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Effect of subthalamic stimulation on distal and proximal upper limb movements in Parkinson's disease
Brain Research 1648 (2016) 438–444
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Effect of subthalamic stimulation on distal and proximal upper limb movements in Parkinson's disease Gertrúd Tamás a,n, Andrea Kelemen a, Péter Radics a, István Valálik b, Dustin Heldman c, Péter Klivényi d, László Vécsei d,e, Eszter Hidasi f, László Halász g, Dávid Kis h, Péter Barsi i, Péter Golopencza j, Loránd Erőss g a
Department of Neurology, Semmelweis University, Balassa utca 6, 1083 Budapest, Hungary Department of Neurosurgery, University of Debrecen, Móricz Zsigmond körút 22, 4032 Debrecen, Hungary c Great Lakes NeuroTechnologies Inc., 10055 Sweet Valley Dr, Cleveland, OH, USA d Department of Neurology, University of Szeged, Semmelweis u. 6, 6725 Szeged, Hungary e MTA-SZTE Neuroscience Research Group, Semmelweis u. 6, 6725 Szeged, Hungary f Department of Neurology, University of Debrecen, Móricz Zsigmond körút 22, 4032 Debrecen, Hungary g National Institute of Clinical Neurosciences, Amerikai út 57, 1145 Budapest, Hungary h Department of Neurosurgery, University of Szeged, Semmelweis u. 6, 6725 Szeged, Hungary i MR Research Centre, Semmelweis University, Balassa utca 6, 1083 Budapest, Hungary j Department of Anaesthesiology and Intensive Therapy, Semmelweis University, Kútvölgyi u. 4, 1125 Budapest, Hungary b
art ic l e i nf o
a b s t r a c t
Article history: Received 31 January 2016 Received in revised form 17 July 2016 Accepted 15 August 2016 Available online 16 August 2016
Introduction: A different innervation pattern of proximal and distal muscles from the contra- and ipsilateral motor circuits raises the question as to whether bilateral, contra- and ipsilateral subthalamic stimulation may have different effects on the distal and proximal movements of the upper limb. To answer this question, we performed kinematic analyzes in patients with Parkinson's disease. Methods: Twenty-eight Parkinsonian patients treated by bilateral subthalamic stimulation were examined with an age-matched control group of 28 healthy subjects. They performed 14 s of finger tapping, hand grasping and pronation-supination. The patient group performed these sessions in four conditions (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON) after withdrawal of dopaminergic medication for 12 h and a fifth condition after taking medication (BOTH ON-MED ON). A motion sensor with a three-dimensional gyroscope was worn on the index finger. Speed, amplitude, rhythm and decrement of movements were calculated and compared across these conditions. Results: Speed and amplitude of the more distal movements were improved similarly by contra- and bilateral stimulation. Bilateral stimulation was more effective than contralateral stimulation for the more proximal movements. Contra- and bilateral stimulation ameliorated the rhythm similarly in each movement task. Decrement of distal and proximal movements was not affected by the stimulation conditions. Conclusion: This is the first study to show that the outcome of bi- and unilateral subthalamic stimulation on proximal and distal upper limb movements should be evaluated separately postulating the different somatotopic organization of subloops in the cortico-basal ganglia motor circuits. & 2016 Elsevier B.V. All rights reserved.
Keywords: Parkinson's disease Deep brain stimulation Distal movement Proximal movement Unilateral stimulation Bilateral stimulation
1. Introduction
Abbreviations: BOTH OFF: bilateral stimulation is off; BOTH ON: bilateral stimulation is on; BOTH ON-MED ON: bilateral stimulation is on plus best medication effect; CAPSIT-PD: Core Assessment Program for Surgical Interventional Therapies for Parkinson's Disease; CONTRA ON: contralateral stimulation is on; FT: finger tapping; HG: hand grasping; IPSI ON: ipsilateral stimulation is on; PPN: pedunculopontine nucleus; PS: pronation-supination; STN: subthalamic nucleus; UPDRS: Unified Parkinson's Disease Rating Scale n Corresponding author. E-mail address: [email protected] (G. Tamás). http://dx.doi.org/10.1016/j.brainres.2016.08.019 0006-8993/& 2016 Elsevier B.V. All rights reserved.
Bilateral stimulation of the subthalamic nucleus (STN) can effectively ameliorate bradykinesia, rigidity and tremor in appropriately selected patients with idiopathic Parkinson's disease (PD) (Limousin et al., 1998; Deuschl et al., 2006; Deli et al., 2015). However, the underlying mechanism of STN stimulation is not well understood. Bilateral stimulation provides more pronounced clinical recovery than unilateral stimulation (Bastian et al., 2003). According to previous clinical observations, 6–18 months after surgery improvement in Unified Parkinson's Disease Rating Scale
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(UPDRS) Part III is 53.8–60% (Fahn et al., 1987), with 55.1–62.2% improvement in bradykinesia subscores (Limousin et al., 1998; Deuschl et al., 2006; Deli et al., 2015; Kumar et al., 1999). Axial motor scores (UPDRS III item 29–30) also decrease by 21–78% 3–18 months after surgery (Bejjani et al., 2000; Krack et al., 2003; Kumar et al., 1999; Limousin et al., 1998; Samii et al., 2007). Although unilateral subthalamic stimulation has a predominant clinical effect on the contralateral side, it affects the ipsilateral hemibody as well (improvement in UPDRS III total score: contralateral stimulation: 30.1–72.4%, ipsilateral stimulation: 1.2 to 20%) and moderately improves the axial symptoms (UPDRS III. item 29-30: 15–39% 3–18 months after surgery) (Kumar et al., 1999; Linazasoro et al., 2003; Germano et al., 2004; Chung et al., 2006; Samii et al., 2007; Slowinski et al., 2007). Proximal muscles have bilateral, while distal muscles have primarily contralateral innervation from the cortico-basal ganglia motor circuits (Alexander and DeLong, 1986; Montgomery et al., 2013). This raises the question whether uni- and bilateral subthalamic stimulation can influence distal and proximal movements of the upper limb differently. Therefore, in the present study, we investigated the effects of bilateral, contra- and ipsilateral subthalamic stimulation on distal and proximal movements of the upper limbs. Motor outcome of unilateral stimulation was assessed by the Unified Parkinson's Disease Rating Scale part III (Fahn et al., 1987) in the aforementioned studies; however, in this study we used a three-dimensional motion capture device. Kinematic analyses of various types of upper limb movements have been reported in a few studies (Bastian et al., 2003; Wenzelburger et al., 2003; Timmermann et al., 2008; Tabbal et al., 2008) and have been shown to be more sensitive, more quantitative and more reliable than clinical scoring (Tabbal et al., 2008; Heldman et al., 2014). Our aim was to better understand the motor control and mechanism of STN stimulation. Our primary hypothesis was that distal movements are improved primarily by contralateral stimulation while bilateral stimulation is superior to contralateral stimulation for proximal movements. Our secondary hypothesis was that quantitative kinematic analysis might provide additional information about the mechanism of action of STN stimulation.
