Subthalamic stimulation improves orienting gaze movements in Parkinson’s disease

Clinical Neurophysiology 119 (2008) 1857–1863 www.elsevier.com/locate/clinph

Subthalamic stimulation improves orienting gaze movements in Parkinson’s disease Paul Sauleaua, Pierre Pollakb,c, Paul Krackb,c, Jean-Hubert Courjond,e, Alain Vighettod,e, Alim-Louis Benabidb,c, Denis Pe´lissond,e, Caroline Tiliketed,e,* a Department of Neurophysiology, University Hospital of Rennes, University of Rennes 1, France Department of Clinical and Biological Neurosciences, University Hospital of Grenoble, Grenoble, France c INSERM U 318, University of Grenoble 1, Grenoble, France d UMR-S 864 INSERM Espace et Action, University of Lyon 1, 16 av Doyen Lepine, 69676 Bron, France e Neuro-Ophthalmology Unit, University Hospital of Lyon, Hospices Civils de Lyon, University of Lyon 1, Bron, France b

Accepted 16 April 2008

Abstract Objective: To determine the effect of subthalamic stimulation on visually triggered eye and head movements in patients with Parkinson’s disease (PD). Methods: We compared the gain and latency of visually triggered eye and head movements in 12 patients bilaterally implanted into the subthalamic nucleus (STN) for severe PD and six age-matched control subjects. Visually triggered movements of eye (head restrained), and of eye and head (head unrestrained) were recorded in the absence of dopaminergic medication. Bilateral stimulation was turned OFF and then turned ON with voltage and contact used in chronic setting. The latency was determined from the beginning of initial horizontal eye movements relative to the target onset, and the gain was defined as the ratio of the amplitude of the initial movement to the amplitude of the target movement. Results: Without stimulation, the initiation of the head movement was significantly delayed in patients and the gain of head movement was reduced. Our patients also presented significantly prolonged latencies and hypometry of visually triggered saccades in the head-fixed condition and of gaze in head-free condition. Bilateral STN stimulation with therapeutic parameters improved performance of orienting gaze, eye and head movements towards the controls’ level Conclusions: These results demonstrate that visually triggered saccades and orienting eye–head movements are impaired in the advanced stage of PD. In addition, subthalamic stimulation enhances amplitude and shortens latency of these movements. Significance: These results are likely explained by alteration of the information processed by the superior colliculus (SC), a pivotal visuomotor structure involved in both voluntary and reflexive saccades. Improvement of movements with stimulation of the STN may be related to its positive input either on the STN–Substantia Nigra–SC pathway or on the parietal cortex–SC pathway. Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. Keywords: Parkinson’s disease; Subthalamic stimulation; Visually triggered saccades; Gaze movements; Head movements

1. Introduction Orienting movements involve the coordination of different parts of the body such as the eyes, the head and the * Corresponding author. Address: UMR-S 864 INSERM Espace et Action, University of Lyon 1, 16 av Doyen Lepine, 69676 Bron, France. Tel.: +33 4 72 91 34 28; fax: +33 4 72 91 34 01. E-mail address: [email protected] (C. Tilikete).

trunk, shifting the gaze from one point to another in space. Voluntary self-triggered orienting movements may be distinguished from less intentional orienting movements, triggered by a newly occurring target (Pierrot-Deseilligny, 1994). In Parkinson’s disease (PD), as part of the general motor impairment, disturbances of these orienting movements may participate in the handicap of the patients. At the initial stages of the disease, voluntary orienting sac-

1388-2457/$34.00 Ó 2008 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.clinph.2008.04.013

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cades are hypometric and delayed (Briand et al., 1999). Visually triggered saccades seem to be impaired in more severe stages of the disease (White et al., 1983; Warabi et al., 1986; Rascol et al., 1989; Kitagawa et al., 1994). Only few studies questioned more ecological orienting movements such as visually triggered eye and head movements (Kennard et al., 1982; Bronstein and Kennard, 1985; White et al., 1988; Hansen et al., 1990). A positive effect of stimulation of the subthalamic nucleus (STN) on memorized saccades has already been established but has never been tested on gaze and head performance (Rivaud-Pechoux et al., 2000). To this aim, the current study was designed (1) to compare visually triggered eye, head and gaze (combined eye and head) shifts performances of patients with severe PD and without medical treatment with the performances of healthy subjects, and (2) to assess the effect of subthalamic stimulation on such movements. The underlying objective was to assess the role of the STN in the control of visually triggered head and eye movements (gaze shifts).

