# Interaction of Noradrenergic Pharmacological Manipulation and Subthalamic Stimulation on Movement Initiation Control in Parkinson's Disease

Marion Albares, Stéphane Thobois, Emilie Favre, Emmanuel Broussolle, Gustavo Polo, Philippe Domenech, Philippe Boulinguez, Benedicte Ballanger

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## To cite this version:

Marion Albares, Stéphane Thobois, Emilie Favre, Emmanuel Broussolle, Gustavo Polo, et al. Interaction of Noradrenergic Pharmacological Manipulation and Subthalamic Stimulation on Movement Initiation Control in Parkinson's Disease. Brain Stimulation, 2015, 8 (1), pp.27-35. 10.1016/j.brs.2014.09.002. hal-02115089

HAL Id: hal-02115089

https://hal.science/hal-02115089

Submitted on 6 Feb 2024

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<figure><img src="image_1.png" /></figure>

Original Articles

# Interaction of Noradrenergic Pharmacological Manipulation and Subthalamic Stimulation on Movement Initiation Control in Parkinson's Disease

<figure><img src="image_2.png" /></figure>

CrossMark

Marion Albares<sup>a,b,c</sup>, Stéphane Thobois<sup>a,b,c,d</sup>, Emilie Favre<sup>a,b,c,d</sup>, Emmanuel Broussolle<sup>a,b,c,d</sup>, Gustavo Polo<sup>d</sup>, Philippe Domenech<sup>e,f</sup>, Philippe Boulinguez<sup>a,b,c</sup>, Bénédicte Ballanger<sup>a,b,c,*</sup>

## ARTICLE INFO

**Article history:**
Received 17 March 2014
Received in revised form
11 August 2014
Accepted 4 September 2014
Available online 3 October 2014

**Keywords:**
Noradrenaline
STN-DBS
Akinesia
Reaction time
Executive control

## ABSTRACT

**Background:** Slowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic).

**Objective:** To test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity.

**Methods:** Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (×2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON- or OFF-DBS), and two with a 150 µg oral dose of clonidine (ON- or OFF-DBS).

**Results:** In the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON-DBS state.

**Conclusions:** Overall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic "tonus" may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency.

© 2015 Elsevier Inc. All rights reserved.

## Introduction

Parkinson's disease (PD) is a progressive degenerative disorder of the central nervous system characterized by major motor symptoms, but also by various non-motor symptoms [1–3]. PD is associated with major dopaminergic depletion, yet, the neuro-pathophysiology of the disease involves more than dopamine cell loss within the midbrain [4–7]. This multifaceted aspect of the disease does not ease diagnosis, nor does it facilitate targeted therapy [8–12]. Among the cardinal symptoms of the disease, akinesia is illustrative of this problem. Indeed, akinesia, which

<footnote><sup>a</sup>Université de Lyon, F-69622, Lyon, France</footnote>

<footnote><sup>b</sup>Université Lyon 1, Villeurbanne, France</footnote>

<footnote><sup>c</sup>CNRS, UMR5229, Centre de Neuroscience Cognitive, Bron, France</footnote>

<footnote><sup>d</sup>Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France</footnote>

<footnote><sup>e</sup>Laboratoire de Neurosciences Cognitives, ENS/INSERM-U960, Paris, France</footnote>

<footnote><sup>f</sup>Innovation Thérapeutique Fonctionnelle, Service de Neurochirurgie, CHU Henri Mondor, Creteil, France</footnote>

<footnote>This work was supported by Fyssen Fundation [081446 to B.B].</footnote>

<footnote>Financial disclosure: E.B and S.T received funding from Medtronic, France for travel expenses and congress registration in 2013. The neurological and neurosurgical movement disorders DBS team of the Pierre Wertheimer neurological hospital received technical aid for improving organization of the care of patients treated by deep brain stimulation in 2013–2014. Apart from the above, the authors report no financial conflict of interest and do not have to disclose any commercial considerations, such an equity interest, patent rights, or corporate affiliation, including consultant ships, for any product or process mentioned in the submission.</footnote>

<footnote>* Corresponding author. Centre de Neuroscience Cognitive, ISC, 67 Bd Pinel, 69675 Bron Cedex, France. Tel.: +33 (0)4 37 91 12 27.</footnote>

<footnote>E-mail address: benedicte ballanger@isc.cnrs.fr (B. Ballanger).</footnote>
<figure><img src="image_3.png" /></figure>

Original Articles

# Interaction of Noradrenergic Pharmacological Manipulation and Subthalamic Stimulation on Movement Initiation Control in Parkinson's Disease

<figure><img src="image_4.png" /></figure>

CrossMark

Marion Albares<sup>a,b,c</sup>, Stéphane Thobois<sup>a,b,c,d</sup>, Emilie Favre<sup>a,b,c,d</sup>, Emmanuel Broussolle<sup>a,b,c,d</sup>, Gustavo Polo<sup>d</sup>, Philippe Domenech<sup>e,f</sup>, Philippe Boulinguez<sup>a,b,c</sup>, Bénédicte Ballanger<sup>a,b,c,*</sup>

## ARTICLE INFO

**Article history:**

Received 17 March 2014

Received in revised form

11 August 2014

Accepted 4 September 2014

Available online 3 October 2014

**Keywords:**

Noradrenaline

STN-DBS

Akinesia

Reaction time

Executive control

## ABSTRACT

**Background:** Slowness in movement initiation (akinesia) is a cardinal feature of Parkinson's disease (PD), which is still poorly understood. Notably, akinesia is restored by subthalamic nucleus deep brain stimulation (STN-DBS) but not fully reversed by current dopaminergic treatments. It was recently suggested that this disorder is of executive nature (related to inhibitory control of response) and of non-dopaminergic origin (possibly noradrenergic).

**Objective:** To test the double hypothesis that: 1) the ability to control movement initiation is modified by noradrenergic neurotransmission modulation, and 2) this effect is mediated by the regulation of STN activity.

**Methods:** Sixteen STN-DBS PD patients were enrolled in a placebo-controlled study investigating the effects of noradrenergic attenuation by clonidine (×2-adrenergic receptor agonist). Movement initiation latency was assessed by means of a cue-target reaction time task. Patients, who remained on their chronic dopaminergic medication, were tested on four sessions: two with placebo (ON- or OFF-DBS), and two with a 150 µg oral dose of clonidine (ON- or OFF-DBS).

**Results:** In the OFF stimulation condition, patients were locked into a mode of control maintaining inappropriate response inhibition. This dysfunctional executive setting was overcome by STN-DBS. Clonidine, however, was found to impair specifically the ability to release inhibitory control in the ON-DBS state.

**Conclusions:** Overall our results suggest an important implication of the noradrenergic system in the pathophysiology of akinesia in PD. Reducing the noradrenergic "tonus" may even block the positive action of STN-DBS on akinesia, suggesting, at least by part, a noradrenergic-dependent STN-DBS efficiency.

© 2015 Elsevier Inc. All rights reserved.

## Introduction

Parkinson's disease (PD) is a progressive degenerative disorder of the central nervous system characterized by major motor symptoms, but also by various non-motor symptoms [1–3]. PD is associated with major dopaminergic depletion, yet, the neuro-pathophysiology of the disease involves more than dopamine cell loss within the midbrain [4–7]. This multifaceted aspect of the disease does not ease diagnosis, nor does it facilitate targeted therapy [8–12]. Among the cardinal symptoms of the disease, akinesia is illustrative of this problem. Indeed, akinesia, which

<footnote><sup>a</sup>Université de Lyon, F-69622, Lyon, France</footnote>

<footnote><sup>b</sup>Université Lyon 1, Villeurbanne, France</footnote>

<footnote><sup>c</sup>CNRS, UMR5229, Centre de Neuroscience Cognitive, Bron, France</footnote>

<footnote><sup>d</sup>Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, France</footnote>

<footnote><sup>e</sup>Laboratoire de Neurosciences Cognitives, ENS/INSERM-U960, Paris, France</footnote>

<footnote><sup>f</sup>Innovation Thérapeutique Fonctionnelle, Service de Neurochirurgie, CHU Henri Mondor, Creteil, France</footnote>

<footnote>This work was supported by Fyssen Foundation [081446 to B.B].</footnote>

<footnote>Financial disclosure: E.B and S.T received funding from Medtronic, France for travel expenses and congress registration in 2013. The neurological and neurosurgical movement disorders DBS team of the Pierre Wertheimer neurological hospital received technical aid for improving organization of the care of patients treated by deep brain stimulation in 2013–2014. Apart from the above, the authors report no financial conflict of interest and do not have to disclose any commercial considerations, such an equity interest, patent rights, or corporate affiliation, including consultant ships, for any product or process mentioned in the submission.</footnote>

<footnote>* Corresponding author. Centre de Neuroscience Cognitive, ISC, 67 Bd Pinel, 69675 Bron Cedex, France. Tel.: +33 (0)4 37 91 12 27.</footnote>

<footnote>E-mail address: benedicte ballanger@isc.cnrs.fr (B. Ballanger).</footnote>
refers to slowness and dysfunction in movement initiation [13], is still poorly understood and unsuccessfully alleviated by standard therapies. In a previous study [14], we suggested that movement initiation disorders that resist dopaminergic medication are due to executive, inhibitory, not motor, dysfunctions. Indeed, we observed that PD patients were impaired in their ability to gate movement initiation in anticipation of external stimulation to prevent premature or erroneous responses to upcoming events when the context is uncertain. Specifically, PD patients were found to maintain inappropriate proactive response inhibition in situations that did not require action restraint. This deficit was restored by deep brain stimulation of the subthalamic nucleus (STN-DBS), but not by dopaminergic medication. These findings emphasize the role of the STN as an interface between executive and motor systems that support switching from controlled to automatic sensorimotor processing. However, these results left the question of the neurochemical basis of akinesia in PD unanswered.

A growing body of evidence points to the possible role of the noradrenergic system in proactive control of movement initiation and related dysfunctions. First, the caudo-rostral degeneration theory assumes that the noradrenergic system is depleted in PD before the dopaminergic system [15]. Given that the locus coeruleus (LC), the major structure for brain synthesis of noradrenaline (NA), projects to the STN [16–18], it is likely that STN activity is directly modulated by the NA system [19,20]. Although assessing direct noradrenergic brain activity in humans is tricky in the absence of specific PET tracer, consistent clues are provided by pharmacological studies in humans [21–24] and animals [19,25–27]. For instance, it has been shown that gait disorders could also be partly related to a dysfunction of the NA system as methylphenidate improves gait hypokinesia and freezing in PD patients [21,23]. However, as methylphenidate modulates both dopaminergic and noradrenergic neurotransmission, a specific involvement of the NA system is still hypothetical. In parallel, animal studies have only evidenced a direct and undisputable role of NA in the discharge pattern of the STN [19,26]. Here, we analyzed the ability of PD patients to control movement initiation in a placebo-controlled study testing the interaction of STN-DBS and NA neurotransmission modulation by means of clonidine, a specific ~2 adrenergic receptor (AR) agonist.

## Materials and methods

### Participants

Sixteen parkinsonian patients (aged 59.3 ± 5.2 years old, 4 females, with normal or corrected-to-normal vision) treated with bilateral STN stimulation participated in the experiment. The implantation of the electrodes (Model 3389; Medtronic, Minneapolis, MN, USA) was performed under local anesthesia, guided by stereotactic magnetic resonance imaging (MRI), and microelectrode recordings. The accurate placement of the electrodes was confirmed on postoperative CT scan. The electrodes were connected to a pulse generator (Kinetra or Soletra, Medtronic, Minneapolis, MN, USA). The main demographic and clinical characteristics of the patients, the stimulation parameters used, the levodopa equivalent dose, and the effects of STN stimulation on the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores are presented in Table 1. The patients did not exhibit major signs of tremor and were not demented (MATTIS > 130). Of note, two patients (P3, P8) presented pathological gambling and compulsive shopping tendencies while one (P14) reported dopaminergic addiction and nocturnal hyperactivity well before STN-DBS surgery (at least three years ago). These symptoms have been totally suppressed by stopping dopaminergic agonists. Furthermore, all patients were submitted before the experiment to the Ardouin scale [28]. Hyperdopaminergic abnormalities were not reported in any patient.

Participant consent was obtained according to the code of ethics of the World Medical Association (Declaration of Helsinki) and the experimental protocol was approved by the local Ethical Committee in Biomedical Research (Comité de Protection des Personnes sud-est IV, N° CPP 12/039).