2. Results Twenty-eight Parkinsonian patients implanted with bilateral STNDBS and a healthy control group performed 14 s of UPDRS-directed
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repetitive finger tapping (FT), hand grasping (HG) and pronationsupination (PS) as quickly as possible (Fahn et al., 1987). Both hands were tested separately. The patient group repeated these sessions in four experimental DBS conditions (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON) in counterbalanced order after withdrawal of dopaminergic medication for 12 h. A fifth and final condition (BOTH ON-MED ON) was then evaluated during a period of maximal clinical benefit after administration of a levodopa dose 1.5 times higher than the patient's usual morning dose (Krack et al., 2003). A one-hour time interval was maintained as a resting period between data acquisitions in the different conditions. A Kinesia (Great Lakes NeuroTechnologies Inc., Cleveland, OH) motion sensor captured kinematic parameters of the upper limb movement in each condition (Giuffrida et al., 2009; Heldman et al., 2011; Espay et al., 2011; Heldman et al., 2014). Speed, amplitude, rhythm (coefficient of variation), and the decrement of speed and amplitude were calculated. All of the aforementioned parameters were represented as their ratio (hereafter relative values) to the mean values of the right hand in the control group. Relative speed, amplitude, rhythm, and the decrement of speed and amplitude were compared with ANOVA for repeated measures, separately for the three tasks. Within group factors included: CONDITION (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON, BOTH ON-MED ON) and HAND (more affected, less affected). We confirmed the anatomical locations of the stimulating contacts in our patient group. In 54 out of the 56 hemispheres, the active contact was located within or on the border of the dorsolateral STN (Table 1). For the remaining two hemispheres, active contacts were located dorsal to the border of the STN. Values of relative speed, amplitude and rhythm related to the more and less affected hand are presented in Fig. 1. ANOVA results and significant results of the post hoc comparisons are summarized in Table 2. Differences of relative speed, amplitude and the rhythm between the more and less affected hand were not different across the five conditions. HAND factor was not significant (p Z0.05) in the three tasks. The differential effects of bilateral and contralateral stimulation in the three tasks are presented in Fig. 2. 2.1. Speed CONDITION effect was significant when analyzing the relative speed values in all three tasks (Table 2). Relative speed was significantly higher in the BOTH ON condition than it was in BOTH OFF and IPSI ON conditions, but was similar to BOTH ON-MED ON condition (FT: p ¼ 0.99; HG: p ¼ 0.99; PS: p¼ 0.85). Relative speed
Table 1 Preoperative clinical data of the patients, details of the postoperative therapy. Disease duration (years, mean 7 SD) Time after operation (years, mean 7 SD) Levodopa equivalent dose (mg/ Before operation day) At the time of assessment Preoperative scores UPDRS III (max: 108) UPDRS IV (max: 23) Hoehn-Yahr scale (worst stage: 5) DBS Programming parameters Configuration (L/R) Impulse width (us) Amplitude (V) Frequency (Hz) Test dose of levodopa for the study (mg) Active contact location (L/R) Direct visualization Distances from the middle commissural point (mm; mean 7 SD)
13.2 7 5.07 2.17 1.28 820.6 7318.0 294.4 7174.43 46.9 716.51 7.9 7 3.56 3.2 70.70 Monopolar: 22/23 contacts Bipolar: 6/5 contacts 60us: 16/16 contacts 90us: 12/12 contacts 2.78 70.72/ 2.78 7 0.77 130.2 7 6.73/ 130.2 7 6.73 113.4 7 61.91 Inside the dorsolateral STN: 25/24 X: 11.6 7 1.49/12.6 7 1.4
-values: X-left; Y-posterior; Z-caudal; L: left hemisphere, R: right hemisphere.
On the dorsal border of STN: 2/3 Y: 1.8 7 1.8/ 1.5 7 1.57
Dorsal to the border of STN: 1/1 Z: 3.5 7 1.79/ 3.88 71.9
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Fig. 1. Relative speed, amplitude and rhythm in finger tapping, hand grasping and pronation-supination. Relative values represent the ratio of absolute parameters to the mean values of the right hand in the control group. A ratio of 1 is indicated by the dotted line. The mean, standard error and standard deviation are presented. Plots of the more affected hand are shown in grey, while that of the less affected hand are shown in white. Significant differences between stimulation conditions in each movement tasks are depicted by asterisks (p o0.05).
was also similar in BOTH OFF and IPSI ON conditions (FT: p ¼0.99; HG: p ¼ 0.94; PS: p ¼0.99). Relative speed of finger tapping in CONTRA ON condition was similar to the BOTH ON condition (p ¼0.07); however, it was significantly lower than it was in BOTH ON-MED ON condition. In the HG and PS tasks, relative speed was significantly lower in CONTRA ON condition than in BOTH ON and BOTH ON-MED ON conditions (Fig. 2). 2.2. Amplitude The effect of CONDITION on amplitude was significant in all three tasks (Table 2). In FT and HG tasks, relative amplitude was similar in BOTH ON and CONTRA ON conditions (FT: p ¼0.83; HG: p ¼0.34). In PS task, the effect of stimulation was significantly lower in CONTRA ON than in BOTH ON condition. In all three tasks, relative amplitude was similar in CONTRA ON and BOTH ON-MED ON (FT: p¼ 0.52; HG: p ¼ 0.92; PS: p¼ 0.18) and BOTH ON and BOTH ON-MED ON conditions (FT: p ¼0.98; HG: p ¼0.83; PS: p ¼0.57), and all were significantly higher than in BOTH OFF and IPSI ON conditions. BOTH OFF and IPSI ON conditions did not differ in the three tasks (FT: p ¼0.99; HG: p ¼0.99; PS: p ¼0.99). The p values were similar in many comparisons for frequency and amplitude (Table 2) because patients presented the worst
motor performance in BOTH OFF and IPSI ON conditions and the best motor performance in BOTH-ON, CONTRA ON and BOTH ONMED ON conditions. Therefore individual frequency and amplitude values were similar in the corresponding conditions. 2.3. Rhythm Regarding relative coefficient of variation (rhythm), CONDITION effect was significant in the three tasks. Rhythm improved similarly by bilateral and contralateral stimulation, in each task (FT: p¼ 0.99; HG: p ¼0.99; PS: p ¼0.68). Movements were significantly less rhythmic in BOTH OFF and IPSI ON than in other conditions during FT task (p o0.05). This trend could be observed in the other two tasks, although significant differences were not overserved in all comparisons (Figs. 1 and 2). 2.4. Decrement of speed and amplitude For decrement of speed, the CONDITION effect was significant in the HG and PS tasks but not in the FT task. For decrement of amplitude, the CONDITION effect was significant only in the HG task. Post hoc comparisons of the two parameters across stimulation conditions were not significant in the three tasks, with the
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Table 2 Statistical analysis of the kinematic parameters. Control absolute values ANOVA results of the relative values
Speed
Amplitude
Rhythm
Decrement of Speed
Decrement of Amplitude
All effects
CONDITION effect
215.9 7 54.89 deg/s
F1,22 ¼ 197.65; p o0.05
F4,88 ¼ 39.43; p o 0.05
HG 253.2 7 53.32 deg/s
F1,22 ¼ 190.65; po 0.05
PS
314.6 7 76.14 deg/s
F1,22 ¼ 158.65; po 0.05
FT
11.3 7 3.39 deg
F1,22 ¼ 254.6; p o 0.05
FT
HG 17.7 7 3.52 deg
F1,22 ¼ 358.95; po 0.05
PS
28.1 74.02 deg
F1,22 ¼ 697.86; p o 0.05
FT
0.147 0.07
F1,22 ¼ 248.14; p o 0.05
HG 0.09 7 0.07 PS 0.067 0.03
F1,22 ¼ 118.82; po 0.05 F1,22 ¼ 240.13; p o 0.05
0.87 7 0.08 0.95 7 0.12 0.97 70.08 0.88 7 0.11 0.96 7 0.11 0.99 7 0.04
F1,22 ¼ 2607,2; p o 0.05 F1,22 ¼ 3152.9; p o 0.05 F1,22 ¼ 4283,6; po 0.05 F1,22 ¼ 7341.9; p o 0.05 F1,22 ¼ 6037.1; p o 0.05 F1,22 ¼ 7006.5; po 0.05
FT HG PS FT HG PS
Tukey post hoc comparisons
