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Deep brain stimulation of subthalamic nucleus helps in improving late phase motor planning in Parkinson’s disease
Clinical Neurology and Neurosurgery 160 (2017) 30–37
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Deep brain stimulation of subthalamic nucleus helps in improving late phase motor planning in Parkinson’s disease
MARK
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Patil Ashlesha, Sood Sanjay Kumara, Kochhar Kanwal Preeta, , Goyal Vinayb a b
Department of Physiology, All India Institute of Medical Sciences, New Delhi, India Department of Neurology, All India Insitute of Medical Sciencest, New Delhi, India
A R T I C L E I N F O
A B S T R A C T
Keywords: Deep brain stimulation Subthalamic nucleus Parkinson’s disease Bereitschaftspotentials Motor planning.
Objective: Deep brain stimulation of subthalamic nucleus (DBS-STN) is a well-accepted treatment for Parkinson’s disease (PD) but its effect on motor planning in the disease is yet unclear. This study examines the effect of switching the stimulation ON and OFF on components of bereitschaftspotentials in PD. Patients and methods: Scalp bereitschaftspotentials were recorded during self-paced right wrist extensions at Fz, Cz, Pz, C3 and C4 sites in patients on DBS-STN plus medications (DBS-STN group) as treatment modality or on medications only (Med group) and compared with age matched healthy controls. In DBS-STN group, the potentials were recorded in stimulation ON, stimulation OFF, and again after re-switching stimulation ON-2. Offline analysis of potentials was done to calculate peak amplitude, late slope (−500 to 0 ms) and early slope (−1500 to −500 ms). Results: We observed that the two components of bereitschaftspotentials in stimulation ON state were comparable to those in age matched controls. The late slope was found to be significantly reduced during stimulation OFF as compared to stimulation ON at Cz (p < 0.001), C3 (p < 0.001) and C4 (p < 0.01) electrode sites. This parameter failed to improve on re-switching stimulation ON at Cz (p < 0.01). No significant change was observed in early part of bereitschaftspotentials among any of the conditions. Conclusion: Our study shows that DBS-STN along with anti-parkinsonian medications helps in improving both components of bereitschaftspotentials in PD. Switching stimulation OFF for fifteen minutes principally affects the late component i.e. the execution part of motor planning; which cannot be reversed by re-switching ON. Thus the chronic and acute effects of switching DBS-STN ON are different and principally affect the later part of motor planning.
1. Introduction Bereitschaftspotentials (BP) are negative cortical evoked potentials that begin 1000–1500 milliseconds (ms) prior to the onset of a selfpaced movement [1]; they represent the cortical activity before the actual onset of the movement. Recording scalp BP has helped to study motor planning in health as well as in disease [2,3]. Two major components of BP can be distinguished associated with voluntary movement viz early and late BP. The early component is bilaterally symmetrical across the scalp with maximal amplitude recorded at the vertex and with a principal source in the bilateral supplementary motor area [4,5]. Late BP reflects premovement activity localized to the contralateral motor cortex and supplementary motor area [4,5]. Though some studies have observed near normal BP in PD compared to age match controls [6,7]; many other studies have found BP abnormalities in PD [8–14]. The duration and amplitude of BP recorded at the
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Corresponding Author: Department of Physiology, AIIMS, New Delhi, India. E-mail address: [email protected] (K.K. Preet).
http://dx.doi.org/10.1016/j.clineuro.2017.06.011 Received 19 January 2017; Received in revised form 10 May 2017; Accepted 13 June 2017 Available online 15 June 2017 0303-8467/ © 2017 Elsevier B.V. All rights reserved.
Cz (vertex) are reduced in Parkinsonism and levodopa treatment is associated with changes in these parameters of BP [11]. Based on this observation they suggested that these premovement readiness potentials are influenced by the basal ganglia output to supplementary motor area via dopaminergic control [11]. BP are even affected by lesions in basal ganglia circuitry; both early BP and late BP are flatter in patients with bilateral lesions in basal ganglia [8]. Further, it was shown that it is the early component of BP that is significantly reduced in PD during externally cued movements, implying defective activation of supplementary motor area [9]. Few electrophysiological studies have explored the properties of scalp BP during and after DBS as the treatment modality. They have demonstrated recordable BP over the scalp as well as at different sites in the basal ganglia [15–17]. These studies point towards the role of basal ganglia nuclei during motor preparation. Only one study has evaluated the effect of switching DBS ON and OFF on these potentials; Brown and
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1.3. Recording protocol
his colleagues observed that after STN stimulation there were improvements in the time taken for movement and force of contraction while no prominent effect on time for initiating movement. However, as the BP amplitudes were small in some patients they could not study different components of BP during ON and OFF stimulation states [18]. Given that DBS-STN effectively modulates the whole basal ganglia circuitry, which plays an important role in motor planning, we postulate that switching stimulation OFF may differentially influence the components of BP and re-switching ON would revert the changes back to the initial ON condition. By studying the effect of switching stimulation ON and OFF on bereitschaftspotentials in Parkinson's disease, we aim to understand the mechanism behind motor improvement after deep brain stimulation of subthalamic nucleus.
The potentials were recorded using Evoked Potential Recorder Neuropack 8 (Nihon Kohden, Japan). All the recordings were taken in medication ON state in both patient groups. Electroencephalography was recorded from the scalp using silver/silver chloride surface electrodes and International 10–20 system for electrode placement. Potentials were recorded at Fz, Cz, Pz, C3 and C4 electrode sites placed according to international 10–20 system with linked earlobes electrodes as reference and a forehead electrode (Fpz) used as ground. The EEG signal was amplified with a gain of 10,000 by the in-build amplifiers of Neuropack 8 through a filter band pass 0.05–45 Hz for scalp recordings; such a setting helps in reducing stimulation artifacts in the EEG data. The electromyogram from the extensor carpi radialis was used as a trigger for collection of bereitschaftspotentials. Filter band pass for EMG was 0.05–3 KHz with sensitivity set at 200 μV/div. Impedance was kept less than 5KΩ throughout the recording. Participants were seated comfortably in an armchair with eyes open and fix on a screen during the recording. They were trained to perform precise right wrist extensions (50–60 degree from horizontal position) once every 5–10 s, for a duration not more than 0.5 s (Fig. 1). To ensure active participation during the task, the subjects were asked to keep the interval between the contractions random but always more than 5 s. They were given feedback to stop whenever the researcher observed that the contractions were rhythmic and averaging was paused. The onset of EMG signal was used as trigger for back averaging BP. Neuropack 8 was programmed to back average the EEG 3.0 s prior to and 0.5 s after the EMG onset. Sweeps of each of the trials were inspected for eye blinks (Fp1-A1 and Fp2–A2 electrode pairs) or other artifacts. Sweeps with EEG amplitudes of more than 60 μV or EMG signal lasting for more than 0.5 s were excluded from the averaging. Online artifact rejection was thus done. 100 such artifact free sweeps (trials) were averaged to obtain BP. Analysis of the waveform components was done offline. An initial recording in DBS-STN group with the stimulation ON and medication ON state (the first day when the participant was enrolled and in whom stimulation was ON for more than 72 h without any interference) was considered as DBS ON/DRUGS ON i.e. a baseline BP record. To study the effect of switching DBS OFF or ON two addition sessions were recorded for DBS group on separate days. In another session, BP was recorded in medication ON but stimulation OFF state (waiting for a period of 15 min after switching OFF) this was considered as DBS OFF/DRUGS ON. In the third session, BP was recorded in medication ON but after re-switching stimulation ON (waiting for a period of 15 min after switching OFF and another 15 min after reswitching ON); this was considered as DBS ON-2/DRUGS ON. Apart from sweep rejection criteria mentioned before, only trials where the EMG amplitude was more than 60% of EMGmax (noted on day 1) were included for averaging in all the conditions for the given individual to reduce intra-individual variation. Offline analysis of BP parameters mentioned below was done for each participant separately.