### General method of assessment

The behavioral task was reproduced from Favre and colleagues [14]. This experiment was intended to test the ability of PD patients to initiate simple movements in response to visual targets while maintaining their capacity to refrain from reacting to other visual stimulations. As demonstrated in previous studies, this can be achieved by using a simple cue-target reaction time (RT) task, provided

<table><caption>**Table 1**
Demographic and clinical characteristics of the Parkinson's disease patients treated with deep brain stimulation of the subthalamic nucleus.</caption><thead><tr><th rowspan="2">Patient</th><th rowspan="2">Sex</th><th rowspan="2">Age<br>(years)</th><th rowspan="2">DD<br>(years)</th><th colspan="2">UPDRS III</th><th rowspan="2">LED<br>(mg/day)</th><th colspan="2">Stimulation parameters</th><th rowspan="2">TSS<br>(months)</th><th rowspan="2">Predominant symptoms</th></tr><tr><th>ON<sup>a</sup></th><th>OFF<sup>a</sup></th><th>LS (plot/Hz/µS/V)</th><th>RS (plot/Hz/µS/V)</th></tr></thead><tbody><tr><td>1</td><td>H</td><td>59</td><td>10</td><td>13</td><td>33</td><td>350</td><td>1–/130/60/3.4</td><td>9–/130/60/3.5</td><td>8</td><td>Dysarthria, dyskinesia</td></tr><tr><td>2</td><td>H</td><td>61</td><td>14</td><td>23</td><td>48</td><td>465.5</td><td>2–/130/60/3.2</td><td>7– and 6–/130/90/3</td><td>51</td><td>Freezing, postural instability, hypertonia</td></tr><tr><td>3</td><td>H</td><td>61</td><td>7</td><td>7</td><td>23</td><td>399</td><td>3–/130/65/3.25 mA</td><td>2–/130/65/3 mA</td><td>6</td><td>Freezing</td></tr><tr><td>4</td><td>H</td><td>50</td><td>26</td><td>6</td><td>19</td><td>160</td><td>1–/130/90/3.3</td><td>6–/130/90/3.3</td><td>35</td><td>Dystonia</td></tr><tr><td>5</td><td>H</td><td>65</td><td>12</td><td>8</td><td>20</td><td>450</td><td>2–/130/60/3.5</td><td>5–/130/90/3.6</td><td>36</td><td>Dyskinesia, mild akinesia</td></tr><tr><td>6</td><td>F</td><td>64</td><td>24</td><td>20</td><td>24</td><td>880</td><td>2–/130/60/3.5</td><td>5–/130/60/3</td><td>81</td><td>Dyskinesia</td></tr><tr><td>7</td><td>F</td><td>64</td><td>15</td><td>12</td><td>24</td><td>660</td><td>3–/160/90/3.4</td><td>7–/160/90/2.9</td><td>34</td><td>Bradykinesia,</td></tr><tr><td>8</td><td>H</td><td>58</td><td>12</td><td>18</td><td>44</td><td>300</td><td>1–/130/60/3</td><td>5–/130/60/3.2</td><td>42</td><td>Akinesia, postural instability</td></tr><tr><td>9</td><td>F</td><td>61</td><td>10</td><td>10</td><td>30</td><td>0</td><td>2–/130/60/2.5</td><td>10–/130/60/2.9</td><td>8</td><td>Dystonia</td></tr><tr><td>10</td><td>H</td><td>61</td><td>14</td><td>29</td><td>50</td><td>1160</td><td>2– and 1–/130/90/3.6</td><td>5–/130/90/3.6</td><td>61</td><td>Facial dyskinesia, dysarthria</td></tr><tr><td>11</td><td>F</td><td>65</td><td>9</td><td>12</td><td>18</td><td>150</td><td>2–/130/60/2.6</td><td>11–/130/60/2.8</td><td>6</td><td>Mild akinesia, mild dyskinesia,</td></tr><tr><td>12</td><td>H</td><td>65</td><td>12</td><td>4</td><td>23</td><td>660</td><td>2–/160/90/2.6</td><td>6–/160/90/2.4</td><td>53</td><td>Mild akinesia</td></tr><tr><td>13</td><td>H</td><td>55</td><td>14</td><td>10</td><td>36</td><td>560</td><td>2–/130/60/2.4</td><td>10+ and 11–/130/60/2.5</td><td>4</td><td>Dyskinesia, mild rigidity</td></tr><tr><td>14</td><td>H</td><td>48</td><td>12</td><td>14</td><td>38</td><td>300</td><td>11–/160/90/3.6</td><td>1– and 2+/160/60/2.9</td><td>3</td><td>Mild tremor</td></tr><tr><td>15</td><td>H</td><td>56</td><td>12</td><td>2</td><td>6</td><td>1542.5</td><td>3– and 2–/130/90/2.9</td><td>11–/130/60/3.5</td><td>3</td><td>Akinesia, rigidity</td></tr><tr><td>16</td><td>H</td><td>56</td><td>7</td><td>13</td><td>31</td><td>1275</td><td>3–/160/90/3.6</td><td>11–/160/60/3</td><td>5</td><td>Mild tremor</td></tr><tr><td>Mean</td><td></td><td>59.3</td><td>13.1</td><td>12.5</td><td>29.2</td><td>582</td><td></td><td></td><td>27.2</td><td></td></tr><tr><td>SE</td><td></td><td>5.2</td><td>5.2</td><td>7.1</td><td>11.9</td><td>433.5</td><td></td><td></td><td>25.2</td><td></td></tr></tbody></table>

DD = disease duration; UPDRS III = motor score at the Unified Parkinson Disease Rating Scale; LED = levodopa equivalent dose [85]; TSS = time since surgery; M = male; F = female; SE = standard error; LS = Left Side; RS = Right Side.

<footnote>ª UPDRS III scores represent ON and OFF STN-DBS states while patients were screened under their usual dopaminergic medication for both DBS conditions.</footnote>
refers to slowness and dysfunction in movement initiation [13], is still poorly understood and unsuccessfully alleviated by standard therapies. In a previous study [14], we suggested that movement initiation disorders that resist dopaminergic medication are due to executive, inhibitory, not motor, dysfunctions. Indeed, we observed that PD patients were impaired in their ability to gate movement initiation in anticipation of external stimulation to prevent premature or erroneous responses to upcoming events when the context is uncertain. Specifically, PD patients were found to maintain inappropriate proactive response inhibition in situations that did not require action restraint. This deficit was restored by deep brain stimulation of the subthalamic nucleus (STN-DBS), but not by dopaminergic medication. These findings emphasize the role of the STN as an interface between executive and motor systems that support switching from controlled to automatic sensorimotor processing. However, these results left the question of the neurochemical basis of akinesia in PD unanswered.

A growing body of evidence points to the possible role of the noradrenergic system in proactive control of movement initiation and related dysfunctions. First, the caudo-rostral degeneration theory assumes that the noradrenergic system is depleted in PD before the dopaminergic system [15]. Given that the locus coeruleus (LC), the major structure for brain synthesis of noradrenaline (NA), projects to the STN [16–18], it is likely that STN activity is directly modulated by the NA system [19,20]. Although assessing direct noradrenergic brain activity in humans is tricky in the absence of specific PET tracer, consistent clues are provided by pharmacological studies in humans [21–24] and animals [19,25–27]. For instance, it has been shown that gait disorders could also be partly related to a dysfunction of the NA system as methylphenidate improves gait hypokinesia and freezing in PD patients [21,23]. However, as methylphenidate modulates both dopaminergic and noradrenergic neurotransmission, a specific involvement of the NA system is still hypothetical. In parallel, animal studies have only evidenced a direct and undisputable role of NA in the discharge pattern of the STN [19,26]. Here, we analyzed the ability of PD patients to control movement initiation in a placebo-controlled study testing the interaction of STN-DBS and NA neurotransmission modulation by means of clonidine, a specific ~2 adrenergic receptor (AR) agonist.

## Materials and methods

### Participants

Sixteen parkinsonian patients (aged 59.3 ± 5.2 years old, 4 females, with normal or corrected-to-normal vision) treated with bilateral STN stimulation participated in the experiment. The implantation of the electrodes (Model 3389; Medtronic, Minneapolis, MN, USA) was performed under local anesthesia, guided by stereotactic magnetic resonance imaging (MRI), and microelectrode recordings. The accurate placement of the electrodes was confirmed on postoperative CT scan. The electrodes were connected to a pulse generator (Kinetra or Soletra, Medtronic, Minneapolis, MN, USA). The main demographic and clinical characteristics of the patients, the stimulation parameters used, the levodopa equivalent dose, and the effects of STN stimulation on the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores are presented in Table 1. The patients did not exhibit major signs of tremor and were not demented (MATTIS > 130). Of note, two patients (P3, P8) presented pathological gambling and compulsive shopping tendencies while one (P14) reported dopaminergic addiction and nocturnal hyperactivity well before STN-DBS surgery (at least three years ago). These symptoms have been totally suppressed by stopping dopaminergic agonists. Furthermore, all patients were submitted before the experiment to the Ardouin scale [28]. Hyperdopaminergic abnormalities were not reported in any patient.

Participant consent was obtained according to the code of ethics of the World Medical Association (Declaration of Helsinki) and the experimental protocol was approved by the local Ethical Committee in Biomedical Research (Comité de Protection des Personnes sud-est IV, N° CPP 12/039).

### General method of assessment

The behavioral task was reproduced from Favre and colleagues [14]. This experiment was intended to test the ability of PD patients to initiate simple movements in response to visual targets while maintaining their capacity to refrain from reacting to other visual stimulations. As demonstrated in previous studies, this can be achieved by using a simple cue-target reaction time (RT) task, provided

<table><caption>**Table 1**
Demographic and clinical characteristics of the Parkinson's disease patients treated with deep brain stimulation of the subthalamic nucleus.</caption><thead><tr><th rowspan="2">Patient</th><th rowspan="2">Sex</th><th rowspan="2">Age<br>(years)</th><th rowspan="2">DD<br>(years)</th><th colspan="2">UPDRS III</th><th rowspan="2">LED<br>(mg/day)</th><th colspan="2">Stimulation parameters</th><th rowspan="2">TSS<br>(months)</th><th rowspan="2">Predominant symptoms</th></tr><tr><th>ON<sup>a</sup></th><th>OFF<sup>a</sup></th><th>LS (plot/Hz/µS/V)</th><th>RS (plot/Hz/µS/V)</th></tr></thead><tbody><tr><td>1</td><td>H</td><td>59</td><td>10</td><td>13</td><td>33</td><td>350</td><td>1–/130/60/3.4</td><td>9–/130/60/3.5</td><td>8</td><td>Dysarthria, dyskinesia</td></tr><tr><td>2</td><td>H</td><td>61</td><td>14</td><td>23</td><td>48</td><td>465.5</td><td>2–/130/60/3.2</td><td>7– and 6–/130/90/3</td><td>51</td><td>Freezing, postural instability, hypertonia</td></tr><tr><td>3</td><td>H</td><td>61</td><td>7</td><td>7</td><td>23</td><td>399</td><td>3–/130/65/3.25 mA</td><td>2–/130/65/3 mA</td><td>6</td><td>Freezing</td></tr><tr><td>4</td><td>H</td><td>50</td><td>26</td><td>6</td><td>19</td><td>160</td><td>1–/130/90/3.3</td><td>6–/130/90/3.3</td><td>35</td><td>Dystonia</td></tr><tr><td>5</td><td>H</td><td>65</td><td>12</td><td>8</td><td>20</td><td>450</td><td>2–/130/60/3.5</td><td>5–/130/90/3.6</td><td>36</td><td>Dyskinesia, mild akinesia</td></tr><tr><td>6</td><td>F</td><td>64</td><td>24</td><td>20</td><td>24</td><td>880</td><td>2–/130/60/3.5</td><td>5–/130/60/3</td><td>81</td><td>Dyskinesia</td></tr><tr><td>7</td><td>F</td><td>64</td><td>15</td><td>12</td><td>24</td><td>660</td><td>3–/160/90/3.4</td><td>7–/160/90/2.9</td><td>34</td><td>Bradykinesia,</td></tr><tr><td>8</td><td>H</td><td>58</td><td>12</td><td>18</td><td>44</td><td>300</td><td>1–/130/60/3</td><td>5–/130/60/3.2</td><td>42</td><td>Akinesia, postural instability</td></tr><tr><td>9</td><td>F</td><td>61</td><td>10</td><td>10</td><td>30</td><td>0</td><td>2–/130/60/2.5</td><td>10–/130/60/2.9</td><td>8</td><td>Dystonia</td></tr><tr><td>10</td><td>H</td><td>61</td><td>14</td><td>29</td><td>50</td><td>1160</td><td>2– and 1–/130/90/3.6</td><td>5–/130/90/3.6</td><td>61</td><td>Facial dyskinesia, dysarthria</td></tr><tr><td>11</td><td>F</td><td>65</td><td>9</td><td>12</td><td>18</td><td>150</td><td>2–/130/60/2.6</td><td>11–/130/60/2.8</td><td>6</td><td>Mild akinesia, mild dyskinesia,</td></tr><tr><td>12</td><td>H</td><td>65</td><td>12</td><td>4</td><td>23</td><td>660</td><td>2–/160/90/2.6</td><td>6–/160/90/2.4</td><td>53</td><td>Mild akinesia</td></tr><tr><td>13</td><td>H</td><td>55</td><td>14</td><td>10</td><td>36</td><td>560</td><td>2–/130/60/2.4</td><td>10+ and 11–/130/60/2.5</td><td>4</td><td>Dyskinesia, mild rigidity</td></tr><tr><td>14</td><td>H</td><td>48</td><td>12</td><td>14</td><td>38</td><td>300</td><td>11–/160/90/3.6</td><td>1– and 2+/160/60/2.9</td><td>3</td><td>Mild tremor</td></tr><tr><td>15</td><td>H</td><td>56</td><td>12</td><td>2</td><td>6</td><td>1542.5</td><td>3– and 2–/130/90/2.9</td><td>11–/130/60/3.5</td><td>3</td><td>Akinesia, rigidity</td></tr><tr><td>16</td><td>H</td><td>56</td><td>7</td><td>13</td><td>31</td><td>1275</td><td>3–/160/90/3.6</td><td>11–/160/60/3</td><td>5</td><td>Mild tremor</td></tr><tr><td>Mean</td><td></td><td>59.3</td><td>13.1</td><td>12.5</td><td>29.2</td><td>582</td><td></td><td></td><td>27.2</td><td></td></tr><tr><td>SE</td><td></td><td>5.2</td><td>5.2</td><td>7.1</td><td>11.9</td><td>433.5</td><td></td><td></td><td>25.2</td><td></td></tr></tbody></table>

DD = disease duration; UPDRS III = motor score at the Unified Parkinson Disease Rating Scale; LED = levodopa equivalent dose [85]; TSS = time since surgery; M = male; F = female; SE = standard error; LS = Left Side; RS = Right Side.

<footnote>a UPDRS III scores represent ON and OFF STN-DBS states while patients were screened under their usual dopaminergic medication for both DBS conditions.</footnote>
that some methodological requirements have been satisfied [29–31]. Specifically, the ability to react to visual stimuli was assessed in separate blocks of trials in which only visual targets were presented (inducing no uncertainty about upcoming stimuli, i.e., no need for subjects to refrain from reacting). In this condition, short RTs are expected because subjects can react automatically to any upcoming event. This condition represents the control condition in which subjects are supposed not to implement proactive inhibitory control. The ability to refrain from reacting to non-targets was assessed on the basis of other blocks of trials mixing targets and cues (inducing uncertainty about upcoming stimuli, i.e., requiring proactive inhibitory control). To this end, the analysis of RT is complementary to classical analyses of commission and omission errors. Indeed, when a target is not preceded by a cue in this uncertain context, proactive inhibitory control can only be lifted after the visual target has been identified, leading to a dramatic increase in RT. Manipulating the time separating cue presentation from target occurrence in cued trials (cue-target delay) allowed the assessment of the dynamics of release of proactive inhibitory control. Indeed, in this case, proactive inhibition can be released by the predictive cue, leading to a rapid decrease in RT, which pinpoints the switch from controlled to automatic sensorimotor processing (Fig. 1).

PD patients were tested in the morning (at around 9 am) on two consecutive days, with and without STN-DBS treatment (ON and OFF conditions) while taking their usual anti-Parkinsonian drugs. The order of the ON and OFF conditions was counterbalanced across participants. The stimulator was switched off in the OFF condition 30 min before testing. The fact that patients were tested at the same time schedule in the ON and OFF conditions ensured that the effect of dopaminergic medication was identical in both states (see Table 1 for the demographic characteristics).