p1–2 ¼ 0.00012; p1–4 ¼0.00012; p2–3 ¼ 0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p3–5 ¼ 0.0197; p4–5 ¼ 0.00012 F4,88 ¼ 46.45; p o 0.05 p1–2 ¼ 0.00012; p1–3 ¼ 0.0093; p1–4 ¼0.00012; p2–3 ¼0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p3–5 ¼ 0.027; p4–5 ¼ 0.00012 F4,88 ¼ 71.9; po 0.05 p1–2 ¼ 0.00012; p1–3 ¼0.00012; p1–4 ¼ 0.00012; p2–3 ¼ 0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p3–5 ¼ 0.00028; p4–5 ¼ 0.00012 F4,88 ¼ 25.257; p o 0.05 p1–2 ¼ 0.00012; p1–4 ¼0.00012; p2–3 ¼ 0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p4–5 ¼ 0.00012 F4,88 ¼ 21.92; po 0.05 p1–2 ¼ 0.00012; p1–4 ¼0.00012; p2–3 ¼ 0.00013; p2–5 ¼ 0.00012; p3–4 ¼ 0.00015; p4–5 ¼0.00012 F4,88 ¼ 39.47; p o 0.05 p1–2 ¼ 0.00012; p1–3 ¼ 0.0033; p1–4 ¼0.00012; p2–3 ¼ 0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p4–5 ¼ 0.00012 F4,88 ¼ 7.23; p o 0.05 p1–2 ¼ 0.004; p1–4 ¼ 0.012; p2–3 ¼0.0082; p2–5 ¼ 0.0024; p3–4 ¼ 0.023; p4–5 ¼ 0.0072 F4,88 ¼ 5.38; p o 0.05 p1–4 ¼ 0.03; p3–4 ¼ 0.0086; p4–5 ¼ 0.007 F4,88 ¼ 7.37; po 0.05 p1–2 ¼ 0.00037; p1–4 ¼ 0.0046; p2–3 ¼0.022; p2–5 ¼ 0.0027; p4–5 ¼ 0.03 F4,88 ¼ 1.7; p ¼ 0,157 F4,88 ¼ 3.494; p ¼ 0.01 p1–4 ¼ 0.008 F4,88 ¼ 3.06; p ¼ 0.02 F4,88 ¼ 1.93; p ¼ 0.11 F4,88 ¼ 2.98; p ¼0.023 F4,88 ¼ 1.688; p¼ 0.16
FT: Finger Tapping, HG: Hand Grasping, PS: Pronation-Supination of the arm, for post-hoc comparisons: 1: BOTH ON, 2: BOTH OFF, 3: CONTRA ON, 4: IPSI ON, 5: BOTH ONMED ON.
Fig. 2. Effects of bilateral and contralateral stimulation. Relative speed, amplitude and rhythm values are averaged across the two hands and represented during bi- and contralateral stimulation in the three tasks. We show the mean, standard error and standard deviation of the values. Asterisks mark significant differences between the effects of the two stimulation conditions (po 0.05). Parameter differences between bi-and contralateral stimulation were calculated in each patient. The mean, standard error and standard deviation of these paired differences are presented and indicated by grey.
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exception that relative decrement of speed was larger in the IPSI ON than in the BOTH ON condition in the HG task (Table 2).
3. Discussion We report the kinematic analysis of proximal and distal upper limb movements in Parkinson's disease during different conditions of subthalamic stimulation. We confirmed that bilateral and contralateral stimulation significantly improved the speed and amplitude of finger tapping, hand grasping and pronation-supination as well as the rhythm of finger tapping and pronation-supination in comparison to the stimulation off state. Decrement of speed and amplitude were not influenced by any of the stimulation conditions, which is similar to the outcome of levodopa challenge test in an earlier investigation (Espay et al., 2011). In all therapy conditions, speed and rhythm, but not amplitude, were lower in the patient group than in the control group in all of the three tasks, particularly in the proximal movement. This suggests that they are irreversibly affected to some extent in Parkinson's disease and cannot be improved to the normal level by STN stimulation or levodopa therapy. Bastian et al. (2003) also concluded similar finding about the speed of fast reaching upper limb movement and walking parameters. The speed of finger movement and diadochokinesis was also found to be lower during bilateral stimulation and levodopa therapy in PD than in control subjects (Timmermann et al., 2008); however, this trend had not been analyzed for the rhythm. Levodopa had a larger effect on distal but not proximal arm movements than bilateral STN stimulation in the study by Wenzelburger et al. (2003). In our study, there was no difference between the BOTH ON and the BOTH ONMED ON conditions in either task, though slightly different anatomical locations of the stimulation field in the two studies cannot be excluded as an explanation. Ipsilateral STN stimulation alone had no effect on the speed, amplitude and rhythm of distal and proximal muscles in our study. This agrees with earlier reports where 20% or less improvement was documented during ipsilateral stimulation when compared to the STIM OFF condition (Kumar et al., 1999; Linazasoro et al., 2003; Germano et al., 2004; Chung et al., 2006; Samii et al., 2007; Slowinski et al., 2007). Contralateral and bilateral stimulation increased speed and amplitude of distal hand movement similarly. Bilateral stimulation was superior in improving speed and amplitude of proximal arm movements, as was earlier demonstrated by Tabbal et al. (2008). Rhythm of both distal and proximal movements was ameliorated similarly by contra- and bilateral stimulation. The bilateral effect of STN stimulation can be linked back to the proximal muscles on different anatomical levels. Orthodromic stimulation affects the globus pallidus internus and the substantia nigra pars reticulata, which have predominantly contralateral, but bilateral innervation to the thalamus and brainstem, including the pedunculopontine nucleus (PPN) (Parent and Hazrati, 1995). The latter has further bilateral projections and innervation from the contralateral PPN (Martinez-Gonzalez et al., 2011). It is also hypothesized that antidromic effect of STN stimulation acts on motor cortex areas through corticosubthalamic projections (Kang and Lowery 2014). However, these projections are restricted to the ipsilateral side (Nambu et al., 1997; Inase et al., 1999; Takada et al., 2001), it has been proved that proximal muscles are innervated bilaterally from motor cortical areas, especially from dorsal premotor and with the greatest extent from the supplementary motor cortex (Alexander and DeLong, 1986; Montgomery et al., 2013) with contralateral dominance (Montgomery et al., 2013; Boudrias et al., 2010). Conversely, the source of efferent innervation for the distal muscles is mainly confined to the contralateral primary
motor cortex (Montgomery et al., 2013). It was demonstrated in animals that corticosubthalamic fibers from the primary motor cortex (Haynes and Haber, 2013) and the caudal cingulate area (Takada et al., 2001) are localized laterally, whereas projections from the supplementary (Inase et al., 1999), premotor (Nambu et al., 1997) and rostral cingulate motor areas (Takada et al., 2001) connect more medially to the STN. Based on the animal anatomical structure of STN and parallel processing theory postulating different subloops with a somatotopic organization in the corticobasal ganglia motor circuit (Miyachi et al., 2006; Nambu, 2011), the more lateral stimulation may act antidromically, predominantly on the primary motor cortex with distal limb representation. Our results are congruent with these anatomical findings. Previous studies recommend bilateral STN stimulation as clinical practice in Parkinson's disease (Samii et al., 2007), but a unilateral procedure is also applied in older patients and in cases with highly asymmetric symptoms (Kumar et al., 1999; Linazasoro et al., 2003; Germano et al., 2004; Chung et al., 2006; Slowinski et al., 2007). These reports of unilateral and bilateral (Bejjani et al., 2000; Krack et al., 2003; Kumar et al., 1999; Limousin et al., 1998; Samii et al., 2007) STN stimulation did not evaluate distal and proximal bradykinesia separately and missed the fact that bilateral STN stimulation is more beneficial for the proximal upper limb movements than is contralateral stimulation. Although patterns of stimulation vary moderately on proximal and distal muscles, our results carry valuable information to understand the mechanism of STN stimulation. They also have important clinical implications such as bilateral stimulation may be the optimal choice in cases with highly asymmetric bradykinesia and stimulation parameters should not be set in a greatly asymmetric manner. In summary, stimulation effects on proximal and distal arm movements should be evaluated separately, possibly due to the different somatotopic organization of subloops in the cortico-basal ganglia motor circuits. Further studies are needed to map the organization of these subloops in humans.