1.1. Material and methods This study was approved by institute ethical committee and in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). All the participants were well informed about the nature and purpose of the study and written informed consent was obtained from each. 1.2. Participants The participants in this study consisted of three groups viz. DBS-STN plus medications (DBS-STN group), patients on medications only (Med group), and healthy age matched controls (Control group). The DBSSTN group consisted of patients with age between 50 and 70 years affected by idiopathic Parkinson’s disease and on bilateral DBS-STN. Only patients with post implant interval of > 4 weeks were included and had electrodes implanted in bilateral subthalamic nucleus with similar optimal stimulation settings (bipolar, 2.9 ± 0.35 V, 62.5 ± 8.6 ms, 139.1 ± 9 Hz). Furthermore to study the effect of stimulation on BP the DBS-STN group was divided into three conditions: DBS ON/DRUGS ON, DBS OFF/DRUGS ON and DBS ON-2/DRUGS ON (discussed in recording protocol). Med group also consisted of patients with age between 50 and 70 years affected by idiopathic Parkinson’s disease but only on levodopa medications. Only right handed [19] participants with bilateral disease (right > left) and those who could perform the task with recordable BP were included in this study. Participants with any history of head trauma, stroke or any other neurological complications, or psychiatric disorders were excluded from the study. Based on DBS-STN group other groups were age and gender matched with each group having 8 males and 4 females participants. (DBS-STN group: mean age = 57.08 ± 5.62 years; Med group: mean age = 54.25 ± 4.14 years; and Control group: mean age = 54.50 ± 4.93 years). Clinical severity assessment of patients with PD was done using Unified Parkinson’s Disease Rating Scale (UPDRS) [20]. Table 1 shows the details of the patients group. Table 1 Clinical details of the patients in the study. Groups → Parameters ↓
Med Group
Age (years) Duration of disease (years) UPDRS III Motor Score
54.25 ± 4.14 8.83 ± 4.73
57.08 ± 5.62 9.42 ± 3.03
37.08 ± 4.58
27.67 ± 2.61
1.4. Analysis and statistics
DBS-STN group DBS ON/ DRUGS ON
DBS OFF/ DRUGS ON
DBS ON-2/ DRUGS ON
39.83 ± 2.92
27.75 ± 2.30
The BP morphology was analysed for following parameters: peak amplitude, early slope, and late slope. Baseline activity was calculated from −2500 ms to −2000 ms i.e. prior to the onset of BP in all recordings. The maximum amplitude of bereitschaftspotentials occurring near the time of movement (around −50 ms) was noted as peak amplitude. Early slope was calculated as an average slope over the period of −1500 to −500 ms prior to EMG onset using linear regression; this slope represents the activity associated with the early component of BP [10]. Similarly late slope was calculated as average slope over the period from −500 ms to peak BP. Cortical activity during the time period of −500 ms to peak BP represents the late component of these potentials. BP parameters were compared between controls vs Med
DBS-STN group was divided into three conditions: DBS ON/DRUGS ON, DBS OFF/DRUGS ON and DBS ON-2/DRUGS ON. Values represented as mean ± SD.
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Fig. 1. Schematic representation of the wrist extension task used for BP recording. Participants were seated comfortably in an armchair with eyes open and fix on a screen during the recording. They were trained to perform precise right wrist extensions (50–60° from horizontal position). This figure shows BP recording at Cz location using EMG from extensor carpi radialis as trigger. We can also see the Fp2-A2 sites, which were used to detect eye blink artifacts.
group, controls vs DBS ON/DRUGS ON, controls vs DBS OFF/DRUGS ON, controls vs DBS ON-2/DRUGS ON, Med group vs DBS ON/DRUGS ON, Med group vs DBS OFF/DRUGS ON, and Med group vs DBS ON-2/ DRUGS ON using analysis of variance (ANOVA). For comparison between the three conditions (DBS ON/DRUGS ON vs DBS OFF/DRUGS ON vs DBS ON-2/DRUGS ON) repeated measures ANOVA was used. Post hoc analysis was done using Tukey multiple comparison tests. Unpaired t-test was used to compare UPDRS III motor scores and duration of disease between the DBS and PD group. All statistical tests used were two-tailed with p < 0.05 used to determine statistical significance. Correlation studies between the three BP parameters and severity/duration of disease were done using Pearson test using Bonferroni correction for multiple correlation.
= 7.860,p < 0.0001], C3[F(4,55) = 3.983, p = 0.0066] and C4[F (4,55) = 3.895, p = 0.0074]; while it was not significantly different at electrode sites Fz [F(4,55) = 1.268, p = 0.2937] and Pz[F(4,55) = 0.3479,p = 0.8444]. Post hoc Tukey multiple comparison test showed that late slope was significantly less in Med group compared to controls at Cz (p < 0.01), C3 (p < 0.05)and C4 (p < 0.05) electrode sites. Late slope was significantly less in DBS OFF/DRUGS ON compared to control group at Cz (p < 0.01), C3 (p < 0.01) and C4 (p < 0.01) electrode sites and remained reduced in DBS ON-2/DRUGS ON as compared to controls at Cz (p < 0.001). There was no significant difference seen in late slope among other groups.