## Apparatus and procedure

A panel equipped with light-emitting diodes (LEDs – Ø5 mm, 8800 mcd) was used to present the visual stimuli. One LED was placed in the centre of the panel and set at the subject's eye level. This served as a fixation point for the eyes. The target stimuli were composed of nine LEDs forming a diamond (3.44° of visual angle) located 16° to the left or right of the fixation point (duration 50 ms). The cue was composed of eight LEDs forming two peripheral green squares (3.4° of visual angle each) located 16° to the left and right of the fixation point (duration 50 ms). The subjects were asked to react as quickly as possible to the presentation of one of the two visual targets by pressing a single button with the right thumb. The visual target might or might not be preceded by the cue, depending on the experimental conditions (Fig. 1). Stimuli were presented and behavioral data were acquired using a real-time acquisition system (ADwin-Pro, Keithley Instruments, Cleveland, OH) controlled by laboratory-made software (Docometre) by courtesy of Franck Buloup (Institut des Sciences du Mouvement, Marseille).

Pre-stimulus delays (time between the lightening of the central fixation point and stimulus presentation, i.e., the time during which proactive inhibitory control had to be sustained) varied from two to four seconds in steps of one second. In cue trials, Cue-Target Onset Asynchrony (CTOA) was manipulated so that the cue-target delay varied randomly across nine conditions: from 100 to 2100 ms by steps of 250 ms. Since a lengthening of the time necessary to release the inhibitory control after a cue has been presented can be expected as a possible effect of clonidine intake, CTOA duration was increased with respect to the landmark study [14] to maximize the chances of catching the complete dynamics of the process.

The control condition was performed in two separate blocks of trials composed of visual targets only. The uncertainty condition was performed in two other blocks of trials mixing cue- and no-cue trials.

<figure><img src="image_3.png" /><figcaption>**Figure 1.** Principles and overview of the task design. (A) Experimental set-up used to assess proactive inhibitory control (cue-target detection task). (B) Behavioural markers of the dynamics of proactive inhibitory control in healthy subjects (mean age 57 years old; data taken from Ref. [14]). Proactive inhibitory control operates as a gating mechanism acting on movement initiation processes by anticipation of stimulus occurrence when the context is uncertain to prevent automatic responses to potentially inappropriate stimuli. Proactive inhibition can be released reactively by the appropriate target stimulus or anticipatorily by a predictive cue. In other words, proactive inhibitory control does not only account for the ability to counteract inappropriate actions, it also strongly accounts for the latency of initiation of appropriate movements [29–31]. When there is no uncertainty about the upcoming stimulus, no proactive inhibitory control is required. Responses can be triggered automatically. This means that 1) the effect of a simple warning cue mainly consists in unbolting the gate before a target occurs, and 2) proactive inhibitory control can be easily assessed with appropriate cue-target reaction time tasks. Accordingly, no-cue trials in cue-target protocols show a dramatic increase in RT with respect to no-cue trials performed apart in pure-blocks. If a warning cue is presented sufficiently in advance of the target (long cue-target delays), proactive inhibitory control has already been released at target occurrence and fast automatic responses to subsequent stimuli are generated in a similar way to no-cue trials performed apart in pure-blocks. The time required to switch from a controlled proactive inhibitory state to a state of automatic reactivity can be estimated by means of the dynamics of cued trials RT.</figcaption></figure>

These four blocks were presented in a counterbalanced order for each condition of stimulation × drug. Control blocks were composed of 48 trials each. Mixed blocks were composed of 96 trials each. Each subject performed 288 trials for each condition of stimulation × drug, equal to 1152 trials in total. Subjects were instructed to comply with a maximum error rate of 10% on pain of being discarded from the analysis. When an overt response was given before target occurrence (false alarm), or no response was given within a one-second-time window (omission), the trial was aborted.

## Drugs procedure

Clonidine was used to induce noradrenergic modulations (×2-AR agonist). Specifically, clonidine is thought to decrease NA
that some methodological requirements have been satisfied [29–31]. Specifically, the ability to react to visual stimuli was assessed in separate blocks of trials in which only visual targets were presented (inducing no uncertainty about upcoming stimuli, i.e., no need for subjects to refrain from reacting). In this condition, short RTs are expected because subjects can react automatically to any upcoming event. This condition represents the control condition in which subjects are supposed not to implement proactive inhibitory control. The ability to refrain from reacting to non-targets was assessed on the basis of other blocks of trials mixing targets and cues (inducing uncertainty about upcoming stimuli, i.e., requiring proactive inhibitory control). To this end, the analysis of RT is complementary to classical analyses of commission and omission errors. Indeed, when a target is not preceded by a cue in this uncertain context, proactive inhibitory control can only be lifted after the visual target has been identified, leading to a dramatic increase in RT. Manipulating the time separating cue presentation from target occurrence in cued trials (cue-target delay) allowed the assessment of the dynamics of release of proactive inhibitory control. Indeed, in this case, proactive inhibition can be released by the predictive cue, leading to a rapid decrease in RT, which pinpoints the switch from controlled to automatic sensorimotor processing (Fig. 1).

PD patients were tested in the morning (at around 9 am) on two consecutive days, with and without STN-DBS treatment (ON and OFF conditions) while taking their usual anti-Parkinsonian drugs. The order of the ON and OFF conditions was counterbalanced across participants. The stimulator was switched off in the OFF condition 30 min before testing. The fact that patients were tested at the same time schedule in the ON and OFF conditions ensured that the effect of dopaminergic medication was identical in both states (see Table 1 for the demographic characteristics).

## Apparatus and procedure

A panel equipped with light-emitting diodes (LEDs – Ø5 mm, 8800 mcd) was used to present the visual stimuli. One LED was placed in the centre of the panel and set at the subject's eye level. This served as a fixation point for the eyes. The target stimuli were composed of nine LEDs forming a diamond (3.44° of visual angle) located 16° to the left or right of the fixation point (duration 50 ms). The cue was composed of eight LEDs forming two peripheral green squares (3.4° of visual angle each) located 16° to the left and right of the fixation point (duration 50 ms). The subjects were asked to react as quickly as possible to the presentation of one of the two visual targets by pressing a single button with the right thumb. The visual target might or might not be preceded by the cue, depending on the experimental conditions (Fig. 1). Stimuli were presented and behavioral data were acquired using a real-time acquisition system (ADwin-Pro, Keithley Instruments, Cleveland, OH) controlled by laboratory-made software (Docometre) by courtesy of Franck Buloup (Institut des Sciences du Mouvement, Marseille).

Pre-stimulus delays (time between the lightening of the central fixation point and stimulus presentation, i.e., the time during which proactive inhibitory control had to be sustained) varied from two to four seconds in steps of one second. In cue trials, Cue-Target Onset Asynchrony (CTOA) was manipulated so that the cue-target delay varied randomly across nine conditions: from 100 to 2100 ms by steps of 250 ms. Since a lengthening of the time necessary to release the inhibitory control after a cue has been presented can be expected as a possible effect of clonidine intake, CTOA duration was increased with respect to the landmark study [14] to maximize the chances of catching the complete dynamics of the process.

The control condition was performed in two separate blocks of trials composed of visual targets only. The uncertainty condition was performed in two other blocks of trials mixing cue- and no-cue trials.

<figure><img src="image_5.png" /><figcaption>**Figure 1.** Principles and overview of the task design. (A) Experimental set-up used to assess proactive inhibitory control (cue-target detection task). (B) Behavioural markers of the dynamics of proactive inhibitory control in healthy subjects (mean age 57 years old; data taken from Ref. [14]). Proactive inhibitory control operates as a gating mechanism acting on movement initiation processes by anticipation of stimulus occurrence when the context is uncertain to prevent automatic responses to potentially inappropriate stimuli. Proactive inhibition can be released reactively by the appropriate target stimulus or anticipatorily by a predictive cue. In other words, proactive inhibitory control does not only account for the ability to counteract inappropriate actions, it also strongly accounts for the latency of initiation of appropriate movements [29–31]. When there is no uncertainty about the upcoming stimulus, no proactive inhibitory control is required. Responses can be triggered automatically. This means that 1) the effect of a simple warning cue mainly consists in unbolting the gate before a target occurs, and 2) proactive inhibitory control can be easily assessed with appropriate cue-target reaction time tasks. Accordingly, no-cue trials in cue-target protocols show a dramatic increase in RT with respect to no-cue trials performed apart in pure-blocks. If a warning cue is presented sufficiently in advance of the target (long cue-target delays), proactive inhibitory control has already been released at target occurrence and fast automatic responses to subsequent stimuli are generated in a similar way to no-cue trials performed apart in pure-blocks. The time required to switch from a controlled proactive inhibitory state to a state of automatic reactivity can be estimated by means of the dynamics of cued trials RT.</figcaption></figure>

These four blocks were presented in a counterbalanced order for each condition of stimulation × drug. Control blocks were composed of 48 trials each. Mixed blocks were composed of 96 trials each. Each subject performed 288 trials for each condition of stimulation × drug, equal to 1152 trials in total. Subjects were instructed to comply with a maximum error rate of 10% on pain of being discarded from the analysis. When an overt response was given before target occurrence (false alarm), or no response was given within a one-second-time window (omission), the trial was aborted.

## Drugs procedure

Clonidine was used to induce noradrenergic modulations (×2-AR agonist). Specifically, clonidine is thought to decrease NA
release through presynaptic ~2-AR activation. Each patient was tested in four experimental sessions combining all conditions of stimulation (STN-DBS ON; STN-DBS OFF) and drug (Clonidine; Placebo). The first (S1) and the second (S2) sessions were separated by 24 h. The third (S3) and fourth (S4) sessions took place three months later, separated by 24 h. Since the long half-life of clonidine does not allow complete withdrawal from the body from one day to the next, patients always received placebo first (at S1 and S3), and then received a clonidine (at S2 and S4, 150 µg oral dose), in a simple blind design. The drug was administered 90 min before testing to maximize the effect. Since clonidine has well-established anti-hypertensive properties, the blood pressure was monitored every 30 min from intake time to one hour after the experiment. The order of the ON and OFF conditions of STN-DBS was counter-balanced across participants (Fig. 2).

## Statistical analyses

### Reaction time

We first assessed the dynamics of release of inhibitory control after a cue had been presented within each experimental condition of Stimulation by Drug, by means of one-way analyses of variance (ANOVA) applied to mean RT data. No significant differences were observed between CTOA 600 and longer CTOAs for any experimental condition. Thus, these conditions were collapsed and referred to as “CTOA550+” for further RT analyses.

Then, for the sake of design optimization and clarity, statistical analyses were performed in successive steps by means of ANOVA applied to mean RTs (excluding RTs exceeding ±3 standard deviations). First, the effect of STN-DBS was tested in the placebo condition in order to compare the present results with those of the reference study of Favre and colleagues [14]. A 2 STN-DBS (ON, OFF) × 5 Trial (no-cue mixed-block, no-cue pure-block, CTOA100, CTOA350, CTOA550+) design was used. Second, the effect of the drug was tested in the OFF STN-DBS condition by means of a 2 Drug (Clonidine, Placebo) × 5 Trial (no-cue mixed-block, no-cue pure-block, CTOA100, CTOA350, CTOA550+) design. Third, the effect of the drug was tested in the ON STN-DBS condition by means of a 2 Drug (Clonidine, Placebo) × 5 Trial (no-cue mixed-block, no-cue pure-block, CTOA100, CTOA350, CTOA550+) design. Post-hoc comparisons were performed when necessary using Newman-Keuls tests. All tests were two-sided and *P* < 0.05 was considered significant.

### Response accuracy

Joint analyses were performed to assess the error rates. False alarms and abnormally short RTs (<150 ms) were pooled together (anticipations). Omissions were considered separately. The percentages of anticipations and omissions were submitted to separate ANOVAs after ArcSine transforms. By contrast with RT analyses, CTOA does not represent a variable of interest and was not considered in error analyses. This reduction of the number of degrees of freedom allowed the setting-up of a unique statistical design in the form of a 2 Drug (Clonidine, Placebo) × 2 STN-DBS (ON, OFF) × 2 Condition (mixed-block, pure-block) ANOVA.

## Results

### Errors

On average, the global error rate was 5.3 ± 7.5%.

### Anticipations

A main effect of the trial (F(1,15) = 81.53, *P* < 0.001), not surprisingly, was that the rate of anticipations was higher in the mixed-block than in the pure-block condition (0.0027 vs. 0.0008). As has been abundantly reported previously, this effect is simply due to the fact that cue-induced automatic motor activations usually cause false alarms [32]. No significant effects of the drug or STN-DBS, nor any significant interaction, were observed.

### Omissions

A main effect of the drug was observed (F(1,15) = 11.56, *P* < 0.01) revealing that clonidine broadly increases the number of omissions with respect to a placebo condition (0.0046 vs. 0.0031). A significant interaction of the drug with the trial (F(1,15) = 5.9, *P* < 0.05) specified, however, that this effect was mainly due to the increase of the rate of omissions in the pure-block condition (0.0044 vs. 0.0025 for the clonidine and placebo conditions, respectively, *P* < 0.001).

### Reaction time

#### Effect of STN-DBS in the placebo condition

A main effect of STN-DBS (F(1,15) = 7.84, *P* < 0.01) was observed, revealing a broad RT decrease under STN stimulation (501.2 vs. 446.4 ms, for the OFF and ON STN-DBS conditions, respectively). The STN-DBS × Trial interaction just failed to reach the conventional statistical threshold (F(4,60) = 2.32, *P* = 0.067). However, this trend yielded similar results to those previously reported [14]: a specific effect of STN-DBS was observed in the control condition (no-cue, pure-block). While PD patients are impaired OFF stimulation (RT are longer in this control condition than in the CTOA 550 + Trial: 488 vs. 429.5 ms, *P* < 0.001), STN-DBS restores a normal pattern of results by reducing RT in the no-cue pure-block trial (405.3 vs. 391 ms, *P* = 0.21) and wiping out the RT difference observed when OFF-DBS (Fig. 3).

#### Effect of clonidine in the OFF STN-DBS condition

A main effect of Trial (F(4,56) = 38.99, *P* < 0.001) revealing the typical OFF STN-DBS pattern such as i) the longest RT was observed for the no-cue mixed-block condition (553.5 ms), ii) RT decreased

<figure><img src="image_4.png" /><figcaption>**Figure 2.** Overview of the study design.</figcaption></figure>
release through presynaptic ~2-AR activation. Each patient was tested in four experimental sessions combining all conditions of stimulation (STN-DBS ON; STN-DBS OFF) and drug (Clonidine; Placebo). The first (S1) and the second (S2) sessions were separated by 24 h. The third (S3) and fourth (S4) sessions took place three months later, separated by 24 h. Since the long half-life of clonidine does not allow complete withdrawal from the body from one day to the next, patients always received placebo first (at S1 and S3), and then received a clonidine (at S2 and S4, 150 µg oral dose), in a simple blind design. The drug was administered 90 min before testing to maximize the effect. Since clonidine has well-established anti-hypertensive properties, the blood pressure was monitored every 30 min from intake time to one hour after the experiment. The order of the ON and OFF conditions of STN-DBS was counter-balanced across participants (Fig. 2).

