Deep Brain Stimulation of the Pedunculopontine Nucleus Area in Parkinson Disease: MRI-Based Anatomoclinical Correlations and Optimal Target

Deep Brain Stimulation of the Pedunculopontine Nucleus Area in Parkinson Disease: MRI-Based... Abstract BACKGROUND Experimental studies led to testing of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) as a new therapy to treat freezing of gait (FOG) in Parkinson disease (PD). Despite promising initial results fueling a growing interest toward that approach, several clinical studies reported heterogeneity in patient responses. Variation in the position of electrode contacts within the rostral brainstem likely contributes to such heterogeneity. OBJECTIVE To provide anatomoclinical correlations of the effect of DBS of the caudal mesencephalic reticular formation (cMRF) including the PPN to treat FOG by comparing the normalized positions of the active contacts among a series of 11 patients at 1- and 2-yr follow-up and to provide an optimal target through an open-label study. METHODS We defined a brainstem normalized coordinate system in relation to the pontomesencephalic junction. Clinical evaluations were based on a composite score using objective motor measurements and questionnaires allowing classification of patients as “bad responders” (2 patients), “mild responders” (1 patient) and “good responders” (6 patients). Two patients, whose long-term evaluation could not be completed, were excluded from the analysis. RESULTS Most effective DBS electrode contacts to treat FOG in PD patients were located in the posterior part of the cMRF (encompassing the posterior PPN and cuneiform nucleus) at the level of the pontomesencephalic junction. CONCLUSION In the present exploratory study, we performed an anatomoclinical analysis using a new coordinate system adapted to the brainstem in 9 patients who underwent PPN area DBS. We propose an optimal DBS target that allows a safe and efficient electrode implantation in the cMRF. Pedunculopontine nucleus, Deep brain stimulation, Parkinson disease, Freezing of gait, Cuneiform nucleus, Mesencephalic reticular formation, Mesencephalic locomotor region ABBREVIATIONS ABBREVIATIONS BNCS brainstem normalized coordinate system ChAT choline acetyltransferase cMRF caudal mesencephalic reticular formation DBS deep brain stimulation FOG freezing of gait MRI magnetic resonance imaging PC posterior commissure PD Parkinson disease PMJ pontomesencephalic junction PPN pedunculopontine nucleus STN subthalamic nucleus UPDRS unified Parkinson Disease Rating Scale The caudal mesencephalic reticular formation (cMRF) contains 2 structures involved in the supraspinal control of locomotion: the pedunculopontine nucleus (PPN; Nucleus tegmentalis pedunculopontinus) and the cuneiform nucleus (CfN; Nucleus cuneiformis).1-5 Because of the limited knowledge of the precise anatomy of the caudal mesencephalon in humans,6 in a previous study we also referred to this region as a PPN area.7 TABLE 1. Clinical and Demographic Characteristics of the Patients at the Time of Inclusion Patients #1 #2 #3 #4 #5 #6 #7 Mean ± SD Patients (1-7) #8 #9 #10 #11 Mean ± SD Patients (8-11) Sex M F M M F M M M F M M Age at PD diagnosis 55 50 49 44 31 27 36 41.7 ± 10.5 32 63 38 42 43.8 ± 11.7 Age at STN surgery 64 64 65 53 53 47 52 56.9 ± 7.3 – – – – – Age at MRF surgery 68 68 72 57 59 56 61 63.0 ± 6.3 60 71 65 63 64.8 ± 4 Disease duration 13 18 23 13 28 29 28 21.3 ± 6.7 28 8 27 22 21.3 ± 8 LEDD (mg) 1025 550 800 1170 400 0 890 678 ± 397 578 636 610 760 646 ± 80 Improvement in UPDRS motor score ON levodopa/OFF STN stim. (%) 55 23 23 44 46 NLTa 63 – 42 5 51 21 – FOG (OFF med) 4 3 3 3 1 3 3 – 4 3 3 3 – FOG (ON med) 4 3 3 0 1 – 3 2 3 2 2 Postural instability (OFF med)b yes yes yes no yes yes no – yes yes no no Postural instability (ON med) yes yes yes no no – no yes yes no no Giladi FOG score (/24) 16 20 23 11 16 16 16 20 19 19 19 Patients #1 #2 #3 #4 #5 #6 #7 Mean ± SD Patients (1-7) #8 #9 #10 #11 Mean ± SD Patients (8-11) Sex M F M M F M M M F M M Age at PD diagnosis 55 50 49 44 31 27 36 41.7 ± 10.5 32 63 38 42 43.8 ± 11.7 Age at STN surgery 64 64 65 53 53 47 52 56.9 ± 7.3 – – – – – Age at MRF surgery 68 68 72 57 59 56 61 63.0 ± 6.3 60 71 65 63 64.8 ± 4 Disease duration 13 18 23 13 28 29 28 21.3 ± 6.7 28 8 27 22 21.3 ± 8 LEDD (mg) 1025 550 800 1170 400 0 890 678 ± 397 578 636 610 760 646 ± 80 Improvement in UPDRS motor score ON levodopa/OFF STN stim. (%) 55 23 23 44 46 NLTa 63 – 42 5 51 21 – FOG (OFF med) 4 3 3 3 1 3 3 – 4 3 3 3 – FOG (ON med) 4 3 3 0 1 – 3 2 3 2 2 Postural instability (OFF med)b yes yes yes no yes yes no – yes yes no no Postural instability (ON med) yes yes yes no no – no yes yes no no Giladi FOG score (/24) 16 20 23 11 16 16 16 20 19 19 19 aNo levodopa treatment. bScore ≥ 2/4 on item 29 UPDRS III. PD = Parkinson disease; STN: subthalamic nucleus; cMRF: caudal mesencephalic reticular formation; UPDRS: Unified Parkinson Disease Rating Scale; med: medication; FOG: freezing of gait; Stim: stimulation; LEDD: levodopa equivalent daily dose.15 View Large TABLE 1. Clinical and Demographic Characteristics of the Patients at the Time of Inclusion Patients #1 #2 #3 #4 #5 #6 #7 Mean ± SD Patients (1-7) #8 #9 #10 #11 Mean ± SD Patients (8-11) Sex M F M M F M M M F M M Age at PD diagnosis 55 50 49 44 31 27 36 41.7 ± 10.5 32 63 38 42 43.8 ± 11.7 Age at STN surgery 64 64 65 53 53 47 52 56.9 ± 7.3 – – – – – Age at MRF surgery 68 68 72 57 59 56 61 63.0 ± 6.3 60 71 65 63 64.8 ± 4 Disease duration 13 18 23 13 28 29 28 21.3 ± 6.7 28 8 27 22 21.3 ± 8 LEDD (mg) 1025 550 800 1170 400 0 890 678 ± 397 578 636 610 760 646 ± 80 Improvement in UPDRS motor score ON levodopa/OFF STN stim. (%) 55 23 23 44 46 NLTa 63 – 42 5 51 21 – FOG (OFF med) 4 3 3 3 1 3 3 – 4 3 3 3 – FOG (ON med) 4 3 3 0 1 – 3 2 3 2 2 Postural instability (OFF med)b yes yes yes no yes yes no – yes yes no no Postural instability (ON med) yes yes yes no no – no yes yes no no Giladi FOG score (/24) 16 20 23 11 16 16 16 20 19 19 19 Patients #1 #2 #3 #4 #5 #6 #7 Mean ± SD Patients (1-7) #8 #9 #10 #11 Mean ± SD Patients (8-11) Sex M F M M F M M M F M M Age at PD diagnosis 55 50 49 44 31 27 36 41.7 ± 10.5 32 63 38 42 43.8 ± 11.7 Age at STN surgery 64 64 65 53 53 47 52 56.9 ± 7.3 – – – – – Age at MRF surgery 68 68 72 57 59 56 61 63.0 ± 6.3 60 71 65 63 64.8 ± 4 Disease duration 13 18 23 13 28 29 28 21.3 ± 6.7 28 8 27 22 21.3 ± 8 LEDD (mg) 1025 550 800 1170 400 0 890 678 ± 397 578 636 610 760 646 ± 80 Improvement in UPDRS motor score ON levodopa/OFF STN stim. (%) 55 23 23 44 46 NLTa 63 – 42 5 51 21 – FOG (OFF med) 4 3 3 3 1 3 3 – 4 3 3 3 – FOG (ON med) 4 3 3 0 1 – 3 2 3 2 2 Postural instability (OFF med)b yes yes yes no yes yes no – yes yes no no Postural instability (ON med) yes yes yes no no – no yes yes no no Giladi FOG score (/24) 16 20 23 11 16 16 16 20 19 19 19 aNo levodopa treatment. bScore ≥ 2/4 on item 29 UPDRS III. PD = Parkinson disease; STN: subthalamic nucleus; cMRF: caudal mesencephalic reticular formation; UPDRS: Unified Parkinson Disease Rating Scale; med: medication; FOG: freezing of gait; Stim: stimulation; LEDD: levodopa equivalent daily dose.15 View Large Functionally, the area is also referred to as the mesencephalic locomotor region5 and is part of the reticular activating system.8 Deep brain stimulation (DBS) of the PPN was proposed as a new therapy to treat levodopa-resistant gait disorders in Parkinson disease (PD).9,10 Several studies stressed the variability of clinical responses6,7,11-13 possibly related to patient selection, stimulation parameters and/or position of the electrode within the PPN.14 Based on a new brainstem normalized coordinate system (BNCS) associated with the pontomesencephalic junction (PMJ), the aim of the present study was to evaluate the anatomoclinical correlations between active contacts position and clinical outcomes at 24 mo follow-up, in PD patients implanted in the cMRF for severe gait disorders. METHODS Patients Eleven patients with PD and severe gait disorders were included in a bilateral cMRF implantation protocol. The protocol was approved by the local ethic committee (06-CHUG-21) and all patients provided written informed consent. See Table 1 for patient clinical and demographic characteristics. Of the 11 patients, 7 had undergone a prior subthalamic nucleus (STN)-DBS electrode implantation. The 4 remaining patients received only bilateral cMRF-DBS electrodes. Inclusion and Exclusion Criteria Detailed criteria have previously been described.7 Briefly, patients were included if gait disorders and freezing of gait (FOG) were their main complaint, while other PD signs were satisfactorily controlled by medication and/or STN stimulation. Clinical Evaluation Evaluation was assessed using both objective motor measures and questionnaires. The same evaluations were carried out prior to surgery and 1 and 2 yr after, under both OFF and ON medication conditions. Assessments were performed after an overnight fasting and withdrawal of medication, and then after administration of 120% of the usual preoperative morning levodopa dose. STN stimulation was ON during the evaluations. Patient #6 was treated only by STN stimulation and therefore was not tested ON medication. Clinical evaluations included the unified Parkinson Disease Rating Scale (UPDRS) parts II (activities of daily living) and III (motor part), as well as a gait test including FOG provoking circumstances.7 A composite gait score was computed based on the sum of items 14 (freezing) and 15 (gait) of the UPDRS II and item 30 (gait) of the UPDRS III. Postural stability was examined using a composite score based on the sum of item 13 (falls unrelated to freezing) of UPDRS II and item 29 (postural stability) of UPDRS III. Quality of life was assessed using the PDQ-39, with special attention to the mobility subscore. For quantitative assessment, the gait test was performed while wearing adapted shoes (Stride Analyzer, B&L Engineering, Santa Ana, California) that enabled acquisition of foot-floor contact data. Finally, patients recorded FOG episodes and falls on a diary that was examined at each visit. Classification of the patients into good and bad responders was based on the results of the objective assessments 2 yr after surgery, the PDQ-39 scores, the patients’ diary and the clinical observation made during patients’ regular visits. When the sets of observations were not fully congruent, we favored those reflecting the daily condition of the patients. Imaging Protocol Preoperative 1.5 T, stereotactic T1 and T2 magnetic resonance images were acquired and fused (Voxim, Chemnitz, Germany). Ventriculographic landmarks were also obtained by direct injection of iopamiron® using perioperative X-ray sequences (BioScan, Geneva, Switzerland). Postoperative, T1, and T2 magnetic resonance imaging (MRI) control was performed in all patients. Targeting For the first 6 patients, cMRF targeting was performed with the central electrode trajectory parallel to the floor of the fourth ventricle, passing through posterior commissure (PC) plane with a 14°-20° lateromedian angle (see Figure 1). Target depth was set at –13 mm below PC and 6 mm lateral. Using a Bengun, a second trajectory was defined 2 mm posterior to the central one. An additional third trajectory was occasionally performed 2 mm anterior or lateral to the central trajectory. For the last 5 consecutive patients, we targeted the cMRF on purpose more posteriorly based on accumulated experience. Coordinates were AP = 2 to 3 mm posterior to PC, Lat = 6 mm; depth = level of the PMJ, angle adapted to the brainstem orientation. FIGURE 1. View largeDownload slide cMRF intraoperative biorthogonal X-ray. A, Final intraoperative X-Ray (lateral view) merged with the ventriculography sequence (lateral view) allowing a precise localization of the ventricular landmarks. Visualization of the aqueduct of Sylvius and the fourth ventricle allows determining a trajectory parallel to the floor of the fourth ventricle. B, Final intraoperative X-Ray (frontal view). Note that in A and B, the patient had undergone a prior STN DBS electrode implantation. C and D, Final intraoperative X-ray sequences (lateral view) with the 2 chronic DBS electrodes implanted in the cMRF. Note in C that the 2 electrodes are superimposed. FIGURE 1. View largeDownload slide cMRF intraoperative biorthogonal X-ray. A, Final intraoperative X-Ray (lateral view) merged with the ventriculography sequence (lateral view) allowing a precise localization of the ventricular landmarks. Visualization of the aqueduct of Sylvius and the fourth ventricle allows determining a trajectory parallel to the floor of the fourth ventricle. B, Final intraoperative X-Ray (frontal view). Note that in A and B, the patient had undergone a prior STN DBS electrode implantation. C and D, Final intraoperative X-ray sequences (lateral view) with the 2 chronic DBS electrodes implanted in the cMRF. Note in C that the 2 electrodes are superimposed. Surgery Surgery was performed under local anesthesia and was similar to that previously used in routine for all DBS cases.16-18 A chronic DBS electrode (Model 3389, Medtronic, Dublin, Ireland) was inserted along the trajectory in which the highest thresholds of side effect together with highest cell activities were obtained. Intraoperative Assessment of Micro and Macro/DBS Electrode Position Positions of the macro contacts were monitored all along the trajectory using a biorthogonal X-ray system (see Figure 1). The Brainstem Normalized Coordinate System To overcome brainstem anatomic variability, we defined a new BNCS based on rostral brainstem landmarks centered on the PMJ (see Figure 2; Appendix, Supplemental Digital Content 1). FIGURE 2. View largeDownload slide BNCS: definition on the axis and units based on rostral brainstem landmarks centered on the PMJ. MRI images in the right column illustrate the BNCS in axial-PMJ and midsagittal planes. Orientations are indicated in each image. Coordinates were defined based on the orthogonal projections on the 3 axes. Normalized coordinates were labeled as Xbn, Ybn, and Zbn for normalized brainstem laterality, anteriority and rostrocaudality, respectively. For details on coordinate calculation and normalization procedures, see Appendix, Supplemental Digital Content 1. FIGURE 2. View largeDownload slide BNCS: definition on the axis and units based on rostral brainstem landmarks centered on the PMJ. MRI images in the right column illustrate the BNCS in axial-PMJ and midsagittal planes. Orientations are indicated in each image. Coordinates were defined based on the orthogonal projections on the 3 axes. Normalized coordinates were labeled as Xbn, Ybn, and Zbn for normalized brainstem laterality, anteriority and rostrocaudality, respectively. For details on coordinate calculation and normalization procedures, see Appendix, Supplemental Digital Content 1. Normalization Procedure DBS active contact coordinates were first measured from X-Ray ventriculography in the Talairach system then transferred on the 3-D MRI according to the same ventricular landmarks and finally were plotted onto the BNCS. For normalization procedure, see Appendix, Supplemental Digital Content 1. Graphical Representation Three-dimensional graphical representations were created using a software developed in Python with the BrainVisa/Anatomist toolbox.19 All electrode contacts were displayed as spheres on a PD patient template image. For all patients, only cathode contacts were plotted. For patients who were stimulated using 1 anode and 2 cathodes, the 2 active contacts were included in the analysis. Immunohistochemistry Postmortem human brain tissue was obtained from a female deceased from a non-neurodegenerative disease. The choline acetyltransferase (ChAT), immunostaining was done using a standard immunoperoxidase method, as previously described.20 Statistics Description of active contact coordinates’ distribution was performed by calculating the mean, standard deviation and range. Mann–Whitney U-test was used to test the differences of normalized coordinates between the groups of responders. After verifying the normality of distributions, 2 (medication OFF–medication ON) by 3 (presurgery—12 mo of follow-up–24 mo of follow-up) ANOVAs with repeated measures for the 2 factors were performed to examine the effect of cMRF surgery on the composite gait score, composite postural stability score, and PDQ-mobility subscore. RESULTS Surgery Safety Surgery was uneventful. In patients who were implanted in STN prior to cMRF surgery, no single interference with the previous electrodes was