60 0.43 0.71 0.41 0.36 0.57 0.69 0.62

26 25 29 26 27 30 30 30 30 29 28

8 8 13 8 13 18 12 13 8 13 8

Mean

61.40

7.85

639.30

2.23

17.8

0.51

28.15

11.45

(SD)

8.89

2.56

275.87

0.38

4014

0.15

1.9

3.39

Table 2. Clinical data of PD patients with left-dominant disease participating in the experiment. For each patient sex, age, years since diagnosis, L-dopa equivalents/kg, Hoehn & Yahr scores (indicating the stage of PD disease) after the assumption of the habitual dose of Levodopa medication (ON therapy), UPDRS-3 in ON therapy, the asymmetry index, the MMSE, and the years of education (see text for further details) are given.

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 Mean

Sex

Age

F F M F F M F M M M M M M F M F M F F M

65 59 70 65 70 68 69 61 71 64 64 65 53 62 70 55 62 61 58 65 63.8 5

Years since diagnosis

L-DOPA eq/Kg

Hoehn& Yahr

UPDRS 3 (ON therapy)

Asymmetry index

MMSE

Years of education

9 6 10 7 11 9 10 18 5 18 4 7 10 6 14 9 7 12 6 10

700 513 550 1075 695 575 1368 1008 500 730 363 400 600 400 1166 450 400 760 300 350

2.5 2 2 3 2 2 3 3 2 3 2 2 2.5 2 3 2 2 2 2 2

22 21.5 16 25 18 21 18 20 22 20 10 10 19 11 19.5 18 28 21 25 22

-0.70 -0.38 -0.31 -0.67 -0.31 -0.34 -0.60 -0.43 -0.81 -0.32 -0.43 -0.51 -0.30 -0.34 -0.42 -0.43 -0.83 -0.74 -0.33 -0.37

26 25 30 30 25 26 26 27 25 29 30 30 28 30 25 30 30 29 29 28

8 10 18 13 8 13 8 12 8 18 18 13 8 13 13 13 13 5 10 11

9.40

645.15

2.3

19.3

-0.48

27.9

11.65

7

Asymmetry of Parkinson's Disease and inhibitory control 5.08

(SD)

3.84

298.67

0.44

4.77

0.04

2.05

3.63

All participants gave their informed consent and were free to withdraw from the study at any time. The general procedures were approved by the Institutional Ethics Committee of IRCCS Neuromed Hospital and were performed in accordance with the ethical standards laid down in the Declaration of Helsinki of 1964.

2.2 Experimental apparatus Subjects were seated in a darkened and silent room, with their head restrained by a chin rest so that their eyes were kept 40 cm away from a 17-inch PC monitor (CRT non-interlaced, refresh rate 75 Hz, 640  480 resolution, 32-bit color depth) on which visual stimuli, consisting of red circles (2.43 cd/m2) with a diameter of 4.0 dva (2.6 cm) against a dark background of uniform luminance (<0.01cd/m2), were presented. The PC monitor was equipped with a touch screen (MicroTouch; sampling rate 200 Hz) for touch-position monitoring. CORTEX, a free, noncommercial software package (http://www.nimh.nih.gov/labs-at-nimh/research-areas/clinics-andlabs/ln/shn/software-projects.shtml), was used to control stimulus presentation and to collect behavioral responses. The temporal arrangements of stimulus presentation were synchronized with the monitor update rate.

2.3 Task Parkinson’s patients performed a reaching version of the countermanding task (e.g. see Mirabella et al. 2009). It consisted of a random mix of 67% no-stop trials and 33% stop trials (Fig. 1A). In no-stop trials participants had to reach and hold a central stimulus until it disappeared and, at the same time, a peripheral target appeared (go-signal). Upon target appearance participants had to perform a speeded reaching movement toward the target. On the other hand, in stop trials 8

Asymmetry of Parkinson's Disease and inhibitory control participants were instructed to suppress their movements when a stop signal (indicated by the reappearance of the central stimulus) was presented at a variable delay (stop-signal delay; SSD) after the presentation of the go-signal. We defined stop-success trials as those trials in which subjects successfully withheld the movement. We define stop-failure trials as those in which they moved the arm despite the stop signal. Auditory feedback was given for correct responses. The SSD represents the critical dependent variable in this paradigm because stopping becomes increasingly difficult with the lengthening of the SSD. During the course of the task, the length of the SSDs was changed using an adaptive staircase procedure (Levitt 1971; Osman et al. 1986) with a 50% performance criterion. The SSD duration varied from one stop trial to the next according to the behavioral performance of the subjects: If participants succeeded in withholding the response then the SSD increased by three refresh rates (or 39.9 ms); If they failed, SSD decreased by the same amount of time. The staircase started from an SSD of 119.7 ms (nine refresh rates), which pilot experiments showed to be an appropriate delay for quickly obtaining the 50% success rate in stop trials.

9

Asymmetry of Parkinson's Disease and inhibitory control

Figure 1 (A) Temporal sequence of the visual displays for go-only, no-stop and stop trials. All trials began with the appearance of a central stimulus. The subject had to reach and hold it with the index of the right (dominant) arm for a variable period of 500-800 ms (some subjects performed the task both with the right and with the left, non-dominant, arm). In the go-only task and in the no-stop trials of the countermanding task the central stimulus disappeared and, simultaneously, a target appeared 13.5 cm or 18.6 dva to the right (or to the left, when subjects used the left non-dominant arm), acting as a go-signal. Subjects were instructed to perform a speeded reaching movement 10

Asymmetry of Parkinson's Disease and inhibitory control toward the peripheral target and to hold it for a variable period of 300-400 ms. Randomly, in the 33% of trials of the countermanding task (stop trials) the central stimulus (stop-signal) reappeared at a variable delay after the go signal (stop signal delay, SSD), indicating that the subject should cancel the pending movement. In these stop trials, if subjects countermanded the planned movement keeping the arm on the central stimulus for a period of 400-600 ms, the trial was scored as a stopsuccess trial. Otherwise, if subjects executed the reaching movement the trial was scored as a stopfailure trial (not shown). The dotted circle (which was not visible to the subjects) indicates the size of the tolerance window for the touches (3.5 cm or 5 dva of diameter). (B) Estimate of the SSRT with the integration method. This method is grounded on the independence assumption of the race model, which implies that the distribution of reaction times (RTs) on stop trials (whether a response is cancelled or not) is the same as the distribution of RTs of no-stop trials. The SSRT is obtained by subtracting the starting time of the stop process, given by the mean SSD, from its finishing time, which is calculated by integrating the no-stop trials RT distribution from the onset of the go-signal until the integral equals the corresponding observed proportion of stop-failure trials [p(failure)].