## Statistical analyses

### Reaction time

We first assessed the dynamics of release of inhibitory control after a cue had been presented within each experimental condition of Stimulation by Drug, by means of one-way analyses of variance (ANOVA) applied to mean RT data. No significant differences were observed between CTOA 600 and longer CTOAs for any experimental condition. Thus, these conditions were collapsed and referred to as “CTOA550+” for further RT analyses.

Then, for the sake of design optimization and clarity, statistical analyses were performed in successive steps by means of ANOVA applied to mean RTs (excluding RTs exceeding ±3 standard deviations). First, the effect of STN-DBS was tested in the placebo condition in order to compare the present results with those of the reference study of Favre and colleagues [14]. A 2 STN-DBS (ON, OFF) × 5 Trial (no-cue mixed-block, no-cue pure-block, CTOA100, CTOA350, CTOA550+) design was used. Second, the effect of the drug was tested in the OFF STN-DBS condition by means of a 2 Drug (Clonidine, Placebo) × 5 Trial (no-cue mixed-block, no-cue pure-block, CTOA100, CTOA350, CTOA550+) design. Third, the effect of the drug was tested in the ON STN-DBS condition by means of a 2 Drug (Clonidine, Placebo) × 5 Trial (no-cue mixed-block, no-cue pure-block, CTOA100, CTOA350, CTOA550+) design. Post-hoc comparisons were performed when necessary using Newman-Keuls tests. All tests were two-sided and *P* < 0.05 was considered significant.

### Response accuracy

Joint analyses were performed to assess the error rates. False alarms and abnormally short RTs (<150 ms) were pooled together (anticipations). Omissions were considered separately. The percentages of anticipations and omissions were submitted to separate ANOVAs after ArcSine transforms. By contrast with RT analyses, CTOA does not represent a variable of interest and was not considered in error analyses. This reduction of the number of degrees of freedom allowed the setting-up of a unique statistical design in the form of a 2 Drug (Clonidine, Placebo) × 2 STN-DBS (ON, OFF) × 2 Condition (mixed-block, pure-block) ANOVA.

## Results

### Errors

On average, the global error rate was 5.3 ± 7.5%.

### Anticipations

A main effect of the trial (F(1,15) = 81.53, *P* < 0.001), not surprisingly, was that the rate of anticipations was higher in the mixed-block than in the pure-block condition (0.0027 vs. 0.0008). As has been abundantly reported previously, this effect is simply due to the fact that cue-induced automatic motor activations usually cause false alarms [32]. No significant effects of the drug or STN-DBS, nor any significant interaction, were observed.

### Omissions

A main effect of the drug was observed (F(1,15) = 11.56, *P* < 0.01) revealing that clonidine broadly increases the number of omissions with respect to a placebo condition (0.0046 vs. 0.0031). A significant interaction of the drug with the trial (F(1,15) = 5.9, *P* < 0.05) specified, however, that this effect was mainly due to the increase of the rate of omissions in the pure-block condition (0.0044 vs. 0.0025 for the clonidine and placebo conditions, respectively, *P* < 0.001).

### Reaction time

#### Effect of STN-DBS in the placebo condition

A main effect of STN-DBS (F(1,15) = 7.84, *P* < 0.01) was observed, revealing a broad RT decrease under STN stimulation (501.2 vs. 446.4 ms, for the OFF and ON STN-DBS conditions, respectively). The STN-DBS × Trial interaction just failed to reach the conventional statistical threshold (F(4,60) = 2.32, *P* = 0.067). However, this trend yielded similar results to those previously reported [14]: a specific effect of STN-DBS was observed in the control condition (no-cue, pure-block). While PD patients are impaired OFF stimulation (RT are longer in this control condition than in the CTOA 550 + Trial: 488 vs. 429.5 ms, *P* < 0.001), STN-DBS restores a normal pattern of results by reducing RT in the no-cue pure-block trial (405.3 vs. 391 ms, *P* = 0.21) and wiping out the RT difference observed when OFF-DBS (Fig. 3).

#### Effect of clonidine in the OFF STN-DBS condition

A main effect of Trial (F(4,56) = 38.99, *P* < 0.001) revealing the typical OFF STN-DBS pattern such as i) the longest RT was observed for the no-cue mixed-block condition (553.5 ms), ii) RT decreased

<figure><img src="image_6.png" /><figcaption>**Figure 2.** Overview of the study design.</figcaption></figure>
<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /><figcaption>**Figure 3.** Respective effects of clonidine administration and STN-DBS on proactive inhibitory control impairment as assessed with reaction time.</figcaption></figure>

as CTOA increased (535.3 vs. 462 vs. 424 ms for CTOA100, CTOA350 and CTOA550+, respectively, all *Ps* < 0.001), but iii) RT was longer in the no-cue pure-block trial with respect to the CTOA550 + Trial (484.6 vs. 423.9 ms, *P* < 0.001). Clonidine intake did not have any effect in the OFF STN-DBS condition (Fig. 3A).

### Effect of clonidine in the ON STN-DBS condition

A significant Trial × Drug interaction (F(4,60) = 4.99, *P* < 0.01) revealed a specific effect of clonidine. With respect to placebo, clonidine increased RT in the CTOA100 and the no-cue pure-block trials only (519 vs. 487.9 ms, 452.3 vs. 405.3 ms, all *Ps* < 0.001). However, in the placebo condition, RT was not different in the no-cue pure-block and the CTOA550 + conditions (405.3 vs. 391 ms, *P* = 0.22), while in the clonidine condition, RT was longer in the no-cue pure-block condition than in the CTOA550 + condition (452.3 vs. 393.2 ms, *P* < 0.001). In other words, the effect of clonidine can be summarized as a return to the abnormal pattern observed in the OFF STN-DBS state in the placebo condition (Fig. 3B).

### Correlation analyses

Complementary analyses were performed in order to test a possible interaction between the two types of medication administered to the patients (the noradrenergic modulation by clonidine and the dopaminergic modulation by levodopa or similar medication). More precisely, we tested the hypothesis that the behavioral effect of clonidine observed in the no-cue pure-block in the ON STN-DBS condition could be related to the levodopa equivalent dose – LED. To this aim, we exploited the inter-individual variability of LED due to variable *time since surgery* across subjects (Table 1). We used as a behavioral index of the drug effect the mean individual

difference in the no-cue pure-block RT between the ON and the OFF STN-DBS states. This variable (ΔRT) was associated with the corresponding individual LED value. No significant correlation was found (*r*² = 0.13, *P* = 0.17).

Additionally, since *time since surgery* is a determinant factor of STN-DBS efficacy [33], we assessed a possible relationship with the effect of clonidine as revealed by our behavioral index (ΔRT). No significant correlation was found (*r*² = 0.04, *P* = 0.45).

### Discussion

Here, we confirm the basic result of our previous work suggesting that: i) PD patients are impaired in their ability to switch from a proactive, inhibitory mode of control of movement initiation to a reactive, automatic mode of sensorimotor processing, ii) STN-DBS specifically acts by regaining control of the state of “self-initiated automaticity” when appropriate [14]. This was seen through i) an increase in RT in the OFF STN-DBS state specifically when the situation prompted to release control (no cue, no uncertainty, pure-block), and ii) the return to a normal pattern of RT in the ON STN-DBS state (Fig. 3). In other words, slowness in movement initiation in PD patients might partly be due to the fact that patients are locked into a mode of executive control maintaining inappropriate response inhibition. STN-DBS would restore the ability to voluntarily release the default, executive control mechanism which normally refrains from reacting in uncertain contexts.

There are substantial reasons to assume that STN activity is directly modulated by the NA system [19,20], but direct evidence from human studies is missing. There are several issues here, all of which are hotly discussed. First, a number of important questions about the basal ganglia (BG) circuitry remain unresolved, including the issue of the exact roles of the striatum and STN, the two input stations of the BG [34–37]. Second, identifying interactions between STN activity and the NA system might usefully inform the current debate on non-dopaminergic approaches to medical and surgical therapies [38–42].

### Relevance to anatomo-functional models of motor control

Movement control heavily relies on the ability to suppress undesired or inappropriate motor activations. Importantly, inhibitory control not only accounts for the ability to counteract inappropriate actions, it also strongly accounts for the latency of initiation of appropriate movements [32].<fnref n="1" /> This complex and multifaceted function is supported by parallel cortico-BG-thalamo-cortical circuits [50,51]. A refined model of the BG circuitry states that motor cortical signals are first transmitted through the cortico-STN-pallidal hyperdirect pathway, producing early excitation in the internal globus pallidus (GPi), and inhibiting inappropriate movements [52,53]. Then, signals through the cortico-striato-pallidal direct pathway are thought to induce inhibition in the GPi and release appropriate movements. Finally, the cortico-striato-pallido (external GP)-STN-pallidal indirect pathway is supposed to mediate late excitation in the GPi and stop movements. In

<footnote n="1">¹ Here, we did not find evidence for STN-DBS induced impulsivity. Yet, the effect is not automatic and the mechanisms of action that induce impulsive behaviors under STN-DBS still remain obscure [43]. Several reasons might explain this inconclusiveness. Given the multifaceted aspect of response inhibition [44], it is likely that the effect is conditioned upon several factors related to the characteristics of the experimental task (e.g., go/nogo or high conflict situations would favor the observation of impulsivity [45,46]), the characteristics of the patients (e.g., psychosocial factors such as male gender increase the risk of impulsivity [47,48]), or the characteristics of stimulation (e.g., stimulation of the ventral STN region would facilitate impulsivity [49]).</footnote>
<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /><figcaption>**Figure 3.** Respective effects of clonidine administration and STN-DBS on proactive inhibitory control impairment as assessed with reaction time.</figcaption></figure>

as CTOA increased (535.3 vs. 462 vs. 424 ms for CTOA100, CTOA350 and CTOA550+, respectively, all *Ps* < 0.001), but iii) RT was longer in the no-cue pure-block trial with respect to the CTOA550 + Trial (484.6 vs. 423.9 ms, *P* < 0.001). Clonidine intake did not have any effect in the OFF STN-DBS condition (Fig. 3A).

### Effect of clonidine in the ON STN-DBS condition

A significant Trial × Drug interaction (F(4,60) = 4.99, *P* < 0.01) revealed a specific effect of clonidine. With respect to placebo, clonidine increased RT in the CTOA100 and the no-cue pure-block trials only (519 vs. 487.9 ms, 452.3 vs. 405.3 ms, all *Ps* < 0.001). However, in the placebo condition, RT was not different in the no-cue pure-block and the CTOA550 + conditions (405.3 vs. 391 ms, *P* = 0.22), while in the clonidine condition, RT was longer in the no-cue pure-block condition than in the CTOA550 + condition (452.3 vs. 393.2 ms, *P* < 0.001). In other words, the effect of clonidine can be summarized as a return to the abnormal pattern observed in the OFF STN-DBS state in the placebo condition (Fig. 3B).

### Correlation analyses

Complementary analyses were performed in order to test a possible interaction between the two types of medication administered to the patients (the noradrenergic modulation by clonidine and the dopaminergic modulation by levodopa or similar medication). More precisely, we tested the hypothesis that the behavioral effect of clonidine observed in the no-cue pure-block in the ON STN-DBS condition could be related to the levodopa equivalent dose – LED. To this aim, we exploited the inter-individual variability of LED due to variable time since surgery across subjects (Table 1). We used as a behavioral index of the drug effect the mean individual

difference in the no-cue pure-block RT between the ON and the OFF STN-DBS states. This variable (ΔRT) was associated with the corresponding individual LED value. No significant correlation was found (*r*² = 0.13, *P* = 0.17).

Additionally, since time since surgery is a determinant factor of STN-DBS efficacy [33], we assessed a possible relationship with the effect of clonidine as revealed by our behavioral index (ΔRT). No significant correlation was found (*r*² = 0.04, *P* = 0.45).

### Discussion

Here, we confirm the basic result of our previous work suggesting that: i) PD patients are impaired in their ability to switch from a proactive, inhibitory mode of control of movement initiation to a reactive, automatic mode of sensorimotor processing, ii) STN-DBS specifically acts by regaining control of the state of “self-initiated automaticity” when appropriate [14]. This was seen through i) an increase in RT in the OFF STN-DBS state specifically when the situation prompted to release control (no cue, no uncertainty, pure-block), and ii) the return to a normal pattern of RT in the ON STN-DBS state (Fig. 3). In other words, slowness in movement initiation in PD patients might partly be due to the fact that patients are locked into a mode of executive control maintaining inappropriate response inhibition. STN-DBS would restore the ability to voluntarily release the default, executive control mechanism which normally refrains from reacting in uncertain contexts.

There are substantial reasons to assume that STN activity is directly modulated by the NA system [19,20], but direct evidence from human studies is missing. There are several issues here, all of which are hotly discussed. First, a number of important questions about the basal ganglia (BG) circuitry remain unresolved, including the issue of the exact roles of the striatum and STN, the two input stations of the BG [34–37]. Second, identifying interactions between STN activity and the NA system might usefully inform the current debate on non-dopaminergic approaches to medical and surgical therapies [38–42].