2. Methods 2.1. Subjects Twelve patients (Table 1) bilaterally implanted into the STN for severe PD aged 53 ± 6 (mean ± SD) years were compared to six healthy volunteers aged 54 ± 4 years. Both the groups had the same gender ratio (50%). Motor evaluation was performed with the stimulation turned OFF (Stim OFF) and with bilateral stimulation (Stim ON), without medication (Med OFF) and after administration of a suprathreshold dose of levodopa (Med ON). The score of the Unified Parkinson’s Disease Rating Scale (UPDRS) part III is given in Table 1 for each condition. The antiparkinsonian effect was achieved with monopolar stimulation (60 ls, 130 Hz) through a quadripolar electrode (DBS-

3389, Medtronic, Minneapolis, MN). Patients had no other organic pathology, neither cognitive deterioration. With chronic parameters, no patients experienced any stimulation-induced eyelid or ocular disturbances i.e. ipsilateral ocular deviation (attributed to current spread into oculomotor nuclei or nerve fibers), conjugate eye movements or eyelid opening apraxia. Eye and head movements were recorded after a 12-h overnight withdrawal of antiparkinsonian medication, with a mean post-implantation delay of 17 months. All subjects provided written informed consent before the tests and the procedure was approved by the Ethical Committee of our Institution. 2.2. Eye and head movement recording Eye movements were recorded in darkness with a helmet bearing two infrared cameras registering eye image at 250 Hz frequency (SMI EyeLink system, Germany). Horizontal and vertical positions of each eye in the orbit were measured in real time by a method of contrast detection. Head movements were recorded using two infrared transmitters fixed 20 cm apart sagittally on the helmet. Sagittal and antero-posterior positions of each transmitter were recorded at 200 Hz frequency through a third infrared camera (Hamamatsu) fixed on the ceiling of the exploration room. Eye and head position signals were simultaneously sampled at 400 Hz by an acquisition software (DataWave software, Berthoud, USA). 2.3. Visual stimulation design Target presentation (DataWave software, Berthoud, USA) consisted in illumination of diodes situated at 0°, 11° or 32° in the head-fixed condition and 0°, 32° or 40° in the head-free condition, on each side of the sagittal plane. Distance of the targets from the eyes was 1.04 m and the size of the targets was 3 mm. Targets were pre-

Table 1 Characteristics of the 12 patients included in the study Patient

1 2 3 4 5 6 7 8 9 10 11 12

Age

54 44 55 57 65 52 58 55 55 52 46 49

Disease’s duration (years)

9 7 10 14 8 9 17 11 20 15 10 7

UPDRS (Part III)

Dopaminergic medication (mg)

STN stimulation (Volts)