To discourage participants from slowing down responses as much as possible, we used a common strategy to make the inhibition on stop trials easier for participants: We verbally informed participants about the tracking procedure, and informed them that the probability of stopping would be approximately 50%, irrespective of whether they were postponing their response or not. In addition, we set an upper RT limit for no-stop trials: Whenever the RTs were >800 ms, no-stop trials were signaled as errors to the subjects and aborted. However, those trials were kept for the final analyses. Patients completed either three (n=31) or four blocks (n=9) of 120 trials, Therefore, each subject performed either 360 or 480 trials using the right hand. Resting periods were allowed between blocks whenever requested. In order to measure simple RTs of reaching arm movements, all participants also completed one block of 80 go-only trials (except four: two performed 120 trials and the other two performed 140 trials)1, always using the right hand. These trials were the same as no-stop trials but subjects were aware of the fact that in this task stop-signals could never be

1

The different numbers of trials were due to technical mistakes during data collection 11

Asymmetry of Parkinson's Disease and inhibitory control presented. Participants always received the go-only task before the countermanding task. In addition, 30 of the 40 patients (15 LPD and 15 RPD) which performed the countermanding task and the go-only task with the right arm also performed them using the left arm, always completing three blocks of 120 trials. Importantly, in this version of the task the peripheral target appeared on the horizontal plane at 8 cm to the left of the central stimulus. Sessions in which patients had to use the right arm were counterbalanced with sessions in which they had to employ the left arm. Before starting the task, ~50 practice trials were given to familiarize participants with the apparatus. Agematched healthy subjects performed a single countermanding block consisting of 480 trials (except three: One performed 240 trials and the other two performed 360 trials)1 and a block of 120 go-only trials (except nine: four performed 80 trials and the other five performed 140 trials) 1.

2.4 Behavioral data analysis RTs, MTs and SSRTs were taken as behavioral parameters. RTs were determined as the time difference between the time of the occurrence of the go-signal and the movement onset. MTs were determined as the difference between the time of movement onset and the time at which subjects touched the peripheral target. For each participant, those trials in which the RTs were lower than 80 ms were eliminated, as they were considered premature responses. In addition, trials with RTs longer than the mean plus three SDs and shorter than the mean minus three SDs were excluded from the analysis. In total 3.1% of the data were discarded. The SSRT was estimated applying the so-called integration method, as it has been shown to produce unbiased SSRT estimates under conditions in which proactive slowing may occur (Verbruggen et al. 2012). The integration method is grounded in the independence assumption of the race model (Logan and Cowan 1984), which implies that the distribution of RTs on stop trials is the same as the distribution of RTs of no-stop trials. Thus, the SSRT is obtained by subtracting the starting time of the stop process from its finishing time (see Fig. 1B; Logan and Cowan 1984; Logan 1994; Band et al. 2003). The starting time of the stop process is given by the mean SSD while the finishing time is calculated by 12

Asymmetry of Parkinson's Disease and inhibitory control integrating the no-stop trials RT distribution from the onset of the go-signal until the integral equals the corresponding observed proportion of stop-failure trials [p(failure)]. For instance, if the responses are not stopped on 51% of the stop trials, the finishing time of the stop processes is on average equal to the 51st percentile of the RT distribution. The value of the mean SSD was computed using the mid-run estimates method (see Levitt, 1971), as follows. In each session, the sequence of SSDs displayed either consists of increasing values or consists of decreasing values according to the performance of the subject. The mean SSD was estimated by averaging the SSDs from the midpoints of every second ramp. Research has shown that the SSRT obtained using a staircase algorithm is very reliable, as it is derived from the central part of the RT distribution of nostop trials and hence is relatively insensitive to violations of the assumptions of the race model (Band et al., 2003; Logan et al., 1997).

2. 5 Statistics Analyses of variance (ANOVAs) were employed for assessing changes in the values of RTs, MTs and SSRTs across the experimental conditions. Mauchley’s test was used to evaluate the sphericity assumption and, when appropriate, correction of the degrees of freedom were made according to the Greenhouse–Geisser procedure. Bonferroni corrections were applied for all multiple comparisons, and across all ANOVAs by dividing the alpha value (0.05) by the total number of tests performed. The two-sample-Kolmogorov–Smirnov test was used for contrasting cumulative distributions of RTs obtained in no-stop, stop-failure and go-only trials, and of MTs obtained in no-stop and go-only trials. In order to provide a measure of the effect-size, we computed partial omega-squared (ωp2) for each ANOVA with values of 0.139, 0.058, and 0.01 indicating large, medium, and small effects, respectively, and Cohen's d as the effect size for t-tests with values of 0.2, 0.5, and 0.8 indicating large, medium, and small effects (see Cohen 1988; Lakens 2013). The ωp2 and Cohen's d are reported because they allow the comparison between the effect of a given manipulation regardless 13

Asymmetry of Parkinson's Disease and inhibitory control of other factors that have been manipulated. Confidence intervals are computed around mean differences for simple effects and around omega-squared for F-tests. When we believe statistically supporting the absence of a relatively large effect was theoretically important, non-significant tests (p > 0.05) are followed by equivalence tests and Bayesian hypothesis testing based on the Bayes Factor. Although it is never statistically possible to conclusively show an effect is completely absent, equivalence tests can be used to examine whether the observed effect is statistically smaller than a specified equivalence bound (Schuirmann, 1987). In the current study, we set equivalence bounds at effects we had 80% power to reject, given our sample size and an alpha level of 0.05 (Lakens, 2017). In addition, a default Bayesian t-test was performed (Rouder, Speckman, Sun, Morey, & Iverson, 2009), where Bayes factors smaller than 0.1 provide strong, and Bayes factors smaller than 0.33 provide moderate support for a null model compared to the alternative model. a default Bayesian t-test was performed (Rouder, Speckman, Sun, Morey, & Iverson, 2009), where Bayes factors smaller than 0.1 provide strong, and Bayes factors smaller than 0.33 provide moderate support for the null hypothesis. All data will be freely available to anyone who will request them from the ethics committee of the IRCCS Neuromed hospital, and summary data and the analysis files are available from https://osf.io/g8z3w/.