### Relevance to anatomo-functional models of motor control

Movement control heavily relies on the ability to suppress undesired or inappropriate motor activations. Importantly, inhibitory control not only accounts for the ability to counteract inappropriate actions, it also strongly accounts for the latency of initiation of appropriate movements [32].<fnref n="1" /> This complex and multifaceted function is supported by parallel cortico-BG-thalamo-cortical circuits [50,51]. A refined model of the BG circuitry states that motor cortical signals are first transmitted through the cortico-STN-pallidal hyperdirect pathway, producing early excitation in the internal globus pallidus (GPi), and inhibiting inappropriate movements [52,53]. Then, signals through the cortico-striato-pallidal direct pathway are thought to induce inhibition in the GPi and release appropriate movements. Finally, the cortico-striato-pallido (external GP)-STN-pallidal indirect pathway is supposed to mediate late excitation in the GPi and stop movements. In

<footnote n="1">¹ Here, we did not find evidence for STN-DBS induced impulsivity. Yet, the effect is not automatic and the mechanisms of action that induce impulsive behaviors under STN-DBS still remain obscure [43]. Several reasons might explain this inconclusiveness. Given the multifaceted aspect of response inhibition [44], it is likely that the effect is conditioned upon several factors related to the characteristics of the experimental task (e.g., go/nogo or high conflict situations would favor the observation of impulsivity [45,46]), the characteristics of the patients (e.g., psychosocial factors such as male gender increase the risk of impulsivity [47,48]), or the characteristics of stimulation (e.g., stimulation of the ventral STN region would facilitate impulsivity [49]).</footnote>
compliance with the dynamics inferred from this anatomo-
functional model, most studies interested in response inhibition
have focused on the cascade of events launched by cortical re-
sponses to the external stimuli subjects must refrain from reacting
to. However, psychophysical and neuroimaging studies in healthy
subjects strongly suggest that response inhibition processes might
also implement action restraint in anticipation, before any stimulus
is provided to the subject [29–31,54–57]. By setting up a method
that makes it possible to isolate this function, the present study
suggests that the STN probably plays a pivotal role: While perfor-
mance is impaired in a pathological state, direct high-frequency
stimulation provides specific beneficial effects. The precise mode
of action of STN-DBS cannot be inferred from the present study.
Theoretically, STN-DBS might disrupt both the indirect and hyper-
direct pathways, with subsequent potential effects on both slow
tonic and fast phasic brain activity. It is indeed equally possible that
STN-DBS acts by restoring normal cortico-BG tonic activity in the
executive and motor networks, or acts by facilitating specifically the
phasic activity supporting switches from controlled to automatic
sensorimotor processing. Consistent with this view, growing evi-
dence demonstrates anticipatory changes in STN local field poten-
tial activity in humans [58–60]. The present data call for this issue
to be assessed, with greater resources being brought to bear on the
whole brain activity preceding (not only the brain activity induced
by) external stimulation with respect to the contextual re-
quirements for movement initiation control.

Noradrenergic modulation of STN activity and movement initiation control

Up to now, there has been no direct evidence of the role of the
noradrenergic system in movement initiation control in humans.
The present results reveal specific effects of clonidine on the ability
to switch from controlled to automatic behavior. This effect was
inferred from an increase in RT with respect to the placebo condi-
tion in the control trials in which patients were invited to volun-
tarily release proactive inhibition (Fig. 3B). This interpretation in
terms of α2-AR agonist-induced executive dysfunction is consis-
tent with the observation that patients made more omissions (did
not respond at all) under clonidine in this condition. A somewhat
lower effect on RT was also observed in the CTOA100 condition
(Fig. 3B), meaning that clonidine also delayed the cue-induced
release of proactive inhibitory control. Taken together, these re-
sults suggest that the difficulties experienced by PD patients to
voluntarily release the default mode of executive control that
maintains action restraint could be related to the activity of the
noradrenergic system. Following our initial suggestion about the
non-motor and non-dopaminergic origin of akinesia [14,61], we
now assume that troubles and slowness in movement initiation
rely, at least partly, on the modulatory action of noradrenaline. In
good agreement with this idea, Moreau and colleagues have also
recently showed that NA system might be involved in the patho-
physiology of gait disorders in PD, such as freezing of gait which can
be viewed as a failure to initiate movement [23].

Traditionally, it is believed that the noradrenergic system plays a
non-specific role in cognition as it is essentially involved in arousal,
attention and vigilance [62–64]. This idea is still very influential
[65]. Yet, it has been proposed – mainly on the basis of animal
studies – that the noradrenergic system has a more subtle and
specific function in the control of behavior. It is involved in the top-
down control of task execution, and hence participates in the
adaptive regulation of performance [66]. The results of the present
study are consistent with this view, and further specify some of the
mechanisms that might be involved in this broad function. Indeed,
we did not find non-specific effects of clonidine, as predicted by

attentional accounts, but conversely we found highly specific ef-
fects of executive origin. By acting as a gating mechanism, whose
function is to prevent responses in uncertain situations, proactive
inhibitory control probably plays a pivotal role in behavioral control
in general. In this respect, it is worthwhile recalling that previous
behavioral and neuroimaging studies in healthy humans have
suggested that most of the effects observed in experiments using
classical cueing methods to probe attentional functions are in fact
due to the executive mechanisms that are mandatory to refrain
from reacting to cues. This reinterpretation especially concerns
alertness [29,30] and visuospatial orientation [67], and raises the
more general question of the integrative modeling of these intrin-
sically related psychological functions. Besides these conceptual
issues, but consistent with our view, pharmacological manipulation
studies (recently reviewed by Chamberlain and Robbins [68]) have
demonstrated that the NA system exerts variable but profound
influences on various cognitive functions, including attention,
working memory, cognitive flexibility as well as response
inhibition.

A second major finding of the present study is that clonidine was
found to cancel the beneficial effect of STN-DBS (Fig. 3B). This
suggests that the modulatory action of NA might be mediated by
the STN. At least, a regulated activity of the STN (ON STN-DBS state)
is a prerequisite for revealing the effect of clonidine (Fig. 3A vs.
Fig. 3B).

NA has long been considered as having a minor influence on STN
regulation [17,18]. However, recent reports have contradicted this
view. Animal studies have demonstrated that STN neurons are
under the control of ∝ 1- and ∝ 2-AR, further supporting the role of
NA dysregulation in PD symptomatology. Notably, it has been
shown that ∝ 2-AR agonist induces an increase in the spontaneous
activity of rats' STN neurons [19]. More recently, Delaville and col-
leagues [26] have demonstrated that NA depletion by DSP-4
induces profound behavioral (hypolocomotor activity) and elec-
rophysiological (STN neurons discharging with a burst and irreg-
ular pattern) alterations in rats that resemble those observed in
Parkinsonian patients [69,70]. Additional arguments are also pro-
vided by clinical studies. In PD patients provided with a β1-AR
antagonist during STN-DBS surgery, Coenen and colleagues [24]
found a reduction of motor symptoms coupled to a suppression
of STN spiking activity. Finally, combined together, recent neuro-
imaging studies assessing respectively the modulations of activity
induced by STN-DBS in PD patients with PET [45], and the modu-
lations of activity induced by clonidine in non-implanted patients
and healthy controls with event-related functional MRI [71], pro-
vide indirect support for an interaction of the NA system and STN
activity. Indeed, DBS and NA pharmacological manipulation were
both found to induce activity changes in structures already known
to be involved in proactive inhibitory control.<fnref n="2" /> Interestingly, both
the STN and the cortical structures mediating proactive control
(such as the medial prefrontal cortex, the posterior cingulate cor-
tex/precuneus and the pre-supplementary motor area) receive
noradrenergic inputs [20,72,73]. All these elements strongly
suggest a functional coupling between STN activity and the
noradrenergic system. They demonstrate the anatomo-functional

<footnote n="2">² In controls, clonidine was found to increase brain activation in the medial parietofrontal network initially identified by Jaffard and colleagues [29,30]. The difficulties in movement initiation observed in PD were associated with activity changes in the posterior node of this network (mainly in the posterior cingulate cortex/precuneus), consistent with the dysfunctions of this region observed in cases of DBS-induced impulsivity [45]. Under clonidine, inappropriate implementation of inhibitory setting and consequent slowness in movement initiation were enhanced and more closely associated with modulation of the anterior node of the proactive control network (medial frontal cortex).</footnote>
compliance with the dynamics inferred from this anatomo-
functional model, most studies interested in response inhibition
have focused on the cascade of events launched by cortical re-
sponses to the external stimuli subjects must refrain from reacting
to. However, psychophysical and neuroimaging studies in healthy
subjects strongly suggest that response inhibition processes might
also implement action restraint in anticipation, before any stimulus
is provided to the subject [29–31,54–57]. By setting up a method
that makes it possible to isolate this function, the present study
suggests that the STN probably plays a pivotal role: While perfor-
mance is impaired in a pathological state, direct high-frequency
stimulation provides specific beneficial effects. The precise mode
of action of STN-DBS cannot be inferred from the present study.
Theoretically, STN-DBS might disrupt both the indirect and hyper-
direct pathways, with subsequent potential effects on both slow
tonic and fast phasic brain activity. It is indeed equally possible that
STN-DBS acts by restoring normal cortico-BG tonic activity in the
executive and motor networks, or acts by facilitating specifically the
phasic activity supporting switches from controlled to automatic
sensorimotor processing. Consistent with this view, growing evi-
dence demonstrates anticipatory changes in STN local field poten-
tial activity in humans [58–60]. The present data call for this issue
to be assessed, with greater resources being brought to bear on the
whole brain activity preceding (not only the brain activity induced
by) external stimulation with respect to the contextual re-
quirements for movement initiation control.

Noradrenergic modulation of STN activity and movement initiation control

Up to now, there has been no direct evidence of the role of the
noradrenergic system in movement initiation control in humans.
The present results reveal specific effects of clonidine on the ability
to switch from controlled to automatic behavior. This effect was
inferred from an increase in RT with respect to the placebo condi-
tion in the control trials in which patients were invited to volun-
tarily release proactive inhibition (Fig. 3B). This interpretation in
terms of α2-AR agonist-induced executive dysfunction is consis-
tent with the observation that patients made more omissions (did
not respond at all) under clonidine in this condition. A somewhat
lower effect on RT was also observed in the CTOA100 condition
(Fig. 3B), meaning that clonidine also delayed the cue-induced
release of proactive inhibitory control. Taken together, these re-
sults suggest that the difficulties experienced by PD patients to
voluntarily release the default mode of executive control that
maintains action restraint could be related to the activity of the
noradrenergic system. Following our initial suggestion about the
non-motor and non-dopaminergic origin of akinesia [14,61], we
now assume that troubles and slowness in movement initiation
rely, at least partly, on the modulatory action of noradrenaline. In
good agreement with this idea, Moreau and colleagues have also
recently showed that NA system might be involved in the patho-
physiology of gait disorders in PD, such as freezing of gait which can
be viewed as a failure to initiate movement [23].

Traditionally, it is believed that the noradrenergic system plays a
non-specific role in cognition as it is essentially involved in arousal,
attention and vigilance [62–64]. This idea is still very influential
[65]. Yet, it has been proposed – mainly on the basis of animal
studies – that the noradrenergic system has a more subtle and
specific function in the control of behavior. It is involved in the top-
down control of task execution, and hence participates in the
adaptive regulation of performance [66]. The results of the present
study are consistent with this view, and further specify some of the
mechanisms that might be involved in this broad function. Indeed,
we did not find non-specific effects of clonidine, as predicted by

attentional accounts, but conversely we found highly specific ef-
fects of executive origin. By acting as a gating mechanism, whose
function is to prevent responses in uncertain situations, proactive
inhibitory control probably plays a pivotal role in behavioral control
in general. In this respect, it is worthwhile recalling that previous
behavioral and neuroimaging studies in healthy humans have
suggested that most of the effects observed in experiments using
classical cueing methods to probe attentional functions are in fact
due to the executive mechanisms that are mandatory to refrain
from reacting to cues. This reinterpretation especially concerns
alertness [29,30] and visuospatial orientation [67], and raises the
more general question of the integrative modeling of these intrin-
sically related psychological functions. Besides these conceptual
issues, but consistent with our view, pharmacological manipulation
studies (recently reviewed by Chamberlain and Robbins [68]) have
demonstrated that the NA system exerts variable but profound
influences on various cognitive functions, including attention,
working memory, cognitive flexibility as well as response
inhibition.

A second major finding of the present study is that clonidine was
found to cancel the beneficial effect of STN-DBS (Fig. 3B). This
suggests that the modulatory action of NA might be mediated by
the STN. At least, a regulated activity of the STN (ON STN-DBS state)
is a prerequisite for revealing the effect of clonidine (Fig. 3A vs.
Fig. 3B).

NA has long been considered as having a minor influence on STN
regulation [17,18]. However, recent reports have contradicted this
view. Animal studies have demonstrated that STN neurons are
under the control of ∝ 1- and ∝ 2-AR, further supporting the role of
NA dysregulation in PD symptomatology. Notably, it has been
shown that ∝ 2-AR agonist induces an increase in the spontaneous
activity of rats' STN neurons [19]. More recently, Delaville and col-
leagues [26] have demonstrated that NA depletion by DSP-4
induces profound behavioral (hypolocomotor activity) and elec-
rophysiological (STN neurons discharging with a burst and irreg-
ular pattern) alterations in rats that resemble those observed in
Parkinsonian patients [69,70]. Additional arguments are also pro-
vided by clinical studies. In PD patients provided with a β1-AR
antagonist during STN-DBS surgery, Coenen and colleagues [24]
found a reduction of motor symptoms coupled to a suppression
of STN spiking activity. Finally, combined together, recent neuro-
imaging studies assessing respectively the modulations of activity
induced by STN-DBS in PD patients with PET [45], and the modu-
lations of activity induced by clonidine in non-implanted patients
and healthy controls with event-related functional MRI [71], pro-
vide indirect support for an interaction of the NA system and STN
activity. Indeed, DBS and NA pharmacological manipulation were
both found to induce activity changes in structures already known
to be involved in proactive inhibitory control.<fnref n="2" /> Interestingly, both
the STN and the cortical structures mediating proactive control
(such as the medial prefrontal cortex, the posterior cingulate cor-
tex/precuneus and the pre-supplementary motor area) receive
noradrenergic inputs [20,72,73]. All these elements strongly
suggest a functional coupling between STN activity and the
noradrenergic system. They demonstrate the anatomo-functional

<footnote n="2">² In controls, clonidine was found to increase brain activation in the medial parietofrontal network initially identified by Jaffard and colleagues [29,30]. The difficulties in movement initiation observed in PD were associated with activity changes in the posterior node of this network (mainly in the posterior cingulate cortex/precuneus), consistent with the dysfunctions of this region observed in cases of DBS-induced impulsivity [45]. Under clonidine, inappropriate implementation of inhibitory setting and consequent slowness in movement initiation were enhanced and more closely associated with modulation of the anterior node of the proactive control network (medial frontal cortex).</footnote>
plausibility of our interpretation of the present behavioral results, namely that clonidine-induced activation of post-synaptic α2-AR interferes with STN-DBS effects by switching STN activity back to a pathological pattern that induces executive deficits.