4. Experimental procedure The work was carried out in accordance with the Declaration of Helsinki and the Uniform Requirements for manuscripts submitted to Biomedical journals. Ethical approval (Reference number: 271/ 2013) was obtained from the Regional and Institutional Committee of Science and Research Ethics, Semmelweis University and patients signed informed consent forms. 4.1. Patient selection Twenty-eight patients (10 females and 18 males) with Parkinson's disease after bilateral STN-DBS implantation were invited to participate in the study. Their mean age ( 7SD) was 59.2 78.60 years (normal distribution, p ¼0.26). An age-matched control group (mean age: 54.6 7 14.95 years; normal distribution, p¼ 0.085; unpaired Student's t-test: p ¼0.128) of 28 healthy subjects was also recruited (18 females and 10 males). The patients fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria (Hughes et al., 1992). The Core Assessment Program for Surgical Interventional Therapies for Parkinson's Disease (CAPSIT-PD; Defer et al., 1999) was followed for preoperative evaluation. A levodopa challenge was performed before implantation (as well as in the present study) with soluble levodopa at a dosage 50% higher than the usual morning dosage of equivalent, after a 12-hour withdrawal of dopaminergic medication. The preoperative clinical data as well as the details of the current therapy are summarized in Table 1. According to symptom predominance, six patients were tremor-dominant, 13 patients
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were akinetic-rigid, and nine patients had a mixed subtype of Parkinson's disease (Hughes et al., 1993).
the second 7 s time interval to the values in the first 7 s time interval for each 14 s task.
4.2. Neurosurgical procedure
4.4. Statistical analysis
Each patient underwent bilateral DBS lead (type 3389, Medtronic, Minneapolis) and pulse generator (IPG) implantation simultaneously. For individual anatomical planning, stereotactic contrast-enhanced CT sequences were acquired with a Leksell G frame placed on the patient's head on the day of the surgery. Preoperative planning was carried out using Medtronic FrameLink 5 software. Contrast-enhanced 3D T1 weighted images with a slice thickness of 1 mm and T2 weighted images with a slice thickness of 2 mm, acquired on 3T Phillips Achieva MRI scanner no more than six months in advance of implantation, were merged with the stereotactic CT images. The individual anatomical target in the STN was selected according to standard stereotactic principles (Andrade-Souza et al., 2005), 3 mm lateral to the intersection of the anterior and lateral border of the red nucleus at the level of its widest portion. Trajectories were selected according to individual anatomical structures. Dopaminergic medication was suspended 12 h before the operation. Electrophysiological mapping was executed with five microelectrodes, while clinical symptoms were controlled through macrostimulation. Lead implantation was carried out using local anesthetics and IPG implantation was carried out under general anesthesia. Lead implantation was assisted by fluoroscopy. Postoperative contrast-enhanced CT scans with a slice thickness of 1 mm were acquired six weeks after implantation. Postoperative CT and preoperative MR images were fused using Medtronic FrameLink 5 software and registration was verified at multiple levels for errors. CT images were thresholded resulting in the electrode contacts being the only visible points. The most distal point of the first contact (0) and a center point of a proximal contact were selected for three-dimensional Euclidian vector calculations. Locations of the active contacts were calculated at 0.75, 2.75, 4.75, and 6.75 mm and their relation to the STN were visually verified on T2 sequences. The most distal contact of the lead was indicated as 0 (zero) and the most proximal contact as 3 on both sides. For long-term therapy, stimulation parameters were adjusted to achieve optimal motor responses without evoking any side effect or hyperkinesia. Patients enrolled in this study were on stable therapy for at least one month. Parameters of the stimulation are summarized in Table 1.
All of the above mentioned parameters were represented as their ratio (hereafter relative values) to the mean values of the right hand in the control group (Table 2). Relative speed, amplitude, rhythm and decrement of speed and amplitude in the three tasks in the five therapy conditions had normal distributions according to the Kolmogorov-Smirnov test. These parameters were compared using ANOVA for repeated measures, separately in the three tasks. Within group factors were: CONDITION (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON, BOTH ON-MED ON) and HAND (more affected, less affected). For post hoc comparisons, we used the Tukey Honest Significant Difference test. We subtracted the speed, amplitude and rhythm values measured in CONTRA ON condition from the values of the BOTH ON condition. We show the results of these subtractions in Fig. 2. Normal distribution of age in the patient and the control group was also confirmed by Kolmogorov-Smirnov test. These data were compared by unpaired Student t-test. Level of significance was p o0.05. All analyses were performed using Statistica software (StatSoft Inc., Tulsa, OK, USA).
4.3. Kinematic analysis A Kinesia (Great Lakes NeuroTechnologies Inc., Cleveland, OH) motion sensor consisting of a three-dimensional gyroscope and accelerometer was worn on the index finger to capture kinematic parameters of the upper limb movement in each condition (Giuffrida et al., 2009; Heldman et al., 2011; Espay et al., 2011; Heldman et al., 2014). Since the three movement tasks were primarily rotational, the gyroscopes were used for this analysis. Motion data were band pass filtered from 0.3 to 16 Hz using a second order Butterworth filter. To minimize errors resulting from slight variations in the orientation the sensors on the finger, the magnitudes (Euclidean norm) of the angular velocities around the x-, y-, and z-axes were calculated. Kinematic features representing speed as root mean square angular velocity, amplitude as root mean square excursion angle and rhythm as the coefficient of variation (standard deviation of a one-second sliding window of the RMS excursion angle divided by the mean) were calculated (Heldman et al., 2011, Espay et al., 2011). A higher coefficient of variation is a sign of worse rhythmicity. The decrement of the speed and amplitude were computed as the ratios of the values in
Contributions Conception of the study: GT, LE. Organization of the study: GT, IV, PK, LV, EH, DK, LE. Execution of the study: GT, AK, PR, IV, DH, PK, EH, LH, DK, PB, PG, LE. Data analysis: GT, AK, DH. Writing the manuscript: GT, LH, DH. Review and Critique: AK, IV, PK, LV, EH, DK, PB, LE.
Disclosure DH has received compensation from Great Lakes NeuroTechnologies for employment. Other authors have declared no conflict of interest related to this study.
Acknowledgements We would like to thank our patients for their participation in the study.