2. Results
We observed a visible change in BP morphology by switching DBS OFF and by re-switching DBS ON as compared to baseline BP in all participants. On Repeated ANOVA the peak amplitude was observed to be significantly differed across the conditions at electrode sites Cz [F (2,11) = 11.78,p = 0.0003], C3[F(2,11) = 11.32,p = 0.0004] and C4[F(2,11) = 6.954,p = 0.0046]; while it was not significantly different at electrode sites Fz[F(2,11) = 0.8908,p = 0.4246] and Pz[F (2,11) = 0.06150, p = 0.9939]. Post hoc Tukey multiple comparison test showed that peak amplitude was significantly decreased in DBS OFF/DRUGS ON compared to DBS ON/DRUGS ON at Cz (p < 0.001), C3 (p < 0.001) and C4 (p < 0.01) electrode sites. In addition, peak amplitude remained significantly less in DBS ON-2/DRUGS ON compared to DBS ON/DRUGS ON at Cz (p < 0.01) electrode site. Peak amplitude significantly improved at C3 electrode site in DBS ON-2/ DRUGS ON as compared to DBS OFF/DRUGS ON. The early slope was not significantly different across the conditions at any electrode site Cz [F(2,11) = 3.576, p = 0.4523], C3[F(2,11) = 0.7443,p = 0.4867], C4[F(2,11) = 0.4368, p = 0.8602], Fz [F(2,11) = 0.5135, p = 0.6054] and Pz [F(2,11) = 0.2682, p = 0.7672]. The late slope significantly differed across the conditions at electrode sites Cz[F(2,11) = 6.383,p = 0.0065], C3[F(2,11) = 4.270, p = 0.0271] and C4[F (2,11) = 4.263,p = 0.0272]; while it was not significantly different at electrode sites Fz[F(2,11) = 0.6533,p = 0.5301] and Pz[F(2,11) = 0.06496,p = 0.9373]. Post hoc Tukey multiple comparison tests showed that late slope was significantly decreased in DBS OFF/DRUGS ON compared to DBS ON/DRUGS ON at Cz (p < 0.001), C3 (p < 0.001) and C4 (p < 0.01) electrode sites. Also late slope remained significantly decreased in DBS ON-2/DRUGS ON compared to DBS ON/DRUGS ON at Cz (p < 0.01) electrode site. There was no
2.2. Effect of switching stimulation ON or OFF on bereitschaftspotentials
2.1. Comparison of bereitschaftspotentials among the groups A negative potential prior to EMG onset was observed in all participants (Fig. 2). Fig. 3 shows comparison of BP parameters among the groups at Cz, C3 and C4 sites. For comparison of BP parameters at other sites (Fz & Pz) see Supplementary Fig. 5. The peak amplitude significantly differed across the groups at electrode sites Cz [F(4,55) = 13.47,p < 0.0001], C3[F(4,55) = 11.60,p = 0.0018] and C4[F (4,55) = 7.393,p = 0.0061]; while it was not significantly different at electrode sites Fz[F(4,55) = 0.7739,p = 0.5469] and Pz[F(4,55) = 0.3806,p = 0.8215]. Post hoc Tukey multiple comparison tests showed that peak amplitude was significantly less in Med group compared to controls at Cz(p < 0.001), C3(p < 0.01) and C4(p < 0.01) electrode sites. Peak amplitude was also significantly less in Med group compared to DBS-STN group at Cz (p < 0.01) electrode sites. There was no significant difference in peak amplitude between DBS ON/ DRUGS ON and controls. Peak amplitude was significantly reduced in DBS OFF/DRUGS ON as compared to control group at Cz(p < 0.001), C3(p < 0.001) and C4(p < 0.001) electrode sites. It remained significantly reduced on re-switching on (DBS ON-2/DRUGS ON) as compared to control group at Cz(p < 0.001), C3(p < 0.01) and C4(p < 0.05) electrode sites. The early slope was not significantly different when compared among the groups at any electrode site Cz[F (4,55) = 3.530,p = 0.1246], C3[F(4,55) = 1.549,p = 0.2010], C4[F (4,55) = 2.230,p = 0.0776], Fz [F(4,55) = 0.2612, p = 0.9015] and Pz[F(4,55) = 0.5249, p = 0.7178]. ANOVA showed that late slope of BP significantly differed across the groups at electrode sites Cz[F(4,55) 32
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Fig. 2. Mean BP waveforms at various scalp electrode sites among the different groups. The dotted vertical line marks the start of EMG signal. The inset on top left side shows the scalp electrode sites according to 10–20 International System for electrode placement. Note the sensitivity is different for BP and EMG signal.
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Fig. 3. Comparison of BP parameters across Cz, C3 and C4 scalp electrode sites among the different groups. Values expressed as follows: (3a). Peak amplitude (μV, mean ± SD), (3b). Early slope (μV/s, mean ± SD) and (3c). Late slope (μV/s, mean ± SD); *p < 0.05; **p < 0.01; ***p < 0.001. *: represents comparison with control group. #: repeated ANOVA comparison with DBS ON/DRUGS ON. ○: repeated ANOVA comparison with DBS OFF/DRUGS ON. Fig. 4. Correlation between BP amplitude and UPDRS III motor scores among various groups. 4(a-d), shows correlation between peak amplitude at Cz electrode site and UPDRS III motor scores among all the groups. Peak amplitude (μV); *p < 0.05; **p < 0.01; ***p < 0.001.
significant difference in late slope between DBS OFF/DRUGS ON and DBS ON-2/DRUGS ON.
8.83 ± 4.73 years p = 0.7223). There was no significant difference in severity of the disease (UPDRS-III) between Med group (37.08 ± 4.58) as compared with DBS OFF/DRUGS ON of DBS-STN group (39.83 ± 2.92). UPDRS-III motor scores were significantly different in the three conditions [F(2,11) = 115.0, p < 0.0001]. UPDRS-III motor scores were significantly worse in DBS OFF/DRUGS ON (39.83 ± 2.92, p < 0.001) as compared to DBS ON/DRUGS ON
2.3. Clinical evaluation and correlation There was no significant different in duration of disease between the two patient groups (DBS-STN: 9.42 ± 3.03 years; Med: 34
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3.2. Switching stimulation off reverses the improvement in late component of BP
(27.67 ± 2.61) and improved on re switching on i.e. DBS ON-2/ DRUGS ON (27.75 ± 2.30, p < 0.001). BP was seen maximum at Cz electrode site in all the participants. So in order to explore nature of BP in the disease, we compared BP parameters at Cz electrode site with clinical motor scores (Fig. 4). A significant negative correlation was observed between the BP parameter (peak amplitude) and UPDRS III motor scores in Med group, DBS ON/DRUGS ON and DBS OFF/DRUGS ON, but not for DBS ON-2/DRUGS ON. No significant correlation was seen between other BP parameters (early slope or late slope) and UPDRS III motor scores in patient groups.
To further understand the temporal effects of DBS-STN on motor planning we looked upon for the effect of switching OFF and the reswitching ON of DBS-STN on BP. We found that amplitude and late slope were reduced by switching stimulation OFF (DBS OFF/DRUGS ON); while there was no change in early component among the conditions. Brown et al. found that switching DBS-STN OFF did not significantly affect the amplitude of BP [18]. On the other hand, in the same year, it was observed that amplitude of contingent negative variation (CNV) was decreased after switching DBS-STN OFF as compared to DBS-STN ON [36]. CNV are also negative cortical potentials that develop between a warning stimulus (S1) and an imperative stimulus (S2); they reflect the preparatory activity of the cortex to the response [37,38]. The late part of CNV is considered to be related with BP [39]. CNV amplitude is impaired in PD and this reflects that the preparation to a response is affected in the disease [36,39]; as it is with decreased BP amplitude reflecting impaired preparation of movement in PD [10,39]. The decreased CNV amplitude observed by switching DBS OFF [36]; suggests that DBS-STN improves the cortical functioning of the frontal cortex. Our results show that the BP amplitude is decreased by switching stimulation OFF; this supports that DBS-STN was improving the activity of motor related cortices. Patients in medication OFF state were unable to perform our task due to tremors hence; we could not include combined stimulation OFF and medication OFF condition in our study. Therefore, all recordings in our study were in medication ON state. Levodopa has been observed to increase early component of BP [39,40]; this probably explains the no effect observed on early BP in DBS OFF/DRUGS ON and DBS ON-2/DRUGS ON. However, medication OFF state in the disease is more pathological state as it would be characterized by dopaminergic reduction. Imaging study shows that there is increased synchronous activity between STN and sensorimotor cortex in PD in medication OFF state [41]. Hence, studying BP in such medication OFF state would give better insight on effect of sole DBSSTN ON or OFF conditions. The firing pattern of neurons in basal ganglia, which is abnormally synchronized in PD [42], is changed to random pattern after stimulation [43]; DBS-STN drives the basal ganglia output neurons in such a way that results in decreased inhibition of thalamus [44]. Moreover, as mentioned before DBS-STN stimulates the cortex [45]. Imaging studies also show activation of supplementary motor cortex during movement and a reduction of hyperactivity in primary motor cortex after DBS-STN stimulation [26]. When stimulation is switched OFF all these effects are absent; this probably explains the decrease in the BP amplitude and late slope in DBS OFF/DRUGS ON. However, future studies can include DBS OFF/ ON states with medication ON/OFF states i.e. four possible conditions to explore the effects of these combinations of treatment modalities on BP responses.