noticed. One patient showed severe retropulsion postoperatively that resolved within a week. Another patient had 2 epileptic seizures 1 wk after surgery. These patients fully recovered from these adverse effects. No severe adverse event was recorded except in 1 patient (#9) who fell down due to postural instability both OFF and ON stimulation and resulted in a vertebral fracture. Postoperative MRI did not reveal any hematoma. At 2-yr follow-up, no hardware-related complications were reported. During surgery, microstimulation tests on each trajectory, at different depths, did not yield any clinical response regarding either akinesia or rigidity. Clinical Follow-up Detailed clinical evaluation of the cMRF DBS at 24 mo postsurgery is provided in Table 2. In patients with both STN and cMRF electrodes, STN stimulation parameters were unchanged after cMRF surgery. One patient (#8) was not evaluated at 12-mo follow-up, as he had stopped complying with the experimental protocol after the sixth month. Patient (#9) experienced a severe backward fall the week before the 12-mo follow-up evaluation. As postural instability has continued to worsen ever since, no postoperative evaluation has been carried out and cMRF stimulation was discontinued in this case. Therefore, postoperative evaluations were carried out on 9 patients. Yet, another patient (#3) displayed severe akinesia and was unable to perform the objective gait assessment when OFF medication at the 12-mo follow-up assessment. TABLE 2. Clinical Evaluation at 24 mo Postsurgery Bad responders Mild responder Good responders ON Stim cMRF 24-mo postsurgery P2 P6 P5 P1 P3 P4 P7 P10 P11 FOG (off med/on med) 4/4 3/– 1/1 2/0 2/1 2/0 1/0 0/0 3/3 Postural instability (off med/on med) 3/3 1/– 2/2 0/0 0/1 1/0 0/0 1/0 0/0 Giladi FOG score (/24) 22 18 12 13 14 11 8.5 0 15 Composite gait score E0/E24 (off med) 11/10.5 8/8.5 8/6 9.5/4 10.5/4 8/2 7/3 6.5/2 6.5/6.5 Composite gait score E0/E24 (on med) 8/10.5 – 6/5 9/0.5 9.5/3 0.5/0 5.5/1 8/2 8/7 % FOG during gait assessment E0/E24 (off med) 46.8/50.7 50.4/37.6 18.9/21.3 17.6/2.4 46.5/3.5 50.6/0 52.2/1.1 23.7/0.5 14.2/8.9 % FOG during gait assessment E0/E24 (on med) 25.1/39.3 – 8/1.7 25.5/4.1 68/6.7 5.4/0.8 7.2/0 28.4/0.1 14.8/38.1 PDQ E0/E24 12.9/14.1 10.7/8.2 7.3/9.7 6/5.7 8.1/5.1 MD/7.1 6.4/5 5/1.4 9.5/3.5 PDQ mobility subscore E0/E24 92.5/85 90/55 82.5/62.5 45/40 97.5/32.5 MD/22.5 55/22.5 60/0 85/52.5 Bad responders Mild responder Good responders ON Stim cMRF 24-mo postsurgery P2 P6 P5 P1 P3 P4 P7 P10 P11 FOG (off med/on med) 4/4 3/– 1/1 2/0 2/1 2/0 1/0 0/0 3/3 Postural instability (off med/on med) 3/3 1/– 2/2 0/0 0/1 1/0 0/0 1/0 0/0 Giladi FOG score (/24) 22 18 12 13 14 11 8.5 0 15 Composite gait score E0/E24 (off med) 11/10.5 8/8.5 8/6 9.5/4 10.5/4 8/2 7/3 6.5/2 6.5/6.5 Composite gait score E0/E24 (on med) 8/10.5 – 6/5 9/0.5 9.5/3 0.5/0 5.5/1 8/2 8/7 % FOG during gait assessment E0/E24 (off med) 46.8/50.7 50.4/37.6 18.9/21.3 17.6/2.4 46.5/3.5 50.6/0 52.2/1.1 23.7/0.5 14.2/8.9 % FOG during gait assessment E0/E24 (on med) 25.1/39.3 – 8/1.7 25.5/4.1 68/6.7 5.4/0.8 7.2/0 28.4/0.1 14.8/38.1 PDQ E0/E24 12.9/14.1 10.7/8.2 7.3/9.7 6/5.7 8.1/5.1 MD/7.1 6.4/5 5/1.4 9.5/3.5 PDQ mobility subscore E0/E24 92.5/85 90/55 82.5/62.5 45/40 97.5/32.5 MD/22.5 55/22.5 60/0 85/52.5 View Large TABLE 2. Clinical Evaluation at 24 mo Postsurgery Bad responders Mild responder Good responders ON Stim cMRF 24-mo postsurgery P2 P6 P5 P1 P3 P4 P7 P10 P11 FOG (off med/on med) 4/4 3/– 1/1 2/0 2/1 2/0 1/0 0/0 3/3 Postural instability (off med/on med) 3/3 1/– 2/2 0/0 0/1 1/0 0/0 1/0 0/0 Giladi FOG score (/24) 22 18 12 13 14 11 8.5 0 15 Composite gait score E0/E24 (off med) 11/10.5 8/8.5 8/6 9.5/4 10.5/4 8/2 7/3 6.5/2 6.5/6.5 Composite gait score E0/E24 (on med) 8/10.5 – 6/5 9/0.5 9.5/3 0.5/0 5.5/1 8/2 8/7 % FOG during gait assessment E0/E24 (off med) 46.8/50.7 50.4/37.6 18.9/21.3 17.6/2.4 46.5/3.5 50.6/0 52.2/1.1 23.7/0.5 14.2/8.9 % FOG during gait assessment E0/E24 (on med) 25.1/39.3 – 8/1.7 25.5/4.1 68/6.7 5.4/0.8 7.2/0 28.4/0.1 14.8/38.1 PDQ E0/E24 12.9/14.1 10.7/8.2 7.3/9.7 6/5.7 8.1/5.1 MD/7.1 6.4/5 5/1.4 9.5/3.5 PDQ mobility subscore E0/E24 92.5/85 90/55 82.5/62.5 45/40 97.5/32.5 MD/22.5 55/22.5 60/0 85/52.5 Bad responders Mild responder Good responders ON Stim cMRF 24-mo postsurgery P2 P6 P5 P1 P3 P4 P7 P10 P11 FOG (off med/on med) 4/4 3/– 1/1 2/0 2/1 2/0 1/0 0/0 3/3 Postural instability (off med/on med) 3/3 1/– 2/2 0/0 0/1 1/0 0/0 1/0 0/0 Giladi FOG score (/24) 22 18 12 13 14 11 8.5 0 15 Composite gait score E0/E24 (off med) 11/10.5 8/8.5 8/6 9.5/4 10.5/4 8/2 7/3 6.5/2 6.5/6.5 Composite gait score E0/E24 (on med) 8/10.5 – 6/5 9/0.5 9.5/3 0.5/0 5.5/1 8/2 8/7 % FOG during gait assessment E0/E24 (off med) 46.8/50.7 50.4/37.6 18.9/21.3 17.6/2.4 46.5/3.5 50.6/0 52.2/1.1 23.7/0.5 14.2/8.9 % FOG during gait assessment E0/E24 (on med) 25.1/39.3 – 8/1.7 25.5/4.1 68/6.7 5.4/0.8 7.2/0 28.4/0.1 14.8/38.1 PDQ E0/E24 12.9/14.1 10.7/8.2 7.3/9.7 6/5.7 8.1/5.1 MD/7.1 6.4/5 5/1.4 9.5/3.5 PDQ mobility subscore E0/E24 92.5/85 90/55 82.5/62.5 45/40 97.5/32.5 MD/22.5 55/22.5 60/0 85/52.5 View Large As already reported,7 optimal effects were obtained at low frequency stimulation 10 to 30 Hz (see Table 3). In addition, maintenance of beneficial effects of cMRF stimulation required regular parameter adjustments. In all patients with favorable outcome, the initial benefit waned within 4 to 6 wk of continuous stimulation. Therefore, all patients were stimulated on a cyclic schedule, with night arrests. TABLE 3. cMRF Stimulation Parameters Stimulation parameters Mode Frequency Voltage Patients Target Contact no. (Hz) (V) #1 (STN) cMRF 0–; 1–; 2+ 25 2.7 4–; 5–; 6+ 25 3.3 #2 (STN) cMRF 0–; 1–; 2+ 20 2.5 4–; 5–; 6+ 20 2.5 #3 (STN) cMRF 0–; 1–; 2+ 30 2.8 4–; 5–; 6+ 30 2.4 #4 (STN) cMRF 0–; 1+ 15 2.4 5–; 6+ 15 2.3 #5 (STN) cMRF 0–; 1+ 20 2.5 5–; 6+ 20 2.0 #6 (STN) cMRF 0–; 1–; 2+ 15 3.8 4–; 5–; 6+ 15 1.2 #7 (STN) cMRF 0– 25 1.4 4– 25 1.6 #8 cMRF 1– 20 0.8 5– 20 1.0 #9 cMRF 1–; 2– 10 1.7 5–; 6– 10 1.4 #10 cMRF 1– 10 2.0 5– 10 1.5 #11 cMRF 1+; 2– 15 1.0 6– 15 0.8 Stimulation parameters Mode Frequency Voltage Patients Target Contact no. (Hz) (V) #1 (STN) cMRF 0–; 1–; 2+ 25 2.7 4–; 5–; 6+ 25 3.3 #2 (STN) cMRF 0–; 1–; 2+ 20 2.5 4–; 5–; 6+ 20 2.5 #3 (STN) cMRF 0–; 1–; 2+ 30 2.8 4–; 5–; 6+ 30 2.4 #4 (STN) cMRF 0–; 1+ 15 2.4 5–; 6+ 15 2.3 #5 (STN) cMRF 0–; 1+ 20 2.5 5–; 6+ 20 2.0 #6 (STN) cMRF 0–; 1–; 2+ 15 3.8 4–; 5–; 6+ 15 1.2 #7 (STN) cMRF 0– 25 1.4 4– 25 1.6 #8 cMRF 1– 20 0.8 5– 20 1.0 #9 cMRF 1–; 2– 10 1.7 5–; 6– 10 1.4 #10 cMRF 1– 10 2.0 5– 10 1.5 #11 cMRF 1+; 2– 15 1.0 6– 15 0.8 Contacts n° 0 to 3 and contacts 4 to 7 refer respectively to the contacts of the electrodes of the right and left hemisphere. Xbn, Ybn, and Zbn correspond to the coordinates in the BNCS. Xb, Yb, and Zb correspond to coordinates in the BNCS expressed in mm. Mean and SD are indicated. Electrode contacts are the negative active contact used chronically. View Large TABLE 3. cMRF Stimulation Parameters Stimulation parameters Mode Frequency Voltage Patients Target Contact no. (Hz) (V) #1 (STN) cMRF 0–; 1–; 2+ 25 2.7 4–; 5–; 6+ 25 3.3 #2 (STN) cMRF 0–; 1–; 2+ 20 2.5 4–; 5–; 6+ 20 2.5 #3 (STN) cMRF 0–; 1–; 2+ 30 2.8 4–; 5–; 6+ 30 2.4 #4 (STN) cMRF 0–; 1+ 15 2.4 5–; 6+ 15 2.3 #5 (STN) cMRF 0–; 1+ 20 2.5 5–; 6+ 20 2.0 #6 (STN) cMRF 0–; 1–; 2+ 15 3.8 4–; 5–; 6+ 15 1.2 #7 (STN) cMRF 0– 25 1.4 4– 25 1.6 #8 cMRF 1– 20 0.8 5– 20 1.0 #9 cMRF 1–; 2– 10 1.7 5–; 6– 10 1.4 #10 cMRF 1– 10 2.0 5– 10 1.5 #11 cMRF 1+; 2– 15 1.0 6– 15 0.8 Stimulation parameters Mode Frequency Voltage Patients Target Contact no. (Hz) (V) #1 (STN) cMRF 0–; 1–; 2+ 25 2.7 4–; 5–; 6+ 25 3.3 #2 (STN) cMRF 0–; 1–; 2+ 20 2.5 4–; 5–; 6+ 20 2.5 #3 (STN) cMRF 0–; 1–; 2+ 30 2.8 4–; 5–; 6+ 30 2.4 #4 (STN) cMRF 0–; 1+ 15 2.4 5–; 6+ 15 2.3 #5 (STN) cMRF 0–; 1+ 20 2.5 5–; 6+ 20 2.0 #6 (STN) cMRF 0–; 1–; 2+ 15 3.8 4–; 5–; 6+ 15 1.2 #7 (STN) cMRF 0– 25 1.4 4– 25 1.6 #8 cMRF 1– 20 0.8 5– 20 1.0 #9 cMRF 1–; 2– 10 1.7 5–; 6– 10 1.4 #10 cMRF 1– 10 2.0 5– 10 1.5 #11 cMRF 1+; 2– 15 1.0 6– 15 0.8 Contacts n° 0 to 3 and contacts 4 to 7 refer respectively to the contacts of the electrodes of the right and left hemisphere. Xbn, Ybn, and Zbn correspond to the coordinates in the BNCS. Xb, Yb, and Zb correspond to coordinates in the BNCS expressed in mm. Mean and SD are indicated. Electrode contacts are the negative active contact used chronically. View Large Objective Measures Statistical analyses revealed a significant effect of both medication (F[1,7] = 8.12, P < .02) and surgery (F[2,14] =4.28, P < .03) on the composite gait score with cMRF ON stimulation. Further analyses showed that OFF medication, the composite gait score differed between presurgery vs 12-mo postsurgery (P < .0.3) and vs 24-mo postsurgery (P < .01), with no difference between the 12- and 24-mo assessments. ON medication, the difference was significant at the 24-mo follow-up only (presurgery vs 24-mo postsurgery, P < .02). Regarding postural stability, analyses revealed a significant effect of medication (F[1, 7] = 10.72, P < .01). The interaction between medication and surgery approached significance (F[2, 14] = 3.54, P = .057). Further examination of this trend showed that medication improved postural stability before surgery (P < .03) but no longer after surgery. In addition, the postural stability subscore was improved at the 24-mo follow-up (P < .01) OFF medication only. For the objective evaluation of FOG, we computed the percent of FOG relative to the total duration of the test.7 Overall, FOG duration decreased by about 58% when patients were tested OFF medication at 1 yr, an effect that was sustained at 2 yr with a mean reduction of 57%. This reduction was significant at the 2 follow-up assessments (P = .02). ON medication, the overall decrease in FOG during assessment was 51% at 1 yr and 41% at 2 yr. However, there was a great variability between patients and the improvement was not significant. OFF medication, the reduction ranged from 37% to 95% in patients 1, 3, 4, 5, 6, 7, and 10, while it increased by 10% and 25% in patients 2 and 11. Similarly, ON medication the reduction ranged from 45% to 95% in patients 1, 3, 4, 5, 7, and 10, while it increased by 22% in patients 2 and 11. At the individual level, the benefit of cMRF DBS for FOG was not predicted by FOG responsiveness to levodopa prior to surgery. Subjective Measures Analyses revealed a significant improvement of the mobility subscore of the PDQ-39 both at 1- and 2-yr follow-up compared to the preoperative state (F[2, 12] = 10.62, P < .01). The PDQ mobility subscore improved from 76 ± 19.7 presurgery to 55 ± 21.5 at 1-yr follow-up, and 41.4 ± 25.4 at 2-yr follow-up. In their diaries, patients 1, 3, 4, 7, 10, and 11 consistently reported a significant reduction of FOG episodes (up to total disappearance in patients 7 and 10), as well as a dramatic reduction of falls related to FOG. Patient 5 reported a moderate decrease in FOG episode, whereas patient 6 reported a highly fluctuating benefit that had waned out 1 yr after surgery. Patient 2 experienced a worsening of her condition. Case Grouping According to the clinical evaluations at 24-mo follow-up, patients were classified as “bad responders” (patients 2 and 6), “mild responders” (patient 5), and “good responders” (patients 1, 3, 4, 7, 10, and 11). Among the “good responders,” 2 patients (7 and 10) were considered “very good responders” because of total alleviation from FOG. Patient 6 was considered a “bad responder,” because of the lack of actual clinical benefit seen in his diary and frequent clinical evaluations performed during the follow-up period although the occurrence of FOG during the objective gait test was greatly reduced after surgery. cMRF stimulation was switched off after 2 yr as no parameters’ setting could provide sustained improvement of FOG. The data collected from the 2 patients who dropped out of the trial were analyzed and clustered in a group labeled as “No evaluation.” Anatomoclinical Correlations and Optimal Target in the cMRF Table 4 provides the coordinates of all active contacts of the good responders in the standard and BNCS systems. Table, Supplemental Digital Content 2 provides the coordinates of all the electrode contacts in the Talairach and BNCS. Figure 3 provides the positions of DBS electrodes implanted in the 11 patients on postoperative MRI. Three-dimensional representations of the 11 patients’ active contacts are shown in Figures 4A-4E. The normalized localization of “very good responders” active contacts is provided in Figure 4F and showed that they were located slightly more posterior than any other “good responders” active contacts and located around the PMJ. FIGURE 3. View largeDownload slide Visualization of all the 22 DBS electrodes implanted in the cMRF on postoperative MRI sequences in the axial, sagittal, and coronal planes. FIGURE 3. View largeDownload slide Visualization of all the 22 DBS electrodes implanted in the cMRF on postoperative MRI sequences in the axial, sagittal, and coronal planes. FIGURE 4. View largeDownload slide cMRF active contacts normalized positions of the 11 patients displayed on PD patient brain T1-weighted MRI sequences used as templates. Green spheres: “good responders”; red spheres: “bad responders.” Orange spheres: “Mild responders” and yellow spheres: “no evaluation.” In image F, light green spheres represent “very good responders” subgroup. Images A, B, E and F were taken from a lateral view above the PMJ level as described in the Methods section. Tinted spheres are those located below the PMJ. A, Axial transverse plane of the brainstem at the level of the PMJ with all patient's active contacts. B, Upper lateral view with all patient active contacts. C and D, represent left and right sagittal planes respectively at 6.5 mm lateral from the midline with all patient active contacts. The dashed line represents the PMJ at this laterality. Tinted spheres are those located more medially than the slice. E, All patient active contacts located on a fusion sequence between axial and coronal slices at the level of the PMJ and parallel to the brainstem long axis. The intersection between the 2 slices is at the level of the aqueduct of Sylvius. F, view similar to image B but representing only the active contacts position of the 4 “good responders” (dark green spheres) and the 2 “very good responders” (light green spheres). The position of the mean coordinates of the overall 6 “good responders” active contacts is represented with a cyan sphere. Orientations of the different images are indicated in the left superior corner. P: posterior. A: anterior. Ro: rostral. C: caudal. L and R correspond to the left and right hemisphere orientations. FIGURE 4. View largeDownload slide cMRF active contacts normalized positions of the 11 patients displayed on PD patient brain T1-weighted MRI sequences used as templates. Green spheres: “good responders”; red spheres: “bad responders.” Orange spheres: “Mild responders” and yellow spheres: “no evaluation.” In image F, light green spheres represent “very good responders” subgroup. Images A, B, E and F were taken from a lateral view above the PMJ level as described in the Methods section. Tinted spheres are those located below the PMJ. A, Axial transverse plane of the brainstem at the level of the PMJ with all patient's active contacts. B, Upper lateral view with all patient active contacts. C and D, represent left and right sagittal planes respectively at 6.5 mm lateral from the midline with all patient active contacts. The dashed line represents the PMJ at this laterality. Tinted spheres are those located more medially than the slice. E, All patient active contacts located on a fusion sequence between axial and coronal slices at the level of the PMJ and parallel to the brainstem long axis. The intersection between the 2 slices is at the level of the aqueduct of Sylvius. F, view similar to image B but representing only the active contacts position of the 4 “good responders” (dark green spheres) and the 2 “very good responders” (light green spheres). The position of the mean coordinates of the overall 6 “good responders” active contacts is represented with a cyan sphere. Orientations of the different images are indicated in the left superior corner. P: posterior. A: anterior. Ro: rostral. C: caudal. L and R correspond to the left and right hemisphere orientations. TABLE 4. Electrodes Contacts Coordinates of the “Good Responders” Group in the BNCS Good responders brainstem normalized coordinate system Electrode contact Laterality Anteropost. Rostro-caud. Patient