Before implantation

One year after implantation

Med OFF

Med ON

Stim OFF/ Med OFF

Stim ON/ Med OFF

Stim OFF/ Med ON

Stim ON/ Med ON

Before implantation

Date of tests

Right

Left

25.5 48.5 57.5 43.5 34.5 27.5 36.0 28.0 63.5 35.5 46.0 48

6.5 8.0 16.0 7.5 11.0 4 19.5 5.0 15.5 14.0 8.0 23

36 26.5 33 52 44.5 48 38.0 19.5 42.0 40.0 31.0 36.5

20 8 24 30.5 17.5 28.5 22.5 10.5 17.5 19.5 7.0 20.5

8.5 4.5 19.5 13 10 9 22 5.0 13.5 19.5 10.0 14

6.5 3 13.5 7.5 7 5 20 5.0 10.5 10.5 5.5 7

975 1050 725 975 705 1325 800 1050 1400 860 2050 1000

150 300 200 300 240 500 390 175 1000 0 400 150

3.2 2.5 3.3 2.4 2.2 3.6 3.5 1.6 3.2 2.2 2.7 3.5

3.1 2.0 2.4 2.5 2.4 3.3 3.4 3.0 3.4 2.9 3.2 2.2

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sented successively, first in the central position, then in the lateral position, and then back to the central position. Patients were instructed to gaze toward the newly illuminated diode as soon as it appeared. There were four lateral target locations for each condition, presented in an unpredictable order. Furthermore, timing was randomized at two times, 3.4 and 3.8 s, in the head-fixed condition and at two times, 2.7 and 3.1 s, in the head-free condition. Head-free condition was performed first in order to get head movements as natural as possible, unimpeded by any interference from a previous head restrained condition. In a second set, the head was restrained on a chin holder (head-fixed condition). Data acquisition started immediately after each target presentation and lasted 2.2 s in the head-free condition and 1.5 s in the head-fixed condition. A block of 40 saccades, 10 for each target, was performed for each condition. 2.4. Stimulation parameters In both the head-free and head-fixed conditions, recordings started after the stimulation had been turned OFF bilaterally for at least 30 min. Eye and head movements were then recorded with bilateral stimulation turned ON with the voltage and the contact used in a chronic setting for each patient.

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of groups of subjects (control vs. patient with stimulation turned OFF), and the effect of target location (four locations). Then, repeated-measures two-way ANOVAs tested the effect of stimulation in the patient group (patient with stimulation turned OFF vs. patient with stimulation turned ON, within-subject’s factor), and the effect of target location (four locations, within-subject’s factor). Finally, twoway ANOVAs tested the effect of groups of subjects (control vs. patient with stimulation turned ON), and the effect of target location (four locations). All the statistics were performed using Statistica software (Statsoft France). A 95% confidence interval was used to establish statistical significance. 3. Results The mean values of the six variables and the statistical results are summarized in Table 2. During recording, patients did not experience any stimulation-induced eyelid or ocular disturbance or dyskinesia in limbs, head or eyes. Rejected data represented 18% of the total sample. The first paragraph presents the effect of PD on orienting movements by comparing patients OFF with controls. The second paragraph deals with the effect of stimulation in the group of patients. The last paragraph compares patients ON and controls.

2.5. Data analysis Cyclopean eye position, computed as the average data from the two eyes, was considered for all the subsequent data analyses. In the head-free condition, we recorded the amplitude of the displacement of gaze in space (=eye in the orbit + head in space). Thus, in the following, we will refer the movements of eyes in the head-fixed condition as saccades and the movements of gaze (combined eye– head saccades) in the head-free condition as gaze shifts. After waveform filtering (FIR low-pass filter, 70-Hz cutoff), eye and head movements were detected on the basis of velocity threshold criteria of 40 and 15°/s, respectively. Rejected data included traces contaminated by eyelid blinks, gaze shifts or saccades starting at more than 5° from the fixation stimulus or with a latency outside a 90 to 700 ms range. The latency of saccades and gaze shifts was determined by the recorded time when the primary (initial) horizontal eye movement reaches the velocity threshold. The gain of each response was calculated as the ratio between the movement amplitude (final position minus initial position of gaze or head) and the expected amplitude of the initial movement (target position minus initial position of gaze or head). Six variables were therefore used for statistical analysis: gain and latency of either saccades (headfixed), gaze (head-free) and head (head-free). 2.6. Statistical analysis Statistical analysis was performed separately on these six variables. First of all, two-way ANOVAs tested the effect

3.1. Comparison of controls vs. patients with stimulation turned OFF 3.1.1. Head-free condition We observed a main effect of ‘group’ on gaze gain [F(1, 64) = 22, p < 0.001], head gain [F(1, 64) = 8, p < 0.01], gaze latency [F(1, 64) = 19, p < 0.001] and head latency [F(1, 64) = 20, p < 0.001] in the head-free condition. This main effect was due to reduced gaze gain and head gain, and increased gaze latency and head latency in the patient group as compared to the control group. We did not observe any effect of target position nor interaction of target position and group on gaze gain (position effect: F(3, 64) = 1, p = 0.3; interaction effect: F(3, 64) = 1, p = 0.4), head gain (position effect: F(3, 64) = 0.3, p = 0.8; interaction effect: F(3, 64) = 0.07, p = 1), gaze latency (position effect: F(3, 64) = 1, p = 0.4; interaction effect: F(3, 64) = 0.3, p = 0.8) and head latency (position effect: F(3, 64) = 0.3, p = 0.8; interaction effect: F(3, 64) = 0.1, p = 1). 3.1.2. Head-fixed condition We observed a main effect of ‘group’ on saccade gain [F(1, 64) = 17, p < 0.001] and saccade latency [F(1, 64) = 16, p < 0.001] in the head-fixed condition. This main effect was due to reduced saccade gain and increased saccade latency in the patient group as compared to the control group. We observed an effect of target position on saccade gain [F(3, 64) = 5, p < 0.01]. This effect was due to reduced