3. RESULTS 3.1 Reactive inhibition: differences of SSRT in Parkinson’s patients versus healthy controls First of all, we checked whether the staircase algorithm worked equally well in all experimental conditions. To this end, we compared the average proportion of stop-failure trials [P(failure)] using a one-way ANOVA (levels: RPD, LPD and Controls). We found that there were no significant differences in the P(failure) values across groups, F(2,57)=2.65, p=0.08, ωp2=0.05, CI [-0.04; 0.19], suggesting that the staircase algorithm produced similar behavioral outcomes (see also Table 3).

14

Asymmetry of Parkinson's Disease and inhibitory control Table 3. Summary of behavioral values for right- and left-dominant Parkinson’s disease (RPD and LPD, respectively) patients and for age-matched controls during the countermanding and the go-only. Task performance accuracy is defined as the ratio between the number of trials correctly executed and the total number of trials delivered, given by the sum of trials correctly executed, trials in which participants missed the target, trials in participants remained still on the central stimulus for more than two seconds, and trials in which they did not hold the central stimulus or the target for the requested amount of time. In all cases the average value across the samples (±SD) is reported. RPD

LPD

Age- Matched Controls

Mean SSD

254.2± 124.3

218.5± 107.8

284.1± 116.6

P(failure)

0.51± 0.05

0.52± 0.05

0.49± 0.04

SSRT

254.2± 37.2

262.1± 42.6

224.3± 31.5

RT no-stop trials

500.3± 107.7

486.9± 98.6

523.6± 104.4

RT stop-failure trials

385.1± 77.9

383.6± 81.2

413.8± 91.7

RT go only trials

292.7± 46.4

288.9± 32.3

276.4± 42.9

MT no-stop trials

607.9± 200.1

572.3± 223.1

338.7± 89.2

MT go only trials

590.8± 154.8

576.2± 221.7

386.1± 116.2

0.91± 0.08

0.90± 0.08

0.92± 0.06

0.90± 0.08

0.89± 0.07

0.90± 0.08

Task Performance accuracy go only trials Task Performance accuracy no-stop trials

Second, we checked whether the basic assumption of the race model, i.e. the context independence between the go process (the process initiated by the go-signal leading to the execution of the movement) and the stop process (the process initiated by the stop-signal leading to the inhibition of the movement), was satisfied (Boucher et al., 2007; Logan and Cowan 1984). We tested this assumption by comparing the RTs of no-stop trials and the stop-failure trials. In both these trials movements are produced, but stop-failure trials were initiated because the go process 15

Asymmetry of Parkinson's Disease and inhibitory control finished before the stop process. Thus, if the distribution of RTs on stop trials is the same as the distribution of RTs of no-stop trials, as the model assumes, it follows that the responses that escape inhibition should be those corresponding to reaching movements that had RTs shorter than the SSD plus the estimated SSRT. Therefore, the mean RT of stop-failure trials should be shorter than the mean RT of no-stop trials (Logan and Cowan 1984). A two-way mixed design ANOVA [betweensubjects factor: Group (RPD, LPD, Controls); within-repeated-subject factor: Trial type (RT nostop trials, RT stop-failure trials)] showed that stop-failure trials (M = 394, SD = 84) were faster than no-stop trials (M = 503, SD = 103), F[1,57]=369.7, p<0.0001, ωp2=0.86, CI [0.79; 0.90]. No other significant effects were found. Furthermore, for all sixty subjects we found that the distributions of the RTs of stop-failure trials were different from those of no-stop trials (twosample-Kolmogorov–Smirnov test, all p<0.05), because the former trials were faster than the latter. Overall, these results indicate that the collected data allowed us to compute a reliable estimate of the SSRT. In a next step, we compared the SSRTs across the three groups of subjects (see Fig. 2 and Table 3). A one-way ANOVA (levels: RPD, LPD and Controls) showed a main effect, (see Table 4). Post hoc tests revealed that controls had significantly better reactive inhibitory control than either RPD ( or LPD patients. In contrast, the SSRT of RPD and LPD patients did not differ. Table 4. Results of the statistical analysis (one-way ANOVA) of SSRTs across RPD, LPD and controls. Post hoc tests had an adjusted alpha level equal to 0.05/3=0.016. Value of parameters

p values

Effect Size

95% CI

Main effect: SSRT

F(2,57)=5.68

0.006

ωp2 = 0.13

[-0.02:0.29]

Post hoc test: RPD vs. Controls Post hoc test: LPD vs. Controls Post hoc test: RPD vs. LPD

t(38) = 2.74 t(38)=3.19 t(38) = 0.63,

0.009 0.003 0.54

d = 0.64 d = 0.75 d = 0.13

[8; 52] [14; 62] [-18; 34]

Mdiff

29.85 ms 38 ms 8 ms

Because the lack of a significant effect does not imply the lack of an effect, we tested for equivalence using the two one-sided tests procedure. Based on a power analysis for equivalence 16

Asymmetry of Parkinson's Disease and inhibitory control tests, our sample size of 20 participants in each between subject condition provided 80% power with an alpha level of 0.05 to statistically reject effect sizes larger than d = 0.9. Thus, we tested whether the difference between RPD and LPD patients was statistically smaller than an effect of d = 0.9, which it was, p = 0.016. A default Bayesian t-test with an r-scale of 0.707 further supported the idea that the data provided moderate relative evidence for the null model, BF10 = 0.362. The effect size estimate, together with the equivalence test and Bayesian t-test support the conclusion that inhibitory control of RPD and LPD patients do not show large differences.