Target Xbn Xb Ybn Yb Zbn Zn n° – (mm) – (mm) – (mm) #1 STN and MRF 0 0.69 8.12 0.46 5.63 0.09 1.22 1 0.74 8.70 0.47 5.80 0.24 3.10 4 0.58 7.13 0.45 5.63 0.05 0.72 5 0.65 8.03 0.46 5.73 0.21 2.73 #3 STN and MRF 0 0.68 7.53 0.60 7.36 –0.05 –0.58 1 0.72 8.02 0.60 7.39 0.12 1.38 4 0.71 8.04 0.60 7.42 –0.01 –0.15 5 0.78 8.76 0.61 7.46 0.16 1 .85 #4 STN and MRF 0 0.29 3.73 0.45 5.52 –0.26 –2.78 5 0.61 7.37 0.38 4.67 –0.09 –0.94 #7 STN and MRF 0 0.47 5.10 0.32 3.54 –0.14 –1.87 4 0.59 8.31 0.29 3.97 –0.31 –2.53 #10 MRF 1 0.50 6.13 0.21 2.90 0.10 1.23 5 0.53 6.14 0.21 2.92 0.17 2.07 #11 MRF 2 0.79 8.37 0.29 3.36 0.03 0.36 6 0.55 6.00 0.22 2.59 0.05 0.74 Mean SD 0.62 7.22 0.41 5.12 0.02 0.41 0.13 1.43 0.14 1.75 0.16 1.77 Good responders brainstem normalized coordinate system Electrode contact Laterality Anteropost. Rostro-caud. Patient Target Xbn Xb Ybn Yb Zbn Zn n° – (mm) – (mm) – (mm) #1 STN and MRF 0 0.69 8.12 0.46 5.63 0.09 1.22 1 0.74 8.70 0.47 5.80 0.24 3.10 4 0.58 7.13 0.45 5.63 0.05 0.72 5 0.65 8.03 0.46 5.73 0.21 2.73 #3 STN and MRF 0 0.68 7.53 0.60 7.36 –0.05 –0.58 1 0.72 8.02 0.60 7.39 0.12 1.38 4 0.71 8.04 0.60 7.42 –0.01 –0.15 5 0.78 8.76 0.61 7.46 0.16 1 .85 #4 STN and MRF 0 0.29 3.73 0.45 5.52 –0.26 –2.78 5 0.61 7.37 0.38 4.67 –0.09 –0.94 #7 STN and MRF 0 0.47 5.10 0.32 3.54 –0.14 –1.87 4 0.59 8.31 0.29 3.97 –0.31 –2.53 #10 MRF 1 0.50 6.13 0.21 2.90 0.10 1.23 5 0.53 6.14 0.21 2.92 0.17 2.07 #11 MRF 2 0.79 8.37 0.29 3.36 0.03 0.36 6 0.55 6.00 0.22 2.59 0.05 0.74 Mean SD 0.62 7.22 0.41 5.12 0.02 0.41 0.13 1.43 0.14 1.75 0.16 1.77 View Large TABLE 4. Electrodes Contacts Coordinates of the “Good Responders” Group in the BNCS Good responders brainstem normalized coordinate system Electrode contact Laterality Anteropost. Rostro-caud. Patient Target Xbn Xb Ybn Yb Zbn Zn n° – (mm) – (mm) – (mm) #1 STN and MRF 0 0.69 8.12 0.46 5.63 0.09 1.22 1 0.74 8.70 0.47 5.80 0.24 3.10 4 0.58 7.13 0.45 5.63 0.05 0.72 5 0.65 8.03 0.46 5.73 0.21 2.73 #3 STN and MRF 0 0.68 7.53 0.60 7.36 –0.05 –0.58 1 0.72 8.02 0.60 7.39 0.12 1.38 4 0.71 8.04 0.60 7.42 –0.01 –0.15 5 0.78 8.76 0.61 7.46 0.16 1 .85 #4 STN and MRF 0 0.29 3.73 0.45 5.52 –0.26 –2.78 5 0.61 7.37 0.38 4.67 –0.09 –0.94 #7 STN and MRF 0 0.47 5.10 0.32 3.54 –0.14 –1.87 4 0.59 8.31 0.29 3.97 –0.31 –2.53 #10 MRF 1 0.50 6.13 0.21 2.90 0.10 1.23 5 0.53 6.14 0.21 2.92 0.17 2.07 #11 MRF 2 0.79 8.37 0.29 3.36 0.03 0.36 6 0.55 6.00 0.22 2.59 0.05 0.74 Mean SD 0.62 7.22 0.41 5.12 0.02 0.41 0.13 1.43 0.14 1.75 0.16 1.77 Good responders brainstem normalized coordinate system Electrode contact Laterality Anteropost. Rostro-caud. Patient Target Xbn Xb Ybn Yb Zbn Zn n° – (mm) – (mm) – (mm) #1 STN and MRF 0 0.69 8.12 0.46 5.63 0.09 1.22 1 0.74 8.70 0.47 5.80 0.24 3.10 4 0.58 7.13 0.45 5.63 0.05 0.72 5 0.65 8.03 0.46 5.73 0.21 2.73 #3 STN and MRF 0 0.68 7.53 0.60 7.36 –0.05 –0.58 1 0.72 8.02 0.60 7.39 0.12 1.38 4 0.71 8.04 0.60 7.42 –0.01 –0.15 5 0.78 8.76 0.61 7.46 0.16 1 .85 #4 STN and MRF 0 0.29 3.73 0.45 5.52 –0.26 –2.78 5 0.61 7.37 0.38 4.67 –0.09 –0.94 #7 STN and MRF 0 0.47 5.10 0.32 3.54 –0.14 –1.87 4 0.59 8.31 0.29 3.97 –0.31 –2.53 #10 MRF 1 0.50 6.13 0.21 2.90 0.10 1.23 5 0.53 6.14 0.21 2.92 0.17 2.07 #11 MRF 2 0.79 8.37 0.29 3.36 0.03 0.36 6 0.55 6.00 0.22 2.59 0.05 0.74 Mean SD 0.62 7.22 0.41 5.12 0.02 0.41 0.13 1.43 0.14 1.75 0.16 1.77 View Large Comparisons of normalized coordinates of “good” vs “bad” responders revealed significant differences in the anteroposterior normalized coordinates Ybn (P < .01, Mann–Whitney U-test; Figure 5). FIGURE 5. View largeDownload slide Coordinates distributions of the “good responders” (white boxes) vs “bad responders” (grey boxes). Coordinates are expressed in the brainstem normalized units. The cross in the “good responders” boxes represents the mean values of the normalized coordinates of the 6 “good responders” represented as a cyan sphere in 3-D figures. Each box extends from the 25th percentile to the 75th percentile; the middle line represents the median; the whiskers demonstrate the range of the distribution. Horizontal line y = 0 represents the origin of the Brainstem Normalized Coordinate System. Xbn = Brainstem normalized laterality; Ybn = Brainstem normalized antero-posteriority; Zbn = Brainstem normalized rostro-caudality. (**Significant P < .01, Mann–Withney U-test). FIGURE 5. View largeDownload slide Coordinates distributions of the “good responders” (white boxes) vs “bad responders” (grey boxes). Coordinates are expressed in the brainstem normalized units. The cross in the “good responders” boxes represents the mean values of the normalized coordinates of the 6 “good responders” represented as a cyan sphere in 3-D figures. Each box extends from the 25th percentile to the 75th percentile; the middle line represents the median; the whiskers demonstrate the range of the distribution. Horizontal line y = 0 represents the origin of the Brainstem Normalized Coordinate System. Xbn = Brainstem normalized laterality; Ybn = Brainstem normalized antero-posteriority; Zbn = Brainstem normalized rostro-caudality. (**Significant P < .01, Mann–Withney U-test). Based on the coordinate's mean value of all the good and very good responders (Table 5) the optimal target within the cMRF can be proposed as follows: Laterality: Xbn = 2/3 ObnXbn Anteriority: Ybn = 2/5 ObnYbn Depth: Zbn = Ponto-mesencephalic junction TABLE 5. Mean Normalized Coordinates of the Electrode Active Contacts Per Group of Responders cMRF DBS active plot normalized coordinates Mean normalized coordinates SD Range Good responder (1; 3; 4; 7; 10; 11) Xbn +0.62 0.13 [0.13–0.79] Ybn +0.41 0.14 [0.21–0.61] Zbn +0.02 0.16 [−0.31 to 0.20] Bad responder (2-6) Xbn 0.71 0.15 [0.49–0.88] Ybn 0.73 0.05 [0.65–0.79] Zbn +0.05 0.16 [−0.23 to 0.24] Mild responder (5) Xbn +0.72 0.07 [0.67–0.77] Ybn +0.64 0.01 [0.63–0.65] Zbn +0.18 0.04 [0.15–0.20] cMRF DBS active plot normalized coordinates Mean normalized coordinates SD Range Good responder (1; 3; 4; 7; 10; 11) Xbn +0.62 0.13 [0.13–0.79] Ybn +0.41 0.14 [0.21–0.61] Zbn +0.02 0.16 [−0.31 to 0.20] Bad responder (2-6) Xbn 0.71 0.15 [0.49–0.88] Ybn 0.73 0.05 [0.65–0.79] Zbn +0.05 0.16 [−0.23 to 0.24] Mild responder (5) Xbn +0.72 0.07 [0.67–0.77] Ybn +0.64 0.01 [0.63–0.65] Zbn +0.18 0.04 [0.15–0.20] View Large TABLE 5. Mean Normalized Coordinates of the Electrode Active Contacts Per Group of Responders cMRF DBS active plot normalized coordinates Mean normalized coordinates SD Range Good responder (1; 3; 4; 7; 10; 11) Xbn +0.62 0.13 [0.13–0.79] Ybn +0.41 0.14 [0.21–0.61] Zbn +0.02 0.16 [−0.31 to 0.20] Bad responder (2-6) Xbn 0.71 0.15 [0.49–0.88] Ybn 0.73 0.05 [0.65–0.79] Zbn +0.05 0.16 [−0.23 to 0.24] Mild responder (5) Xbn +0.72 0.07 [0.67–0.77] Ybn +0.64 0.01 [0.63–0.65] Zbn +0.18 0.04 [0.15–0.20] cMRF DBS active plot normalized coordinates Mean normalized coordinates SD Range Good responder (1; 3; 4; 7; 10; 11) Xbn +0.62 0.13 [0.13–0.79] Ybn +0.41 0.14 [0.21–0.61] Zbn +0.02 0.16 [−0.31 to 0.20] Bad responder (2-6) Xbn 0.71 0.15 [0.49–0.88] Ybn 0.73 0.05 [0.65–0.79] Zbn +0.05 0.16 [−0.23 to 0.24] Mild responder (5) Xbn +0.72 0.07 [0.67–0.77] Ybn +0.64 0.01 [0.63–0.65] Zbn +0.18 0.04 [0.15–0.20] View Large Figure 6 illustrates the optimal localization on transverse and sagittal planes. The target can also be seen on the Figure 4F as a blue sphere. FIGURE 6. View largeDownload slide Optimal target in the cMRF based on the mean coordinates of the good responders group. Cyan spheres represent the target point equivalent to the mean coordinates of the 6 good responders active contacts. A, Axial view at the PMJ level. B, Sagittal view: projection of the target point on the mid-sagittal view. FIGURE 6. View largeDownload slide Optimal target in the cMRF based on the mean coordinates of the good responders group. Cyan spheres represent the target point equivalent to the mean coordinates of the 6 good responders active contacts. A, Axial view at the PMJ level. B, Sagittal view: projection of the target point on the mid-sagittal view. In Figure 7, we provide the localization of the human cholinergic PPN neurons on postmortem tissue in 2 sagittal slices of the brainstem as anatomic information. Note that most of cholinergic neurons are located in the caudal midbrain with few cholinergic neurons found below the PMJ. FIGURE 7. View largeDownload slide ChAT immunostaining on 2 sagittal human brainstem sections obtained from a female deceased from a non-neurodegenerative disease from the Human Brain Bank of the CERVO Institute in Quebec City. Immunostaining was done using a standard immunoperoxidase method, as previously described.20 The sections (50-μm thick) were cut at 4.9 and 6.9 mm from the midline. The light green areas provide the extent of the PPN cholinergic neurons at this laterality. Images in the left upper corner are enlargement of the main image centered on the PPN that allows distinguishing the 2 pars of the PPN based on cellular density. Note that on the 2 sections from 4.9 to 6.9 mm from the midline, most cholinergic neurons are located in the caudal part of the mesencephalon at the level of the IC while only very few neurons were found below the PMJ towards the latero dorsal tegmental nucleus. Together, the 2 neuronal populations form a cholinergic column also known as CH5-CH6 complex.29 AC: Anterior commissure; PB: parabrachial nucleus; CfN: cuneiform nucleus; IC: inferior colliculus; PCp: Posterior commissure (projection from midline); PMJ: ponto-mesencephalic junction; PPN: pedunculopontine nucleus; PPNc: PPN pars compacta; PPNd: PPN pars dissipata; RRA: retrorubral area; SC: superior colliculus; SCP: superior cerebellar peduncle; SN: substantia nigra; IVf: trochlear nerve fibers. FIGURE 7. View largeDownload slide ChAT immunostaining on 2 sagittal human brainstem sections obtained from a female deceased from a non-neurodegenerative disease from the Human Brain Bank of the CERVO Institute in Quebec City. Immunostaining was done using a standard immunoperoxidase method, as previously described.20 The sections (50-μm thick) were cut at 4.9 and 6.9 mm from the midline. The light green areas provide the extent of the PPN cholinergic neurons at this laterality. Images in the left upper corner are enlargement of the main image centered on the PPN that allows distinguishing the 2 pars of the PPN based on cellular density. Note that on the 2 sections from 4.9 to 6.9 mm from the midline, most cholinergic neurons are located in the caudal part of the mesencephalon at the level of the IC while only very few neurons were found below the PMJ towards the latero dorsal tegmental nucleus. Together, the 2 neuronal populations form a cholinergic column also known as CH5-CH6 complex.29 AC: Anterior commissure; PB: parabrachial nucleus; CfN: cuneiform nucleus; IC: inferior colliculus; PCp: Posterior commissure (projection from midline); PMJ: ponto-mesencephalic junction; PPN: pedunculopontine nucleus; PPNc: PPN pars compacta; PPNd: PPN pars dissipata; RRA: retrorubral area; SC: superior colliculus; SCP: superior cerebellar peduncle; SN: substantia nigra; IVf: trochlear nerve fibers. Stimulation of STN and cMRF vs Stimulation of cMRF Alone Clinical outcomes of the 7 patients implanted in both STN and cMRF showed that 4 were “good responders,” 1 was a “mild responder,” and 2 were “bad responders.” Concerning the 4 patients implanted in the cMRF alone, 2 were good responders, and 2 patients could not be evaluated. DISCUSSION Clinical Evaluation At the group level, evaluation at 1 yr showed a significant improvement of gait and FOG. This effect was sustained at 2 yr. Although it was mainly seen OFF medication, the benefit of cMRF DBS was confirmed by a durable improvement in the PDQ-39 mobility subscore as well as the patients’ reports. The effect on postural stability was marginal. While in some patients FOG greatly improved at 2 yr of follow-up, others patients did not benefit from the procedure. Overall, the results of the objective FOG measurements during the gait test, the composite gait score and the daily recordings of the patients were consistent. Patient 6 did not benefit at the clinical level from cMRF-DBS despite a great improvement of objective measures of FOG. In contrast, patient 11, a good responder, experienced more FOG episodes during objective testing, but his diary recordings, routine clinical evaluation, and improvement of the mobility subscale of the PDQ-39 clearly showed that FOG was significantly reduced under cMRF stimulation. Because improvement of symptoms under conditions of daily living is the ultimate goal of medical care, we classified this patient as good responder. These contradictory effects likely reflect the highly unpredictable nature of FOG, as well as its susceptibility to context and setting.21 The clustering of the patients in good vs bad responders made sense when examining the location of the active contacts. Brainstem Normalized Coordinate System The “Talairach coordinate system” is not ideally suited for the brainstem. Proton density MRI sequences to localize the PPN based on its position in atlases22,23 were proposed for direct targeting24 and further used in different studies.13,25,26 However, coordinates calculation based on pontine and cerebellar landmarks is debatable. We previously expressed contact coordinates in a coordinate system based upon the PMJ.7 This approach was further used by others.11,25,27 However, coordinate normalization and specific lateral coordinates computation were impossible. The BNCS is based on PMJ, the floor of the fourth ventricle and the lateral mesencephalic sulci which are well delineated on MRI and provide an indirect definition of the target, which can complement the direct PPN targeting.24,28 Anatomoclinical Correlation We found that the electrode active contacts in good responders were located in the posterior and central part of the cMRF at the level of the PMJ, that contains the PPN (posterior pars dissipata and pars compacta) and the CfN. However, we would like to stress the caution that should be observed in extrapolating postoperative MRI data of parkinsonian patient (known to have degeneration of some brainstem structures including PPN) to anatomic data provided in brainstem atlas obtained on normal subject following immunohistological procedures. Nevertheless, we provided an immunohistological localization of the cholinergic neurons in sagittal sections of a human brainstem. This allows localizing the human PPN in the caudal midbrain and at the PMJ level where the majority of PPN neurons lie. The PPN located in the cMRF forms, with the laterodorsal tegmental nucleus (in the rostral pons), a column of cholinergic neurons also known as CH5-CH6 complex.29 In the Paxinos and Huang atlas,22 the active contacts of the “good responders” were located at the PMJ level (Plate Obex + 31 mm and Obex + 32 mm), corresponding to the PPN pars dissipata. In patients 4 and 7, the active contacts were located just below the PMJ in a more medial position in the pontine-cMRF closed to the superior cerebellar peduncle and the nucleus pontis oralis (Nucleus reticularis pontis rostralis) and the ventrolateral tegmental area. This beneficial site of stimulation, which lies caudal the PPN, was also recently reported11,30 and will require further examination. Where to Stimulate Within the cMRF? Using the BNCS, we proposed an optimal target associated with normalized coordinates (see Figure 6). We propose to have the penultimate contact (n° 1 and n° 5) on the target at the PMJ. This allows to have the lowest contact (n° 0 and n° 4) 2 mm below the PMJ and if necessary, to stimulate rostral pontine areas. The mechanism of action of cMRF-DBS is still hypothetical. Whether the beneficial effect on FoG is obtained by stimulation of the remaining PPN cholinergic neurons and other noncholinergic neurons of the cMRF (including CfN neurons) or simultaneous stimulation of surrounding fiber system remains an open question. Also, the integrative role of the cMRF in the control of locomotion and attention31,32 must be considered and could explain the need for regular parameter adjustments to maintain beneficial effect. A review of the studies reporting PPN DBS implantations highlighted a large heterogeneity in the electrode positioning within the cMRF.14 Some studies including our own preliminary report, showed electrode implantation within the caudal midbrain,7,13,26 while others advocated an electrode implantation in the pons below the PMJ,11,25,27,33,34 with beneficial clinical outcomes.35 Unlike a study demonstrated no relation between the position of the electrode and clinical outcomes,36 the present study provides convincing evidences that the position of the electrode could explain, to some extent, the variability of clinical response. This will have to be confirmed on a larger cohort of patients implanted in the cMRF. In this regard, the use of the BNCS could allow comparing sites of implantation gathered elsewhere, to improve the localization of the optimal target(s). Limitations Unlike our initial study at 6 mo based on a double-blind protocol, the present study at 2-yr follow-up is an open-label trial, thus requiring caution when interpreting the clinical outcomes similar to every open-label clinical study. We would like to stress the difficulty to conduct a double-blind study with Parkinson disease patients in advanced stages of the disease. Another limit of the present study is the small number of patients included in the protocol (11 patients) and only 9 patients in the anatomoclinical evaluation due to the impossibility to evaluate 2 patients at long-term evaluation. As an exploratory study based on a small number of patients, it will have to be confirmed in a larger cohort of patients. We think that the use of the BNCS will allow to include more patients in the analysis and, finally, to refine the target position. CONCLUSION Variability in clinical response of PPN-DBS remains an open question. Using a new stereotactic procedure adapted to the brainstem, the present anatomoclinical study, while based on a small number of patients, provides arguments for a safe electrode implantation in the posterior cMRF at the level of the PMJ to treat FoG. Whether different sites for electrode implantation in the rostral brainstem provide similar benefit outcomes, opens exciting perspectives in our understanding of this promising but demanding therapeutic approach. Disclosures This work was supported by The Michael J. Fox Foundation, the Fondation de France, and the Centre Hospitalier Universitaire de Grenoble Alpes. Medtronic provided the pulse generators free of charge. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr Chabardès serves as consultant for Boston Scientific and for Medtronic and has received financial support from Medtronic for preclinical research purposes in the field of DBS. Notes The meeting of the “World Society for Stereotactic and Functional Neurosurgery,” Tokyo, Japan, May 30, 2013, Oral presentation (Laurent Goetz). REFERENCES 1. Le Ray D , Juvin L , Ryczko D , Dubuc R . Chapter 4-supraspinal control of locomotion: the mesencephalic locomotor region . Prog Brain Res . 2011 ; 188 : 51 - 70 . Google Scholar CrossRef Search ADS PubMed 2. Grillner S , Wallén P , Saitoh K , Kozlov A , Robertson B . Neural bases of goal-directed locomotion in vertebrates–an overview . Brain Res Rev . 2008 ; 57 ( 1 ): 2 - 12 . Google Scholar CrossRef Search ADS PubMed 3. Goetz L , Piallat B , Bhattacharjee M , Mathieu H , David O , Chabardes S . On the role of the pedunculopontine nucleus and mesencephalic reticular formation in locomotion in nonhuman primates . J Neurosci . 2016 ; 36 ( 18 ): 4917 - 4929 . Google Scholar CrossRef Search ADS PubMed 4. Takakusaki K , Habaguchi T , Ohtinata-Sugimoto J , Saitoh K , Sakamoto T . Basal ganglia efferents to the brainstem centers controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal ganglia dysfunction . Neuroscience . 2003 ; 119 ( 1 ): 293 - 308 . Google Scholar CrossRef Search ADS PubMed 5. Ryczko D , Dubuc R . The multifunctional mesencephalic locomotor region . Curr Pharm Des . 2013 ; 19 ( 24 ): 4448 - 4470 . Google Scholar CrossRef Search ADS PubMed 6. Alam M , Schwabe K , Krauss JK . The pedunculopontine nucleus area: critical evaluation of interspecies differences relevant for its use as a target for deep brain stimulation . Brain . 2011 ; 134 ( 1 ): 11 - 23 . Google Scholar CrossRef Search ADS PubMed 7. Ferraye MU , Debu B , Fraix V et al. Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease . Brain . 2010 ; 133 ( 1 ): 205 - 214 . Google Scholar CrossRef Search ADS PubMed 8. Garcia-Rill E . Waking and the Reticular Activating System in Health and Disease . Academic Press , San Diego ; 2015 . 9. Plaha P , Gill SS . Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson's disease . Neuroreport . 2005 ; 16 ( 17 ): 1883 - 1887 . Google Scholar CrossRef Search ADS PubMed 10. Mazzone P , Lozano A , Stanzione P et al. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson's disease . Neuroreport . 2005 ; 16 ( 17 ): 1877 - 1881 . Google Scholar CrossRef Search ADS PubMed 11. Thevathasan W , Coyne TJ , Hyam JA et al. Pedunculopontine nucleus stimulation improves gait freezing in parkinson disease . Neurosurgery . 2011 ; 69 ( 6 ): 1248 - 1254 . Google Scholar CrossRef Search ADS PubMed 12. Golestanirad L , Elahi B , Graham SJ , Das S , Wald LL . Efficacy and safety of pedunculopontine nuclei (PPN) Deep brain stimulation in the treatment of gait disorders: a meta-analysis of clinical studies . Can J Neurol Sci . 2016 ; 43 ( 01 ): 120 - 126 . Google Scholar CrossRef Search ADS PubMed 13. Moro E , Hamani C , Poon Y-Y et al. Unilateral pedunculopontine stimulation improves falls in Parkinson's disease . Brain . 2010 ; 133 ( 1 ): 215 - 224 . Google Scholar CrossRef Search ADS PubMed 14. Hamani C , Lozano AM , Mazzone PAM et al. Pedunculopontine nucleus region deep brain stimulation in Parkinson disease: surgical techniques, side effects, and postoperative imaging . Stereotact Funct Neurosurg . 2016 ; 94 ( 5 ): 307 - 319 . Google Scholar CrossRef Search ADS PubMed 15. Lozano AM , Lang AE , Galvez-Jimenez N , Miyasaki J . Effect of GPi pallidotomy on motor function in Parkinson's disease . Lancet North Am Ed . 1995 ; 346 ( 8987 ): 1383 - 1387 . Google Scholar CrossRef Search ADS 16. Benabid A-L , Chabardès S , Mitrofanis J , Pollak P . Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease . Lancet Neurol . 2009 ; 8 ( 1 ): 67 - 81 . Google Scholar CrossRef Search ADS PubMed 17. Pollak P , Krack P , Fraix V et al. Intraoperative micro- and macrostimulation of the subthalamic nucleus in Parkinson's disease . Mov Disord . 2002 ; 17 ( S3 ): S155 - S161 . Google Scholar CrossRef Search ADS PubMed 18. Piallat B , Polosan M , Fraix V et al. Subthalamic neuronal firing in obsessive-compulsive disorder and Parkinson disease . Ann Neurol . 2011 ; 69 ( 5 ): 793 - 802 . Google Scholar CrossRef Search ADS PubMed 19. Cointepas Y , Geffroy D , Souedet N , Denghien I . The Brain VISA Project: A Shared Software Development Infrastructure for Biomedical Imaging Research : Proceedings, 16th annual meeting of the Organization for Human Brain Mapping , Barcelona , 2010 . 20. Bédard C , Wallman M-J , Pourcher E , Gould PV , Parent A , Parent M . Serotonin and dopamine striatal innervation in Parkinson's disease and Huntington's chorea . Parkinsonism Relat Disord . 2011 ; 17 ( 8 ): 593 - 598 . Google Scholar CrossRef Search ADS PubMed 21. Nonnekes J , Snijders AH , Nutt JG , Deuschl G , Giladi N , Bloem BR . Freezing of gait: a practical approach to management . Lancet Neurol . 2015 ; 14 ( 7 ): 768 - 778 . Google Scholar CrossRef Search ADS PubMed 22. Paxinos G , Huang XF . Atlas of the Human Brainstem . Academic Press , San Diego ; 1995 . 23. Afshar F , Watkins ES , Yap JC . Stereotaxic Atlas of the Human Brainstem and Cerebellar Nuclei . New York : Raven Press ; 1978 . 24. Zrinzo L , Zrinzo LV , Tisch S et al. Stereotactic localization of the human pedunculopontine nucleus: atlas-based coordinates and validation of a magnetic resonance imaging protocol for direct localization . Brain . 2008 ; 131 ( 6 ): 1588 - 1598 . Google Scholar CrossRef Search ADS PubMed 25. Insola A , Valeriani M , Mazzone P . Targeting the pedunculopontine nucleus . Neurosurgery . 2012 ; 71 ( 1 ): 96 - 103 . Google Scholar PubMed 26. Shimamoto SA , Larson PS , Ostrem JL , Glass GA , Turner RS , Starr PA . Physiological identification of the human pedunculopontine nucleus . J Neurol Neurosurg Psychiatry . 2010 ; 81 ( 1 ): 80 - 86 . Google Scholar CrossRef Search ADS PubMed 27. Thevathasan W , Pogosyan A , Hyam JA et al. Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism . Brain . 2012 ; 135 ( 1 ): 148 - 160 . Google Scholar CrossRef Search ADS PubMed 28. Zrinzo L , Zrinzo LV , Massey LA et al. Targeting of the pedunculopontine nucleus by an MRI-guided approach: a cadaver study . J Neural Transm . 2011 ; 118 ( 10 ): 1487 - 1495 . Google Scholar CrossRef Search ADS PubMed 29. Mesulam MM , Geula C , Bothwell MA , Hersh LB . Human reticular formation: cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei and some cytochemical comparisons to forebrain cholinergic neurons . J Comp Neurol . 1989 ; 283 ( 4 ): 611 - 633 . Google Scholar CrossRef Search ADS PubMed 30. Mazzone P , Filho OV , Viselli F et al. Our first decade of experience in deep brain stimulation of the brainstem: elucidating the mechanism of action of stimulation of the ventrolateral pontine tegmentum . J Neural Transm . 2016 ; 123 :( 75 ) 1 - 767 . Google Scholar PubMed 31. Goetz L , Piallat B , Bhattacharjee M , Mathieu H , David O , Chabardès S . The primate pedunculopontine nucleus region: towards a dual role in locomotion and waking state . J Neural Transm . 2016 ; 123 ( 7 ): 667 - 678 . Google Scholar CrossRef Search ADS PubMed 32. Lau B , Welter M-L , Belaid H et al. The integrative role of the pedunculopontine nucleus in human gait . Brain . 2015 ; 138 ( 5 ): 1284 - 1296 . Google Scholar CrossRef Search ADS PubMed 33. Androulidakis AG , Mazzone P , Litvak V et al. Oscillatory activity in the pedunculopontine area of patients with Parkinson's disease . Exp Neurol . 2008 ; 211 ( 1 ): 59 - 66 . Google Scholar CrossRef Search ADS PubMed 34. Tattersall TL , Stratton PG , Coyne TJ et al. Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus . Nat Neurosci . 2014 ; 17 ( 3 ): 449 - 454 . Google Scholar CrossRef Search ADS PubMed 35. Peppe A , Pierantozzi M , Chiavalon C et al. Deep brain stimulation of the pedunculopontine tegmentum and subthalamic nucleus: Effects on gait in Parkinson's disease . Gait Posture . 2010 ; 32 ( 4 ): 512 - 518 . Google Scholar CrossRef Search ADS PubMed 36. Mazzone P , Sposato S , Insola A , Scarnati E . The clinical effects of deep brain stimulation of the pedunculopontine tegmental nucleus in movement disorders may not be related to the anatomical target, leads location, and setup of electrical stimulation . Neurosurgery . 2013 ; 73 ( 5 ): 894 - 906 . Discussion 905-906 . Google Scholar CrossRef Search ADS PubMed Supplemental digital content is available for this article at www.neurosurgery-online.com. Supplemental Digital Content 1. Brainstem Normalized Coordinate System. Supplemental Digital Content 2. Coordinates of the DBS electrode contacts in the Talairach system and in the BNCS. COMMENT The authors have correctly carried out their work giving appropriate attention to the clinical evaluation and stereotactic methodology. They have provided an accurate description of stereotactic procedure that will be useful in functional neurosurgery. They have properly considered their approach in a way that fits with my belief on PPTg (PPN) DBS.1,2,3 I fully agree and share their innovative neurosurgical planning that considers anatomical landmarks and neuroimaging to target brainstem structures, thus overcoming the limits of traditional stereotactic methods.3 This applies in particular for PPTg DBS.3,4 According to my experience on a good number of implanted patients, I agree with the site that the authors indicate as the most useful. This would be the site to consider as the most useful “endpoint” when planning the electrode position to achieve the best clinical outcome. Moreover, I am convinced that when a brain region loses neurons, as it occurs in these patients, the effects of stimulation should be ascribed to the effects of the electric field on neuronal pathways linking brain structures rather than to a local action on neurons. This interpretation better explains the possibility to control symptoms in those patients in whom the stimulating electrode was positioned not exactly in the planned site owing to stochastic variations in the procedure.3 This may also explain the positive result that may be obtained with different stimulation parameters and using different contacts, especially when using octopolar electrodes. This conclusion is also supported by the results of other groups that are on the way to be published. The revision of the work by the authors has been meticulous, proving very useful for myself, having first introduced the PPTg DBS to control axial symptoms that are not satisfactorily controlled by other treatments.5 I dare to encourage publication of papers like this one, ie, characterized by a correct approach and by a rich exposition of data, rather that reviews that in most cases have been merely speculative without offering any substantial contribution to improving DBS in brainstem structures and to understand its mechanism of action. Undoubtedly, the introduction of PPTg DBS has provided new insight for understanding DBS. Paolo Aurelio Maria Mazzone Rome, Italy 1. Insola A , Padua L , Mazzone P , Scarnati E , Valeriani M . Low and high-frequency somatosensory evoked potentials recorded from the human pedunculopontine nucleus . Clin Neurophysiol . 2014 ; pii:S1388-2457(14)00007-8. doi: 10.1016/j.clinph.2013.12.112. [Epub ahead of print] 2. Insola A , Valeriani M , Mazzone P . Targeting the pedunculopontine nucleus: a new neurophysiological method based on somatosensory evoked potentials to calculate the distance of DBS lead from the Obex . Neurosurgery 2012 . doi: 10.1227/NEU.0b013e318249c726 . 3. Mazzone P , Sposato S , Insola A , Scarnati E . The deep brain stimulation of the pedunculopontine tegmental nucleus: towards a new stereotactic neurosurgery . J Neural Transm . 2011 ; 118 ( 10 ): 1431 - 51 . Google Scholar CrossRef Search ADS PubMed 4. Mazzone P , Garcia-Rill E , Scarnati E . Progress in deep brain stimulation of the pedunculopontine nucleus and other structures: implications for motor and non-motor disorders . J Neural Transm (Vienna) . 2016 ; 123 ( 7 ): 653 - 4 . Google Scholar CrossRef Search ADS PubMed 5. Mazzone P , Vitale F , Capozzo A , Viselli F , Scarnati E . Deep Brain Stimulation of the Pedunculopontine Tegmental Nucleus improves static balance in Parkinson's Disease . By Elliot KE , Hunter P , Ali R , (Eds.) Comprehensive Textbook of Principles, Technologies, and Therapies , 2nd Edition . Chapter 79, Section IX; Vol. 2 of: Neuromodulation (book) Academic Press . Hardcover ISBN: 9 780 128 053 539 . 2018 . Google Scholar CrossRef Search ADS Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Liang Chen, MD. Department of Neurosurgery Huashan Hospital Shanghai, China Chinese: Liang Chen, MD. Department of Neurosurgery Huashan Hospital Shanghai, China Close English: Oluwakemi Aderonke Badejo, MBBS, FWACS. Department of Surgery College of Medicine University of Ibadan Ibadan, Nigeria English: Oluwakemi Aderonke Badejo, MBBS, FWACS. Department of Surgery College of Medicine University of Ibadan Ibadan, Nigeria Close Italian: Francesco Cardinale, MD, PhD. “Claudio Munari” Centre for Epilepsy and Parkinson Surgery-Niguarda Ca' Granda Hospital Milano, Italy Italian: Francesco Cardinale, MD, PhD. “Claudio Munari” Centre for Epilepsy and Parkinson Surgery-Niguarda Ca' Granda Hospital Milano, Italy Close Japanese: Yoshinori Higuchi, MD, PhD. Department of Neurological Surgery Chiba University Graduate School of Medicine Chiba City, Japan Japanese: Yoshinori Higuchi, MD, PhD. Department of Neurological Surgery Chiba University Graduate School of Medicine Chiba City, Japan Close Korean: Tae Gon Kim, MD. Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Korean: Tae Gon Kim, MD. Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Close Portuguese: Tae Gon Kim, MD. Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Portuguese: Tae Gon Kim, MD. Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Close Greek: George Georgoulis, MD. Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Greek: George Georgoulis, MD. Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Close Spanish: George Georgoulis, MD. Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Spanish: George Georgoulis, MD. Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Close Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

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Abstract