3. Discussion 3.1. Bilateral deep brain stimulation of subthalamic nucleus along with medications improves premovement cortical activity in parkinson’s disease In this study, we explored the effect of treatment modality on motor planning using BP as a tool to assess cortical activity before the actual movement (premovement cortical activity). The degeneration of dopaminergic neurons in PD results in defective motor planning and movement; observed as a reduction in the amplitude and slope of BP compared to controls [10,14,21,22]. In our study, we found BP parameters in DBS ON/DRUGS ON not significantly different from those seen in the control group. This suggests that the stimulation of the subthalamic nucleus along with medications is improving the impaired BP in PD. As both the components of BP were comparable to controls in DBS ON/DRUGS ON state, it points towards the ability of additional stimulation therapy to rectify the temporal sequence of cortical activation back to near normal in PD. This result is supported by previous imaging studies in DBS-STN treated patients. DBS-STN increases activation of the supplementary motor area [23,24] which is the principal source for generation of BP. High frequency stimulation of STN also reduces blood flow to the motor areas during rest while allowing selective activation during movement [25,26]. Neurophysiological studies in DBS-STN treated patients show that the activation of cortex during movement is via stimulation of pallido-thalamic fibres in the STN [27]. Rodent studies also suggest direct activation of afferent fibres projecting from cortex to STN [28]. The mechanism by which DBS-STN is ameliorating the pathological oscillations in basal ganglia might be due to both orthodromic as well as antidromic stimulation of cortical connections with STN [29]. DBS-STN results in stimulation of efferents from STN to globus pallidus pars interna and globus pallidus pars externa; which changes the neuronal firing patterns in these nuclei and this may be one of the mechanisms behind therapeutic benefits of stimulation in PD [30]. Both neurophysiological and imaging studies suggest that the BP with sources in the supplementary motor area and primary motor cortex will also be affected by DBS-STN. Provided the symptomatic improvement offered by DBS-STN; changes in these cortical areas must be leading to better planning reflected in BP parameters. As DBS-STN is known to reduce overactivity of motor areas at rest and improving connectivity between thalamus and motor cortices [26,31], and thereby allowing selective activation during movement, this may be the reason for better motor related potentials. In this study, we found improvement in the cortical activity prior to wrist extension movement following DBS-STN stimulation. However, this may not be applied for legs and trunk movement since gait and postural instability are not greatly improved by DBS-STN and are DOPA-resistant motor symptoms [32]. In this regard it is noteworthy that DBS of the pedunculopontine nucleus (PPN), a pontomesencephalic nucleus rich in cholinergic neurons [33], helps in improving gait freezing [34] and facilitates in gait initiation in PD [35], thus suggesting a role of these neurons in posture and gait disturbances in PD. Thus, future studies should be done to explore the effects on DBS-PPN on BP prior to gait/ lower limb movements.
3.3. Acute and chronic stimulation have different effects on BP On the contrary, though UPDRS III motor scores were improved, yet peak amplitude and late slope were observed to be reduced even after re-switching ON (DBS ON-2/DRUGS ON) at Cz electrode site. However, peak amplitude and late slope did improve at other sites. Significant improvement was seen in peak amplitude at C3 site in DBS ON-2/ DRUGS ON as compared to DBS OFF/DRUGS ON, Further, we analysed correlation between BP amplitude and clinical status in the patients. We found a negative correlation between the BP amplitude (Cz) and UPDRS III motor scores in both the Med group as well as DBS ON/DRUGS ON state. While no correlation was found between the BP amplitude (Cz) and the duration of disease. Similar results were found by Simpson et al; where amplitude of BP recorded at Cz (vertex) electrode site correlated with the disease severity (Webster scales) but not with the duration of disease [11]. Another study shows correlation between the motor 35
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improvement and the increased regional blood flow to pre-SMA in DBSSTN treated patients supporting our findings [46]. The correlation between BP amplitude and UPDRS III motor score was also seen after switching OFF, but not after re-switching ON. Such discrepancy points toward the inability of DBS ON-2/DRUGS ON state to sufficiently improve the motor planning and suggests that re-switching stimulation ON requires time to improve the BP at the vertex. The improvement of BP amplitude at C3 (contralateral cortex) probably point towards the role of orthodromic or/and antidromic stimulation of motor cortex as suggested in earlier studies; yet re-switching ON was not able to fully reverse the functionality of all the motor associated cortices as reflected by reduced BP at the vertex. This points towards the differences of acute and chronic stimulation on BP in PD. Although, DBS-STN reduces beta band oscillations immediately post stimulation, chronic stimulation results in much more reduction [47]. By switching the stimulation OFF the abnormal basal ganglia circuitry restarts, while on re-switching stimulation ON it would require further time for stimulation to reset this abnormal circuitry probably involving some time-consuming mechanisms. Though neurochemistry studies of basal ganglia in animal models after DBS-STN have shown varied results [48]. High frequency stimulation of STN in a rat model does lead to increase in extracellular glutamate in substantia nigra and globus pallidum and it also leads to increase in GABA in substantia nigra [48,49]. Yet, the exact neurotransmitter mechanism responsible for decreased BP in DBS ON-2/ DRUGS ON state needs to be explored. To compare the effect of DBSSTN ON and OFF we fixed the interval of fifteen minutes based on a pilot study; this study design limitation may have been insufficient for DBS ON-2/DRUGS ON i.e. re-switching stimulation ON to provide beneficial effect on motor planning. However, we do not conclude on the changes seen in BP waveform as permanent, as we have not studied the potentials beyond 15 min. In this study we have recorded BP for right wrist movements and found equivocal responses in BP at bilateral motor hemispheres viz. C3 and C4. The late component of BP arises principally from the contralateral cortex, but studies also show ipsilateral motor cortex contribution in this phase of motor planning [5]. Future studies should also include left wrist/arm movement and calculate lateralized readiness potentials (LRP) [50], which would help in evaluating the asymmetrical components of the BP [4]. Such inclusion will help in understanding effects of DBS-STN on unilateral vs. bilateral motor hemispheres. Bilateral deep brain stimulation of subthalamic nucleus along with medications improves premovement cortical activity in Parkinson’s disease. The improved BP after stimulation is probably due to both antidromic and orthodromic stimulation of the cortex as well as by changing the abnormal firing pattern within the basal-ganglia circuitry. Acute effect of switching DBS-STN OFF was observed as reduction in later part of motor planning as reflected by decreased BP amplitude and late slope. On the other hand, re-switching DBS-STN ON did not return BP to normal even after 15 min implying that apart from stimulation of motor cortical areas, DBS-STN acts via basal ganglia circuitry probably involving time consuming mechanisms. These findings must be considered in future research queries by the scientific world to study the structural and neurotransmitter changes after DBS-STN. It is worthwhile to note for the physicians that, the chronic effects and acute effects of switching DBS-STN ON or OFF do have different time lags for beneficial improvement in motor planning. These findings might also be helpful while devising newer DBS strategies in PD, like the closed loop stimulation [51] or brain computer interface controlled [52], which are aimed at providing personalized stimulation.