Figure 2 SSRT in age-matched controls (n=20), right-dominant PD (RPD, n=20) and left-dominant PD (LPD) patients (n=20). In the box plots, the boundary of the box closest to zero indicates the first quartile, a red line within the box marks the median, and the boundary of the box farthest from zero indicates the third quartile. Whiskers indicate values 1.5 times the inter-quartile range below the first quartile and above the third quartile. Outliers are represented by crosses. Star indicates a significant difference.

3.2 Proactive control and the ‘context effect’

2

Note that Bayes Factors represent continuous evidence, and should not be interpreted as dichotomous threshold, such that a Bayes Factor of 0.36 indicates only slightly less moderate evidence than a Bayes Factor of 0.33 17

Asymmetry of Parkinson's Disease and inhibitory control In order to assess whether the context effect is affected by PD, we took three different approaches. Firstly, we combined data from single participants to create cumulative distributions of RTs and of MTs of go-only versus no-stop trials at the population level (Figure 3A, B and C). As expected, the two experimental paradigms had opposite effects on RTs and MTs of healthy controls (Mirabella et al. 2008). In fact, they exhibited longer RTs and shorter MTs in no-stop trials than in go-only trials (Figure 3A). In contrast to controls, RPD and LPD patients showed a qualitatively different pattern (Fig 3B). While faster MTs (<600 ms) tended to be faster in no-stop trials compared to go-only trials, slower MTs (>600 ms) tended to be even slower. Secondly, we compared the means of RTs and MTs (Fig. 3D and 3E, respectively). A two-way mixed design ANOVA [between-subjects factor: Group (RPD, LPD and Controls); within-subjects factor: Trial type (RT no-stop trials, RT go-only trials)] showed only that subjects always had shorter RTs when executing go-only trials (M = 286, SD = 41) than when executing no-stop trials (M = 503, SD = 103, see Table 5). . The same analysis was performed on MTs showed only a main effect of group due to the fact that controls had faster MTs (see Table 3) than both RPD patients ) and LPD patients, while the length of MTs of RPD and LPD patients did not statistically differ (post hoc:). Overall the speed of MTs of go-only trials was not statistically different from that of no-stop trials. Table 5. Results of the statistical analyses (two-way mixed design ANOVAs) of RTs and MTs across RPD, LPD and controls. Post hoc tests had an adjusted alpha level equal to 0.05/3=0.016.

Main effect RT: Trial type (RT no-stop trials, RT go-only trials) Main effect RT: Group (RPD, LPD and Controls) Main effect Interaction RT: Trial type * Group Main effect MT: Trial type (RT no-stop trials, RT go-only trials)

Value of parameters

p values

Effect Size

95% CI

F(1,57) = 261.86

<0.0001

ωp2 = 0.82

[0.72; 0.87]

F(2,57) = 0.22

0.80

ωp2=-0.03

[-0.04; 0.04]

F(2,57) = 1.25

0.29

ωp2=0.01

[-0.04; 0.13]

F(1,57)= 0.58

0.45

ωp2=0.00

[-0.02; 0.10]

Mdiff

18

Asymmetry of Parkinson's Disease and inhibitory control Main effect MT: Group (RPD, LPD and Controls) Main effect Interaction MT: Trial type * Group Post hoc tests of Group (MT): RPD vs. Controls Post hoc tests of Group (MT): LPD vs. Controls Post hoc tests of Group (MT): RPD vs. LPD

F(2,57)=12.36

< 0.0001

ωp2=0.27

[0.07; 0.43]

F(2,57)= 1.62

0.21

ωp2=0.02,

[-0.04; 0.15]

t(38) = 5.42

< 0.0001

d = 1.21

[148; 325]

237 ms

t(38) = 4.10

< 0.001

d = 0.92

[107; 316]

212 ms

t(38) = 0.42

0.68

d = 0.09

[-97; 147]

25 ms

19

Asymmetry of Parkinson's Disease and inhibitory control

Figure 3 Context effect in age-matched controls, Parkinson’s patients with right-dominant disease (RPD) and Parkinson’s patients with left-dominant disease (LPD). (A) Cumulative distributions of 20

Asymmetry of Parkinson's Disease and inhibitory control RTs (solid lines) and MTs (dotted lines) of healthy subjects (n=20) for go-only trials (grey) and nostop trials (black). These cumulative distributions were obtained by collapsing together the cumulative distributions of RTs and MTs of no-stop and of go-only trials of single subjects. Twosample-Kolmogorov–Smirnov test: i) RTs, D=0.67, p < 0.0001; ii) MTs, D=0.19, p < 0.0001.. (B) Cumulative distributions of RTs and MTs of RPD patients (n=20) and (C) LPD patients (n=20) for go-only and no-stop trials. Same conventions as panel A. RPD patients, two-sample-Kolmogorov– Smirnov test: i) RTs, D=0.54, p < 0.0001; ii) MTs, D=0.06, p = 0.0002; and 3C, LPD patients twosample-Kolmogorov–Smirnov test: i) RTs, D=0.59, p < 0.0001; ii) MTs, D=0.07, p < 0.0001. (D) Box plot of RTs, and (E) of MTs of no-stop and go-only trials in age-matched controls, RPD patients and LPD patients. All conventions as in Figure 2. (F) Percentage of age-matched controls, RPD patients and LPD patients showing either (i) simultaneously a significant increase in RTs and a significant decrease in MTs in no-stop trials with respect to go-only trials (‘context’), (ii) a significant lengthening of both RTs and MTs in no-stop trials with respect to go-only trials (‘reversed context’) or (iii) a significant increase in reaction times (RTs) in no-stop trials with respect to go-only trials, but MTs of no-stop trials were not different from those of go-only trials (‘no context’).