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Research report
Effect of subthalamic stimulation on distal and proximal upper limb movements in Parkinson's disease Gertrúd Tamás a,n, Andrea Kelemen a, Péter Radics a, István Valálik b, Dustin Heldman c, Péter Klivényi d, László Vécsei d,e, Eszter Hidasi f, László Halász g, Dávid Kis h, Péter Barsi i, Péter Golopencza j, Loránd Erőss g a
Department of Neurology, Semmelweis University, Balassa utca 6, 1083 Budapest, Hungary Department of Neurosurgery, University of Debrecen, Móricz Zsigmond körút 22, 4032 Debrecen, Hungary c Great Lakes NeuroTechnologies Inc., 10055 Sweet Valley Dr, Cleveland, OH, USA d Department of Neurology, University of Szeged, Semmelweis u. 6, 6725 Szeged, Hungary e MTA-SZTE Neuroscience Research Group, Semmelweis u. 6, 6725 Szeged, Hungary f Department of Neurology, University of Debrecen, Móricz Zsigmond körút 22, 4032 Debrecen, Hungary g National Institute of Clinical Neurosciences, Amerikai út 57, 1145 Budapest, Hungary h Department of Neurosurgery, University of Szeged, Semmelweis u. 6, 6725 Szeged, Hungary i MR Research Centre, Semmelweis University, Balassa utca 6, 1083 Budapest, Hungary j Department of Anaesthesiology and Intensive Therapy, Semmelweis University, Kútvölgyi u. 4, 1125 Budapest, Hungary b
art ic l e i nf o
a b s t r a c t
Article history: Received 31 January 2016 Received in revised form 17 July 2016 Accepted 15 August 2016 Available online 16 August 2016
Introduction: A different innervation pattern of proximal and distal muscles from the contra- and ipsilateral motor circuits raises the question as to whether bilateral, contra- and ipsilateral subthalamic stimulation may have different effects on the distal and proximal movements of the upper limb. To answer this question, we performed kinematic analyzes in patients with Parkinson's disease. Methods: Twenty-eight Parkinsonian patients treated by bilateral subthalamic stimulation were examined with an age-matched control group of 28 healthy subjects. They performed 14 s of finger tapping, hand grasping and pronation-supination. The patient group performed these sessions in four conditions (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON) after withdrawal of dopaminergic medication for 12 h and a fifth condition after taking medication (BOTH ON-MED ON). A motion sensor with a three-dimensional gyroscope was worn on the index finger. Speed, amplitude, rhythm and decrement of movements were calculated and compared across these conditions. Results: Speed and amplitude of the more distal movements were improved similarly by contra- and bilateral stimulation. Bilateral stimulation was more effective than contralateral stimulation for the more proximal movements. Contra- and bilateral stimulation ameliorated the rhythm similarly in each movement task. Decrement of distal and proximal movements was not affected by the stimulation conditions. Conclusion: This is the first study to show that the outcome of bi- and unilateral subthalamic stimulation on proximal and distal upper limb movements should be evaluated separately postulating the different somatotopic organization of subloops in the cortico-basal ganglia motor circuits. & 2016 Elsevier B.V. All rights reserved.
Keywords: Parkinson's disease Deep brain stimulation Distal movement Proximal movement Unilateral stimulation Bilateral stimulation
1. Introduction
Abbreviations: BOTH OFF: bilateral stimulation is off; BOTH ON: bilateral stimulation is on; BOTH ON-MED ON: bilateral stimulation is on plus best medication effect; CAPSIT-PD: Core Assessment Program for Surgical Interventional Therapies for Parkinson's Disease; CONTRA ON: contralateral stimulation is on; FT: finger tapping; HG: hand grasping; IPSI ON: ipsilateral stimulation is on; PPN: pedunculopontine nucleus; PS: pronation-supination; STN: subthalamic nucleus; UPDRS: Unified Parkinson's Disease Rating Scale n Corresponding author. E-mail address: [email protected] (G. Tamás). http://dx.doi.org/10.1016/j.brainres.2016.08.019 0006-8993/& 2016 Elsevier B.V. All rights reserved.
Bilateral stimulation of the subthalamic nucleus (STN) can effectively ameliorate bradykinesia, rigidity and tremor in appropriately selected patients with idiopathic Parkinson's disease (PD) (Limousin et al., 1998; Deuschl et al., 2006; Deli et al., 2015). However, the underlying mechanism of STN stimulation is not well understood. Bilateral stimulation provides more pronounced clinical recovery than unilateral stimulation (Bastian et al., 2003). According to previous clinical observations, 6–18 months after surgery improvement in Unified Parkinson's Disease Rating Scale
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(UPDRS) Part III is 53.8–60% (Fahn et al., 1987), with 55.1–62.2% improvement in bradykinesia subscores (Limousin et al., 1998; Deuschl et al., 2006; Deli et al., 2015; Kumar et al., 1999). Axial motor scores (UPDRS III item 29–30) also decrease by 21–78% 3–18 months after surgery (Bejjani et al., 2000; Krack et al., 2003; Kumar et al., 1999; Limousin et al., 1998; Samii et al., 2007). Although unilateral subthalamic stimulation has a predominant clinical effect on the contralateral side, it affects the ipsilateral hemibody as well (improvement in UPDRS III total score: contralateral stimulation: 30.1–72.4%, ipsilateral stimulation: 1.2 to 20%) and moderately improves the axial symptoms (UPDRS III. item 29-30: 15–39% 3–18 months after surgery) (Kumar et al., 1999; Linazasoro et al., 2003; Germano et al., 2004; Chung et al., 2006; Samii et al., 2007; Slowinski et al., 2007). Proximal muscles have bilateral, while distal muscles have primarily contralateral innervation from the cortico-basal ganglia motor circuits (Alexander and DeLong, 1986; Montgomery et al., 2013). This raises the question whether uni- and bilateral subthalamic stimulation can influence distal and proximal movements of the upper limb differently. Therefore, in the present study, we investigated the effects of bilateral, contra- and ipsilateral subthalamic stimulation on distal and proximal movements of the upper limbs. Motor outcome of unilateral stimulation was assessed by the Unified Parkinson's Disease Rating Scale part III (Fahn et al., 1987) in the aforementioned studies; however, in this study we used a three-dimensional motion capture device. Kinematic analyses of various types of upper limb movements have been reported in a few studies (Bastian et al., 2003; Wenzelburger et al., 2003; Timmermann et al., 2008; Tabbal et al., 2008) and have been shown to be more sensitive, more quantitative and more reliable than clinical scoring (Tabbal et al., 2008; Heldman et al., 2014). Our aim was to better understand the motor control and mechanism of STN stimulation. Our primary hypothesis was that distal movements are improved primarily by contralateral stimulation while bilateral stimulation is superior to contralateral stimulation for proximal movements. Our secondary hypothesis was that quantitative kinematic analysis might provide additional information about the mechanism of action of STN stimulation.