## Relevance to non-dopaminergic approaches to medical and surgical therapies

The present results might open the way towards two different therapeutic perspectives. First, after surgery, PD patients under STN-DBS might develop impulsivity [46,47,74–77]. So far, management options are not entirely satisfactory as they mainly consist of reducing dopaminergic medications with the risk of developing the so-called dopamine agonist withdrawal syndrome [78–80]. The present results suggest that introducing α2-AR agonist might be relevant for reducing this aversive effect. In the same vein, clonidine has recently been shown to induce inhibition of glutamate release onto the ventral tegmental area (VTA) [81], a brain structure central to reward processing and addiction, which is overdosed by dopamine-replacement levels that are therapeutic for motor symptoms in PD patients with impulse control disorders [48,82]. Finally, it is worth mentioning that clonidine is effective in reducing impulsivity in other pathological conditions. This is especially the case for attention-deficit/hyperactivity disorder [83], Tourette's syndrome [84], and tic disorders [85,86].

Second, given that clonidine, an α2-AR agonist, induces specific executive deficits, it might be relevant to explore the effect of an α2-AR antagonist in PD. Indeed, it is tempting to speculate on the basis of the present results that this kind of agent might conversely improve these specific executive functions. We obviously have in mind the potential benefit of a complementary α2-AR antagonist medication on refractory symptoms such as akinesia. In fact, it has previously been shown that α2-AR antagonists improve tremor and rigidity in the reserpinized rat [87], have a potent effect on levodopa-induced dyskinesia (LID) in a monkey model of PD [88,89], and can extend the anti-Parkinsonian effect of levodopa in MPTP-treated monkeys [90,91]. In PD patients, although conflicting results have been reported, preliminary clinical trials have suggested that this therapeutic approach reduces bradykinesia and rigidity [92] as well as LID when given in combination with levodopa [93]. In other terms, there is a broad spectrum of possible outcomes for this class of drugs, but its effects on movement initiation control have so far never been explored.

In light of the aforementioned studies, the importance of the possible interaction between noradrenergic and dopaminergic medications must be stressed out. Although our data did not provide direct evidence in favor of this hypothesis, the results of the correlation between the behavioral marker of the effect of clonidine and the LED neither allowed rejecting this possibility. It is clear, especially from the animal literature, that there is a cross-talk between the noradrenergic and dopaminergic systems [94]. For instance, NA activity from the LC might modulate dopamine (DA) neuronal activity in the VTA [95–97], as well as DA can influence the neuronal activity of LC-NA neurons since the LC is reciprocally innervated by the VTA [97,98]. Further studies are needed to address the issue of the mutual modulations of the noradrenergic and dopaminergic systems in humans, in relation with the acknowledged role of the latter in ICD [48,99,100]. In particular, a deeper understanding of the interplay between VTA, LC and the two input stations of the BG (Striatum and STN) may reveal a deeper insight into the possible combined influence of noradrenergic and dopaminergic medications on motor and inhibitory control.

In conclusion, we assume that clinical symptoms such as akineic freezing (possibly linked to the inability to release proactive

inhibitory control) or impulsivity (possibly linked to the inability to implement proactive inhibitory control), which probably represent the opposite ends of the same continuum of executive dysfunction [14,45,101], might benefit from different medications targeting NA dysfunction [102]. Obviously, the present study only provides a proof-of-concept, and further pharmacological investigations are warranted to support this hypothesis.

## Acknowledgments

The authors thank the Hospices Civils de Lyon for promoting this research program.

## References

[1] Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 2006;5:235–45.

[2] Antonelli F, Ray N, Strafella AP. Imaging cognitive and behavioral symptoms in Parkinson's disease. Neurotherapeutics 2010;10:1827–38.

[3] Weintraub D, Burn DJ. Parkinson's disease: the quintessential neuropsychiatric disorder. Mov Disord 2011;26:1022–31.

[4] Barone P. Neurotransmission in Parkinson's disease: beyond dopamine. Eur J Neurol 2010;17:364–76.

[5] Ferrer I, López-Gonzalez I, Carmona M, Dalfó E, Pujol A, Martínez A. Neurochemistry and the non-motor aspects of PD. Neurobiol Dis 2012;46:508–26.

[6] Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res 2004;318:121–34.

[7] Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson's disease. Parkinsonism Relat Disord 2010;16:79–84.

[8] Pilleri M, Koutsikos K, Antonini A. Is there room for new non-dopaminergic treatments in Parkinson's disease? J Neural Transm 2012;120:349–52.

[9] Fox SH. Non-dopaminergic treatments for motor control in Parkinson's disease. Drugs 2013;73:1405–15.

[10] Olanow CW, Schapira A. Therapeutic prospects for Parkinson's disease. Ann Neurol 2013;74:337–47.

[11] Benarroch EE. Serotonergic modulation of basal ganglia circuits: complexity and therapeutic opportunities. Neurology 2009;73:880–6.

[12] Devos D, Defebvre L, Bordet R. Dopaminergic and non-dopaminergic pharmacological hypotheses for gait disorders in Parkinson's disease. Fundam Clin Pharmacol 2010;24:407–21.

[13] Hallett M. Clinical neurophysiology of akinesia. Rev Neurol (Paris) 1990;146:585–90.

[14] Favre E, Ballanger B, Thobois S, Broussolle E, Boulinguez P. Deep brain stimulation of the subthalamic nucleus, but not dopaminergic medication, improves proactive inhibitory control of movement initiation in Parkinson's disease. Neurotherapeutics 2013;10:154–67.

[15] Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197–211.

[16] Rinvik E, Grofova I, Hammond C, Deniau JM, Feger J. Afferent connections to the subthalamic nucleus in the monkey and the cat studied with the HRP technique. New York: Raven Press; 1979. p. 53–70.

[17] Canteras NS, Shammah-Lagnado SJ, Silva BA, Ricardo JA. Afferent connections of the subthalamic nucleus: a combined retrograde and anterograde horse-radish peroxidase study in the rat. Brain Res 1990;513:43–59.

[18] Parent A, Hazrati LN. Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidium in basal ganglia circuitry. Brain Res Rev 1995;20:128–54.

[19] Belujon P, Bezard E, Taupignon A, Bioulac B, Benazzouz A. Noradrenergic modulation of subthalamic nucleus activity: behavioral and electrophysiological evidence in intact and 6-hydroxydopamine-lesioned rats. J Neurosci 2007;27:9595–606.

[20] Delaville C, Deurwaerdère PD, Benazzouz A. Noradrenaline and Parkinson's disease. Front Syst Neurosci 2011;5:31.

[21] Devos D, Krystkowiak P, Clement F, et al. Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson's disease. J Neurol Neurosurg Psychiatry 2007;78:470–5.

[22] Thobois S, Ardouin C, Lhmomm E, et al. Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation. Brain 2010;133:1111–27.

[23] Moreau C, Delval A, Defebvre L, et al. Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol 2012;11:589–96.

[24] Coenen VA, Gielen FLH, Castro-Prado F, Abdel Rahman A, Honey CR. Noradrenergic modulation of subthalamic nucleus activity in human: metoprolol reduces spiking activity in microelectrode recordings during deep brain stimulation surgery for Parkinson's disease. Acta Neurochir 2008;150:757–62.
plausibility of our interpretation of the present behavioral results, namely that clonidine-induced activation of post-synaptic α2-AR interferes with STN-DBS effects by switching STN activity back to a pathological pattern that induces executive deficits.

## Relevance to non-dopaminergic approaches to medical and surgical therapies

The present results might open the way towards two different therapeutic perspectives. First, after surgery, PD patients under STN-DBS might develop impulsivity [46,47,74–77]. So far, management options are not entirely satisfactory as they mainly consist of reducing dopaminergic medications with the risk of developing the so-called dopamine agonist withdrawal syndrome [78–80]. The present results suggest that introducing α2-AR agonist might be relevant for reducing this aversive effect. In the same vein, clonidine has recently been shown to induce inhibition of glutamate release onto the ventral tegmental area (VTA) [81], a brain structure central to reward processing and addiction, which is overdosed by dopamine-replacement levels that are therapeutic for motor symptoms in PD patients with impulse control disorders [48,82]. Finally, it is worth mentioning that clonidine is effective in reducing impulsivity in other pathological conditions. This is especially the case for attention-deficit/hyperactivity disorder [83], Tourette's syndrome [84], and tic disorders [85,86].

Second, given that clonidine, an α2-AR agonist, induces specific executive deficits, it might be relevant to explore the effect of an α2-AR antagonist in PD. Indeed, it is tempting to speculate on the basis of the present results that this kind of agent might conversely improve these specific executive functions. We obviously have in mind the potential benefit of a complementary α2-AR antagonist medication on refractory symptoms such as akinesia. In fact, it has previously been shown that α2-AR antagonists improve tremor and rigidity in the reserpinized rat [87], have a potent effect on levodopa-induced dyskinesia (LID) in a monkey model of PD [88,89], and can extend the anti-Parkinsonian effect of levodopa in MPTP-treated monkeys [90,91]. In PD patients, although conflicting results have been reported, preliminary clinical trials have suggested that this therapeutic approach reduces bradykinesia and rigidity [92] as well as LID when given in combination with levodopa [93]. In other terms, there is a broad spectrum of possible outcomes for this class of drugs, but its effects on movement initiation control have so far never been explored.

In light of the aforementioned studies, the importance of the possible interaction between noradrenergic and dopaminergic medications must be stressed out. Although our data did not provide direct evidence in favor of this hypothesis, the results of the correlation between the behavioral marker of the effect of clonidine and the LED neither allowed rejecting this possibility. It is clear, especially from the animal literature, that there is a cross-talk between the noradrenergic and dopaminergic systems [94]. For instance, NA activity from the LC might modulate dopamine (DA) neuronal activity in the VTA [95–97], as well as DA can influence the neuronal activity of LC-NA neurons since the LC is reciprocally innervated by the VTA [97,98]. Further studies are needed to address the issue of the mutual modulations of the noradrenergic and dopaminergic systems in humans, in relation with the acknowledged role of the latter in ICD [48,99,100]. In particular, a deeper understanding of the interplay between VTA, LC and the two input stations of the BG (Striatum and STN) may reveal a deeper insight into the possible combined influence of noradrenergic and dopaminergic medications on motor and inhibitory control.

In conclusion, we assume that clinical symptoms such as akineic freezing (possibly linked to the inability to release proactive

inhibitory control) or impulsivity (possibly linked to the inability to implement proactive inhibitory control), which probably represent the opposite ends of the same continuum of executive dysfunction [14,45,101], might benefit from different medications targeting NA dysfunction [102]. Obviously, the present study only provides a proof-of-concept, and further pharmacological investigations are warranted to support this hypothesis.

## Acknowledgments

The authors thank the Hospices Civils de Lyon for promoting this research program.

## References

[1] Chaudhuri KR, Healy DG, Schapira AH. Non-motor symptoms of Parkinson's disease: diagnosis and management. Lancet Neurol 2006;5:235–45.

[2] Antonelli F, Ray N, Strafella AP. Imaging cognitive and behavioral symptoms in Parkinson's disease. Neurotherapeutics 2010;10:1827–38.

[3] Weintraub D, Burn DJ. Parkinson's disease: the quintessential neuropsychiatric disorder. Mov Disord 2011;26:1022–31.

[4] Barone P. Neurotransmission in Parkinson's disease: beyond dopamine. Eur J Neurol 2010;17:364–76.

[5] Ferrer I, López-Gonzalez I, Carmona M, Dalfó E, Pujol A, Martínez A. Neurochemistry and the non-motor aspects of PD. Neurobiol Dis 2012;46:508–26.

[6] Braak H, Ghebremedhin E, Rüb U, Bratzke H, Del Tredici K. Stages in the development of Parkinson's disease-related pathology. Cell Tissue Res 2004;318:121–34.

[7] Hawkes CH, Del Tredici K, Braak H. A timeline for Parkinson's disease. Parkinsonism Relat Disord 2010;16:79–84.

[8] Pilleri M, Koutsikos K, Antonini A. Is there room for new non-dopaminergic treatments in Parkinson's disease? J Neural Transm 2012;120:349–52.

[9] Fox SH. Non-dopaminergic treatments for motor control in Parkinson's disease. Drugs 2013;73:1405–15.

[10] Olanow CW, Schapira A. Therapeutic prospects for Parkinson's disease. Ann Neurol 2013;74:337–47.

[11] Benarroch EE. Serotonergic modulation of basal ganglia circuits: complexity and therapeutic opportunities. Neurology 2009;73:880–6.

[12] Devos D, Defebvre L, Bordet R. Dopaminergic and non-dopaminergic pharmacological hypotheses for gait disorders in Parkinson's disease. Fundam Clin Pharmacol 2010;24:407–21.

[13] Hallett M. Clinical neurophysiology of akinesia. Rev Neurol (Paris) 1990;146:585–90.

[14] Favre E, Ballanger B, Thobois S, Broussolle E, Boulinguez P. Deep brain stimulation of the subthalamic nucleus, but not dopaminergic medication, improves proactive inhibitory control of movement initiation in Parkinson's disease. Neurotherapeutics 2013;10:154–67.

[15] Braak H, Del Tredici K, Rüb U, de Vos RAI, Jansen Steur ENH, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 2003;24:197–211.

[16] Rinvik E, Grofova I, Hammond C, Deniau JM, Feger J. Afferent connections to the subthalamic nucleus in the monkey and the cat studied with the HRP technique. New York: Raven Press; 1979. p. 53–70.

[17] Canteras NS, Shammah-Lagnado SJ, Silva BA, Ricardo JA. Afferent connections of the subthalamic nucleus: a combined retrograde and anterograde horse-radish peroxidase study in the rat. Brain Res 1990;513:43–59.

[18] Parent A, Hazrati LN. Functional anatomy of the basal ganglia. II. The place of subthalamic nucleus and external pallidium in basal ganglia circuitry. Brain Res Rev 1995;20:128–54.

[19] Belujon P, Bezard E, Taupignon A, Bioulac B, Benazzouz A. Noradrenergic modulation of subthalamic nucleus activity: behavioral and electrophysiological evidence in intact and 6-hydroxydopamine-lesioned rats. J Neurosci 2007;27:9595–606.

[20] Delaville C, Deurwaerdère PD, Benazzouz A. Noradrenaline and Parkinson's disease. Front Syst Neurosci 2011;5:31.

[21] Devos D, Krystkowiak P, Clement F, et al. Improvement of gait by chronic, high doses of methylphenidate in patients with advanced Parkinson's disease. J Neurol Neurosurg Psychiatry 2007;78:470–5.

[22] Thobois S, Ardouin C, Lhmomm E, et al. Non-motor dopamine withdrawal syndrome after surgery for Parkinson's disease: predictors and underlying mesolimbic denervation. Brain 2010;133:1111–27.

[23] Moreau C, Delval A, Defebvre L, et al. Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial. Lancet Neurol 2012;11:589–96.