In order to take into account, the contribution of each subject we considered whether the individual cumulative distributions of RTs and MTs were significantly different, as assessed via the two-sample-Kolmogorov–Smirnov test. Thus, we computed the percentage of participants who exhibited a ‘context effect’, i.e. a simultaneous decrease in RTs and increase in MTs in no-stop trials with respect to go-only trials (Fig. 3F). We found that 70% controls performed in line with the expected context effect, 20% had no context effect (i.e. MTs of no-stop trials were not different from those of go-only trials) and 10% had a reversed context effect (i.e. MTs of no-stop trials were longer than those of go-only trials). In RPD patients the percentage of subjects with a context effect dropped to 50% (10% had no context effect and 40% had a reversed context effect) a value significantly different from that of controls [p=0.004]. In LPD patients, the percentage of subjects with a context effect was 55% (15% had no context effect and 30% had a reversed context effect), again a value significantly different from that of controls [p=0.028]. 21

Asymmetry of Parkinson's Disease and inhibitory control Finally, as it has been shown that faster responses tend to produce more errors, the so-called speed–accuracy tradeoff phenomenon (Fitts, 1954), we checked whether the task performance accuracy during no-stop trials differed from that of go-only trials (see Table 3). We employed a two-way mixed design ANOVA [between-subjects factor: Group (RPD, LPD and Controls); within-subjects factor: Trial type (% correct no-stop trials, % correct go-only trials)] to compare the percentage of correct responses in those trials across the two types of trials. We did not find any significant effect. We performed an equivalence test for the difference of trial type. Power analysis indicated we had 80% power to observe equivalence for a Cohen’s dz of 0.38 with 60 participants in a within-subject t-test, and the equivalence test indicated the difference between trials was statistically smaller than dz = 0.38, p = 0.01. The default Bayesian paired t-test indicated the data provided moderately strong relative support for a null effect compared to the alternative model, BF10=0.18. We therefore conclude that accuracies were very similar across experimental conditions. All in all, these results suggest that PD affects this context-dependent form of proactive strategy. However, there are no differences between RPD and LPD patients.

3.3 Does the arm employed in the task affect inhibitory control? It is commonly assumed that unilateral limb movements are controlled by motor regions of the contralateral hemisphere. However, there is a growing amount of data showing that motor cortices are activated bilaterally during production of unilateral movements (Kawashima et al. 1998; Rao et al. 1993; Schaefer et al. 2008). Such bilateral activation of the motor cortices is more frequently observed when a simple motor task is performed with the non-dominant hand (Kawashima et al. 1998). The neurophysiological significance of ipsilateral activation remains largely unclear. One theory suggests that ipsilateral activation could reflect an inhibitory influence on the motor cortex ipsilateral to the active hand, exerted by the contralateral hemisphere through callosal fibers (Dennis 1978; Kobayashi et al. 2003).

22

Asymmetry of Parkinson's Disease and inhibitory control Even though limb movement control is not lateralized, if inhibitory control is right lateralized it can be predicted that i) LPD patients should have a better inhibitory control over both right and left arm movements than RPD patients; ii) LPD patients should also exhibit a better inhibitory control over left than over right arm movements. To this end, we asked 15 RPD and 15 LPD patients to execute the countermanding and the go-only task using both the left and the right arms. The results of this are illustrated in Figure 4 and Table 6. To compare the SSRT of RDP and LPD patients we applied a two-way mixed design ANOVA [between-subjects factor: Group (RPD, LPD); within-subjects factor: Arm (Left arm, Right arm)]. This analysis did not reveal any statistical effect (main effect of Group: F(1,28)=0.15, p=0.70, ωp2=-0.03, 95% CI [-0.04; 0.12]; main effect of Arm: F(1,28)=0.27, p=0.61, ωp2=-0.02, 95% CI [-0.04; 0.14]; interaction: F(1,28)=0.01, p=0.90, ωp2=-0.03, 95% CI [-0.04; 0.05]. The equivalence test indicated the observed effect of Group was statistically smaller than d = 0.9, with p = 0.024, and the default Bayesian t-test showed the data were somewhat more likely under the null model, BF10 = 0.37, providing evidence for the lack of a difference in reactive inhibitory control between LPD and RPD patients (Fig. 4A). Table 6. Summary of behavioral values for right- and left-dominant Parkinson’s disease (RPD and LPD, respectively) patients during the countermanding and the go-only sessions performed with the right or with the left arm. In all cases the average value across the samples (±SD) is reported. RPD Right Arm

RDP Left Arm

LPD Right Arm

LPD Left Arm

Mean SSD

220.8±128.7

209.5±99.5

215.2±112

234.2±100.2

P(failure)

0.52±0.05

0.50±0.04

0.52±0.05

0.50±0.04

SSRT

260.3±40.5

256.7±44.7

265.9±41.1

259.9±32.2

RT no-stop trials

494.5±106.5

485±93.3

488.3±95.4

506±107.4

RT stop-failure trials

381.4±73.9

390.2±68.1

389.6±75.5

414.2±89.8

RT go only trials

302.3±48.2

303.6±57.5

296.4±31.4

307.8±64.3

23

Asymmetry of Parkinson's Disease and inhibitory control

MT no-stop trials

670.2±167

678.8±222.2

633.4±209.1

651.7±219.7

MT go only trials

627.2±125.1

667.9±133.2

622.5±222

640.5±179.7

24

Asymmetry of Parkinson's Disease and inhibitory control

Figure 4 Effect of the usage of dominant (right) versus non-dominant (left) arm on the behavioral outcomes of the countermanding task in Parkinson’s patients with right-dominant disease (RPD) and Parkinson’s patients with left-dominant disease (LPD). (A) Box plot of SSRT of RPD patients 25

Asymmetry of Parkinson's Disease and inhibitory control (n=15) and LPD patients (n=15) who performed the experimental tasks with both arms. All conventions as in Figure 2. (B) Percentages of RPD patients and LPD patients showing either (i) simultaneously a significant increase in RTs and a significant decrease in MTs in no-stop trials with respect to go-only-trials (‘context’), (ii) a significant lengthening of both RTs and MTs in no-stop trials with respect to go-only trials (‘reversed context’) or (iii) a significant increase in reaction times (RTs) in no-stop trials with respect to go-only trials, but MTs of no-stop trials were not different from those of go-only trials (‘no context’). (C) Box plots of RTs, and (D) of MTs of nostop and go-only trials in RPD patients (n=15) and LPD patients (n=15) who performed the experimental tasks with both arms. All conventions as in Figure 2.