Abstract BACKGROUND Experimental studies led to testing of deep brain stimulation (DBS) of the pedunculopontine nucleus (PPN) as a new therapy to treat freezing of gait (FOG) in Parkinson disease (PD). Despite promising initial results fueling a growing interest toward that approach, several clinical studies reported heterogeneity in patient responses. Variation in the position of electrode contacts within the rostral brainstem likely contributes to such heterogeneity. OBJECTIVE To provide anatomoclinical correlations of the effect of DBS of the caudal mesencephalic reticular formation (cMRF) including the PPN to treat FOG by comparing the normalized positions of the active contacts among a series of 11 patients at 1- and 2-yr follow-up and to provide an optimal target through an open-label study. METHODS We defined a brainstem normalized coordinate system in relation to the pontomesencephalic junction. Clinical evaluations were based on a composite score using objective motor measurements and questionnaires allowing classification of patients as “bad responders” (2 patients), “mild responders” (1 patient) and “good responders” (6 patients). Two patients, whose long-term evaluation could not be completed, were excluded from the analysis. RESULTS Most effective DBS electrode contacts to treat FOG in PD patients were located in the posterior part of the cMRF (encompassing the posterior PPN and cuneiform nucleus) at the level of the pontomesencephalic junction. CONCLUSION In the present exploratory study, we performed an anatomoclinical analysis using a new coordinate system adapted to the brainstem in 9 patients who underwent PPN area DBS. We propose an optimal DBS target that allows a safe and efficient electrode implantation in the cMRF. Pedunculopontine nucleus, Deep brain stimulation, Parkinson disease, Freezing of gait, Cuneiform nucleus, Mesencephalic reticular formation, Mesencephalic locomotor region ABBREVIATIONS ABBREVIATIONS BNCS brainstem normalized coordinate system ChAT choline acetyltransferase cMRF caudal mesencephalic reticular formation DBS deep brain stimulation FOG freezing of gait MRI magnetic resonance imaging PC posterior commissure PD Parkinson disease PMJ pontomesencephalic junction PPN pedunculopontine nucleus STN subthalamic nucleus UPDRS unified Parkinson Disease Rating Scale The caudal mesencephalic reticular formation (cMRF) contains 2 structures involved in the supraspinal control of locomotion: the pedunculopontine nucleus (PPN; Nucleus tegmentalis pedunculopontinus) and the cuneiform nucleus (CfN; Nucleus cuneiformis).1-5 Because of the limited knowledge of the precise anatomy of the caudal mesencephalon in humans,6 in a previous study we also referred to this region as a PPN area.7 TABLE 1. Clinical and Demographic Characteristics of the Patients at the Time of Inclusion Patients #1 #2 #3 #4 #5 #6 #7 Mean ± SD Patients (1-7) #8 #9 #10 #11 Mean ± SD Patients (8-11) Sex M F M M F M M M F M M Age at PD diagnosis 55 50 49 44 31 27 36 41.7 ± 10.5 32 63 38 42 43.8 ± 11.7 Age at STN surgery 64 64 65 53 53 47 52 56.9 ± 7.3 – – – – – Age at MRF surgery 68 68 72 57 59 56 61 63.0 ± 6.3 60 71 65 63 64.8 ± 4 Disease duration 13 18 23 13 28 29 28 21.3 ± 6.7 28 8 27 22 21.3 ± 8 LEDD (mg) 1025 550 800 1170 400 0 890 678 ± 397 578 636 610 760 646 ± 80 Improvement in UPDRS motor score ON levodopa/OFF STN stim. (%) 55 23 23 44 46 NLTa 63 – 42 5 51 21 – FOG (OFF med) 4 3 3 3 1 3 3 – 4 3 3 3 – FOG (ON med) 4 3 3 0 1 – 3 2 3 2 2 Postural instability (OFF med)b yes yes yes no yes yes no – yes yes no no Postural instability (ON med) yes yes yes no no – no yes yes no no Giladi FOG score (/24) 16 20 23 11 16 16 16 20 19 19 19 Patients #1 #2 #3 #4 #5 #6 #7 Mean ± SD Patients (1-7) #8 #9 #10 #11 Mean ± SD Patients (8-11) Sex M F M M F M M M F M M Age at PD diagnosis 55 50 49 44 31 27 36 41.7 ± 10.5 32 63 38 42 43.8 ± 11.7 Age at STN surgery 64 64 65 53 53 47 52 56.9 ± 7.3 – – – – – Age at MRF surgery 68 68 72 57 59 56 61 63.0 ± 6.3 60 71 65 63 64.8 ± 4 Disease duration 13 18 23 13 28 29 28 21.3 ± 6.7 28 8 27 22 21.3 ± 8 LEDD (mg) 1025 550 800 1170 400 0 890 678 ± 397 578 636 610 760 646 ± 80 Improvement in UPDRS motor score ON levodopa/OFF STN stim. (%) 55 23 23 44 46 NLTa 63 – 42 5 51 21 – FOG (OFF med) 4 3 3 3 1 3 3 – 4 3 3 3 – FOG (ON med) 4 3 3 0 1 – 3 2 3 2 2 Postural instability (OFF med)b yes yes yes no yes yes no – yes yes no no Postural instability (ON med) yes yes yes no no – no yes yes no no Giladi FOG score (/24) 16 20 23 11 16 16 16 20 19 19 19 aNo levodopa treatment. bScore ≥ 2/4 on item 29 UPDRS III. PD = Parkinson disease; STN: subthalamic nucleus; cMRF: caudal mesencephalic reticular formation; UPDRS: Unified Parkinson Disease Rating Scale; med: medication; FOG: freezing of gait; Stim: stimulation; LEDD: levodopa equivalent daily dose.15 View Large TABLE 1. Clinical and Demographic Characteristics of the Patients at the Time of Inclusion Patients #1 #2 #3 #4 #5 #6 #7 Mean ± SD Patients (1-7) #8 #9 #10 #11 Mean ± SD Patients (8-11) Sex M F M M F M M M F M M Age at PD diagnosis 55 50 49 44 31 27 36 41.7 ± 10.5 32 63 38 42 43.8 ± 11.7 Age at STN surgery 64 64 65 53 53 47 52 56.9 ± 7.3 – – – – – Age at MRF surgery 68 68 72 57 59 56 61 63.0 ± 6.3 60 71 65 63 64.8 ± 4 Disease duration 13 18 23 13 28 29 28 21.3 ± 6.7 28 8 27 22 21.3 ± 8 LEDD (mg) 1025 550 800 1170 400 0 890 678 ± 397 578 636 610 760 646 ± 80 Improvement in UPDRS motor score ON levodopa/OFF STN stim. (%) 55 23 23 44 46 NLTa 63 – 42 5 51 21 – FOG (OFF med) 4 3 3 3 1 3 3 – 4 3 3 3 – FOG (ON med) 4 3 3 0 1 – 3 2 3 2 2 Postural instability (OFF med)b yes yes yes no yes yes no – yes yes no no Postural instability (ON med) yes yes yes no no – no yes yes no no Giladi FOG score (/24) 16 20 23 11 16 16 16 20 19 19 19 Patients #1 #2 #3 #4 #5 #6 #7 Mean ± SD Patients (1-7) #8 #9 #10 #11 Mean ± SD Patients (8-11) Sex M F M M F M M M F M M Age at PD diagnosis 55 50 49 44 31 27 36 41.7 ± 10.5 32 63 38 42 43.8 ± 11.7 Age at STN surgery 64 64 65 53 53 47 52 56.9 ± 7.3 – – – – – Age at MRF surgery 68 68 72 57 59 56 61 63.0 ± 6.3 60 71 65 63 64.8 ± 4 Disease duration 13 18 23 13 28 29 28 21.3 ± 6.7 28 8 27 22 21.3 ± 8 LEDD (mg) 1025 550 800 1170 400 0 890 678 ± 397 578 636 610 760 646 ± 80 Improvement in UPDRS motor score ON levodopa/OFF STN stim. (%) 55 23 23 44 46 NLTa 63 – 42 5 51 21 – FOG (OFF med) 4 3 3 3 1 3 3 – 4 3 3 3 – FOG (ON med) 4 3 3 0 1 – 3 2 3 2 2 Postural instability (OFF med)b yes yes yes no yes yes no – yes yes no no Postural instability (ON med) yes yes yes no no – no yes yes no no Giladi FOG score (/24) 16 20 23 11 16 16 16 20 19 19 19 aNo levodopa treatment. bScore ≥ 2/4 on item 29 UPDRS III. PD = Parkinson disease; STN: subthalamic nucleus; cMRF: caudal mesencephalic reticular formation; UPDRS: Unified Parkinson Disease Rating Scale; med: medication; FOG: freezing of gait; Stim: stimulation; LEDD: levodopa equivalent daily dose.15 View Large Functionally, the area is also referred to as the mesencephalic locomotor region5 and is part of the reticular activating system.8 Deep brain stimulation (DBS) of the PPN was proposed as a new therapy to treat levodopa-resistant gait disorders in Parkinson disease (PD).9,10 Several studies stressed the variability of clinical responses6,7,11-13 possibly related to patient selection, stimulation parameters and/or position of the electrode within the PPN.14 Based on a new brainstem normalized coordinate system (BNCS) associated with the pontomesencephalic junction (PMJ), the aim of the present study was to evaluate the anatomoclinical correlations between active contacts position and clinical outcomes at 24 mo follow-up, in PD patients implanted in the cMRF for severe gait disorders. METHODS Patients Eleven patients with PD and severe gait disorders were included in a bilateral cMRF implantation protocol. The protocol was approved by the local ethic committee (06-CHUG-21) and all patients provided written informed consent. See Table 1 for patient clinical and demographic characteristics. Of the 11 patients, 7 had undergone a prior subthalamic nucleus (STN)-DBS electrode implantation. The 4 remaining patients received only bilateral cMRF-DBS electrodes. Inclusion and Exclusion Criteria Detailed criteria have previously been described.7 Briefly, patients were included if gait disorders and freezing of gait (FOG) were their main complaint, while other PD signs were satisfactorily controlled by medication and/or STN stimulation. Clinical Evaluation Evaluation was assessed using both objective motor measures and questionnaires. The same evaluations were carried out prior to surgery and 1 and 2 yr after, under both OFF and ON medication conditions. Assessments were performed after an overnight fasting and withdrawal of medication, and then after administration of 120% of the usual preoperative morning levodopa dose. STN stimulation was ON during the evaluations. Patient #6 was treated only by STN stimulation and therefore was not tested ON medication. Clinical evaluations included the unified Parkinson Disease Rating Scale (UPDRS) parts II (activities of daily living) and III (motor part), as well as a gait test including FOG provoking circumstances.7 A composite gait score was computed based on the sum of items 14 (freezing) and 15 (gait) of the UPDRS II and item 30 (gait) of the UPDRS III. Postural stability was examined using a composite score based on the sum of item 13 (falls unrelated to freezing) of UPDRS II and item 29 (postural stability) of UPDRS III. Quality of life was assessed using the PDQ-39, with special attention to the mobility subscore. For quantitative assessment, the gait test was performed while wearing adapted shoes (Stride Analyzer, B&L Engineering, Santa Ana, California) that enabled acquisition of foot-floor contact data. Finally, patients recorded FOG episodes and falls on a diary that was examined at each visit. Classification of the patients into good and bad responders was based on the results of the objective assessments 2 yr after surgery, the PDQ-39 scores, the patients’ diary and the clinical observation made during patients’ regular visits. When the sets of observations were not fully congruent, we favored those reflecting the daily condition of the patients. Imaging Protocol Preoperative 1.5 T, stereotactic T1 and T2 magnetic resonance images were acquired and fused (Voxim, Chemnitz, Germany). Ventriculographic landmarks were also obtained by direct injection of iopamiron® using perioperative X-ray sequences (BioScan, Geneva, Switzerland). Postoperative, T1, and T2 magnetic resonance imaging (MRI) control was performed in all patients. Targeting For the first 6 patients, cMRF targeting was performed with the central electrode trajectory parallel to the floor of the fourth ventricle, passing through posterior commissure (PC) plane with a 14°-20° lateromedian angle (see Figure 1). Target depth was set at –13 mm below PC and 6 mm lateral. Using a Bengun, a second trajectory was defined 2 mm posterior to the central one. An additional third trajectory was occasionally performed 2 mm anterior or lateral to the central trajectory. For the last 5 consecutive patients, we targeted the cMRF on purpose more posteriorly based on accumulated experience. Coordinates were AP = 2 to 3 mm posterior to PC, Lat = 6 mm; depth = level of the PMJ, angle adapted to the brainstem orientation. FIGURE 1. View largeDownload slide cMRF intraoperative biorthogonal X-ray. A, Final intraoperative X-Ray (lateral view) merged with the ventriculography sequence (lateral view) allowing a precise localization of the ventricular landmarks. Visualization of the aqueduct of Sylvius and the fourth ventricle allows determining a trajectory parallel to the floor of the fourth ventricle. B, Final intraoperative X-Ray (frontal view). Note that in A and B, the patient had undergone a prior STN DBS electrode implantation. C and D, Final intraoperative X-ray sequences (lateral view) with the 2 chronic DBS electrodes implanted in the cMRF. Note in C that the 2 electrodes are superimposed. FIGURE 1. View largeDownload slide cMRF intraoperative biorthogonal X-ray. A, Final intraoperative X-Ray (lateral view) merged with the ventriculography sequence (lateral view) allowing a precise localization of the ventricular landmarks. Visualization of the aqueduct of Sylvius and the fourth ventricle allows determining a trajectory parallel to the floor of the fourth ventricle. B, Final intraoperative X-Ray (frontal view). Note that in A and B, the patient had undergone a prior STN DBS electrode implantation. C and D, Final intraoperative X-ray sequences (lateral view) with the 2 chronic DBS electrodes implanted in the cMRF. Note in C that the 2 electrodes are superimposed. Surgery Surgery was performed under local anesthesia and was similar to that previously used in routine for all DBS cases.16-18 A chronic DBS electrode (Model 3389, Medtronic, Dublin, Ireland) was inserted along the trajectory in which the highest thresholds of side effect together with highest cell activities were obtained. Intraoperative Assessment of Micro and Macro/DBS Electrode Position Positions of the macro contacts were monitored all along the trajectory using a biorthogonal X-ray system (see Figure 1). The Brainstem Normalized Coordinate System To overcome brainstem anatomic variability, we defined a new BNCS based on rostral brainstem landmarks centered on the PMJ (see Figure 2; Appendix, Supplemental Digital Content 1). FIGURE 2. View largeDownload slide BNCS: definition on the axis and units based on rostral brainstem landmarks centered on the PMJ. MRI images in the right column illustrate the BNCS in axial-PMJ and midsagittal planes. Orientations are indicated in each image. Coordinates were defined based on the orthogonal projections on the 3 axes. Normalized coordinates were labeled as Xbn, Ybn, and Zbn for normalized brainstem laterality, anteriority and rostrocaudality, respectively. For details on coordinate calculation and normalization procedures, see Appendix, Supplemental Digital Content 1. FIGURE 2. View largeDownload slide BNCS: definition on the axis and units based on rostral brainstem landmarks centered on the PMJ. MRI images in the right column illustrate the BNCS in axial-PMJ and midsagittal planes. Orientations are indicated in each image. Coordinates were defined based on the orthogonal projections on the 3 axes. Normalized coordinates were labeled as Xbn, Ybn, and Zbn for normalized brainstem laterality, anteriority and rostrocaudality, respectively. For details on coordinate calculation and normalization procedures, see Appendix, Supplemental Digital Content 1. Normalization Procedure DBS active contact coordinates were first measured from X-Ray ventriculography in the Talairach system then transferred on the 3-D MRI according to the same ventricular landmarks and finally were plotted onto the BNCS. For normalization procedure, see Appendix, Supplemental Digital Content 1. Graphical Representation Three-dimensional graphical representations were created using a software developed in Python with the BrainVisa/Anatomist toolbox.19 All electrode contacts were displayed as spheres on a PD patient template image. For all patients, only cathode contacts were plotted. For patients who were stimulated using 1 anode and 2 cathodes, the 2 active contacts were included in the analysis. Immunohistochemistry Postmortem human brain tissue was obtained from a female deceased from a non-neurodegenerative disease. The choline acetyltransferase (ChAT), immunostaining was done using a standard immunoperoxidase method, as previously described.20 Statistics Description of active contact coordinates’ distribution was performed by calculating the mean, standard deviation and range. Mann–Whitney U-test was used to test the differences of normalized coordinates between the groups of responders. After verifying the normality of distributions, 2 (medication OFF–medication ON) by 3 (presurgery—12 mo of follow-up–24 mo of follow-up) ANOVAs with repeated measures for the 2 factors were performed to examine the effect of cMRF surgery on the composite gait score, composite postural stability score, and PDQ-mobility subscore. RESULTS Surgery Safety Surgery was uneventful. In patients who were implanted in STN prior to cMRF surgery, no single interference with the previous electrodes was noticed. One patient showed severe retropulsion postoperatively that resolved within a week. Another patient had 2 epileptic seizures 1 wk after surgery. These patients fully recovered from these adverse effects. No severe adverse event was recorded except in 1 patient (#9) who fell down due to postural instability both OFF and ON stimulation and resulted in a vertebral