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Deep brain stimulation of subthalamic nucleus helps in improving late phase motor planning in Parkinson’s disease
MARK
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Patil Ashlesha, Sood Sanjay Kumara, Kochhar Kanwal Preeta, , Goyal Vinayb a b
Department of Physiology, All India Institute of Medical Sciences, New Delhi, India Department of Neurology, All India Insitute of Medical Sciencest, New Delhi, India
A R T I C L E I N F O
A B S T R A C T
Keywords: Deep brain stimulation Subthalamic nucleus Parkinson’s disease Bereitschaftspotentials Motor planning.
Objective: Deep brain stimulation of subthalamic nucleus (DBS-STN) is a well-accepted treatment for Parkinson’s disease (PD) but its effect on motor planning in the disease is yet unclear. This study examines the effect of switching the stimulation ON and OFF on components of bereitschaftspotentials in PD. Patients and methods: Scalp bereitschaftspotentials were recorded during self-paced right wrist extensions at Fz, Cz, Pz, C3 and C4 sites in patients on DBS-STN plus medications (DBS-STN group) as treatment modality or on medications only (Med group) and compared with age matched healthy controls. In DBS-STN group, the potentials were recorded in stimulation ON, stimulation OFF, and again after re-switching stimulation ON-2. Offline analysis of potentials was done to calculate peak amplitude, late slope (−500 to 0 ms) and early slope (−1500 to −500 ms). Results: We observed that the two components of bereitschaftspotentials in stimulation ON state were comparable to those in age matched controls. The late slope was found to be significantly reduced during stimulation OFF as compared to stimulation ON at Cz (p < 0.001), C3 (p < 0.001) and C4 (p < 0.01) electrode sites. This parameter failed to improve on re-switching stimulation ON at Cz (p < 0.01). No significant change was observed in early part of bereitschaftspotentials among any of the conditions. Conclusion: Our study shows that DBS-STN along with anti-parkinsonian medications helps in improving both components of bereitschaftspotentials in PD. Switching stimulation OFF for fifteen minutes principally affects the late component i.e. the execution part of motor planning; which cannot be reversed by re-switching ON. Thus the chronic and acute effects of switching DBS-STN ON are different and principally affect the later part of motor planning.
1. Introduction Bereitschaftspotentials (BP) are negative cortical evoked potentials that begin 1000–1500 milliseconds (ms) prior to the onset of a selfpaced movement [1]; they represent the cortical activity before the actual onset of the movement. Recording scalp BP has helped to study motor planning in health as well as in disease [2,3]. Two major components of BP can be distinguished associated with voluntary movement viz early and late BP. The early component is bilaterally symmetrical across the scalp with maximal amplitude recorded at the vertex and with a principal source in the bilateral supplementary motor area [4,5]. Late BP reflects premovement activity localized to the contralateral motor cortex and supplementary motor area [4,5]. Though some studies have observed near normal BP in PD compared to age match controls [6,7]; many other studies have found BP abnormalities in PD [8–14]. The duration and amplitude of BP recorded at the
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Corresponding Author: Department of Physiology, AIIMS, New Delhi, India. E-mail address: [email protected] (K.K. Preet).
http://dx.doi.org/10.1016/j.clineuro.2017.06.011 Received 19 January 2017; Received in revised form 10 May 2017; Accepted 13 June 2017 Available online 15 June 2017 0303-8467/ © 2017 Elsevier B.V. All rights reserved.
Cz (vertex) are reduced in Parkinsonism and levodopa treatment is associated with changes in these parameters of BP [11]. Based on this observation they suggested that these premovement readiness potentials are influenced by the basal ganglia output to supplementary motor area via dopaminergic control [11]. BP are even affected by lesions in basal ganglia circuitry; both early BP and late BP are flatter in patients with bilateral lesions in basal ganglia [8]. Further, it was shown that it is the early component of BP that is significantly reduced in PD during externally cued movements, implying defective activation of supplementary motor area [9]. Few electrophysiological studies have explored the properties of scalp BP during and after DBS as the treatment modality. They have demonstrated recordable BP over the scalp as well as at different sites in the basal ganglia [15–17]. These studies point towards the role of basal ganglia nuclei during motor preparation. Only one study has evaluated the effect of switching DBS ON and OFF on these potentials; Brown and
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1.3. Recording protocol
his colleagues observed that after STN stimulation there were improvements in the time taken for movement and force of contraction while no prominent effect on time for initiating movement. However, as the BP amplitudes were small in some patients they could not study different components of BP during ON and OFF stimulation states [18]. Given that DBS-STN effectively modulates the whole basal ganglia circuitry, which plays an important role in motor planning, we postulate that switching stimulation OFF may differentially influence the components of BP and re-switching ON would revert the changes back to the initial ON condition. By studying the effect of switching stimulation ON and OFF on bereitschaftspotentials in Parkinson's disease, we aim to understand the mechanism behind motor improvement after deep brain stimulation of subthalamic nucleus.