We assessed the extent to which the context effect was affected by the arm employed, computing the percentage of participants who exhibited differences of distributions of RTs and MTs for each subject (assessed via the two-sample-Kolmogorov–Smirnov test). We found that the percentage of RPD patients showing a context effect was not significantly different to that that of LPD patients, both when the right arm was employed (33.3% versus 40%, [p=0.3]) and when the left arm was used (40% versus 46.7%, [p=0.32], see Fig. 4B). Finally, we also compared the averages of RTs and MTs (Fig 4C and 4D, respectively) by means of three-way repeated-measures-ANOVAs [between-subjects factor: Group (RPD, LPD); within-subjects factors (Table 7): Arm (Right and Left) and Trial type (RT no-stop trials, RT goonly trials)]. Only the factor trial type was significant, indicating that RTs of go-only trials (M=304, SD=50) were shorter than those recorded during no-stop trials (M=499, SD=99). The same analysis run on MTs did not show any significant effects. Table 7. Results of the statistical analysis (three-way repeated-measures-ANOVAs) of RTs and MTs across RPD, LPD. Post hoc tests had an adjusted alpha level equal to 0.05/3=0.016.

Main effect RT: Trial type (RT no-stop trials, RT go-only trials) Main effect RT: Group (RPD, LPD) Main effect RT:

Value of parameters

p values

Effect Size

95% CI

F(1,28)=108.70

< 0.0001

ωp2=0.78

[0.61; 0.86]

F(1,28)=0.03

0.87

ωp2=-0.03

[-0.04; 0.07]

F[1,28]=0.01

0.93

ωp2=0.03

[-0.04; 0.04]

26

Asymmetry of Parkinson's Disease and inhibitory control Arm (left, Right) Main effect MT: Trial type (MT no-stop trials, MT go-only trials) Main effect MT: Group (RPD, LPD) Main effect MT: Arm (left, Right)

F(1,28)=0.59

0.45

ωp2=-0.01

[-0.04;0.17]

F(1,28)=0.27

0.61

ωp2=-0.02

[-0.04;0.14]

F(1,28)=0.29

0.6

ω2=-0.02

[-0.04;0.14]

Power analysis indicated we had 80% power to observe equivalence for a Cohen’s dz of 0.75 with 15 participants in a within-subject t-test, and the equivalence test indicated the observed effect of Arm on RT’s was statistically smaller than dz = 0.75, p = 0.007, and the default Bayesian paired t-test showed the data were more likely under the null model, BF10 = 0.26. The equivalence test on the observed effect of Arm for MT’s was also statistically smaller than d = 0.75, p < 0.01, with the default Bayesian t-test showed the data were relatively more likely under the null model, BF10 = 0.31, providing moderately strong evidence for the lack of a difference. Overall these results suggest that, at least in right-handed PD patients, inhibitory control does not strongly depend on the arm used in the task.

3.4 Correlations between behavioral measures and the UPDRS3 score In order to explore whether behavioral parameters characterizing the performance in the countermanding task scale with symptom severity, measured on the UPDRS3, we computed both the values of the Pearson’s correlation coefficient (r), which evaluates the linear relationship between two variables, and the values of the Spearman’s correlation coefficient (rho), which evaluates the monotonic relationship between two variables. In none of the instances we found a significant correlation. In our view this finding can be explained by the fact that the items of the UPDRS3 scores measure several different motor skills (e.g. coordination, postural adjustments, balance) and therefore symptoms severity measured on this scale might not be related to the features of the motor function that have been assessed with the current experimental paradigm. 27

Asymmetry of Parkinson's Disease and inhibitory control However, it is noteworthy that this conclusion might be hampered by the relatively small sample size. Table 8. Correlations between the score of the motor symptoms of patients, measured on the UPDRS3 scale, and the mean values of behavioral parameters, characterizing the behavioral performance in the countermanding task (RTs and MTs of no-stop trials; RTs and MTs of go-only trials; and SSRTs). For each behavioral parameter both the value of the Pearson’s correlation coefficient and the value of the Spearman’s correlation coefficient together with the corresponding p-values (2-tails) are reported. RPD RT no

LPD

MT no stop RT go only MT go only SSRT

stop trials

trials

trials

trials

Pearson’s r

0.267

-0.168

-0.212

-0.224

p-value

0.255

0.478

0.370

0.342

Spearman's rho

0.333

-0.248

-0.134

-0.198

p-value

0.151

0.292

0.573

0.404

RT no stop MT no stop RT go only MT go only

SSRT

trials

trials

trials

trials

0.001

-0.092

-0.197

-0.370

-0.121

-0.121

0.998

0.701

0.406

0.108

0.610

0.612

-0.119

-0.193

-0.408

-0.161

-0.009

0.619

0.414

0.074

0.498

0.970

0.069 0.773

4. DISCUSSION 4.1 Inhibitory control in Parkinson’s disease is not asymmetric The lack of inhibitory control is a hallmark of a wide number of clinical populations (see Aron, 2011 for a review). Among them there is PD. Several studies have shown that either reactive (Gauggel et al. 2004) or both reactive and proactive (Obeso et al. 2011) inhibitory control are impaired in this neurodegenerative disease. Both Gauggel et al. (2004) and Obeso et al. (2011), using different versions of the countermanding task, showed that PD patients took significantly longer to suppress pending actions compared to age-matched controls. In addition, Obeso et al. (2011) found that, under a conflictual situation, PD patients took more time to initiate a response than did age-matched controls. However, in none of the previous studies was the dominant side of PD ever considered (or even reported). This seems odd, as one of the most influential hypotheses put forward to explain the neural network subserving inhibitory control of manual movements 28