2. Results Twenty-eight Parkinsonian patients implanted with bilateral STNDBS and a healthy control group performed 14 s of UPDRS-directed
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repetitive finger tapping (FT), hand grasping (HG) and pronationsupination (PS) as quickly as possible (Fahn et al., 1987). Both hands were tested separately. The patient group repeated these sessions in four experimental DBS conditions (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON) in counterbalanced order after withdrawal of dopaminergic medication for 12 h. A fifth and final condition (BOTH ON-MED ON) was then evaluated during a period of maximal clinical benefit after administration of a levodopa dose 1.5 times higher than the patient's usual morning dose (Krack et al., 2003). A one-hour time interval was maintained as a resting period between data acquisitions in the different conditions. A Kinesia (Great Lakes NeuroTechnologies Inc., Cleveland, OH) motion sensor captured kinematic parameters of the upper limb movement in each condition (Giuffrida et al., 2009; Heldman et al., 2011; Espay et al., 2011; Heldman et al., 2014). Speed, amplitude, rhythm (coefficient of variation), and the decrement of speed and amplitude were calculated. All of the aforementioned parameters were represented as their ratio (hereafter relative values) to the mean values of the right hand in the control group. Relative speed, amplitude, rhythm, and the decrement of speed and amplitude were compared with ANOVA for repeated measures, separately for the three tasks. Within group factors included: CONDITION (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON, BOTH ON-MED ON) and HAND (more affected, less affected). We confirmed the anatomical locations of the stimulating contacts in our patient group. In 54 out of the 56 hemispheres, the active contact was located within or on the border of the dorsolateral STN (Table 1). For the remaining two hemispheres, active contacts were located dorsal to the border of the STN. Values of relative speed, amplitude and rhythm related to the more and less affected hand are presented in Fig. 1. ANOVA results and significant results of the post hoc comparisons are summarized in Table 2. Differences of relative speed, amplitude and the rhythm between the more and less affected hand were not different across the five conditions. HAND factor was not significant (p Z0.05) in the three tasks. The differential effects of bilateral and contralateral stimulation in the three tasks are presented in Fig. 2. 2.1. Speed CONDITION effect was significant when analyzing the relative speed values in all three tasks (Table 2). Relative speed was significantly higher in the BOTH ON condition than it was in BOTH OFF and IPSI ON conditions, but was similar to BOTH ON-MED ON condition (FT: p ¼ 0.99; HG: p ¼ 0.99; PS: p¼ 0.85). Relative speed
Table 1 Preoperative clinical data of the patients, details of the postoperative therapy. Disease duration (years, mean 7 SD) Time after operation (years, mean 7 SD) Levodopa equivalent dose (mg/ Before operation day) At the time of assessment Preoperative scores UPDRS III (max: 108) UPDRS IV (max: 23) Hoehn-Yahr scale (worst stage: 5) DBS Programming parameters Configuration (L/R) Impulse width (us) Amplitude (V) Frequency (Hz) Test dose of levodopa for the study (mg) Active contact location (L/R) Direct visualization Distances from the middle commissural point (mm; mean 7 SD)
13.2 7 5.07 2.17 1.28 820.6 7318.0 294.4 7174.43 46.9 716.51 7.9 7 3.56 3.2 70.70 Monopolar: 22/23 contacts Bipolar: 6/5 contacts 60us: 16/16 contacts 90us: 12/12 contacts 2.78 70.72/ 2.78 7 0.77 130.2 7 6.73/ 130.2 7 6.73 113.4 7 61.91 Inside the dorsolateral STN: 25/24 X: 11.6 7 1.49/12.6 7 1.4
-values: X-left; Y-posterior; Z-caudal; L: left hemisphere, R: right hemisphere.
On the dorsal border of STN: 2/3 Y: 1.8 7 1.8/ 1.5 7 1.57
Dorsal to the border of STN: 1/1 Z: 3.5 7 1.79/ 3.88 71.9
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Fig. 1. Relative speed, amplitude and rhythm in finger tapping, hand grasping and pronation-supination. Relative values represent the ratio of absolute parameters to the mean values of the right hand in the control group. A ratio of 1 is indicated by the dotted line. The mean, standard error and standard deviation are presented. Plots of the more affected hand are shown in grey, while that of the less affected hand are shown in white. Significant differences between stimulation conditions in each movement tasks are depicted by asterisks (p o0.05).
was also similar in BOTH OFF and IPSI ON conditions (FT: p ¼0.99; HG: p ¼ 0.94; PS: p ¼0.99). Relative speed of finger tapping in CONTRA ON condition was similar to the BOTH ON condition (p ¼0.07); however, it was significantly lower than it was in BOTH ON-MED ON condition. In the HG and PS tasks, relative speed was significantly lower in CONTRA ON condition than in BOTH ON and BOTH ON-MED ON conditions (Fig. 2). 2.2. Amplitude The effect of CONDITION on amplitude was significant in all three tasks (Table 2). In FT and HG tasks, relative amplitude was similar in BOTH ON and CONTRA ON conditions (FT: p ¼0.83; HG: p ¼0.34). In PS task, the effect of stimulation was significantly lower in CONTRA ON than in BOTH ON condition. In all three tasks, relative amplitude was similar in CONTRA ON and BOTH ON-MED ON (FT: p¼ 0.52; HG: p ¼ 0.92; PS: p¼ 0.18) and BOTH ON and BOTH ON-MED ON conditions (FT: p ¼0.98; HG: p ¼0.83; PS: p ¼0.57), and all were significantly higher than in BOTH OFF and IPSI ON conditions. BOTH OFF and IPSI ON conditions did not differ in the three tasks (FT: p ¼0.99; HG: p ¼0.99; PS: p ¼0.99). The p values were similar in many comparisons for frequency and amplitude (Table 2) because patients presented the worst
motor performance in BOTH OFF and IPSI ON conditions and the best motor performance in BOTH-ON, CONTRA ON and BOTH ONMED ON conditions. Therefore individual frequency and amplitude values were similar in the corresponding conditions. 2.3. Rhythm Regarding relative coefficient of variation (rhythm), CONDITION effect was significant in the three tasks. Rhythm improved similarly by bilateral and contralateral stimulation, in each task (FT: p¼ 0.99; HG: p ¼0.99; PS: p ¼0.68). Movements were significantly less rhythmic in BOTH OFF and IPSI ON than in other conditions during FT task (p o0.05). This trend could be observed in the other two tasks, although significant differences were not overserved in all comparisons (Figs. 1 and 2). 2.4. Decrement of speed and amplitude For decrement of speed, the CONDITION effect was significant in the HG and PS tasks but not in the FT task. For decrement of amplitude, the CONDITION effect was significant only in the HG task. Post hoc comparisons of the two parameters across stimulation conditions were not significant in the three tasks, with the
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Table 2 Statistical analysis of the kinematic parameters. Control absolute values ANOVA results of the relative values
Speed
Amplitude
Rhythm
Decrement of Speed
Decrement of Amplitude
All effects
CONDITION effect
215.9 7 54.89 deg/s
F1,22 ¼ 197.65; p o0.05
F4,88 ¼ 39.43; p o 0.05
HG 253.2 7 53.32 deg/s
F1,22 ¼ 190.65; po 0.05
PS
314.6 7 76.14 deg/s
F1,22 ¼ 158.65; po 0.05
FT
11.3 7 3.39 deg
F1,22 ¼ 254.6; p o 0.05
FT
HG 17.7 7 3.52 deg
F1,22 ¼ 358.95; po 0.05
PS
28.1 74.02 deg
F1,22 ¼ 697.86; p o 0.05
FT
0.147 0.07
F1,22 ¼ 248.14; p o 0.05
HG 0.09 7 0.07 PS 0.067 0.03
F1,22 ¼ 118.82; po 0.05 F1,22 ¼ 240.13; p o 0.05
0.87 7 0.08 0.95 7 0.12 0.97 70.08 0.88 7 0.11 0.96 7 0.11 0.99 7 0.04
F1,22 ¼ 2607,2; p o 0.05 F1,22 ¼ 3152.9; p o 0.05 F1,22 ¼ 4283,6; po 0.05 F1,22 ¼ 7341.9; p o 0.05 F1,22 ¼ 6037.1; p o 0.05 F1,22 ¼ 7006.5; po 0.05
FT HG PS FT HG PS
Tukey post hoc comparisons