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Table 2 Mean and standard deviation (SD) of latency and gain of eye (in head-fixed condition), or gaze (in head-free condition) for controls and patients with the stimulation turned OFF (Stim OFF) and turned ON (Stim ON) for the four targets Head free Controls

Head fixed Patients Stim OFF

Controls *

p

Stim ON

Gaze/saccade latency (ms) 40° 301 ± 72 32° 280 ± 63 11° 11° 32° 277 ± 41 40° 272 ± 44

413 ± 107 395 ± 99

350 ± 110 362 ± 111

346 ± 76 349 ± 79

316 ± 93 316 ± 90

Means ± SD

376 ± 96

282 ± 57

<0.001

336 ± 105

Gaze/saccade gain (%) 40° 87 ± 5 32° 88 ± 3 11° 11° 32° 95 ± 7 40° 92 ± 3

69 ± 18 79 ± 15

78 ± 15 82 ± 11

79 ± 19 64 ± 20

87 ± 9 80 ± 22

Means ± SD

72 ± 20

91 ± 5

Head latency (ms) 40° 312 ± 38 32° 305 ± 17 32° 297 ± 23 40° 292 ± 32

454 ± 144 455 ± 153 425 ± 120 407 ± 122

Means ± SD

302 ± 28

435 ± 138

Head gain (%) 40° 32° 32° 40°

40 ± 11 41 ± 12 41 ± 14 43 ± 13

29 ± 19 31 ± 22 27 ± 20 26 ± 17

Means ± SD

41 ± 12

28 ± 20

* **

<0.001

82 ± 15

**

p

Patients Stim OFF

0.05 ns

ns ns <0.05

<0.001

237 ± 32 201 ± 17 192 ± 17 218 ± 27

318 ± 99 238 ± 55 225 ± 41 308 ± 63

212 ± 28

272 ± 80

90 ± 5 94 ± 7 93 ± 7 87 ± 3

73 ± 18 83 ± 14 89 ± 11 61 ± 20

91 ± 6

77 ± 19

p*

Stim ON

p**

254 ± 60 205 ± 46 198 ± 23 269 ± 59 <0.001

231 ± 59

<0.001

84 ± 14 84 ± 13 99 ± 20 86 ± 19 <0.01

88 ± 18

<0.001

341 ± 91 388 ± 87 359 ± 94 338 ± 83 <0.001

356 ± 92

<0.001

43 ± 19 45 ± 25 42 ± 19 41 ± 17 <0.001

43 ± 20

<0.001

Effect of group (controls and patients) using two-way ANOVAs. Effect of stimulation (OFF and ON) in the patient group using repeated-measures ANOVAs.

saccade gain for leftward saccades as compared to rightward saccades in either group. We did not observe any effect of target position on saccade latency [F(3, 64) = 1, p = 0.4], neither any interaction effect on saccade gain [F(3, 64) = 2, p = 0.2] and saccade latency [F(3, 64) = 0,3, p = 0.8]. In summary, patients showed impairment of both eye and head movements as compared to controls. Latencies of movement were prolonged and gains of both eyes and head were decreased. In many trials, the hypometric primary saccade was followed by an increased number of small corrective saccades so gaze and eye movements were decomposed in a succession of many low-amplitude steps (Fig. 1). 3.2. Comparison of patients with stimulation turned OFF vs. ON The following data pertain to the change in eye and head movements related to subthalamic stimulation since patients were recorded without dopaminergic medication.