Asymmetry of Parkinson's Disease and inhibitory control suggests that this executive function is right-lateralized (Aron et al. 2007). If this is the case, averaging across LPD and RPD might lead to unclear and variable results. To fill this gap, we used a reaching version of the countermanding task (e.g. Mirabella et al. 2008) to investigate inhibitory control in a population of Parkinson’s patients with left- and right-dominant PD, characterized by a larger neurodegeneration of the right and left hemispheres, respectively. Previous reports revealed different cognitive profiles in RPD and LPD patients. In fact, on the one hand there is some evidence that RPD patients tend to have worse performance in some language domains such as verbal expressions, naming and vocabulary (e.g. Blonder et al. 1989; Mohr et al. 1992). On the other hand, LPD patients tend to perform worse on tasks of spatial attention, visuospatial orienting and mental imagery (e.g. Blonder et al. 1989; Lee et al. 2001; Harris et al. 2003; Karádi et al. 2015). Importantly, no differences were found between LPD and RPD patients as far as executive functions, including inhibitory control, are concerned (Blonder et al. 1989; Holtgraves et al. 2010). However, it must be stressed that the results are not clear-cut, and there are several inconsistencies across reports (see Verreyt et al. 2011). Thus, to the best of our knowledge our paper is the first to specifically investigates the issue of asymmetry of PD and inhibitory control by strictly pre-selecting patients with pronounced symptom asymmetry. Our results suggest that reactive inhibition is equally impaired in LPD and RPD with respect to healthy controls. Importantly, we verified that, at least in right-handed PD patients, there is no difference in the length of the SSRT irrespective of which arm was employed to perform the task. The picture emerging from the analyses of proactive control was similar. We assessed proactive control by quantifying the phenomenon of the context effect (Mirabella et al. 2008; 2013). PD patients are clearly less skilled than healthy controls, but there are no differences between RPD and LPD patients. We should note that due to the small sample size, we can only reject large effects. Substantially larger replication studies, and future meta-analyses, are needed to exclude the possibility of a small to medium effect size.

29

Asymmetry of Parkinson's Disease and inhibitory control 4.2 Is inhibitory control right-lateralized, left-lateralized? Or is it computed by both hemispheres? Our results are in contrast with the idea that some cortical and subcortical regions of the right hemisphere play a key role in inhibition (e.g. Aron et al. 2003; Aron & Poldrack 2006; Aron et al. 2007; Chikazoe et al., 2009; Jahfari et al. 2012; Swann et al. 2009; Swann et al, 2012). The difference between our findings and earlier studies could be explained in several ways. First of all, PD might have altered the circuitry underlying inhibitory control hiding the lateralization, which could be found in healthy subjects. However, this possibility is unlikely as two scalp electroencephalography papers have shown that in PD patients the largest modulation of activity of beta band were observed over right frontal cortex, consistent with the hypothesis of the right-lateralization of the stopping network (Swann et al. 2011; George et al 2013). Second, in most papers (e.g. Aron et al. 2003; Aron and Poldrack 2006; Aron et al. 2007; Chikazoe et al., 2009; Jahfari et al. 2012; Swann et al. 2009; Swann et al, 2012), subjects are required to inhibit key-press movements, whereas in the present work we required subjects to inhibit arm-reaching movements. Arm-reaching movements have a different ecological relevance as they are the only ones which allow physical interactions with the environment outside neurophysiology laboratories. A third important element in explaining the contrasting findings is represented by the different task demands between study designs. For instance, Aron and colleagues gave the so-called conditional stop-signal task (e.g. Aron et al. 2007; Swann et al. 2009; see Fig. 5), which is much more demanding than the standard version of the stop-signal task we employed in this study. In the conditional stop-signal task, a subject actively remembers the instructions for four different types of trials, and follows the typical instructions of the stop-signal task only when the arrow cue indicates a ‘critical direction’. In contrast, when the arrow cue points in a ‘non-critical direction’ the subject always has to move, irrespective of whether he or she perceives the tone that in the critical direction represents the stop signal. Under these conditions there are high non-inhibitory cognitive demands on attentional and working memory. Similar observations apply to other versions of the 30

Asymmetry of Parkinson's Disease and inhibitory control countermanding paradigm, in which a cue informs subjects about the probability of a stop-signal occurring (Chikazoe et al. 2009; Swann et al. 2012; Jahfari et al. 2012). Interestingly, it has been shown that some key components of the right-lateralized network, i.e. the right IFG and pre-SMA, have been shown to be activated when experimental tasks require working memory maintenance (e.g. Hampshire et al. 2012), context monitoring (e.g. Chatham et al. 2012) and attentional control (e.g. Corbetta and Shulman 2002; Hampshire et al. 2010; Erika-Florence et al. 2014). Accordingly, Erika-Florence et al. (2014) proposed that this functional network supports ‘a general class of attentional and working memory maintenance processes’, including those required by the stop signal task. However, even following this hypothesis, we should have found that LPD patients had worse inhibitory control than RPD patients, but we did not. This discrepancy can be explained by the fact that the go-signal employed by Hampshire and colleagues (e.g. Erika-Florence et al. 2014; Hampshire et al. 2010) was a centrally presented arrow. It is well known that centrally presented arrows allocate attention to the peripheral locations indicated by the direction of the arrows endogenously, as they rely on the internal processing of the meaning of the cue (Yantis, 2000). Therefore, endogenous shifts of attentions require top-down control. On the other hand, exogenous shifts of attentions, as those occurring when a peripheral stimulus lit up, are reflexive and automatic and thus they require less resources (Mayer et al., 2004). Hence in paradigms in which the go signal is given by the lighting of a peripheral stimulus, as in the case of the one we have employed, less attentional resources are requested and no clear signs of lateralization of inhibitory control have been observed (e.g. see Li et al. 2008; Mirabella et al. 2012; Vink et al. 2005). This might also explain the results obtained by Aron & Poldrack (2006) who employed central arrows. In conclusion, when tasks are cognitively demanding, either because of complex designs or because of the use of stimuli which induce endogenous shifts of attention, a right-lateralized network is activated. However, this does not seem to be specific for inhibitory control.