p1–2 ¼ 0.00012; p1–4 ¼0.00012; p2–3 ¼ 0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p3–5 ¼ 0.0197; p4–5 ¼ 0.00012 F4,88 ¼ 46.45; p o 0.05 p1–2 ¼ 0.00012; p1–3 ¼ 0.0093; p1–4 ¼0.00012; p2–3 ¼0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p3–5 ¼ 0.027; p4–5 ¼ 0.00012 F4,88 ¼ 71.9; po 0.05 p1–2 ¼ 0.00012; p1–3 ¼0.00012; p1–4 ¼ 0.00012; p2–3 ¼ 0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p3–5 ¼ 0.00028; p4–5 ¼ 0.00012 F4,88 ¼ 25.257; p o 0.05 p1–2 ¼ 0.00012; p1–4 ¼0.00012; p2–3 ¼ 0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p4–5 ¼ 0.00012 F4,88 ¼ 21.92; po 0.05 p1–2 ¼ 0.00012; p1–4 ¼0.00012; p2–3 ¼ 0.00013; p2–5 ¼ 0.00012; p3–4 ¼ 0.00015; p4–5 ¼0.00012 F4,88 ¼ 39.47; p o 0.05 p1–2 ¼ 0.00012; p1–3 ¼ 0.0033; p1–4 ¼0.00012; p2–3 ¼ 0.00012; p2–5 ¼ 0.00012; p3–4 ¼ 0.00012; p4–5 ¼ 0.00012 F4,88 ¼ 7.23; p o 0.05 p1–2 ¼ 0.004; p1–4 ¼ 0.012; p2–3 ¼0.0082; p2–5 ¼ 0.0024; p3–4 ¼ 0.023; p4–5 ¼ 0.0072 F4,88 ¼ 5.38; p o 0.05 p1–4 ¼ 0.03; p3–4 ¼ 0.0086; p4–5 ¼ 0.007 F4,88 ¼ 7.37; po 0.05 p1–2 ¼ 0.00037; p1–4 ¼ 0.0046; p2–3 ¼0.022; p2–5 ¼ 0.0027; p4–5 ¼ 0.03 F4,88 ¼ 1.7; p ¼ 0,157 F4,88 ¼ 3.494; p ¼ 0.01 p1–4 ¼ 0.008 F4,88 ¼ 3.06; p ¼ 0.02 F4,88 ¼ 1.93; p ¼ 0.11 F4,88 ¼ 2.98; p ¼0.023 F4,88 ¼ 1.688; p¼ 0.16
FT: Finger Tapping, HG: Hand Grasping, PS: Pronation-Supination of the arm, for post-hoc comparisons: 1: BOTH ON, 2: BOTH OFF, 3: CONTRA ON, 4: IPSI ON, 5: BOTH ONMED ON.
Fig. 2. Effects of bilateral and contralateral stimulation. Relative speed, amplitude and rhythm values are averaged across the two hands and represented during bi- and contralateral stimulation in the three tasks. We show the mean, standard error and standard deviation of the values. Asterisks mark significant differences between the effects of the two stimulation conditions (po 0.05). Parameter differences between bi-and contralateral stimulation were calculated in each patient. The mean, standard error and standard deviation of these paired differences are presented and indicated by grey.
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exception that relative decrement of speed was larger in the IPSI ON than in the BOTH ON condition in the HG task (Table 2).
3. Discussion We report the kinematic analysis of proximal and distal upper limb movements in Parkinson's disease during different conditions of subthalamic stimulation. We confirmed that bilateral and contralateral stimulation significantly improved the speed and amplitude of finger tapping, hand grasping and pronation-supination as well as the rhythm of finger tapping and pronation-supination in comparison to the stimulation off state. Decrement of speed and amplitude were not influenced by any of the stimulation conditions, which is similar to the outcome of levodopa challenge test in an earlier investigation (Espay et al., 2011). In all therapy conditions, speed and rhythm, but not amplitude, were lower in the patient group than in the control group in all of the three tasks, particularly in the proximal movement. This suggests that they are irreversibly affected to some extent in Parkinson's disease and cannot be improved to the normal level by STN stimulation or levodopa therapy. Bastian et al. (2003) also concluded similar finding about the speed of fast reaching upper limb movement and walking parameters. The speed of finger movement and diadochokinesis was also found to be lower during bilateral stimulation and levodopa therapy in PD than in control subjects (Timmermann et al., 2008); however, this trend had not been analyzed for the rhythm. Levodopa had a larger effect on distal but not proximal arm movements than bilateral STN stimulation in the study by Wenzelburger et al. (2003). In our study, there was no difference between the BOTH ON and the BOTH ONMED ON conditions in either task, though slightly different anatomical locations of the stimulation field in the two studies cannot be excluded as an explanation. Ipsilateral STN stimulation alone had no effect on the speed, amplitude and rhythm of distal and proximal muscles in our study. This agrees with earlier reports where 20% or less improvement was documented during ipsilateral stimulation when compared to the STIM OFF condition (Kumar et al., 1999; Linazasoro et al., 2003; Germano et al., 2004; Chung et al., 2006; Samii et al., 2007; Slowinski et al., 2007). Contralateral and bilateral stimulation increased speed and amplitude of distal hand movement similarly. Bilateral stimulation was superior in improving speed and amplitude of proximal arm movements, as was earlier demonstrated by Tabbal et al. (2008). Rhythm of both distal and proximal movements was ameliorated similarly by contra- and bilateral stimulation. The bilateral effect of STN stimulation can be linked back to the proximal muscles on different anatomical levels. Orthodromic stimulation affects the globus pallidus internus and the substantia nigra pars reticulata, which have predominantly contralateral, but bilateral innervation to the thalamus and brainstem, including the pedunculopontine nucleus (PPN) (Parent and Hazrati, 1995). The latter has further bilateral projections and innervation from the contralateral PPN (Martinez-Gonzalez et al., 2011). It is also hypothesized that antidromic effect of STN stimulation acts on motor cortex areas through corticosubthalamic projections (Kang and Lowery 2014). However, these projections are restricted to the ipsilateral side (Nambu et al., 1997; Inase et al., 1999; Takada et al., 2001), it has been proved that proximal muscles are innervated bilaterally from motor cortical areas, especially from dorsal premotor and with the greatest extent from the supplementary motor cortex (Alexander and DeLong, 1986; Montgomery et al., 2013) with contralateral dominance (Montgomery et al., 2013; Boudrias et al., 2010). Conversely, the source of efferent innervation for the distal muscles is mainly confined to the contralateral primary
motor cortex (Montgomery et al., 2013). It was demonstrated in animals that corticosubthalamic fibers from the primary motor cortex (Haynes and Haber, 2013) and the caudal cingulate area (Takada et al., 2001) are localized laterally, whereas projections from the supplementary (Inase et al., 1999), premotor (Nambu et al., 1997) and rostral cingulate motor areas (Takada et al., 2001) connect more medially to the STN. Based on the animal anatomical structure of STN and parallel processing theory postulating different subloops with a somatotopic organization in the corticobasal ganglia motor circuit (Miyachi et al., 2006; Nambu, 2011), the more lateral stimulation may act antidromically, predominantly on the primary motor cortex with distal limb representation. Our results are congruent with these anatomical findings. Previous studies recommend bilateral STN stimulation as clinical practice in Parkinson's disease (Samii et al., 2007), but a unilateral procedure is also applied in older patients and in cases with highly asymmetric symptoms (Kumar et al., 1999; Linazasoro et al., 2003; Germano et al., 2004; Chung et al., 2006; Slowinski et al., 2007). These reports of unilateral and bilateral (Bejjani et al., 2000; Krack et al., 2003; Kumar et al., 1999; Limousin et al., 1998; Samii et al., 2007) STN stimulation did not evaluate distal and proximal bradykinesia separately and missed the fact that bilateral STN stimulation is more beneficial for the proximal upper limb movements than is contralateral stimulation. Although patterns of stimulation vary moderately on proximal and distal muscles, our results carry valuable information to understand the mechanism of STN stimulation. They also have important clinical implications such as bilateral stimulation may be the optimal choice in cases with highly asymmetric bradykinesia and stimulation parameters should not be set in a greatly asymmetric manner. In summary, stimulation effects on proximal and distal arm movements should be evaluated separately, possibly due to the different somatotopic organization of subloops in the cortico-basal ganglia motor circuits. Further studies are needed to map the organization of these subloops in humans.