3.2.1. Head-free condition We observed a main effect of ‘stimulation’ on gaze gain [F(1, 44) = 13, p < 0.001], head gain [F(1, 44) = 46, p < 0.001], gaze latency [F(1, 44) = 7, p < 0.05] and head latency [F(1, 44) = 16, p < 0.001]. This effect was due to increased gaze gain and head gain, and decreased gaze latency and head latency with stimulation ON. We did not observe any effect of target position nor interaction between treatment and target position on gaze gain (position effect: F(3, 44) = 2, p = 0.2; interaction effect: F(3, 44) = 1, p = 0.5), head gain (position effect: F(3, 44) = 0.1, p = 1; interaction effect: F(3, 44) = 0.03, p = 1), gaze latency (position effect: F(3, 44) = 1, p = 0.3; interaction effect: F(3, 44) = 0.3, p = 1) and head latency (position effect: F(3, 44) = 0.5, p = 1; interaction effect: F(3, 44) = 0.3, p = 0.8). 3.2.2. Head-fixed condition We observed a main effect of ‘stimulation’ on saccade gain [F(1, 44) = 16, p < 0.001] and saccade latency [F(1, 44) = 38, p < 0.001] in the head-fixed condition. This main

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Fig. 1. Representative gaze, eye and head movements of a control subject (top left) and of one parkinsonian patient, with both stimulators OFF (bottom left) and with bilateral chronic stimulation (bottom right) for a target located at 32° on the right, in the head-free condition. Positive values in degrees indicate movements to the right. Taking into account the initial position of gaze and head, the primary gain for gaze was 91% for the control, 35% for the patient without stimulation and 92% with stimulation ON. In comparison to the control subject, head movement of the patient with stimulation OFF was delayed and hypometric while eye movements were decomposed in a succession of low-amplitude steps. The latency and the gain of both head and eye movements tended to normalize with the stimulation turned ON.

effect was due to increased saccade gain and decreased saccade latency with stimulation ON. We observed an effect of target position on saccade gain [F(3, 44) = 5, p < 0.01] and interaction between stimulation and target position [F(3, 44) = 3, p < 0.05]. This effect was due to a larger increase in saccade gain for leftward saccades than for rightward saccades. We observed an effect of target position on saccade latency [F(3, 44) = 6, p = 0.01], but no interaction between treatment and target position [F(3, 44) = 1, p = 0.2]. This was due to larger latencies for leftward saccades as compared to rightward saccades, combined with a similar stimulation-related decrease of latency for both directions of saccades. In summary, with stimulation ON as compared to stimulation OFF, all eye and head parameters improved in the patient group (see Fig. 1). 3.3. Comparison of controls vs. patients with stimulation turned ON 3.3.1. Head-free condition We observed a persistent main effect of ‘group’ on gaze gain [F(1, 64) = 7, p < 0.01], gaze latency [F(1, 64) = 5, p < 0.05] and head latency [F(1, 64) = 8, p < 0.01] in the head-free condition. This main group-effect was due to a persistent reduced gaze gain, and increased gain latency and head latency in the patient group as compared to the control group. Only head gain was no more statistically dif-

ferent between the control group and the patient group [F(1, 64) = 0.1, p = 0.8]. We did not observe any effect of target position nor interaction of target position and group on gaze gain (position effect: F(3, 64) = 1, p = 0.3; interaction effect: F(3, 64) = 0.2, p = 0.9), head gain (position effect: F(3, 64) = 0.03, p = 1; interaction effect: F(3, 64) = 0.06, p = 1), gaze latency (position effect: F(3, 64) = 0.5, p = 0.7; interaction effect: F(3, 64) = 0.2, p = 0.9) and head latency (position effect: F(3, 64) = 0.5, p = 0.7; interaction effect: F(3, 64) = 0.3, p = 0.78). 3.3.2. Head-fixed condition We did not observe any remaining difference between control group and patient group on saccade gain [F(1, 64) = 0.6, p = 0.4] nor on saccade latency [F(1, 64) = 3, p = 0.09]. We did not observe any effect of target position on saccade gain [F(3, 64) = 1, p = 0.3] nor any interaction effect on saccade gain [F(3, 64) = 0.9, p = 0.5]. We observed an effect of target position on saccade latency [F(3, 64) = 6, p < 0.05], but no interaction between group and target position [F(3, 64) = 1, p = 0.4]. This observed effect of target position was due to larger latencies for leftward saccades as compared to rightward saccades, combined with a similar grouprelated difference of latency for both directions of saccades. In summary, with stimulation ON, the data in the patient group tended to normalize toward the controls’ val-