[24] Coenen VA, Gielen FLH, Castro-Prado F, Abdel Rahman A, Honey CR. Noradrenergic modulation of subthalamic nucleus activity in human: metoprolol reduces spiking activity in microelectrode recordings during deep brain stimulation surgery for Parkinson's disease. Acta Neurochir 2008;150:757–62.
[25] Sabbar M, Delaville C, De Deurwaerdère P, Benazzouz A, Lakhdar-Ghazal N. Lead intoxication induces noradrenaline depletion, motor nonmotor disabilities, and changes in the firing pattern of subthalamic nucleus neurons. Neuroscience 2012;210:375–83.

[26] Delaville C, Chetrit J, Abdallah K, et al. Emerging dysfunctions consequent to combined monoaminergic depletions in parkinsonism. Neurobiol Dis 2012;45:463–73.

[27] Marien MR, Colpaert FC, Rosenquist AC. Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res Brain Res Rev 2004;45: 38–78.

[28] Ardouin C, Chereau I, Llorca PM, et al. Assessment of hyper- and hypodopaminergic behaviours in Parkinson's disease. Rev Neurol 2009;165: 845–56.

[29] Jaffard M, Benraiss A, Longcamp M, Velay J-L, Boulinguez P. Cueing method biases in visual detection studies. Brain Res 2007;1179:106–18.

[30] Jaffard M, Longcamp M, Velay J-L, et al. Proactive inhibitory control of movement assessed by event-related fMRI. NeuroImage 2008;42:1196–206.

[31] Criaud M, Wardak C, Ben Hamed S, Ballanger B, Boulinguez P. Proactive inhibitory control of response as the default state of executive control. Front Psychol 2012;3:59.

[32] Boulinguez P, Jaffard M, Granjon L, Benraiss A. Warning signals induce automatic EMG activations and proactive volitional inhibition: evidence from analysis of error distribution in simple RT. J Neurophysiol 2008;99:1572–8.

[33] Moro E, Lozano AM, Pollak P, et al. Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease. Mov Disord 2010;25(5):578–86.

[34] Nambu A. Seven problems on the basal ganglia. Curr Opin Neurobiol 2008;18:595–604.

[35] Obeso JA, Lanciego JL. Past, present, and future of the pathophysiological model of the basal ganglia. Front Neuroanat 2011;12:5–39.

[36] Haynes WIA, Haber SN. The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for basal ganglia models and deep brain stimulation. J Neurosci 2013;33:4804–14.

[37] Jin X, Tecuapetla F, Costa RM. Basal ganglia subcircuits distinctively encode the parsing and concatenation of action sequences. Nat Neurosci 2014;17: 423–30.

[38] Guimarães J, Moura E, Silva E, Aguiar P, Garrett C, Vieira-Coelho MA. Locus coeruleus is involved in weight loss in a rat model of Parkinson's disease: an effect reversed by deep brain stimulation. Brain Stimul 2013;6:845–55.

[39] Hung AY, Schwarzschild MA. Treatment of Parkinson's disease: what's in the non-dopaminergic pipeline? Neurotherapeutics 2013;11:34–46.

[40] Stocchi F. Therapy for Parkinson's disease: what is in the pipeline? Neurotherapeutics 2013;11:24–33.

[41] Wagle Shukla A, Okun MS. Surgical treatment of Parkinson's disease: patients, targets, devices, and approaches. Neurotherapeutics 2013;11:47–59.

[42] AIDakheel A, Kalia LV, Lang AE. Pathogenesis-targeted, disease-modifying therapies in Parkinson disease. Neurotherapeutics 2013;11:6–23.

[43] Ray N, Antonelli F, Strafella AP. Imaging impulsivity in Parkinson's disease and the contribution of the subthalamic nucleus. Parkinsons Dis 2011: 594860.

[44] Bari A, Robbins TW. Inhibition and impulsivity: behavioral and neural basis of response control. Prog Neurobiol 2013;108:44–79.

[45] Ballanger B, van Eimeren T, Moro E, et al. Stimulation of the subthalamic nucleus and impulsivity: release your horses. Ann Neurol 2009;66:817–24.

[46] Frank MJ, Samanta J, Moustafa AA, Sherman SJ. Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism. Science 2007;318: 1309–12.

[47] Lim S-Y, O'Sullivan SS, Kotschet K, et al. Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease. J Clin Neurosci 2009;16:1148–52.

[48] Cilia R, van Eimeren T. Impulse control disorders in Parkinson's disease: seeking a roadmap toward a better understanding. Brain Struct Funct 2011; 216:289–99.

[49] Hershey T, Campbell MC, Videen TO, et al. Mapping Go-No-Go performance within the subthalamic nucleus region. Brain 2010;133:3625–34.

[50] Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990;13:266–71.

[51] Mink JW. The basal ganglia: focused selection and inhibition of competing motor programs. Prog Neurobiol 1996;50:381–425.

[52] Nambu A, Tokuno H, Takada M. Functional significance of the cortico-subthalamo-pallidal "hyperdirect" pathway. Neurosci Res 2002;43:111–7.

[53] Nambu A. A new dynamic model of the cortico-basal ganglia loop. Prog Brain Res 2004;143:461–6.

[54] Criaud M, Boulinguez P. Have we been asking the right questions when assessing response inhibition in go/no-go tasks with fMRI? A meta-analysis and critical review. Neurosci Biobehav Rev 2013;37:11–23.

[55] Hikosaka O, Isoda M. Switching from automatic to controlled behavior: cortico-basal ganglia mechanisms. Trends Cogn Sci 2010;14:154–61.

[56] Forstmann BU, Anwander A, Schäfer A, et al. Cortico-striatal connections predict control over speed and accuracy in perceptual decision making. Proc Natl Acad Sci U S A 2010;107:15916–20.

[57] Chiu Y-C, Aron AR. Unconsciously triggered response inhibition requires an executive setting. J Exp Psychol Gen 2014;143:56–61.

[58] Oswal A, Litvak V, Brucke C, et al. Cognitive factors modulate activity within the human subthalamic nucleus during voluntary movement in Parkinson's disease. J Neurosci 2013;33:15815–26.

[59] Kühn AA, Williams D, Kupsch A, et al. Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance. Brain 2004;127:735–46.

[60] Benis D, Davis O, Lachaux JP, et al. Subthalamic nucleus activity dissociates proactive and reactive inhibition in patients with Parkinson's disease. Neuroimage 2014;91:273–81.

[61] Ballanger B, Gil R, Audiffren M, Desmurget M. Perceptual factors contribute to akinesia in Parkinson's disease. Exp Brain Res 2007;179:245–53.

[62] Robbins TW. From arousal to cognition: the integrative role of the prefrontal cortex. Prog Brain Res 2000;126:469–83.

[63] Usher M, Cohen JD, Servan-Schreiber D, Rajkowski J, Aston-Jones G. The role of locus coeruleus in the regulation of cognitive performance. Science 1999;283:549–54.

[64] Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 2009;10:211–23.

[65] Petersen SE, Posner MI. The attention system of the human brain: 20 years after. Annu Rev Neurosci 2012;35:73–89.

[66] Aston-Jones G, Cohen JD. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol 2005;493: 99–110.

[67] Albares M, Criaud M, Wardak C, Nguyen SCT, Hamed SB, Boulinguez P. Attention to baseline: does orienting visuospatial attention really facilitate target detection? J Neurophysiol 2011;106:809–16.

[68] Chamberlain SR, Robbins TW. Noradrenergic modulation of cognition: therapeutic implications. J Psychopharmacol 2013;27:694–718.

[69] Benazzouz A, Breit S, Koudsie A, Pollak P, Krack P, Benabid AL. Intraoperative microrecordings of the subthalamic nucleus in Parkinson's disease. Mov Disord 2002;17:S145–9.

[70] Hutchinson WD, Allan RJ, Opitz H, et al. Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease. Ann Neurol 1998;44:622–8.

[71] Ballanger B, Criaud M, Poisson A, et al. Noradrenergic modulation of movement initiation control in Parkinson's disease: a pharmacological fMRI study with clonidine. Mov Disord 2014;29(S1):S134–5.

[72] Devoto P, Flore G, Saba P, Fà M, Gessa GL. Stimulation of the locus coeruleus elicits noradrenaline and dopamine release in the medial prefrontal and parietal cortex. J Neurochem 2005;92:368–74.

[73] Lapiz MDS, Morilak DA. Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability. Neuroscience 2006;137:1039–49.

[74] Serranová T, Sieger T, Dusek P, et al. Sex, food and threat: startling changes after subthalamic stimulation in Parkinson's disease. Brain Stimul 2013;6: 740–5.

[75] Volkmann J, Daniels C, Witt K. Neuropsychiatric effects of subthalamic neurostimulation in Parkinson disease. Nat Rev Neurol 2010;6:487–98.

[76] Rodriguez-Oroz MC, López-Azcárate J, Garcia-Garcia D, et al. Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson's disease. Brain 2011;134:36–49.

[77] Catsrioto A, Lhommee E, Moro E, Krack P. Review mood and behavioural effects of subthalamic stimulation in Parkinson's disease. Lancet Neurol 2014;13:287–305.

[78] Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol 2010;67:58–63.

[79] Pondal M, Marras C, Miyasaki J, et al. Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic. J Neurol Neurosurg Psychiatry 2013;84:130–5.

[80] Edwards MJ. Dopamine agonist withdrawal syndrome (DAWS): perils of flicking the dopamine "switch". J Neurol Neurosurg Psychiatry 2013;84:120.

[81] Jiménez-Rivera CA, Figueroa J, Vázquez-Torres R, et al. Presynaptic inhibition of glutamate transmission by α2 receptors in the VTA. Eur J Neurosci 2012;35:1406–15.

[82] Cools R. Dopaminergic modulation of cognitive function-implications for l-DOPA treatment in Parkinson's disease. Neurosci Biobehav Rev 2006;30:1–23.

[83] Sallee F, Connor DF, Newcorn JH. A review of the rationale and clinical utilization of α2-adrenoceptor agonists for the treatment of attention-deficit/hyperactivity and related disorders. J Child Adolesc Psychopharmacol 2013;23:308–19.

[84] Waldon K, Hill J, Termine C, Balottin U, Cavanna AE. Trials of pharmacological interventions for Tourette syndrome: a systematic review. Behav Neurol 2013;26:265–73.

[85] Singer HS. Treatment of tics and Tourette syndrome. Curr Treat Options Neurol 2010;12:539–61.

[86] Weisman H, Qureshi IA, Leckman JF, Scahill L, Bloch MH. Systematic review: pharmacological treatment of tic disorders – efficacy of antipsychotic and alpha-2 adrenergic agonist agents. Neurosci Biobehav Rev 2013;37: 1162–71.

[87] Colpaert FC. Pharmacological characteristics of tremor, rigidity and hypokinesia induced by reserpine in rat. Neuropharmacology 1987;26:1431–40.

[88] Bezard E, Brefel C, Tison F, et al. Effect of the alpha 2 adrenoreceptor antagonist, idazoxan, on motor disabilities in MPTP-treated monkey. Prog Neuropsychopharmacol Biol Psychiatry 1999;23:1237–46.
[25] Sabbar M, Delaville C, De Deurwaerdère P, Benazzouz A, Lakhdar-Ghazal N. Lead intoxication induces noradrenaline depletion, motor nonmotor disabilities, and changes in the firing pattern of subthalamic nucleus neurons. Neuroscience 2012;210:375–83.

[26] Delaville C, Chetrit J, Abdallah K, et al. Emerging dysfunctions consequent to combined monoaminergic depletions in parkinsonism. Neurobiol Dis 2012;45:463–73.

[27] Marien MR, Colpaert FC, Rosenquist AC. Noradrenergic mechanisms in neurodegenerative diseases: a theory. Brain Res Brain Res Rev 2004;45: 38–78.

[28] Ardouin C, Chereau I, Llorca PM, et al. Assessment of hyper- and hypodopaminergic behaviours in Parkinson's disease. Rev Neurol 2009;165: 845–56.

[29] Jaffard M, Benraiss A, Longcamp M, Velay J-L, Boulinguez P. Cueing method biases in visual detection studies. Brain Res 2007;1179:106–18.

[30] Jaffard M, Longcamp M, Velay J-L, et al. Proactive inhibitory control of movement assessed by event-related fMRI. NeuroImage 2008;42:1196–206.

[31] Criaud M, Wardak C, Ben Hamed S, Ballanger B, Boulinguez P. Proactive inhibitory control of response as the default state of executive control. Front Psychol 2012;3:59.

[32] Boulinguez P, Jaffard M, Granjon L, Benraiss A. Warning signals induce automatic EMG activations and proactive volitional inhibition: evidence from analysis of error distribution in simple RT. J Neurophysiol 2008;99:1572–8.

[33] Moro E, Lozano AM, Pollak P, et al. Long-term results of a multicenter study on subthalamic and pallidal stimulation in Parkinson's disease. Mov Disord 2010;25(5):578–86.

[34] Nambu A. Seven problems on the basal ganglia. Curr Opin Neurobiol 2008;18:595–604.

[35] Obeso JA, Lanciego JL. Past, present, and future of the pathophysiological model of the basal ganglia. Front Neuroanat 2011;12:5–39.

[36] Haynes WIA, Haber SN. The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for basal ganglia models and deep brain stimulation. J Neurosci 2013;33:4804–14.

[37] Jin X, Tecuapetla F, Costa RM. Basal ganglia subcircuits distinctively encode the parsing and concatenation of action sequences. Nat Neurosci 2014;17: 423–30.

[38] Guimarães J, Moura E, Silva E, Aguiar P, Garrett C, Vieira-Coelho MA. Locus coeruleus is involved in weight loss in a rat model of Parkinson's disease: an effect reversed by deep brain stimulation. Brain Stimul 2013;6:845–55.

[39] Hung AY, Schwarzschild MA. Treatment of Parkinson's disease: what's in the non-dopaminergic pipeline? Neurotherapeutics 2013;11:34–46.

[40] Stocchi F. Therapy for Parkinson's disease: what is in the pipeline? Neurotherapeutics 2013;11:24–33.

[41] Wagle Shukla A, Okun MS. Surgical treatment of Parkinson's disease: patients, targets, devices, and approaches. Neurotherapeutics 2013;11:47–59.

[42] AIDakheel A, Kalia LV, Lang AE. Pathogenesis-targeted, disease-modifying therapies in Parkinson disease. Neurotherapeutics 2013;11:6–23.

[43] Ray N, Antonelli F, Strafella AP. Imaging impulsivity in Parkinson's disease and the contribution of the subthalamic nucleus. Parkinsons Dis 2011: 594860.

[44] Bari A, Robbins TW. Inhibition and impulsivity: behavioral and neural basis of response control. Prog Neurobiol 2013;108:44–79.