The potentials were recorded using Evoked Potential Recorder Neuropack 8 (Nihon Kohden, Japan). All the recordings were taken in medication ON state in both patient groups. Electroencephalography was recorded from the scalp using silver/silver chloride surface electrodes and International 10–20 system for electrode placement. Potentials were recorded at Fz, Cz, Pz, C3 and C4 electrode sites placed according to international 10–20 system with linked earlobes electrodes as reference and a forehead electrode (Fpz) used as ground. The EEG signal was amplified with a gain of 10,000 by the in-build amplifiers of Neuropack 8 through a filter band pass 0.05–45 Hz for scalp recordings; such a setting helps in reducing stimulation artifacts in the EEG data. The electromyogram from the extensor carpi radialis was used as a trigger for collection of bereitschaftspotentials. Filter band pass for EMG was 0.05–3 KHz with sensitivity set at 200 μV/div. Impedance was kept less than 5KΩ throughout the recording. Participants were seated comfortably in an armchair with eyes open and fix on a screen during the recording. They were trained to perform precise right wrist extensions (50–60 degree from horizontal position) once every 5–10 s, for a duration not more than 0.5 s (Fig. 1). To ensure active participation during the task, the subjects were asked to keep the interval between the contractions random but always more than 5 s. They were given feedback to stop whenever the researcher observed that the contractions were rhythmic and averaging was paused. The onset of EMG signal was used as trigger for back averaging BP. Neuropack 8 was programmed to back average the EEG 3.0 s prior to and 0.5 s after the EMG onset. Sweeps of each of the trials were inspected for eye blinks (Fp1-A1 and Fp2–A2 electrode pairs) or other artifacts. Sweeps with EEG amplitudes of more than 60 μV or EMG signal lasting for more than 0.5 s were excluded from the averaging. Online artifact rejection was thus done. 100 such artifact free sweeps (trials) were averaged to obtain BP. Analysis of the waveform components was done offline. An initial recording in DBS-STN group with the stimulation ON and medication ON state (the first day when the participant was enrolled and in whom stimulation was ON for more than 72 h without any interference) was considered as DBS ON/DRUGS ON i.e. a baseline BP record. To study the effect of switching DBS OFF or ON two addition sessions were recorded for DBS group on separate days. In another session, BP was recorded in medication ON but stimulation OFF state (waiting for a period of 15 min after switching OFF) this was considered as DBS OFF/DRUGS ON. In the third session, BP was recorded in medication ON but after re-switching stimulation ON (waiting for a period of 15 min after switching OFF and another 15 min after reswitching ON); this was considered as DBS ON-2/DRUGS ON. Apart from sweep rejection criteria mentioned before, only trials where the EMG amplitude was more than 60% of EMGmax (noted on day 1) were included for averaging in all the conditions for the given individual to reduce intra-individual variation. Offline analysis of BP parameters mentioned below was done for each participant separately.
1.1. Material and methods This study was approved by institute ethical committee and in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). All the participants were well informed about the nature and purpose of the study and written informed consent was obtained from each. 1.2. Participants The participants in this study consisted of three groups viz. DBS-STN plus medications (DBS-STN group), patients on medications only (Med group), and healthy age matched controls (Control group). The DBSSTN group consisted of patients with age between 50 and 70 years affected by idiopathic Parkinson’s disease and on bilateral DBS-STN. Only patients with post implant interval of > 4 weeks were included and had electrodes implanted in bilateral subthalamic nucleus with similar optimal stimulation settings (bipolar, 2.9 ± 0.35 V, 62.5 ± 8.6 ms, 139.1 ± 9 Hz). Furthermore to study the effect of stimulation on BP the DBS-STN group was divided into three conditions: DBS ON/DRUGS ON, DBS OFF/DRUGS ON and DBS ON-2/DRUGS ON (discussed in recording protocol). Med group also consisted of patients with age between 50 and 70 years affected by idiopathic Parkinson’s disease but only on levodopa medications. Only right handed [19] participants with bilateral disease (right > left) and those who could perform the task with recordable BP were included in this study. Participants with any history of head trauma, stroke or any other neurological complications, or psychiatric disorders were excluded from the study. Based on DBS-STN group other groups were age and gender matched with each group having 8 males and 4 females participants. (DBS-STN group: mean age = 57.08 ± 5.62 years; Med group: mean age = 54.25 ± 4.14 years; and Control group: mean age = 54.50 ± 4.93 years). Clinical severity assessment of patients with PD was done using Unified Parkinson’s Disease Rating Scale (UPDRS) [20]. Table 1 shows the details of the patients group. Table 1 Clinical details of the patients in the study. Groups → Parameters ↓
Med Group
Age (years) Duration of disease (years) UPDRS III Motor Score
54.25 ± 4.14 8.83 ± 4.73
57.08 ± 5.62 9.42 ± 3.03
37.08 ± 4.58
27.67 ± 2.61
1.4. Analysis and statistics
DBS-STN group DBS ON/ DRUGS ON
DBS OFF/ DRUGS ON
DBS ON-2/ DRUGS ON
39.83 ± 2.92
27.75 ± 2.30
The BP morphology was analysed for following parameters: peak amplitude, early slope, and late slope. Baseline activity was calculated from −2500 ms to −2000 ms i.e. prior to the onset of BP in all recordings. The maximum amplitude of bereitschaftspotentials occurring near the time of movement (around −50 ms) was noted as peak amplitude. Early slope was calculated as an average slope over the period of −1500 to −500 ms prior to EMG onset using linear regression; this slope represents the activity associated with the early component of BP [10]. Similarly late slope was calculated as average slope over the period from −500 ms to peak BP. Cortical activity during the time period of −500 ms to peak BP represents the late component of these potentials. BP parameters were compared between controls vs Med
DBS-STN group was divided into three conditions: DBS ON/DRUGS ON, DBS OFF/DRUGS ON and DBS ON-2/DRUGS ON. Values represented as mean ± SD.
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Fig. 1. Schematic representation of the wrist extension task used for BP recording. Participants were seated comfortably in an armchair with eyes open and fix on a screen during the recording. They were trained to perform precise right wrist extensions (50–60° from horizontal position). This figure shows BP recording at Cz location using EMG from extensor carpi radialis as trigger. We can also see the Fp2-A2 sites, which were used to detect eye blink artifacts.
group, controls vs DBS ON/DRUGS ON, controls vs DBS OFF/DRUGS ON, controls vs DBS ON-2/DRUGS ON, Med group vs DBS ON/DRUGS ON, Med group vs DBS OFF/DRUGS ON, and Med group vs DBS ON-2/ DRUGS ON using analysis of variance (ANOVA). For comparison between the three conditions (DBS ON/DRUGS ON vs DBS OFF/DRUGS ON vs DBS ON-2/DRUGS ON) repeated measures ANOVA was used. Post hoc analysis was done using Tukey multiple comparison tests. Unpaired t-test was used to compare UPDRS III motor scores and duration of disease between the DBS and PD group. All statistical tests used were two-tailed with p < 0.05 used to determine statistical significance. Correlation studies between the three BP parameters and severity/duration of disease were done using Pearson test using Bonferroni correction for multiple correlation.
= 7.860,p < 0.0001], C3[F(4,55) = 3.983, p = 0.0066] and C4[F (4,55) = 3.895, p = 0.0074]; while it was not significantly different at electrode sites Fz [F(4,55) = 1.268, p = 0.2937] and Pz[F(4,55) = 0.3479,p = 0.8444]. Post hoc Tukey multiple comparison test showed that late slope was significantly less in Med group compared to controls at Cz (p < 0.01), C3 (p < 0.05)and C4 (p < 0.05) electrode sites. Late slope was significantly less in DBS OFF/DRUGS ON compared to control group at Cz (p < 0.01), C3 (p < 0.01) and C4 (p < 0.01) electrode sites and remained reduced in DBS ON-2/DRUGS ON as compared to controls at Cz (p < 0.001). There was no significant difference seen in late slope among other groups.