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ues. However, this normalization reached statistical significance only for head gain in the head-free condition and saccade gain and latency in the head-fixed condition. 4. Discussion In this study, we first showed that our patient group in an advanced stage of PD presented a severe impairment of orienting eye and head movements with reduced gain and increased latency in both the head-free and head-fixed conditions, as compared to controls. Second, we showed that bilateral STN stimulation with therapeutic parameters improved the performance of orienting gaze, eye and head movements that tended towards controls’ performance. Since mild voltages were applied and no adverse effect was induced by stimulation, the improvement was strongly considered to be secondary to stimulation of the STN itself and not to the diffusion of current to the neighboring structures. In patients with severe PD, impairment in orienting eye and head movements is likely to reflect the global akinetic/bradykinetic manifestation of the disease and similarly, STN stimulation may have a positive effect on both limb and eye/head movements. In the following, we will first compare the data obtained in our patients with the previous studies, then discuss the potential pathophysiological explanation of eye and head impairment and the effect of STN stimulation in our patients. Without stimulation, the initiation of head movement was significantly delayed and the gain of head movement was reduced in patients as compared to controls. Impairment of orienting movements of the head has already been demonstrated in patients with PD and it has been proposed that untreated patients preferentially used a gaze strategy based upon ocular rather than head movements (Kennard et al., 1982; Bronstein and Kennard, 1985; White et al., 1988; Hansen et al., 1990). As for reflexive saccades, head movements seem to be preserved at the initial stage of the disease but impaired in the advanced stage (White et al., 1988; Waterston et al., 1996). In addition, the present study shows that these impaired head orienting movements are improved by STN stimulation. Beside its role in the control of eye movement, our results suggest that the STN is involved in the control of orienting head movement. Our patients also presented significantly prolonged latencies and hypometry of visually triggered saccades in the head-fixed condition and of gaze in the head-free condition. We already introduced the notion that voluntary orienting saccades are hypometric and delayed at the initial stages of the disease (Briand et al., 1999, 2001), while more reflexive saccades can be impaired in more severe stages of the disease (White et al., 1983; Warabi et al., 1986; Rascol et al., 1989; Kitagawa et al., 1994). Predominant impairment of voluntary saccades finds its explanation in models of basal ganglia networks. As for other motor behaviours in general, the basal ganglia and the fronto-striatal pathway are thought to be mainly involved in the control of

voluntary (or internally generated) saccades (Hikosaka et al., 2000). The fronto-striatal visual inputs are then transmitted through inhibitory GABAergic projections to the substantia nigra pars reticulata (SNpr) and from there to the superior colliculus (SC) (Hikosaka and Wurtz, 1989). The STN should be involved in this eye movement network. Indeed, there are direct projections from the FEF to the STN (Fujimoto and Kita, 1993; Huerta et al., 1986; Stanton et al., 1988), and eye movement-related activity has been recorded in subthalamic neurons (Fawcett et al., 2005; Matsumura et al., 1992). In monkeys, unilateral GABAergic inactivation of the STN induced contralateral gaze deviation when performed inside but not outside the nucleus (Baron et al., 2002). Finally, memorized saccades were also improved by subthalamic stimulation in patients with PD (Rivaud-Pechoux et al., 2000). In contrast, initiation of reflexive saccade (triggered by the unpredictable presentation of a new target) would arise in the posterior parietal cortex (PPC) directly connected to the SC, bypassing the basal ganglia modulation (Pierrot-Deseilligny, 1994). In this study, we found that patients with severe PD (the mean UPDRS III score before surgery off medication was 41/108) had impaired performance in visually triggered orienting movements and that subthalamic stimulation tended to normalize this performance. This suggests that the STN is also involved in the control of involuntary (self-initiated) visually triggered orienting eye and head movements. In line with the model described above, impairment of involuntary visually triggered saccades in patients with severe PD might be first explained by alteration of the information processed by the SC, a pivotal visuomotor structure involved in both voluntary and reflexive saccades. Neurons in the intermediate layer of the SC project to the pontine paramedian reticular formation that generates saccades (Hepp et al., 1989). The SC receives inhibitory inputs from the SNpr via uncrossed and crossed nigro-collicular projections. During ocular fixation, uncrossed nigro-collicular projection neurons show a strong inhibitory activity. Phasic disruption of this uncrossed SNpr inhibition is thus considered to be crucial for saccade initiation (Hikosaka and Wurtz, 1989). On the other hand, crossed nigro-collicular projection neurons show an inhibitory activity during saccade initiation (Jiang et al., 2003). This suggests that the SNpr can facilitate the collicular visuomotor activity for saccade initiation (uncrossed) and at the same time suppress the activity associated with potentially competing distractors (crossed). The STN projects through glutamatergic excitatory neurons to the SNpr. Since neurons in the STN show a phasic increase in activity during a visually triggered saccade, the STN is considered to inhibit unwanted saccades and facilitate purposive saccadic eye movements (Matsumura et al., 1992; Hikosaka et al., 2000; Fawcett et al., 2005). We might therefore suggest that impairment of orienting movements in this study and in previous studies on patients with severe PD (White et al., 1983; Warabi et al., 1986; Rascol et al., 1989; Kitagawa et al., 1994) may