31

Asymmetry of Parkinson's Disease and inhibitory control

Figure 5 Schematic representation of the conditional stop-signal task. All trials begin with the appearance of a cue ring, with the left half of one color (e.g. gray) and the right half of another color (e.g. black). This cue is designed to remind the participant that one direction is ‘critical’ (black) and the other is ‘non-critical’ (gray). Thereafter, an arrow appears within the cue ring. The ring and the arrow remain on the screen for up to 1 s, after which they disappear. If the arrow points to the critical direction, in the example toward the right side, the participant has to press a right-key as soon as possible (no-stop trials, 66% of total trials) unless a tone occurs after a delay (stop-signal 32

Asymmetry of Parkinson's Disease and inhibitory control delay, SSD). In this instance, the participant must try to suppress the response (stop trials, 33% of total trials). However, if the arrow points to the non-critical direction, in the example toward the left side, the participant has to press a left-key in any case, irrespective of whether no tone occurs (nostop trials type 1, 66% of total trials) or whether it occurs (no-stop trials type 2, 33% of total trials). In other words, in the non-critical direction stop-signals must be ignored. Freely adapted from Swann et al. (2009).

It must be added that the issue of lateralization of inhibitory control is puzzling because results are often contrasting. For instance, Aron et al (2003) tested only patients with damage to the right IFG and, by comparing their performance with that of healthy controls, found that patients were progressively more impaired according to the extent of damage to the right IFG. However, Swick et al., (2008) provided clear evidence that also the integrity of left IFG is critical for achieving a good inhibitory performance. Surprisingly in an fMRI study, Vink et al. (2005), by comparing stop failure with stop successful trials, did not observe increased activation of IFG during successful inhibitions. Conversely, Li et al. (2008) found that inhibitory control relies, among other regions, on the activation of the left IFG. A similar picture emerges when looking at the basal ganglia.. Aron and colleagues (Aron and Poldrack 2006; Aron et al. 2007) assert that the right STN would act as a brake on the motor system by deactivating the motor thalamus. However, some fMRI studies have suggested that STN activation might be more involved in attentional control (e.g. Li et al. 2008; Erika-Florence et al. 2014), while other fMRI studies have not found significant STN activity during the execution of the stop signal task (van Belle et al. 2014; Zandbelt & Vink 2010). Probing STN with deep brain stimulators (DBS) in Parkinson’s patients revealed that reactive (see Van den Wildenberg et al. 2006; Mirabella et al. 2012) and proactive inhibitory control (Mirabella et al. 2013) were significantly improved when and only when both DBS were active Another subcortical region is commonly, but not always (e.g. see Aron et al., 2007), found to be involved in stopping manual responses, the striatum (Li et al. 2008; van Belle et al. 2014; Vink et al. 2005; Zandbelt and Vink 33

Asymmetry of Parkinson's Disease and inhibitory control 2010). Once more there are no clear answers to the issue of laterality. More often the striatum seems to be activated bilaterally (Li et al. 2008; Zandbelt and Vink 2010), but other times there seems to be a prevalence of the activity of the left striatum (van Belle et al. 2014) or of the right striatum (Vink et al, 2005). The bottom line is that previous studies cannot provide firm conclusions about whether the inhibitory network is lateralized not. Such a great variability might arise from heterogeneity in study designs in terms of stimulus modality (e.g. visual, auditory, and tactile stimuli), effector system (e.g. finger, arm, eye, foot), analysis procedures (e.g. sometimes stop-success are contrasted with no-stop trials, other times stop-success are contrasted with stop-failure trials) or it might be due to technical limitations of methodology applied. Interestingly, however, when the same version of the countermanding task design has been employed on different populations of PD patients inhibitory control invariably seems to rely on brain regions of both hemispheres (current study, Mirabella et al 2012 and 2013). Future studies are needed to solve this question.

4.3 Limitations of the study One limitation of the present study is that we included only patients in the middle stage of PD (Hoehn and Yahr stage 2 or 3), thus it might be argued that the lack of difference in inhibitory control between RPD and LPD does not emerge because both hemispheres are affected. However, we do not believe that patients selection might explain our results. First, even though in the later stages of PD, symptoms start to become bilateral, the pattern of asymmetry persists (Djaldetti and Melamed, 2006). Second, we selected patients with a very pronounced asymmetry (mean AI~0.5) presumably reflecting a remarkable asymmetry of the extent of the damage of one hemisphere with respect to the other. Under these circumstances, it is reasonable to argue that in RPD patients the damage to the left hemisphere is consistently larger than that affecting the right hemisphere (and viceversa for LPD patients). Thus, our starting hypothesis remains valid. Indeed, these conclusions are based on the assumption that the relationship between brain damage caused by PD and deficit in 34

Asymmetry of Parkinson's Disease and inhibitory control inhibitory control would be described by a positive linear function. Even though this is a plausible hypothesis, this relationship could take also some other form. For instance, one can hypothesize that above a certain level of severity level of dopaminergic dysfunction, the deficit in inhibitory control performance plateaus. If our assumption of a positive linear relationship does not hold, then the observed indifference in inhibitory control performance between LPD and RPD patients does not necessarily contrast with the hypothesis that inhibitory control relies upon a right-lateralized pathway. Another limitation is given by the fact that we tested patients in ON therapy. Even though there is evidence indicating that dopaminergic medications do not influence inhibitory control in PD (e.g., Claassen et al., 2015; George et al., 2013; Obeso et al., 2011), we cannot exclude the possibility that medication could have partially masked the asymmetric contribution of the two hemispheres.

4.4 Conclusions Taken together, our results do not support the hypothesis that inhibitory control is performed predominantly or even solely by a right-lateralized network of brain regions. Instead, our data suggests that, at least in PD patients, this executive function relies on the cooperation between the two hemispheres. Nevertheless, future studies will be needed to verify whether the same results could be obtained by selecting patients in the early stage of the disease when PD symptoms are shown only in one body side (Hoehn and Yahr stage 1), and to assess the potential effect of dopaminergic medications on inhibitory network lateralization.

Acknowledgments We thank all patients for their participation in the study. We also thank Deborah Lanni for collecting some data.

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Asymmetry of Parkinson's Disease and inhibitory control Competing interests: the authors declare that no competing interests exist

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Highlights     

Voluntary inhibition is thought to rely upon a right-lateralized network Inhibition was assessed in left-, right-dominant Parkinson’s (PD) patients, and in controls PD patients were significantly more impaired in both reactive and proactive inhibition than controls However, no differences were found between left- and right-dominant PD patients At least in PD patients, inhibitory control relies upon a bilateral network

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