4. Experimental procedure The work was carried out in accordance with the Declaration of Helsinki and the Uniform Requirements for manuscripts submitted to Biomedical journals. Ethical approval (Reference number: 271/ 2013) was obtained from the Regional and Institutional Committee of Science and Research Ethics, Semmelweis University and patients signed informed consent forms. 4.1. Patient selection Twenty-eight patients (10 females and 18 males) with Parkinson's disease after bilateral STN-DBS implantation were invited to participate in the study. Their mean age ( 7SD) was 59.2 78.60 years (normal distribution, p ¼0.26). An age-matched control group (mean age: 54.6 7 14.95 years; normal distribution, p¼ 0.085; unpaired Student's t-test: p ¼0.128) of 28 healthy subjects was also recruited (18 females and 10 males). The patients fulfilled the UK Parkinson's Disease Society Brain Bank clinical diagnostic criteria (Hughes et al., 1992). The Core Assessment Program for Surgical Interventional Therapies for Parkinson's Disease (CAPSIT-PD; Defer et al., 1999) was followed for preoperative evaluation. A levodopa challenge was performed before implantation (as well as in the present study) with soluble levodopa at a dosage 50% higher than the usual morning dosage of equivalent, after a 12-hour withdrawal of dopaminergic medication. The preoperative clinical data as well as the details of the current therapy are summarized in Table 1. According to symptom predominance, six patients were tremor-dominant, 13 patients
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were akinetic-rigid, and nine patients had a mixed subtype of Parkinson's disease (Hughes et al., 1993).
the second 7 s time interval to the values in the first 7 s time interval for each 14 s task.
4.2. Neurosurgical procedure
4.4. Statistical analysis
Each patient underwent bilateral DBS lead (type 3389, Medtronic, Minneapolis) and pulse generator (IPG) implantation simultaneously. For individual anatomical planning, stereotactic contrast-enhanced CT sequences were acquired with a Leksell G frame placed on the patient's head on the day of the surgery. Preoperative planning was carried out using Medtronic FrameLink 5 software. Contrast-enhanced 3D T1 weighted images with a slice thickness of 1 mm and T2 weighted images with a slice thickness of 2 mm, acquired on 3T Phillips Achieva MRI scanner no more than six months in advance of implantation, were merged with the stereotactic CT images. The individual anatomical target in the STN was selected according to standard stereotactic principles (Andrade-Souza et al., 2005), 3 mm lateral to the intersection of the anterior and lateral border of the red nucleus at the level of its widest portion. Trajectories were selected according to individual anatomical structures. Dopaminergic medication was suspended 12 h before the operation. Electrophysiological mapping was executed with five microelectrodes, while clinical symptoms were controlled through macrostimulation. Lead implantation was carried out using local anesthetics and IPG implantation was carried out under general anesthesia. Lead implantation was assisted by fluoroscopy. Postoperative contrast-enhanced CT scans with a slice thickness of 1 mm were acquired six weeks after implantation. Postoperative CT and preoperative MR images were fused using Medtronic FrameLink 5 software and registration was verified at multiple levels for errors. CT images were thresholded resulting in the electrode contacts being the only visible points. The most distal point of the first contact (0) and a center point of a proximal contact were selected for three-dimensional Euclidian vector calculations. Locations of the active contacts were calculated at 0.75, 2.75, 4.75, and 6.75 mm and their relation to the STN were visually verified on T2 sequences. The most distal contact of the lead was indicated as 0 (zero) and the most proximal contact as 3 on both sides. For long-term therapy, stimulation parameters were adjusted to achieve optimal motor responses without evoking any side effect or hyperkinesia. Patients enrolled in this study were on stable therapy for at least one month. Parameters of the stimulation are summarized in Table 1.
All of the above mentioned parameters were represented as their ratio (hereafter relative values) to the mean values of the right hand in the control group (Table 2). Relative speed, amplitude, rhythm and decrement of speed and amplitude in the three tasks in the five therapy conditions had normal distributions according to the Kolmogorov-Smirnov test. These parameters were compared using ANOVA for repeated measures, separately in the three tasks. Within group factors were: CONDITION (BOTH ON, BOTH OFF, CONTRA ON, IPSI ON, BOTH ON-MED ON) and HAND (more affected, less affected). For post hoc comparisons, we used the Tukey Honest Significant Difference test. We subtracted the speed, amplitude and rhythm values measured in CONTRA ON condition from the values of the BOTH ON condition. We show the results of these subtractions in Fig. 2. Normal distribution of age in the patient and the control group was also confirmed by Kolmogorov-Smirnov test. These data were compared by unpaired Student t-test. Level of significance was p o0.05. All analyses were performed using Statistica software (StatSoft Inc., Tulsa, OK, USA).
4.3. Kinematic analysis A Kinesia (Great Lakes NeuroTechnologies Inc., Cleveland, OH) motion sensor consisting of a three-dimensional gyroscope and accelerometer was worn on the index finger to capture kinematic parameters of the upper limb movement in each condition (Giuffrida et al., 2009; Heldman et al., 2011; Espay et al., 2011; Heldman et al., 2014). Since the three movement tasks were primarily rotational, the gyroscopes were used for this analysis. Motion data were band pass filtered from 0.3 to 16 Hz using a second order Butterworth filter. To minimize errors resulting from slight variations in the orientation the sensors on the finger, the magnitudes (Euclidean norm) of the angular velocities around the x-, y-, and z-axes were calculated. Kinematic features representing speed as root mean square angular velocity, amplitude as root mean square excursion angle and rhythm as the coefficient of variation (standard deviation of a one-second sliding window of the RMS excursion angle divided by the mean) were calculated (Heldman et al., 2011, Espay et al., 2011). A higher coefficient of variation is a sign of worse rhythmicity. The decrement of the speed and amplitude were computed as the ratios of the values in
Contributions Conception of the study: GT, LE. Organization of the study: GT, IV, PK, LV, EH, DK, LE. Execution of the study: GT, AK, PR, IV, DH, PK, EH, LH, DK, PB, PG, LE. Data analysis: GT, AK, DH. Writing the manuscript: GT, LH, DH. Review and Critique: AK, IV, PK, LV, EH, DK, PB, LE.
Disclosure DH has received compensation from Great Lakes NeuroTechnologies for employment. Other authors have declared no conflict of interest related to this study.
Acknowledgements We would like to thank our patients for their participation in the study.
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