fracture. Postoperative MRI did not reveal any hematoma. At 2-yr follow-up, no hardware-related complications were reported. During surgery, microstimulation tests on each trajectory, at different depths, did not yield any clinical response regarding either akinesia or rigidity. Clinical Follow-up Detailed clinical evaluation of the cMRF DBS at 24 mo postsurgery is provided in Table 2. In patients with both STN and cMRF electrodes, STN stimulation parameters were unchanged after cMRF surgery. One patient (#8) was not evaluated at 12-mo follow-up, as he had stopped complying with the experimental protocol after the sixth month. Patient (#9) experienced a severe backward fall the week before the 12-mo follow-up evaluation. As postural instability has continued to worsen ever since, no postoperative evaluation has been carried out and cMRF stimulation was discontinued in this case. Therefore, postoperative evaluations were carried out on 9 patients. Yet, another patient (#3) displayed severe akinesia and was unable to perform the objective gait assessment when OFF medication at the 12-mo follow-up assessment. TABLE 2. Clinical Evaluation at 24 mo Postsurgery Bad responders Mild responder Good responders ON Stim cMRF 24-mo postsurgery P2 P6 P5 P1 P3 P4 P7 P10 P11 FOG (off med/on med) 4/4 3/– 1/1 2/0 2/1 2/0 1/0 0/0 3/3 Postural instability (off med/on med) 3/3 1/– 2/2 0/0 0/1 1/0 0/0 1/0 0/0 Giladi FOG score (/24) 22 18 12 13 14 11 8.5 0 15 Composite gait score E0/E24 (off med) 11/10.5 8/8.5 8/6 9.5/4 10.5/4 8/2 7/3 6.5/2 6.5/6.5 Composite gait score E0/E24 (on med) 8/10.5 – 6/5 9/0.5 9.5/3 0.5/0 5.5/1 8/2 8/7 % FOG during gait assessment E0/E24 (off med) 46.8/50.7 50.4/37.6 18.9/21.3 17.6/2.4 46.5/3.5 50.6/0 52.2/1.1 23.7/0.5 14.2/8.9 % FOG during gait assessment E0/E24 (on med) 25.1/39.3 – 8/1.7 25.5/4.1 68/6.7 5.4/0.8 7.2/0 28.4/0.1 14.8/38.1 PDQ E0/E24 12.9/14.1 10.7/8.2 7.3/9.7 6/5.7 8.1/5.1 MD/7.1 6.4/5 5/1.4 9.5/3.5 PDQ mobility subscore E0/E24 92.5/85 90/55 82.5/62.5 45/40 97.5/32.5 MD/22.5 55/22.5 60/0 85/52.5 Bad responders Mild responder Good responders ON Stim cMRF 24-mo postsurgery P2 P6 P5 P1 P3 P4 P7 P10 P11 FOG (off med/on med) 4/4 3/– 1/1 2/0 2/1 2/0 1/0 0/0 3/3 Postural instability (off med/on med) 3/3 1/– 2/2 0/0 0/1 1/0 0/0 1/0 0/0 Giladi FOG score (/24) 22 18 12 13 14 11 8.5 0 15 Composite gait score E0/E24 (off med) 11/10.5 8/8.5 8/6 9.5/4 10.5/4 8/2 7/3 6.5/2 6.5/6.5 Composite gait score E0/E24 (on med) 8/10.5 – 6/5 9/0.5 9.5/3 0.5/0 5.5/1 8/2 8/7 % FOG during gait assessment E0/E24 (off med) 46.8/50.7 50.4/37.6 18.9/21.3 17.6/2.4 46.5/3.5 50.6/0 52.2/1.1 23.7/0.5 14.2/8.9 % FOG during gait assessment E0/E24 (on med) 25.1/39.3 – 8/1.7 25.5/4.1 68/6.7 5.4/0.8 7.2/0 28.4/0.1 14.8/38.1 PDQ E0/E24 12.9/14.1 10.7/8.2 7.3/9.7 6/5.7 8.1/5.1 MD/7.1 6.4/5 5/1.4 9.5/3.5 PDQ mobility subscore E0/E24 92.5/85 90/55 82.5/62.5 45/40 97.5/32.5 MD/22.5 55/22.5 60/0 85/52.5 View Large TABLE 2. Clinical Evaluation at 24 mo Postsurgery Bad responders Mild responder Good responders ON Stim cMRF 24-mo postsurgery P2 P6 P5 P1 P3 P4 P7 P10 P11 FOG (off med/on med) 4/4 3/– 1/1 2/0 2/1 2/0 1/0 0/0 3/3 Postural instability (off med/on med) 3/3 1/– 2/2 0/0 0/1 1/0 0/0 1/0 0/0 Giladi FOG score (/24) 22 18 12 13 14 11 8.5 0 15 Composite gait score E0/E24 (off med) 11/10.5 8/8.5 8/6 9.5/4 10.5/4 8/2 7/3 6.5/2 6.5/6.5 Composite gait score E0/E24 (on med) 8/10.5 – 6/5 9/0.5 9.5/3 0.5/0 5.5/1 8/2 8/7 % FOG during gait assessment E0/E24 (off med) 46.8/50.7 50.4/37.6 18.9/21.3 17.6/2.4 46.5/3.5 50.6/0 52.2/1.1 23.7/0.5 14.2/8.9 % FOG during gait assessment E0/E24 (on med) 25.1/39.3 – 8/1.7 25.5/4.1 68/6.7 5.4/0.8 7.2/0 28.4/0.1 14.8/38.1 PDQ E0/E24 12.9/14.1 10.7/8.2 7.3/9.7 6/5.7 8.1/5.1 MD/7.1 6.4/5 5/1.4 9.5/3.5 PDQ mobility subscore E0/E24 92.5/85 90/55 82.5/62.5 45/40 97.5/32.5 MD/22.5 55/22.5 60/0 85/52.5 Bad responders Mild responder Good responders ON Stim cMRF 24-mo postsurgery P2 P6 P5 P1 P3 P4 P7 P10 P11 FOG (off med/on med) 4/4 3/– 1/1 2/0 2/1 2/0 1/0 0/0 3/3 Postural instability (off med/on med) 3/3 1/– 2/2 0/0 0/1 1/0 0/0 1/0 0/0 Giladi FOG score (/24) 22 18 12 13 14 11 8.5 0 15 Composite gait score E0/E24 (off med) 11/10.5 8/8.5 8/6 9.5/4 10.5/4 8/2 7/3 6.5/2 6.5/6.5 Composite gait score E0/E24 (on med) 8/10.5 – 6/5 9/0.5 9.5/3 0.5/0 5.5/1 8/2 8/7 % FOG during gait assessment E0/E24 (off med) 46.8/50.7 50.4/37.6 18.9/21.3 17.6/2.4 46.5/3.5 50.6/0 52.2/1.1 23.7/0.5 14.2/8.9 % FOG during gait assessment E0/E24 (on med) 25.1/39.3 – 8/1.7 25.5/4.1 68/6.7 5.4/0.8 7.2/0 28.4/0.1 14.8/38.1 PDQ E0/E24 12.9/14.1 10.7/8.2 7.3/9.7 6/5.7 8.1/5.1 MD/7.1 6.4/5 5/1.4 9.5/3.5 PDQ mobility subscore E0/E24 92.5/85 90/55 82.5/62.5 45/40 97.5/32.5 MD/22.5 55/22.5 60/0 85/52.5 View Large As already reported,7 optimal effects were obtained at low frequency stimulation 10 to 30 Hz (see Table 3). In addition, maintenance of beneficial effects of cMRF stimulation required regular parameter adjustments. In all patients with favorable outcome, the initial benefit waned within 4 to 6 wk of continuous stimulation. Therefore, all patients were stimulated on a cyclic schedule, with night arrests. TABLE 3. cMRF Stimulation Parameters Stimulation parameters Mode Frequency Voltage Patients Target Contact no. (Hz) (V) #1 (STN) cMRF 0–; 1–; 2+ 25 2.7 4–; 5–; 6+ 25 3.3 #2 (STN) cMRF 0–; 1–; 2+ 20 2.5 4–; 5–; 6+ 20 2.5 #3 (STN) cMRF 0–; 1–; 2+ 30 2.8 4–; 5–; 6+ 30 2.4 #4 (STN) cMRF 0–; 1+ 15 2.4 5–; 6+ 15 2.3 #5 (STN) cMRF 0–; 1+ 20 2.5 5–; 6+ 20 2.0 #6 (STN) cMRF 0–; 1–; 2+ 15 3.8 4–; 5–; 6+ 15 1.2 #7 (STN) cMRF 0– 25 1.4 4– 25 1.6 #8 cMRF 1– 20 0.8 5– 20 1.0 #9 cMRF 1–; 2– 10 1.7 5–; 6– 10 1.4 #10 cMRF 1– 10 2.0 5– 10 1.5 #11 cMRF 1+; 2– 15 1.0 6– 15 0.8 Stimulation parameters Mode Frequency Voltage Patients Target Contact no. (Hz) (V) #1 (STN) cMRF 0–; 1–; 2+ 25 2.7 4–; 5–; 6+ 25 3.3 #2 (STN) cMRF 0–; 1–; 2+ 20 2.5 4–; 5–; 6+ 20 2.5 #3 (STN) cMRF 0–; 1–; 2+ 30 2.8 4–; 5–; 6+ 30 2.4 #4 (STN) cMRF 0–; 1+ 15 2.4 5–; 6+ 15 2.3 #5 (STN) cMRF 0–; 1+ 20 2.5 5–; 6+ 20 2.0 #6 (STN) cMRF 0–; 1–; 2+ 15 3.8 4–; 5–; 6+ 15 1.2 #7 (STN) cMRF 0– 25 1.4 4– 25 1.6 #8 cMRF 1– 20 0.8 5– 20 1.0 #9 cMRF 1–; 2– 10 1.7 5–; 6– 10 1.4 #10 cMRF 1– 10 2.0 5– 10 1.5 #11 cMRF 1+; 2– 15 1.0 6– 15 0.8 Contacts n° 0 to 3 and contacts 4 to 7 refer respectively to the contacts of the electrodes of the right and left hemisphere. Xbn, Ybn, and Zbn correspond to the coordinates in the BNCS. Xb, Yb, and Zb correspond to coordinates in the BNCS expressed in mm. Mean and SD are indicated. Electrode contacts are the negative active contact used chronically. View Large TABLE 3. cMRF Stimulation Parameters Stimulation parameters Mode Frequency Voltage Patients Target Contact no. (Hz) (V) #1 (STN) cMRF 0–; 1–; 2+ 25 2.7 4–; 5–; 6+ 25 3.3 #2 (STN) cMRF 0–; 1–; 2+ 20 2.5 4–; 5–; 6+ 20 2.5 #3 (STN) cMRF 0–; 1–; 2+ 30 2.8 4–; 5–; 6+ 30 2.4 #4 (STN) cMRF 0–; 1+ 15 2.4 5–; 6+ 15 2.3 #5 (STN) cMRF 0–; 1+ 20 2.5 5–; 6+ 20 2.0 #6 (STN) cMRF 0–; 1–; 2+ 15 3.8 4–; 5–; 6+ 15 1.2 #7 (STN) cMRF 0– 25 1.4 4– 25 1.6 #8 cMRF 1– 20 0.8 5– 20 1.0 #9 cMRF 1–; 2– 10 1.7 5–; 6– 10 1.4 #10 cMRF 1– 10 2.0 5– 10 1.5 #11 cMRF 1+; 2– 15 1.0 6– 15 0.8 Stimulation parameters Mode Frequency Voltage Patients Target Contact no. (Hz) (V) #1 (STN) cMRF 0–; 1–; 2+ 25 2.7 4–; 5–; 6+ 25 3.3 #2 (STN) cMRF 0–; 1–; 2+ 20 2.5 4–; 5–; 6+ 20 2.5 #3 (STN) cMRF 0–; 1–; 2+ 30 2.8 4–; 5–; 6+ 30 2.4 #4 (STN) cMRF 0–; 1+ 15 2.4 5–; 6+ 15 2.3 #5 (STN) cMRF 0–; 1+ 20 2.5 5–; 6+ 20 2.0 #6 (STN) cMRF 0–; 1–; 2+ 15 3.8 4–; 5–; 6+ 15 1.2 #7 (STN) cMRF 0– 25 1.4 4– 25 1.6 #8 cMRF 1– 20 0.8 5– 20 1.0 #9 cMRF 1–; 2– 10 1.7 5–; 6– 10 1.4 #10 cMRF 1– 10 2.0 5– 10 1.5 #11 cMRF 1+; 2– 15 1.0 6– 15 0.8 Contacts n° 0 to 3 and contacts 4 to 7 refer respectively to the contacts of the electrodes of the right and left hemisphere. Xbn, Ybn, and Zbn correspond to the coordinates in the BNCS. Xb, Yb, and Zb correspond to coordinates in the BNCS expressed in mm. Mean and SD are indicated. Electrode contacts are the negative active contact used chronically. View Large Objective Measures Statistical analyses revealed a significant effect of both medication (F[1,7] = 8.12, P < .02) and surgery (F[2,14] =4.28, P < .03) on the composite gait score with cMRF ON stimulation. Further analyses showed that OFF medication, the composite gait score differed between presurgery vs 12-mo postsurgery (P < .0.3) and vs 24-mo postsurgery (P < .01), with no difference between the 12- and 24-mo assessments. ON medication, the difference was significant at the 24-mo follow-up only (presurgery vs 24-mo postsurgery, P < .02). Regarding postural stability, analyses revealed a significant effect of medication (F[1, 7] = 10.72, P < .01). The interaction between medication and surgery approached significance (F[2, 14] = 3.54, P = .057). Further examination of this trend showed that medication improved postural stability before surgery (P < .03) but no longer after surgery. In addition, the postural stability subscore was improved at the 24-mo follow-up (P < .01) OFF medication only. For the objective evaluation of FOG, we computed the percent of FOG relative to the total duration of the test.7 Overall, FOG duration decreased by about 58% when patients were tested OFF medication at 1 yr, an effect that was sustained at 2 yr with a mean reduction of 57%. This reduction was significant at the 2 follow-up assessments (P = .02). ON medication, the overall decrease in FOG during assessment was 51% at 1 yr and 41% at 2 yr. However, there was a great variability between patients and the improvement was not significant. OFF medication, the reduction ranged from 37% to 95% in patients 1, 3, 4, 5, 6, 7, and 10, while it increased by 10% and 25% in patients 2 and 11. Similarly, ON medication the reduction ranged from 45% to 95% in patients 1, 3, 4, 5, 7, and 10, while it increased by 22% in patients 2 and 11. At the individual level, the benefit of cMRF DBS for FOG was not predicted by FOG responsiveness to levodopa prior to surgery. Subjective Measures Analyses revealed a significant improvement of the mobility subscore of the PDQ-39 both at 1- and 2-yr follow-up compared to the preoperative state (F[2, 12] = 10.62, P < .01). The PDQ mobility subscore improved from 76 ± 19.7 presurgery to 55 ± 21.5 at 1-yr follow-up, and 41.4 ± 25.4 at 2-yr follow-up. In their diaries, patients 1, 3, 4, 7, 10, and 11 consistently reported a significant reduction of FOG episodes (up to total disappearance in patients 7 and 10), as well as a dramatic reduction of falls related to FOG. Patient 5 reported a moderate decrease in FOG episode, whereas patient 6 reported a highly fluctuating benefit that had waned out 1 yr after surgery. Patient 2 experienced a worsening of her condition. Case Grouping According to the clinical evaluations at 24-mo follow-up, patients were classified as “bad responders” (patients 2 and 6), “mild responders” (patient 5), and “good responders” (patients 1, 3, 4, 7, 10, and 11). Among the “good responders,” 2 patients (7 and 10) were considered “very good responders” because of total alleviation from FOG. Patient 6 was considered a “bad responder,” because of the lack of actual clinical benefit seen in his diary and frequent clinical evaluations performed during the follow-up period although the occurrence of FOG during the objective gait test was greatly reduced after surgery. cMRF stimulation was switched off after 2 yr as no parameters’ setting could provide sustained improvement of FOG. The data collected from the 2 patients who dropped out of the trial were analyzed and clustered in a group labeled as “No evaluation.” Anatomoclinical Correlations and Optimal Target in the cMRF Table 4 provides the coordinates of all active contacts of the good responders in the standard and BNCS systems. Table, Supplemental Digital Content 2 provides the coordinates of all the electrode contacts in the Talairach and BNCS. Figure 3 provides the positions of DBS electrodes implanted in the 11 patients on postoperative MRI. Three-dimensional representations of the 11 patients’ active contacts are shown in Figures 4A-4E. The normalized localization of “very good responders” active contacts is provided in Figure 4F and showed that they were located slightly more posterior than any other “good responders” active contacts and located around the PMJ. FIGURE 3. View largeDownload slide Visualization of all the 22 DBS electrodes implanted in the cMRF on postoperative MRI sequences in the axial, sagittal, and coronal planes. FIGURE 3. View largeDownload slide Visualization of all the 22 DBS electrodes implanted in the cMRF on postoperative MRI sequences in the axial, sagittal, and coronal planes. FIGURE 4. View largeDownload slide cMRF active contacts normalized positions of the 11 patients displayed on PD patient brain T1-weighted MRI sequences used as templates. Green spheres: “good responders”; red spheres: “bad responders.” Orange spheres: “Mild responders” and yellow spheres: “no evaluation.” In image F, light green spheres represent “very good responders” subgroup. Images A, B, E and F were taken from a lateral view above the PMJ level as described in the Methods section. Tinted spheres are those located below the PMJ. A, Axial transverse plane of the brainstem at the level of the PMJ with all patient's active contacts. B, Upper lateral view with all patient active contacts. C and D, represent left and right sagittal planes respectively at 6.5 mm lateral from the midline with all patient active contacts. The dashed line represents the PMJ at this laterality. Tinted spheres are those located more medially than the slice. E, All patient active contacts located on a fusion sequence between axial and coronal slices at the level of the PMJ and parallel to the brainstem long axis. The intersection between the 2 slices is at the level of the aqueduct of Sylvius. F, view similar to image B but representing only the active contacts position of the 4 “good responders” (dark green spheres) and the 2 “very good responders” (light green spheres). The position of the mean coordinates of the overall 6 “good responders” active contacts is represented with a cyan sphere. Orientations of the different images are indicated in the left superior corner. P: posterior. A: anterior. Ro: rostral. C: caudal. L and R correspond to the left and right hemisphere orientations. FIGURE 4. View largeDownload slide cMRF active contacts normalized positions of the 11 patients displayed on PD patient brain T1-weighted MRI sequences used as templates. Green spheres: “good responders”; red spheres: “bad responders.” Orange spheres: “Mild responders” and yellow spheres: “no evaluation.” In image F, light green spheres represent “very good responders” subgroup. Images A, B, E and F were taken from a lateral view above the PMJ level as described in the Methods section. Tinted spheres are those located below the PMJ. A, Axial transverse plane of the brainstem at the level of the PMJ with all patient's active contacts. B, Upper lateral view with all patient active contacts. C and D, represent left and right sagittal planes respectively at 6.5 mm lateral from the midline with all patient active contacts. The dashed line represents the PMJ at this laterality. Tinted spheres are those located more medially than the slice. E, All patient active contacts located on a fusion sequence between axial and coronal slices at the level of the PMJ and parallel to the brainstem long axis. The intersection between the 2 slices is at the level of the aqueduct of Sylvius. F, view similar to image B but representing only the active contacts position of the 4 “good responders” (dark green spheres) and the 2 “very good responders” (light green spheres). The position of the mean coordinates of the overall 6 “good responders” active contacts is represented with a cyan sphere. Orientations of the different images are indicated in the left superior corner. P: posterior. A: anterior. Ro: rostral. C: caudal. L and R correspond to the left and right hemisphere orientations. TABLE 4. Electrodes Contacts Coordinates of the “Good Responders” Group in the BNCS Good responders brainstem normalized coordinate system Electrode contact Laterality Anteropost. Rostro-caud. Patient Target Xbn Xb Ybn Yb Zbn Zn n° – (mm) – (mm) – (mm) #1 STN and MRF 0 0.69 8.12 0.46 5.63 0.09 1.22 1 0.74 8.70 0.47 5.80 0.24 3.10 4 0.58 7.13 0.45 5.63 0.05 0.72 5 0.65 8.03 0.46 5.73 0.21 2.73 #3 STN and MRF 0 0.68 7.53 0.60 7.36 –0.05 –0.58 1 0.72 8.02 0.60 7.39 0.12 1.38 4 0.71 8.04 0.60 7.42 –0.01 –0.15 5 0.78 8.76 0.61 7.46 0.16 1 .85 #4 STN and MRF 0 0.29 