[45] Ballanger B, van Eimeren T, Moro E, et al. Stimulation of the subthalamic nucleus and impulsivity: release your horses. Ann Neurol 2009;66:817–24.

[46] Frank MJ, Samanta J, Moustafa AA, Sherman SJ. Hold your horses: impulsivity, deep brain stimulation, and medication in parkinsonism. Science 2007;318: 1309–12.

[47] Lim S-Y, O'Sullivan SS, Kotschet K, et al. Dopamine dysregulation syndrome, impulse control disorders and punding after deep brain stimulation surgery for Parkinson's disease. J Clin Neurosci 2009;16:1148–52.

[48] Cilia R, van Eimeren T. Impulse control disorders in Parkinson's disease: seeking a roadmap toward a better understanding. Brain Struct Funct 2011; 216:289–99.

[49] Hershey T, Campbell MC, Videen TO, et al. Mapping Go-No-Go performance within the subthalamic nucleus region. Brain 2010;133:3625–34.

[50] Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990;13:266–71.

[51] Mink JW. The basal ganglia: focused selection and inhibition of competing motor programs. Prog Neurobiol 1996;50:381–425.

[52] Nambu A, Tokuno H, Takada M. Functional significance of the cortico-subthalamo-pallidal "hyperdirect" pathway. Neurosci Res 2002;43:111–7.

[53] Nambu A. A new dynamic model of the cortico-basal ganglia loop. Prog Brain Res 2004;143:461–6.

[54] Criaud M, Boulinguez P. Have we been asking the right questions when assessing response inhibition in go/no-go tasks with fMRI? A meta-analysis and critical review. Neurosci Biobehav Rev 2013;37:11–23.

[55] Hikosaka O, Isoda M. Switching from automatic to controlled behavior: cortico-basal ganglia mechanisms. Trends Cogn Sci 2010;14:154–61.

[56] Forstmann BU, Anwander A, Schäfer A, et al. Cortico-striatal connections predict control over speed and accuracy in perceptual decision making. Proc Natl Acad Sci U S A 2010;107:15916–20.

[57] Chiu Y-C, Aron AR. Unconsciously triggered response inhibition requires an executive setting. J Exp Psychol Gen 2014;143:56–61.

[58] Oswal A, Litvak V, Brucke C, et al. Cognitive factors modulate activity within the human subthalamic nucleus during voluntary movement in Parkinson's disease. J Neurosci 2013;33:15815–26.

[59] Kühn AA, Williams D, Kupsch A, et al. Event-related beta desynchronization in human subthalamic nucleus correlates with motor performance. Brain 2004;127:735–46.

[60] Benis D, Davis O, Lachaux JP, et al. Subthalamic nucleus activity dissociates proactive and reactive inhibition in patients with Parkinson's disease. Neuroimage 2014;91:273–81.

[61] Ballanger B, Gil R, Audiffren M, Desmurget M. Perceptual factors contribute to akinesia in Parkinson's disease. Exp Brain Res 2007;179:245–53.

[62] Robbins TW. From arousal to cognition: the integrative role of the prefrontal cortex. Prog Brain Res 2000;126:469–83.

[63] Usher M, Cohen JD, Servan-Schreiber D, Rajkowski J, Aston-Jones G. The role of locus coeruleus in the regulation of cognitive performance. Science 1999;283:549–54.

[64] Sara SJ. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci 2009;10:211–23.

[65] Petersen SE, Posner MI. The attention system of the human brain: 20 years after. Annu Rev Neurosci 2012;35:73–89.

[66] Aston-Jones G, Cohen JD. Adaptive gain and the role of the locus coeruleus-norepinephrine system in optimal performance. J Comp Neurol 2005;493: 99–110.

[67] Albares M, Criaud M, Wardak C, Nguyen SCT, Hamed SB, Boulinguez P. Attention to baseline: does orienting visuospatial attention really facilitate target detection? J Neurophysiol 2011;106:809–16.

[68] Chamberlain SR, Robbins TW. Noradrenergic modulation of cognition: therapeutic implications. J Psychopharmacol 2013;27:694–718.

[69] Benazzouz A, Breit S, Koudsie A, Pollak P, Krack P, Benabid AL. Intraoperative microrecordings of the subthalamic nucleus in Parkinson's disease. Mov Disord 2002;17:S145–9.

[70] Hutchinson WD, Allan RJ, Opitz H, et al. Neurophysiological identification of the subthalamic nucleus in surgery for Parkinson's disease. Ann Neurol 1998;44:622–8.

[71] Ballanger B, Criaud M, Poisson A, et al. Noradrenergic modulation of movement initiation control in Parkinson's disease: a pharmacological fMRI study with clonidine. Mov Disord 2014;29(S1):S134–5.

[72] Devoto P, Flore G, Saba P, Fà M, Gessa GL. Stimulation of the locus coeruleus elicits noradrenaline and dopamine release in the medial prefrontal and parietal cortex. J Neurochem 2005;92:368–74.

[73] Lapiz MDS, Morilak DA. Noradrenergic modulation of cognitive function in rat medial prefrontal cortex as measured by attentional set shifting capability. Neuroscience 2006;137:1039–49.

[74] Serranová T, Sieger T, Dusek P, et al. Sex, food and threat: startling changes after subthalamic stimulation in Parkinson's disease. Brain Stimul 2013;6: 740–5.

[75] Volkmann J, Daniels C, Witt K. Neuropsychiatric effects of subthalamic neurostimulation in Parkinson disease. Nat Rev Neurol 2010;6:487–98.

[76] Rodriguez-Oroz MC, López-Azcárate J, Garcia-Garcia D, et al. Involvement of the subthalamic nucleus in impulse control disorders associated with Parkinson's disease. Brain 2011;134:36–49.

[77] Catsrioto A, Lhommee E, Moro E, Krack P. Review mood and behavioural effects of subthalamic stimulation in Parkinson's disease. Lancet Neurol 2014;13:287–305.

[78] Rabinak CA, Nirenberg MJ. Dopamine agonist withdrawal syndrome in Parkinson disease. Arch Neurol 2010;67:58–63.

[79] Pondal M, Marras C, Miyasaki J, et al. Clinical features of dopamine agonist withdrawal syndrome in a movement disorders clinic. J Neurol Neurosurg Psychiatry 2013;84:130–5.

[80] Edwards MJ. Dopamine agonist withdrawal syndrome (DAWS): perils of flicking the dopamine "switch". J Neurol Neurosurg Psychiatry 2013;84:120.

[81] Jiménez-Rivera CA, Figueroa J, Vázquez-Torres R, et al. Presynaptic inhibition of glutamate transmission by α2 receptors in the VTA. Eur J Neurosci 2012;35:1406–15.

[82] Cools R. Dopaminergic modulation of cognitive function-implications for l-DOPA treatment in Parkinson's disease. Neurosci Biobehav Rev 2006;30:1–23.

[83] Sallee F, Connor DF, Newcorn JH. A review of the rationale and clinical utilization of α2-adrenoceptor agonists for the treatment of attention-deficit/hyperactivity and related disorders. J Child Adolesc Psychopharmacol 2013;23:308–19.

[84] Waldon K, Hill J, Termine C, Balottin U, Cavanna AE. Trials of pharmacological interventions for Tourette syndrome: a systematic review. Behav Neurol 2013;26:265–73.

[85] Singer HS. Treatment of tics and Tourette syndrome. Curr Treat Options Neurol 2010;12:539–61.

[86] Weisman H, Qureshi IA, Leckman JF, Scahill L, Bloch MH. Systematic review: pharmacological treatment of tic disorders – efficacy of antipsychotic and alpha-2 adrenergic agonist agents. Neurosci Biobehav Rev 2013;37: 1162–71.

[87] Colpaert FC. Pharmacological characteristics of tremor, rigidity and hypokinesia induced by reserpine in rat. Neuropharmacology 1987;26:1431–40.

[88] Bezard E, Brefel C, Tison F, et al. Effect of the alpha 2 adrenoreceptor antagonist, idazoxan, on motor disabilities in MPTP-treated monkey. Prog Neuropsychopharmacol Biol Psychiatry 1999;23:1237–46.
[89] Savola J-M, Hill M, Engstrom M, et al. Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Mov Disord 2003;18:872–83.

[90] Henry B, Fox SH, Peggs D, Crossman AR, Brotchie JM. The alpha2-adrenergic receptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of L-dopa in the MPTP-lesioned primate model of Parkinson's disease. Mov Disord 1999;14:744–53.

[91] Domino EF, Ni L, Colpaert F, Marien M. Effects of (+/-)-idazoxan alone and in combination with L-DOPA methyl ester in MPTP-induced hemiparkinsonian monkeys. Receptors Channels 2003;9:335–8.

[92] Brefel-Courbon C, Thalamas C, Saint Paul HP. α2-adrenoceptor antagonists. CNS Drugs 1998;10:189–207.

[93] Rascol O, Arnulf I, Peyro-Saint-Paul H, et al. Idazoxan, an alpha-2 antagonist, and L-DOPA-induced dyskinesias in patients with Parkinson's disease. Mov Disord 2001;16:708–13.

[94] Guiard BP, El Mansari M, Blier P. Cross-talk between dopaminergic and noradrenergic systems in the rat ventral tegmental area, locus coeruleus, and dorsal hippocampus. Mol Pharmacol 2008;74(5): 1463–75.

[95] Simon H, Le Moal M, Stinus L, Calas A. Anatomical relationships between the ventral mesencephalic tegmentum—a 10 region and the locus coeruleus as demonstrated by anterograde and retrograde tracing techniques. J Neural Transm 1979;44:77–86.

[96] Lee A, Wissekerke AE, Rosin DL, Lynch KR. Localization of alpha2C-adrenergic receptor immunoreactivity in catecholaminergic neurons in the rat central nervous system. Neuroscience 1998;84:1085–96.

[97] Guiard BP, El Mansari M, Merali Z, Blier P. Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysiological study in rats with monoaminergic lesions. Int J Neuropsychopharmacol 2008;11(5):625–39.

[98] Ornstein K, Milon H, McRae-Degueurce A, Alvarez C, Berger B, Wurzner HP. Biochemical and radioautographic evidence for dopaminergic afferents of the locus coeruleus originating in the ventral tegmental area. J Neural Transm 1987;70:183–91.

[99] Castrioto A, Funkiewiez A, Debû B, et al. Iowa gambling task impairment in Parkinson's disease can be normalised by reduction of dopaminergic medication after subthalamic stimulation. J Neurol Neurosurg Psychiatry 2014;13(3):287–305.

[100] Antonelli F, Ko JH, Miyasaki J, et al. Dopamine-agonists and impulsivity in Parkinson's disease: impulsive choices vs. impulsive actions. Hum Brain Mapp 2014;35(6):2499–506.

[101] Jahanshahi M. Effects of deep brain stimulation of the subthalamic nucleus on inhibitory and executive control over prepotent responses in Parkinson's disease. Front Syst Neurosci 2013;25(7):118.

[102] Kehagia AA, Housden CR, Regenthal R, Barker RA, Müller U, Rowe J, Sahakian BJ, Robbins TW. Targeting impulsivity in Parkinson's disease using atomoxetine. Brain 2014;137(7):1986–97.
[89] Savola J-M, Hill M, Engstrom M, et al. Fipamezole (JP-1730) is a potent alpha2 adrenergic receptor antagonist that reduces levodopa-induced dyskinesia in the MPTP-lesioned primate model of Parkinson's disease. Mov Disord 2003;18:872–83.

[90] Henry B, Fox SH, Peggs D, Crossman AR, Brotchie JM. The alpha2-adrenergic re-ceptor antagonist idazoxan reduces dyskinesia and enhances anti-parkinsonian actions of L-dopa in the MPTP-lesioned primate model of Parkinson's disease. Mov Disord 1999;14:744–53.

[91] Domino EF, Ni L, Colpaert F, Marien M. Effects of (+/-)-idazoxan alone and in combination with L-DOPA methyl ester in MPTP-induced hemiparkinsonian monkeys. Receptors Channels 2003;9:335–8.

[92] Brefel-Courbon C, Thalamas C, Saint Paul HP. α2-adrenoceptor antagonists. CNS Drugs 1998;10:189–207.

[93] Rascol O, Arnulf I, Peyro-Saint-Paul H, et al. Idazoxan, an alpha-2 antagonist, and L-DOPA-induced dyskinesias in patients with Parkinson's disease. Mov Disord 2001;16:708–13.

[94] Guiard BP, El Mansari M, Blier P. Cross-talk between dopaminergic and noradrenergic systems in the rat ventral tegmental area, locus coeruleus, and dorsal hippocampus. Mol Pharmacol 2008;74(5): 1463–75.

[95] Simon H, Le Moal M, Stinus L, Calas A. Anatomical relationships between the ventral mesencephalic tegmentum—a 10 region and the locus coeruleus as demonstrated by anterograde and retrograde tracing techniques. J Neural Transm 1979;44:77–86.

[96] Lee A, Wissekerke AE, Rosin DL, Lynch KR. Localization of alpha2C-adrenergic receptor immunoreactivity in catecholaminergic neurons in the rat central nervous system. Neuroscience 1998;84:1085–96.

[97] Guiard BP, El Mansari M, Merali Z, Blier P. Functional interactions between dopamine, serotonin and norepinephrine neurons: an in-vivo electrophysio-logical study in rats with monoaminergic lesions. Int J Neuropsychopharmacol 2008;11(5):625–39.

[98] Ornstein K, Milon H, McRae-Degueurce A, Alvarez C, Berger B, Wurzner HP. Biochemical and radioautographic evidence for dopaminergic afferents of the locus coeruleus originating in the ventral tegmental area. J Neural Transm 1987;70:183–91.

[99] Castrioto A, Funkiewiez A, Debû B, et al. Iowa gambling task impairment in Parkinson's disease can be normalised by reduction of dopaminergic medi-cation after subthalamic stimulation. J Neurol Neurosurg Psychiatry 2014;13(3):287–305.

[100] Antonelli F, Ko JH, Miyasaki J, et al. Dopamine-agonists and impulsivity in Parkinson's disease: impulsive choices vs. impulsive actions. Hum Brain Mapp 2014;35(6):2499–506.

[101] Jahanshahi M. Effects of deep brain stimulation of the subthalamic nucleus on inhibitory and executive control over prepotent responses in Parkinson's disease. Front Syst Neurosci 2013;25(7):118.

[102] Kehagia AA, Housden CR, Regenthal R, Barker RA, Müller U, Rowe J, Sahakian BJ, Robbins TW. Targeting impulsivity in Parkinson's disease using atomoxetine. Brain 2014;137(7):1986–97.