2. Results
We observed a visible change in BP morphology by switching DBS OFF and by re-switching DBS ON as compared to baseline BP in all participants. On Repeated ANOVA the peak amplitude was observed to be significantly differed across the conditions at electrode sites Cz [F (2,11) = 11.78,p = 0.0003], C3[F(2,11) = 11.32,p = 0.0004] and C4[F(2,11) = 6.954,p = 0.0046]; while it was not significantly different at electrode sites Fz[F(2,11) = 0.8908,p = 0.4246] and Pz[F (2,11) = 0.06150, p = 0.9939]. Post hoc Tukey multiple comparison test showed that peak amplitude was significantly decreased in DBS OFF/DRUGS ON compared to DBS ON/DRUGS ON at Cz (p < 0.001), C3 (p < 0.001) and C4 (p < 0.01) electrode sites. In addition, peak amplitude remained significantly less in DBS ON-2/DRUGS ON compared to DBS ON/DRUGS ON at Cz (p < 0.01) electrode site. Peak amplitude significantly improved at C3 electrode site in DBS ON-2/ DRUGS ON as compared to DBS OFF/DRUGS ON. The early slope was not significantly different across the conditions at any electrode site Cz [F(2,11) = 3.576, p = 0.4523], C3[F(2,11) = 0.7443,p = 0.4867], C4[F(2,11) = 0.4368, p = 0.8602], Fz [F(2,11) = 0.5135, p = 0.6054] and Pz [F(2,11) = 0.2682, p = 0.7672]. The late slope significantly differed across the conditions at electrode sites Cz[F(2,11) = 6.383,p = 0.0065], C3[F(2,11) = 4.270, p = 0.0271] and C4[F (2,11) = 4.263,p = 0.0272]; while it was not significantly different at electrode sites Fz[F(2,11) = 0.6533,p = 0.5301] and Pz[F(2,11) = 0.06496,p = 0.9373]. Post hoc Tukey multiple comparison tests showed that late slope was significantly decreased in DBS OFF/DRUGS ON compared to DBS ON/DRUGS ON at Cz (p < 0.001), C3 (p < 0.001) and C4 (p < 0.01) electrode sites. Also late slope remained significantly decreased in DBS ON-2/DRUGS ON compared to DBS ON/DRUGS ON at Cz (p < 0.01) electrode site. There was no
2.2. Effect of switching stimulation ON or OFF on bereitschaftspotentials
2.1. Comparison of bereitschaftspotentials among the groups A negative potential prior to EMG onset was observed in all participants (Fig. 2). Fig. 3 shows comparison of BP parameters among the groups at Cz, C3 and C4 sites. For comparison of BP parameters at other sites (Fz & Pz) see Supplementary Fig. 5. The peak amplitude significantly differed across the groups at electrode sites Cz [F(4,55) = 13.47,p < 0.0001], C3[F(4,55) = 11.60,p = 0.0018] and C4[F (4,55) = 7.393,p = 0.0061]; while it was not significantly different at electrode sites Fz[F(4,55) = 0.7739,p = 0.5469] and Pz[F(4,55) = 0.3806,p = 0.8215]. Post hoc Tukey multiple comparison tests showed that peak amplitude was significantly less in Med group compared to controls at Cz(p < 0.001), C3(p < 0.01) and C4(p < 0.01) electrode sites. Peak amplitude was also significantly less in Med group compared to DBS-STN group at Cz (p < 0.01) electrode sites. There was no significant difference in peak amplitude between DBS ON/ DRUGS ON and controls. Peak amplitude was significantly reduced in DBS OFF/DRUGS ON as compared to control group at Cz(p < 0.001), C3(p < 0.001) and C4(p < 0.001) electrode sites. It remained significantly reduced on re-switching on (DBS ON-2/DRUGS ON) as compared to control group at Cz(p < 0.001), C3(p < 0.01) and C4(p < 0.05) electrode sites. The early slope was not significantly different when compared among the groups at any electrode site Cz[F (4,55) = 3.530,p = 0.1246], C3[F(4,55) = 1.549,p = 0.2010], C4[F (4,55) = 2.230,p = 0.0776], Fz [F(4,55) = 0.2612, p = 0.9015] and Pz[F(4,55) = 0.5249, p = 0.7178]. ANOVA showed that late slope of BP significantly differed across the groups at electrode sites Cz[F(4,55) 32
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Fig. 2. Mean BP waveforms at various scalp electrode sites among the different groups. The dotted vertical line marks the start of EMG signal. The inset on top left side shows the scalp electrode sites according to 10–20 International System for electrode placement. Note the sensitivity is different for BP and EMG signal.
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Fig. 3. Comparison of BP parameters across Cz, C3 and C4 scalp electrode sites among the different groups. Values expressed as follows: (3a). Peak amplitude (μV, mean ± SD), (3b). Early slope (μV/s, mean ± SD) and (3c). Late slope (μV/s, mean ± SD); *p < 0.05; **p < 0.01; ***p < 0.001. *: represents comparison with control group. #: repeated ANOVA comparison with DBS ON/DRUGS ON. ○: repeated ANOVA comparison with DBS OFF/DRUGS ON. Fig. 4. Correlation between BP amplitude and UPDRS III motor scores among various groups. 4(a-d), shows correlation between peak amplitude at Cz electrode site and UPDRS III motor scores among all the groups. Peak amplitude (μV); *p < 0.05; **p < 0.01; ***p < 0.001.
significant difference in late slope between DBS OFF/DRUGS ON and DBS ON-2/DRUGS ON.
8.83 ± 4.73 years p = 0.7223). There was no significant difference in severity of the disease (UPDRS-III) between Med group (37.08 ± 4.58) as compared with DBS OFF/DRUGS ON of DBS-STN group (39.83 ± 2.92). UPDRS-III motor scores were significantly different in the three conditions [F(2,11) = 115.0, p < 0.0001]. UPDRS-III motor scores were significantly worse in DBS OFF/DRUGS ON (39.83 ± 2.92, p < 0.001) as compared to DBS ON/DRUGS ON
2.3. Clinical evaluation and correlation There was no significant different in duration of disease between the two patient groups (DBS-STN: 9.42 ± 3.03 years; Med: 34
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3.2. Switching stimulation off reverses the improvement in late component of BP
(27.67 ± 2.61) and improved on re switching on i.e. DBS ON-2/ DRUGS ON (27.75 ± 2.30, p < 0.001). BP was seen maximum at Cz electrode site in all the participants. So in order to explore nature of BP in the disease, we compared BP parameters at Cz electrode site with clinical motor scores (Fig. 4). A significant negative correlation was observed between the BP parameter (peak amplitude) and UPDRS III motor scores in Med group, DBS ON/DRUGS ON and DBS OFF/DRUGS ON, but not for DBS ON-2/DRUGS ON. No significant correlation was seen between other BP parameters (early slope or late slope) and UPDRS III motor scores in patient groups.