3.73 0.45 5.52 –0.26 –2.78 5 0.61 7.37 0.38 4.67 –0.09 –0.94 #7 STN and MRF 0 0.47 5.10 0.32 3.54 –0.14 –1.87 4 0.59 8.31 0.29 3.97 –0.31 –2.53 #10 MRF 1 0.50 6.13 0.21 2.90 0.10 1.23 5 0.53 6.14 0.21 2.92 0.17 2.07 #11 MRF 2 0.79 8.37 0.29 3.36 0.03 0.36 6 0.55 6.00 0.22 2.59 0.05 0.74 Mean SD 0.62 7.22 0.41 5.12 0.02 0.41 0.13 1.43 0.14 1.75 0.16 1.77 Good responders brainstem normalized coordinate system Electrode contact Laterality Anteropost. Rostro-caud. Patient Target Xbn Xb Ybn Yb Zbn Zn n° – (mm) – (mm) – (mm) #1 STN and MRF 0 0.69 8.12 0.46 5.63 0.09 1.22 1 0.74 8.70 0.47 5.80 0.24 3.10 4 0.58 7.13 0.45 5.63 0.05 0.72 5 0.65 8.03 0.46 5.73 0.21 2.73 #3 STN and MRF 0 0.68 7.53 0.60 7.36 –0.05 –0.58 1 0.72 8.02 0.60 7.39 0.12 1.38 4 0.71 8.04 0.60 7.42 –0.01 –0.15 5 0.78 8.76 0.61 7.46 0.16 1 .85 #4 STN and MRF 0 0.29 3.73 0.45 5.52 –0.26 –2.78 5 0.61 7.37 0.38 4.67 –0.09 –0.94 #7 STN and MRF 0 0.47 5.10 0.32 3.54 –0.14 –1.87 4 0.59 8.31 0.29 3.97 –0.31 –2.53 #10 MRF 1 0.50 6.13 0.21 2.90 0.10 1.23 5 0.53 6.14 0.21 2.92 0.17 2.07 #11 MRF 2 0.79 8.37 0.29 3.36 0.03 0.36 6 0.55 6.00 0.22 2.59 0.05 0.74 Mean SD 0.62 7.22 0.41 5.12 0.02 0.41 0.13 1.43 0.14 1.75 0.16 1.77 View Large TABLE 4. Electrodes Contacts Coordinates of the “Good Responders” Group in the BNCS Good responders brainstem normalized coordinate system Electrode contact Laterality Anteropost. Rostro-caud. Patient Target Xbn Xb Ybn Yb Zbn Zn n° – (mm) – (mm) – (mm) #1 STN and MRF 0 0.69 8.12 0.46 5.63 0.09 1.22 1 0.74 8.70 0.47 5.80 0.24 3.10 4 0.58 7.13 0.45 5.63 0.05 0.72 5 0.65 8.03 0.46 5.73 0.21 2.73 #3 STN and MRF 0 0.68 7.53 0.60 7.36 –0.05 –0.58 1 0.72 8.02 0.60 7.39 0.12 1.38 4 0.71 8.04 0.60 7.42 –0.01 –0.15 5 0.78 8.76 0.61 7.46 0.16 1 .85 #4 STN and MRF 0 0.29 3.73 0.45 5.52 –0.26 –2.78 5 0.61 7.37 0.38 4.67 –0.09 –0.94 #7 STN and MRF 0 0.47 5.10 0.32 3.54 –0.14 –1.87 4 0.59 8.31 0.29 3.97 –0.31 –2.53 #10 MRF 1 0.50 6.13 0.21 2.90 0.10 1.23 5 0.53 6.14 0.21 2.92 0.17 2.07 #11 MRF 2 0.79 8.37 0.29 3.36 0.03 0.36 6 0.55 6.00 0.22 2.59 0.05 0.74 Mean SD 0.62 7.22 0.41 5.12 0.02 0.41 0.13 1.43 0.14 1.75 0.16 1.77 Good responders brainstem normalized coordinate system Electrode contact Laterality Anteropost. Rostro-caud. Patient Target Xbn Xb Ybn Yb Zbn Zn n° – (mm) – (mm) – (mm) #1 STN and MRF 0 0.69 8.12 0.46 5.63 0.09 1.22 1 0.74 8.70 0.47 5.80 0.24 3.10 4 0.58 7.13 0.45 5.63 0.05 0.72 5 0.65 8.03 0.46 5.73 0.21 2.73 #3 STN and MRF 0 0.68 7.53 0.60 7.36 –0.05 –0.58 1 0.72 8.02 0.60 7.39 0.12 1.38 4 0.71 8.04 0.60 7.42 –0.01 –0.15 5 0.78 8.76 0.61 7.46 0.16 1 .85 #4 STN and MRF 0 0.29 3.73 0.45 5.52 –0.26 –2.78 5 0.61 7.37 0.38 4.67 –0.09 –0.94 #7 STN and MRF 0 0.47 5.10 0.32 3.54 –0.14 –1.87 4 0.59 8.31 0.29 3.97 –0.31 –2.53 #10 MRF 1 0.50 6.13 0.21 2.90 0.10 1.23 5 0.53 6.14 0.21 2.92 0.17 2.07 #11 MRF 2 0.79 8.37 0.29 3.36 0.03 0.36 6 0.55 6.00 0.22 2.59 0.05 0.74 Mean SD 0.62 7.22 0.41 5.12 0.02 0.41 0.13 1.43 0.14 1.75 0.16 1.77 View Large Comparisons of normalized coordinates of “good” vs “bad” responders revealed significant differences in the anteroposterior normalized coordinates Ybn (P < .01, Mann–Whitney U-test; Figure 5). FIGURE 5. View largeDownload slide Coordinates distributions of the “good responders” (white boxes) vs “bad responders” (grey boxes). Coordinates are expressed in the brainstem normalized units. The cross in the “good responders” boxes represents the mean values of the normalized coordinates of the 6 “good responders” represented as a cyan sphere in 3-D figures. Each box extends from the 25th percentile to the 75th percentile; the middle line represents the median; the whiskers demonstrate the range of the distribution. Horizontal line y = 0 represents the origin of the Brainstem Normalized Coordinate System. Xbn = Brainstem normalized laterality; Ybn = Brainstem normalized antero-posteriority; Zbn = Brainstem normalized rostro-caudality. (**Significant P < .01, Mann–Withney U-test). FIGURE 5. View largeDownload slide Coordinates distributions of the “good responders” (white boxes) vs “bad responders” (grey boxes). Coordinates are expressed in the brainstem normalized units. The cross in the “good responders” boxes represents the mean values of the normalized coordinates of the 6 “good responders” represented as a cyan sphere in 3-D figures. Each box extends from the 25th percentile to the 75th percentile; the middle line represents the median; the whiskers demonstrate the range of the distribution. Horizontal line y = 0 represents the origin of the Brainstem Normalized Coordinate System. Xbn = Brainstem normalized laterality; Ybn = Brainstem normalized antero-posteriority; Zbn = Brainstem normalized rostro-caudality. (**Significant P < .01, Mann–Withney U-test). Based on the coordinate's mean value of all the good and very good responders (Table 5) the optimal target within the cMRF can be proposed as follows: Laterality: Xbn = 2/3 ObnXbn Anteriority: Ybn = 2/5 ObnYbn Depth: Zbn = Ponto-mesencephalic junction TABLE 5. Mean Normalized Coordinates of the Electrode Active Contacts Per Group of Responders cMRF DBS active plot normalized coordinates Mean normalized coordinates SD Range Good responder (1; 3; 4; 7; 10; 11) Xbn +0.62 0.13 [0.13–0.79] Ybn +0.41 0.14 [0.21–0.61] Zbn +0.02 0.16 [−0.31 to 0.20] Bad responder (2-6) Xbn 0.71 0.15 [0.49–0.88] Ybn 0.73 0.05 [0.65–0.79] Zbn +0.05 0.16 [−0.23 to 0.24] Mild responder (5) Xbn +0.72 0.07 [0.67–0.77] Ybn +0.64 0.01 [0.63–0.65] Zbn +0.18 0.04 [0.15–0.20] cMRF DBS active plot normalized coordinates Mean normalized coordinates SD Range Good responder (1; 3; 4; 7; 10; 11) Xbn +0.62 0.13 [0.13–0.79] Ybn +0.41 0.14 [0.21–0.61] Zbn +0.02 0.16 [−0.31 to 0.20] Bad responder (2-6) Xbn 0.71 0.15 [0.49–0.88] Ybn 0.73 0.05 [0.65–0.79] Zbn +0.05 0.16 [−0.23 to 0.24] Mild responder (5) Xbn +0.72 0.07 [0.67–0.77] Ybn +0.64 0.01 [0.63–0.65] Zbn +0.18 0.04 [0.15–0.20] View Large TABLE 5. Mean Normalized Coordinates of the Electrode Active Contacts Per Group of Responders cMRF DBS active plot normalized coordinates Mean normalized coordinates SD Range Good responder (1; 3; 4; 7; 10; 11) Xbn +0.62 0.13 [0.13–0.79] Ybn +0.41 0.14 [0.21–0.61] Zbn +0.02 0.16 [−0.31 to 0.20] Bad responder (2-6) Xbn 0.71 0.15 [0.49–0.88] Ybn 0.73 0.05 [0.65–0.79] Zbn +0.05 0.16 [−0.23 to 0.24] Mild responder (5) Xbn +0.72 0.07 [0.67–0.77] Ybn +0.64 0.01 [0.63–0.65] Zbn +0.18 0.04 [0.15–0.20] cMRF DBS active plot normalized coordinates Mean normalized coordinates SD Range Good responder (1; 3; 4; 7; 10; 11) Xbn +0.62 0.13 [0.13–0.79] Ybn +0.41 0.14 [0.21–0.61] Zbn +0.02 0.16 [−0.31 to 0.20] Bad responder (2-6) Xbn 0.71 0.15 [0.49–0.88] Ybn 0.73 0.05 [0.65–0.79] Zbn +0.05 0.16 [−0.23 to 0.24] Mild responder (5) Xbn +0.72 0.07 [0.67–0.77] Ybn +0.64 0.01 [0.63–0.65] Zbn +0.18 0.04 [0.15–0.20] View Large Figure 6 illustrates the optimal localization on transverse and sagittal planes. The target can also be seen on the Figure 4F as a blue sphere. FIGURE 6. View largeDownload slide Optimal target in the cMRF based on the mean coordinates of the good responders group. Cyan spheres represent the target point equivalent to the mean coordinates of the 6 good responders active contacts. A, Axial view at the PMJ level. B, Sagittal view: projection of the target point on the mid-sagittal view. FIGURE 6. View largeDownload slide Optimal target in the cMRF based on the mean coordinates of the good responders group. Cyan spheres represent the target point equivalent to the mean coordinates of the 6 good responders active contacts. A, Axial view at the PMJ level. B, Sagittal view: projection of the target point on the mid-sagittal view. In Figure 7, we provide the localization of the human cholinergic PPN neurons on postmortem tissue in 2 sagittal slices of the brainstem as anatomic information. Note that most of cholinergic neurons are located in the caudal midbrain with few cholinergic neurons found below the PMJ. FIGURE 7. View largeDownload slide ChAT immunostaining on 2 sagittal human brainstem sections obtained from a female deceased from a non-neurodegenerative disease from the Human Brain Bank of the CERVO Institute in Quebec City. Immunostaining was done using a standard immunoperoxidase method, as previously described.20 The sections (50-μm thick) were cut at 4.9 and 6.9 mm from the midline. The light green areas provide the extent of the PPN cholinergic neurons at this laterality. Images in the left upper corner are enlargement of the main image centered on the PPN that allows distinguishing the 2 pars of the PPN based on cellular density. Note that on the 2 sections from 4.9 to 6.9 mm from the midline, most cholinergic neurons are located in the caudal part of the mesencephalon at the level of the IC while only very few neurons were found below the PMJ towards the latero dorsal tegmental nucleus. Together, the 2 neuronal populations form a cholinergic column also known as CH5-CH6 complex.29 AC: Anterior commissure; PB: parabrachial nucleus; CfN: cuneiform nucleus; IC: inferior colliculus; PCp: Posterior commissure (projection from midline); PMJ: ponto-mesencephalic junction; PPN: pedunculopontine nucleus; PPNc: PPN pars compacta; PPNd: PPN pars dissipata; RRA: retrorubral area; SC: superior colliculus; SCP: superior cerebellar peduncle; SN: substantia nigra; IVf: trochlear nerve fibers. FIGURE 7. View largeDownload slide ChAT immunostaining on 2 sagittal human brainstem sections obtained from a female deceased from a non-neurodegenerative disease from the Human Brain Bank of the CERVO Institute in Quebec City. Immunostaining was done using a standard immunoperoxidase method, as previously described.20 The sections (50-μm thick) were cut at 4.9 and 6.9 mm from the midline. The light green areas provide the extent of the PPN cholinergic neurons at this laterality. Images in the left upper corner are enlargement of the main image centered on the PPN that allows distinguishing the 2 pars of the PPN based on cellular density. Note that on the 2 sections from 4.9 to 6.9 mm from the midline, most cholinergic neurons are located in the caudal part of the mesencephalon at the level of the IC while only very few neurons were found below the PMJ towards the latero dorsal tegmental nucleus. Together, the 2 neuronal populations form a cholinergic column also known as CH5-CH6 complex.29 AC: Anterior commissure; PB: parabrachial nucleus; CfN: cuneiform nucleus; IC: inferior colliculus; PCp: Posterior commissure (projection from midline); PMJ: ponto-mesencephalic junction; PPN: pedunculopontine nucleus; PPNc: PPN pars compacta; PPNd: PPN pars dissipata; RRA: retrorubral area; SC: superior colliculus; SCP: superior cerebellar peduncle; SN: substantia nigra; IVf: trochlear nerve fibers. Stimulation of STN and cMRF vs Stimulation of cMRF Alone Clinical outcomes of the 7 patients implanted in both STN and cMRF showed that 4 were “good responders,” 1 was a “mild responder,” and 2 were “bad responders.” Concerning the 4 patients implanted in the cMRF alone, 2 were good responders, and 2 patients could not be evaluated. DISCUSSION Clinical Evaluation At the group level, evaluation at 1 yr showed a significant improvement of gait and FOG. This effect was sustained at 2 yr. Although it was mainly seen OFF medication, the benefit of cMRF DBS was confirmed by a durable improvement in the PDQ-39 mobility subscore as well as the patients’ reports. The effect on postural stability was marginal. While in some patients FOG greatly improved at 2 yr of follow-up, others patients did not benefit from the procedure. Overall, the results of the objective FOG measurements during the gait test, the composite gait score and the daily recordings of the patients were consistent. Patient 6 did not benefit at the clinical level from cMRF-DBS despite a great improvement of objective measures of FOG. In contrast, patient 11, a good responder, experienced more FOG episodes during objective testing, but his diary recordings, routine clinical evaluation, and improvement of the mobility subscale of the PDQ-39 clearly showed that FOG was significantly reduced under cMRF stimulation. Because improvement of symptoms under conditions of daily living is the ultimate goal of medical care, we classified this patient as good responder. These contradictory effects likely reflect the highly unpredictable nature of FOG, as well as its susceptibility to context and setting.21 The clustering of the patients in good vs bad responders made sense when examining the location of the active contacts. Brainstem Normalized Coordinate System The “Talairach coordinate system” is not ideally suited for the brainstem. Proton density MRI sequences to localize the PPN based on its position in atlases22,23 were proposed for direct targeting24 and further used in different studies.13,25,26 However, coordinates calculation based on pontine and cerebellar landmarks is debatable. We previously expressed contact coordinates in a coordinate system based upon the PMJ.7 This approach was further used by others.11,25,27 However, coordinate normalization and specific lateral coordinates computation were impossible. The BNCS is based on PMJ, the floor of the fourth ventricle and the lateral mesencephalic sulci which are well delineated on MRI and provide an indirect definition of the target, which can complement the direct PPN targeting.24,28 Anatomoclinical Correlation We found that the electrode active contacts in good responders were located in the posterior and central part of the cMRF at the level of the PMJ, that contains the PPN (posterior pars dissipata and pars compacta) and the CfN. However, we would like to stress the caution that should be observed in extrapolating postoperative MRI data of parkinsonian patient (known to have degeneration of some brainstem structures including PPN) to anatomic data provided in brainstem atlas obtained on normal subject following immunohistological procedures. Nevertheless, we provided an immunohistological localization of the cholinergic neurons in sagittal sections of a human brainstem. This allows localizing the human PPN in the caudal midbrain and at the PMJ level where the majority of PPN neurons lie. The PPN located in the cMRF forms, with the laterodorsal tegmental nucleus (in the rostral pons), a column of cholinergic neurons also known as CH5-CH6 complex.29 In the Paxinos and Huang atlas,22 the active contacts of the “good responders” were located at the PMJ level (Plate Obex + 31 mm and Obex + 32 mm), corresponding to the PPN pars dissipata. In patients 4 and 7, the active contacts were located just below the PMJ in a more medial position in the pontine-cMRF closed to the superior cerebellar peduncle and the nucleus pontis oralis (Nucleus reticularis pontis rostralis) and the ventrolateral tegmental area. This beneficial site of stimulation, which lies caudal the PPN, was also recently reported11,30 and will require further examination. Where to Stimulate Within the cMRF? Using the BNCS, we proposed an optimal target associated with normalized coordinates (see Figure 6). We propose to have the penultimate contact (n° 1 and n° 5) on the target at the PMJ. This allows to have the lowest contact (n° 0 and n° 4) 2 mm below the PMJ and if necessary, to stimulate rostral pontine areas. The mechanism of action of cMRF-DBS is still hypothetical. Whether the beneficial effect on FoG is obtained by stimulation of the remaining PPN cholinergic neurons and other noncholinergic neurons of the cMRF (including CfN neurons) or simultaneous stimulation of surrounding fiber system remains an open question. Also, the integrative role of the cMRF in the control of locomotion and attention31,32 must be considered and could explain the need for regular parameter adjustments to maintain beneficial effect. A review of the studies reporting PPN DBS implantations highlighted a large heterogeneity in the electrode positioning within the cMRF.14 Some studies including our own preliminary report, showed electrode implantation within the caudal midbrain,7,13,26 while others advocated an electrode implantation in the pons below the PMJ,11,25,27,33,34 with beneficial clinical outcomes.35 Unlike a study demonstrated no relation between the position of the electrode and clinical outcomes,36 the present study provides convincing evidences that the position of the electrode could explain, to some extent, the variability of clinical response. This will have to be confirmed on a larger cohort of patients implanted in the cMRF. In this regard, the use of the BNCS could allow comparing sites of implantation gathered elsewhere, to improve the localization of the optimal target(s). Limitations Unlike our initial study at 6 mo based on a double-blind protocol, the present study at 2-yr follow-up is an open-label trial, thus requiring caution when interpreting the clinical outcomes similar to every open-label clinical study. We would like to stress the difficulty to conduct a double-blind study with Parkinson disease patients in advanced stages of the disease. Another limit of the present study is the small number of patients included in the protocol (11 patients) and only 9 patients in the anatomoclinical evaluation due to the impossibility to evaluate 2 patients at long-term evaluation. As an exploratory study based on a small number of patients, it will have to be confirmed in a larger cohort of patients. We think that the use of the BNCS will allow to include more patients in the analysis and, finally, to refine the target position. CONCLUSION Variability in clinical response of PPN-DBS remains an open question. Using a new stereotactic procedure adapted to the brainstem, the present anatomoclinical study, while based on a small number of patients, provides arguments for a safe electrode implantation in the posterior cMRF at the level of the PMJ to treat FoG. Whether different sites for electrode implantation in the rostral brainstem provide similar benefit outcomes, opens exciting perspectives in our understanding of this promising but demanding therapeutic approach. Disclosures This work was supported by The Michael J. Fox Foundation, the Fondation de France, and the Centre Hospitalier Universitaire de Grenoble Alpes. Medtronic provided the pulse generators free of charge. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Dr Chabardès serves as consultant for Boston Scientific and for Medtronic and has received financial support from Medtronic for preclinical research purposes in the field of DBS. Notes The meeting of the “World Society for Stereotactic and Functional Neurosurgery,” Tokyo, Japan, May 30, 2013, Oral presentation (Laurent Goetz). REFERENCES 1. Le Ray D , Juvin L , Ryczko D , Dubuc R . Chapter 4-supraspinal control of locomotion: the mesencephalic locomotor region . Prog Brain Res . 2011 ; 188 : 51 - 70 . Google Scholar CrossRef Search ADS PubMed 2. Grillner S , Wallén P , Saitoh K , Kozlov A , Robertson B . Neural bases of goal-directed locomotion in vertebrates–an overview . Brain Res Rev . 2008 ; 57 ( 1 ): 2 - 12 . Google Scholar CrossRef Search ADS PubMed 3. Goetz L , Piallat B , Bhattacharjee M , Mathieu H , David O , Chabardes S . On the role of the pedunculopontine nucleus and mesencephalic reticular formation in locomotion in nonhuman primates . J Neurosci . 2016 ; 36 ( 18 ): 4917 - 4929 . Google Scholar CrossRef Search ADS PubMed 4. Takakusaki K , Habaguchi T , Ohtinata-Sugimoto J , Saitoh K , Sakamoto T . Basal ganglia efferents to the brainstem centers controlling postural muscle tone and locomotion: a new concept for understanding motor disorders in basal ganglia dysfunction . Neuroscience . 2003 ; 119 ( 1 ): 293 - 308 . Google Scholar CrossRef Search ADS PubMed 5. Ryczko D , Dubuc R . The multifunctional mesencephalic locomotor region . Curr Pharm Des . 2013 ; 19 ( 24 ): 4448 - 4470 . Google Scholar CrossRef Search ADS PubMed 6. Alam M , Schwabe K , Krauss JK . The pedunculopontine nucleus area: critical evaluation of interspecies differences relevant for its use as a target for deep brain stimulation . Brain . 2011 ; 134 ( 1 ): 11 - 23 . Google Scholar CrossRef Search ADS PubMed 7. Ferraye MU , Debu B , Fraix V et al. Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease . Brain . 2010 ; 133 ( 1 ): 205 - 214 . Google Scholar CrossRef Search ADS PubMed 8. Garcia-Rill E . Waking and the Reticular Activating System in Health and Disease . Academic Press , San Diego ; 2015 . 9. Plaha P , Gill SS . Bilateral deep brain stimulation of the pedunculopontine nucleus for Parkinson's disease . Neuroreport . 2005 ; 16 ( 17 ): 1883 - 1887 . Google Scholar CrossRef Search ADS PubMed 10. Mazzone P , Lozano A , Stanzione P et al. Implantation of human pedunculopontine nucleus: a safe and clinically relevant target in Parkinson's disease . Neuroreport . 2005 ; 16 ( 17 ): 1877 - 1881 . Google Scholar CrossRef Search ADS PubMed 11. Thevathasan W , Coyne TJ , Hyam JA et al. Pedunculopontine nucleus stimulation improves gait freezing in parkinson disease . Neurosurgery . 2011 ; 69 ( 6 ): 1248 - 1254 . Google Scholar CrossRef Search ADS PubMed 12. Golestanirad L , Elahi B , Graham SJ , Das S , Wald LL . Efficacy and safety of pedunculopontine nuclei (PPN) Deep brain stimulation in the treatment of gait disorders: a meta-analysis of clinical studies . Can J Neurol Sci . 2016 ; 43 ( 01 ): 120 - 126 . Google Scholar CrossRef Search ADS PubMed 13. Moro E , Hamani C , Poon Y-Y et al. Unilateral pedunculopontine stimulation improves falls in Parkinson's disease . Brain . 2010 ; 133 ( 1 ): 215 - 224 . Google Scholar CrossRef Search ADS PubMed 14. Hamani C , Lozano AM , Mazzone PAM et al. Pedunculopontine nucleus region deep brain stimulation in Parkinson disease: surgical techniques, side effects, and postoperative imaging . Stereotact Funct Neurosurg . 2016 ; 94 ( 5 ): 307 - 319 . Google Scholar CrossRef Search ADS PubMed 15. Lozano AM , Lang AE , Galvez-Jimenez N , Miyasaki J . Effect of GPi pallidotomy on motor function in Parkinson's disease . Lancet North Am Ed . 1995 ; 346 ( 8987 ): 1383 - 1387 . Google Scholar CrossRef Search ADS 16. Benabid A-L , Chabardès S , Mitrofanis J , Pollak P . Deep brain stimulation of the subthalamic nucleus for the treatment of Parkinson's disease . Lancet Neurol . 2009 ; 8 ( 1 ): 67 - 81 . Google Scholar CrossRef Search ADS PubMed 17. Pollak P , Krack P , Fraix V et al. Intraoperative micro- and macrostimulation of the subthalamic nucleus in Parkinson's disease . Mov Disord . 2002 ; 17 ( S3 ): S155 - S161 . Google Scholar CrossRef Search ADS PubMed 18. Piallat B , Polosan M , Fraix V et al. Subthalamic neuronal firing in obsessive-compulsive disorder and Parkinson disease . Ann Neurol . 2011 ; 69 ( 5 ): 793 - 802 . Google Scholar CrossRef Search ADS PubMed 19. Cointepas Y , Geffroy D , Souedet N , Denghien I . The Brain VISA Project: A Shared Software Development Infrastructure for Biomedical Imaging Research : Proceedings, 16th annual meeting of the Organization for Human Brain Mapping , Barcelona , 2010 . 20. Bédard C , Wallman M-J , Pourcher E , Gould PV , Parent A , Parent M . Serotonin and dopamine striatal innervation in Parkinson's disease and Huntington's chorea . Parkinsonism Relat Disord . 2011 ; 17 ( 8 ): 593 - 598 . Google Scholar CrossRef Search ADS PubMed 21. Nonnekes J , Snijders AH , Nutt JG , Deuschl G , Giladi N , Bloem BR . Freezing of gait: a practical approach to management . Lancet Neurol . 2015 ; 14 ( 7 ): 768 - 778 . Google Scholar CrossRef Search ADS PubMed 22. Paxinos G , Huang XF . Atlas of the Human Brainstem . Academic Press , San Diego ; 1995 . 23. Afshar F , Watkins ES , Yap JC . Stereotaxic Atlas of the Human Brainstem and Cerebellar Nuclei . New York : Raven Press ; 1978 . 24. Zrinzo L , Zrinzo LV , Tisch S et al. Stereotactic localization of the human pedunculopontine nucleus: atlas-based coordinates and validation of a magnetic resonance imaging protocol for direct localization . Brain . 2008 ; 131 ( 6 ): 1588 - 1598 . Google Scholar CrossRef Search ADS PubMed 25. Insola A , Valeriani M , Mazzone P . Targeting the pedunculopontine nucleus . Neurosurgery . 2012 ; 71 ( 1 ): 96 - 103 . Google Scholar PubMed 26. Shimamoto SA , Larson PS , Ostrem JL , Glass GA , Turner RS , Starr PA . Physiological identification of the human pedunculopontine nucleus . J Neurol Neurosurg Psychiatry . 2010 ; 81 ( 1 ): 80 - 86 . Google Scholar CrossRef Search ADS PubMed 27. Thevathasan W , Pogosyan A , Hyam JA et al. Alpha oscillations in the pedunculopontine nucleus correlate with gait performance in parkinsonism . Brain . 2012 ; 135 ( 1 ): 148 - 160 . Google Scholar CrossRef Search ADS PubMed 28. Zrinzo L , Zrinzo LV , Massey LA et al. Targeting of the pedunculopontine nucleus by an MRI-guided approach: a cadaver study . J Neural Transm . 2011 ; 118 ( 10 ): 1487 - 1495 . Google Scholar CrossRef Search ADS PubMed 29. Mesulam MM , Geula C , Bothwell MA , Hersh LB . Human reticular formation: cholinergic neurons of the pedunculopontine and laterodorsal tegmental nuclei and some cytochemical comparisons to forebrain cholinergic neurons . J Comp Neurol . 1989 ; 283 ( 4 ): 611 - 633 . Google Scholar CrossRef Search ADS PubMed 30. Mazzone P , Filho OV , Viselli F et al. Our first decade of experience in deep brain stimulation of the brainstem: elucidating the mechanism of action of stimulation of the ventrolateral pontine tegmentum . J Neural Transm . 2016 ; 123 :( 75 ) 1 - 767 . Google Scholar PubMed 31. Goetz L , Piallat B , Bhattacharjee M , Mathieu H , David O , Chabardès S . The primate pedunculopontine nucleus region: towards a dual role in locomotion and waking state . J Neural Transm . 2016 ; 123 ( 7 ): 667 - 678 . Google Scholar CrossRef Search ADS PubMed 32. Lau B , Welter M-L , Belaid H et al. The integrative role of the pedunculopontine nucleus in human gait . Brain . 2015 ; 138 ( 5 ): 1284 - 1296 . Google Scholar CrossRef Search ADS PubMed 33. Androulidakis AG , Mazzone P , Litvak V et al. Oscillatory activity in the pedunculopontine area of patients with Parkinson's disease . Exp Neurol . 2008 ; 211 ( 1 ): 59 - 66 . Google Scholar CrossRef Search ADS PubMed 34. Tattersall TL , Stratton PG , Coyne TJ et al. Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus . Nat Neurosci . 2014 ; 17 ( 3 ): 449 - 454 . Google Scholar CrossRef Search ADS PubMed 35. Peppe A , Pierantozzi M , Chiavalon C et al. Deep brain stimulation of the pedunculopontine tegmentum and subthalamic nucleus: Effects on gait in Parkinson's disease . Gait Posture . 2010 ; 32 ( 4 ): 512 - 518 . Google Scholar CrossRef Search ADS PubMed 36. Mazzone P , Sposato S , Insola A , Scarnati E . The clinical effects of deep brain stimulation of the pedunculopontine tegmental nucleus in movement disorders may not be related to the anatomical target, leads location, and setup of electrical stimulation . Neurosurgery . 2013 ; 73 ( 5 ): 894 - 906 . Discussion 905-906 . Google Scholar CrossRef Search ADS PubMed Supplemental digital content is available for this article at www.neurosurgery-online.com. Supplemental Digital Content 1. Brainstem Normalized Coordinate System. Supplemental Digital Content 2. Coordinates of the DBS electrode contacts in the Talairach system and in the BNCS. COMMENT The authors have correctly carried out their work giving appropriate attention to the clinical evaluation and stereotactic methodology. They have provided an accurate description of stereotactic procedure that will be useful in functional neurosurgery. They have properly considered their approach in a way that fits with my belief on PPTg (PPN) DBS.1,2,3 I fully agree and share their innovative neurosurgical planning that considers anatomical landmarks and neuroimaging to target brainstem structures, thus overcoming the limits of traditional stereotactic methods.3 This applies in particular for PPTg DBS.3,4 According to my experience on a good number of implanted patients, I agree with the site that the authors indicate as the most useful. This would be the site to consider as the most useful “endpoint” when planning the electrode position to achieve the best clinical outcome. Moreover, I am convinced that when a brain region loses neurons, as it occurs in these patients, the effects of stimulation should be ascribed to the effects of the electric field on neuronal pathways linking brain structures rather than to a local action on neurons. This interpretation better explains the possibility to control symptoms in those patients in whom the stimulating electrode was positioned not exactly in the planned site owing to stochastic variations in the procedure.3 This may also explain the positive result that may be obtained with different stimulation parameters and using different contacts, especially when using octopolar electrodes. This conclusion is also supported by the results of other groups that are on the way to be published. The revision of the work by the authors has been meticulous, proving very useful for myself, having first introduced the PPTg DBS to control axial symptoms that are not satisfactorily controlled by other treatments.5 I dare to encourage publication of papers like this one, ie, characterized by a correct approach and by a rich exposition of data, rather that reviews that in most cases have been merely speculative without offering any substantial contribution to improving DBS in brainstem structures and to understand its mechanism of action. Undoubtedly, the introduction of PPTg DBS has provided new insight for understanding DBS. Paolo Aurelio Maria Mazzone Rome, Italy 1. Insola A , Padua L , Mazzone P , Scarnati E , Valeriani M . Low and high-frequency somatosensory evoked potentials recorded from the human pedunculopontine nucleus . Clin Neurophysiol . 2014 ; pii:S1388-2457(14)00007-8. doi: 10.1016/j.clinph.2013.12.112. [Epub ahead of print] 2. Insola A , Valeriani M , Mazzone P . Targeting the pedunculopontine nucleus: a new neurophysiological method based on somatosensory evoked potentials to calculate the distance of DBS lead from the Obex . Neurosurgery 2012 . doi: 10.1227/NEU.0b013e318249c726 . 3. Mazzone P , Sposato S , Insola A , Scarnati E . The deep brain stimulation of the pedunculopontine tegmental nucleus: towards a new stereotactic neurosurgery . J Neural Transm . 2011 ; 118 ( 10 ): 1431 - 51 . Google Scholar CrossRef Search ADS PubMed 4. Mazzone P , Garcia-Rill E , Scarnati E . Progress in deep brain stimulation of the pedunculopontine nucleus and other structures: implications for motor and non-motor disorders . J Neural Transm (Vienna) . 2016 ; 123 ( 7 ): 653 - 4 . Google Scholar CrossRef Search ADS PubMed 5. Mazzone P , Vitale F , Capozzo A , Viselli F , Scarnati E . Deep Brain Stimulation of the Pedunculopontine Tegmental Nucleus improves static balance in Parkinson's Disease . By Elliot KE , Hunter P , Ali R , (Eds.) Comprehensive Textbook of Principles, Technologies, and Therapies , 2nd Edition . Chapter 79, Section IX; Vol. 2 of: Neuromodulation (book) Academic Press . Hardcover ISBN: 9 780 128 053 539 . 2018 . Google Scholar CrossRef Search ADS Neurosurgery Speaks (Audio Abstracts) Listen to audio translations of this paper's abstract into select languages by choosing from one of the selections below. Chinese: Liang Chen, MD. Department of Neurosurgery Huashan Hospital Shanghai, China Chinese: Liang Chen, MD. Department of Neurosurgery Huashan Hospital Shanghai, China Close English: Oluwakemi Aderonke Badejo, MBBS, FWACS. Department of Surgery College of Medicine University of Ibadan Ibadan, Nigeria English: Oluwakemi Aderonke Badejo, MBBS, FWACS. Department of Surgery College of Medicine University of Ibadan Ibadan, Nigeria Close Italian: Francesco Cardinale, MD, PhD. “Claudio Munari” Centre for Epilepsy and Parkinson Surgery-Niguarda Ca' Granda Hospital Milano, Italy Italian: Francesco Cardinale, MD, PhD. “Claudio Munari” Centre for Epilepsy and Parkinson Surgery-Niguarda Ca' Granda Hospital Milano, Italy Close Japanese: Yoshinori Higuchi, MD, PhD. Department of Neurological Surgery Chiba University Graduate School of Medicine Chiba City, Japan Japanese: Yoshinori Higuchi, MD, PhD. Department of Neurological Surgery Chiba University Graduate School of Medicine Chiba City, Japan Close Korean: Tae Gon Kim, MD. Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Korean: Tae Gon Kim, MD. Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Close Portuguese: Tae Gon Kim, MD. Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Portuguese: Tae Gon Kim, MD. Division of Vascular Section Department of Neurosurgery Bundang CHA Hospital Seongnam, Republic of Korea Close Greek: George Georgoulis, MD. Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Greek: George Georgoulis, MD. Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Close Spanish: George Georgoulis, MD. Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Spanish: George Georgoulis, MD. Department of Neurosurgery University Hospital of Ioannina Ioannina, Greece Close Copyright © 2018 by the Congress of Neurological Surgeons This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

NeurosurgeryOxford University Press

Published: May 25, 2018

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