P. Sauleau et al. / Clinical Neurophysiology 119 (2008) 1857–1863

result from altered control of the SC by the couple STN– SNpr. This would result from the massive dopaminergic loss encountered in the advanced stages of the disease. Improvement of movements with stimulation would then be conveyed by the same pathway. On the basis of the similarities between skeletal motor and oculomotor control by the basal ganglia (Hikosaka et al., 2000), we suggest that, in severe PD, the abnormal STN activity, either considering its abnormal firing rate (Hutchison et al., 1998) or firing pattern (Hutchison et al., 2004), affects the functioning of the nigro-collicular pathway and impairs all saccades performance. In turn, subthalamic high-frequency stimulation shows beneficial effects on this pathological STN activity , even though the underlying mechanisms are still debated (Garcia et al., 2005). As for motor control, we suggest that subthalamic stimulation would restore a more physiological activity within the SNpr, releasing consequently the superior colliculus. Alternatively, the extension of the degenerative process to the posterior parietal cortex and to the parieto-collicular pathway is also highly presumed (Mentis et al., 2002). In this line, subthalamic stimulation would improve the performance of orienting movements through its positive effect on parietal cortex (Trost et al., 2006). These two mechanisms are not mutually exclusive. The positive effect on orienting movements observed in patients with STN stimulation may thus have an additional benefit on the improvement of their global motor status. References Baron MS, Wichmann T, Ma D, DeLong MR. Effects of transient focal inactivation of the basal ganglia in parkinsonian primates. J Neurosci 2002;22:592–9. Briand KA, Strallow D, Hening W, Poizner H, Sereno AB. Control of voluntary and reflexive saccades in Parkinson’s disease. Exp Brain Res 1999;129:38–48. Briand KA, Hening W, Poizner H, Sereno AB. Automatic orienting of visuospatial attention in Parkinson’s disease. Neuropsychologia 2001;39:1240–9. Bronstein AM, Kennard C. Predictive ocular motor control in Parkinson’s disease. Brain 1985;108(Pt. 4):925–40. Fawcett AP, Dostrovsky JO, Lozano AM, Hutchison WD. Eye movement-related responses of neurons in human subthalamic nucleus. Exp Brain Res 2005;162:357–65. Fujimoto K, Kita H. Response characteristics of subthalamic neurons to the stimulation of the sensorimotor cortex in the rat. Brain Res 1993;609:185–92. Garcia L, D’Alessandro G, Bioulac B, Hammond C. High-frequency stimulation in Parkinson’s disease: more or less? Trends Neurosci 2005;28:209–16. Hansen HC, Gibson JM, Zangemeister WH, Kennard C. The effect of treatment on eye–head coordination in Parkinson’s disease. J Vestibul Res 1990;1:181–6. Hepp K, Henn V, Vilis T, Cohen B. Brainstem regions related to saccade generation. Rev Oculomot Res 1989;3:105–212.

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