To further understand the temporal effects of DBS-STN on motor planning we looked upon for the effect of switching OFF and the reswitching ON of DBS-STN on BP. We found that amplitude and late slope were reduced by switching stimulation OFF (DBS OFF/DRUGS ON); while there was no change in early component among the conditions. Brown et al. found that switching DBS-STN OFF did not significantly affect the amplitude of BP [18]. On the other hand, in the same year, it was observed that amplitude of contingent negative variation (CNV) was decreased after switching DBS-STN OFF as compared to DBS-STN ON [36]. CNV are also negative cortical potentials that develop between a warning stimulus (S1) and an imperative stimulus (S2); they reflect the preparatory activity of the cortex to the response [37,38]. The late part of CNV is considered to be related with BP [39]. CNV amplitude is impaired in PD and this reflects that the preparation to a response is affected in the disease [36,39]; as it is with decreased BP amplitude reflecting impaired preparation of movement in PD [10,39]. The decreased CNV amplitude observed by switching DBS OFF [36]; suggests that DBS-STN improves the cortical functioning of the frontal cortex. Our results show that the BP amplitude is decreased by switching stimulation OFF; this supports that DBS-STN was improving the activity of motor related cortices. Patients in medication OFF state were unable to perform our task due to tremors hence; we could not include combined stimulation OFF and medication OFF condition in our study. Therefore, all recordings in our study were in medication ON state. Levodopa has been observed to increase early component of BP [39,40]; this probably explains the no effect observed on early BP in DBS OFF/DRUGS ON and DBS ON-2/DRUGS ON. However, medication OFF state in the disease is more pathological state as it would be characterized by dopaminergic reduction. Imaging study shows that there is increased synchronous activity between STN and sensorimotor cortex in PD in medication OFF state [41]. Hence, studying BP in such medication OFF state would give better insight on effect of sole DBSSTN ON or OFF conditions. The firing pattern of neurons in basal ganglia, which is abnormally synchronized in PD [42], is changed to random pattern after stimulation [43]; DBS-STN drives the basal ganglia output neurons in such a way that results in decreased inhibition of thalamus [44]. Moreover, as mentioned before DBS-STN stimulates the cortex [45]. Imaging studies also show activation of supplementary motor cortex during movement and a reduction of hyperactivity in primary motor cortex after DBS-STN stimulation [26]. When stimulation is switched OFF all these effects are absent; this probably explains the decrease in the BP amplitude and late slope in DBS OFF/DRUGS ON. However, future studies can include DBS OFF/ ON states with medication ON/OFF states i.e. four possible conditions to explore the effects of these combinations of treatment modalities on BP responses.
3. Discussion 3.1. Bilateral deep brain stimulation of subthalamic nucleus along with medications improves premovement cortical activity in parkinson’s disease In this study, we explored the effect of treatment modality on motor planning using BP as a tool to assess cortical activity before the actual movement (premovement cortical activity). The degeneration of dopaminergic neurons in PD results in defective motor planning and movement; observed as a reduction in the amplitude and slope of BP compared to controls [10,14,21,22]. In our study, we found BP parameters in DBS ON/DRUGS ON not significantly different from those seen in the control group. This suggests that the stimulation of the subthalamic nucleus along with medications is improving the impaired BP in PD. As both the components of BP were comparable to controls in DBS ON/DRUGS ON state, it points towards the ability of additional stimulation therapy to rectify the temporal sequence of cortical activation back to near normal in PD. This result is supported by previous imaging studies in DBS-STN treated patients. DBS-STN increases activation of the supplementary motor area [23,24] which is the principal source for generation of BP. High frequency stimulation of STN also reduces blood flow to the motor areas during rest while allowing selective activation during movement [25,26]. Neurophysiological studies in DBS-STN treated patients show that the activation of cortex during movement is via stimulation of pallido-thalamic fibres in the STN [27]. Rodent studies also suggest direct activation of afferent fibres projecting from cortex to STN [28]. The mechanism by which DBS-STN is ameliorating the pathological oscillations in basal ganglia might be due to both orthodromic as well as antidromic stimulation of cortical connections with STN [29]. DBS-STN results in stimulation of efferents from STN to globus pallidus pars interna and globus pallidus pars externa; which changes the neuronal firing patterns in these nuclei and this may be one of the mechanisms behind therapeutic benefits of stimulation in PD [30]. Both neurophysiological and imaging studies suggest that the BP with sources in the supplementary motor area and primary motor cortex will also be affected by DBS-STN. Provided the symptomatic improvement offered by DBS-STN; changes in these cortical areas must be leading to better planning reflected in BP parameters. As DBS-STN is known to reduce overactivity of motor areas at rest and improving connectivity between thalamus and motor cortices [26,31], and thereby allowing selective activation during movement, this may be the reason for better motor related potentials. In this study, we found improvement in the cortical activity prior to wrist extension movement following DBS-STN stimulation. However, this may not be applied for legs and trunk movement since gait and postural instability are not greatly improved by DBS-STN and are DOPA-resistant motor symptoms [32]. In this regard it is noteworthy that DBS of the pedunculopontine nucleus (PPN), a pontomesencephalic nucleus rich in cholinergic neurons [33], helps in improving gait freezing [34] and facilitates in gait initiation in PD [35], thus suggesting a role of these neurons in posture and gait disturbances in PD. Thus, future studies should be done to explore the effects on DBS-PPN on BP prior to gait/ lower limb movements.
3.3. Acute and chronic stimulation have different effects on BP On the contrary, though UPDRS III motor scores were improved, yet peak amplitude and late slope were observed to be reduced even after re-switching ON (DBS ON-2/DRUGS ON) at Cz electrode site. However, peak amplitude and late slope did improve at other sites. Significant improvement was seen in peak amplitude at C3 site in DBS ON-2/ DRUGS ON as compared to DBS OFF/DRUGS ON, Further, we analysed correlation between BP amplitude and clinical status in the patients. We found a negative correlation between the BP amplitude (Cz) and UPDRS III motor scores in both the Med group as well as DBS ON/DRUGS ON state. While no correlation was found between the BP amplitude (Cz) and the duration of disease. Similar results were found by Simpson et al; where amplitude of BP recorded at Cz (vertex) electrode site correlated with the disease severity (Webster scales) but not with the duration of disease [11]. Another study shows correlation between the motor 35
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improvement and the increased regional blood flow to pre-SMA in DBSSTN treated patients supporting our findings [46]. The correlation between BP amplitude and UPDRS III motor score was also seen after switching OFF, but not after re-switching ON. Such discrepancy points toward the inability of DBS ON-2/DRUGS ON state to sufficiently improve the motor planning and suggests that re-switching stimulation ON requires time to improve the BP at the vertex. The improvement of BP amplitude at C3 (contralateral cortex) probably point towards the role of orthodromic or/and antidromic stimulation of motor cortex as suggested in earlier studies; yet re-switching ON was not able to fully reverse the functionality of all the motor associated cortices as reflected by reduced BP at the vertex. This points towards the differences of acute and chronic stimulation on BP in PD. Although, DBS-STN reduces beta band oscillations immediately post stimulation, chronic stimulation results in much more reduction [47]. By switching the stimulation OFF the abnormal basal ganglia circuitry restarts, while on re-switching stimulation ON it would require further time for stimulation to reset this abnormal circuitry probably involving some time-consuming mechanisms. Though neurochemistry studies of basal ganglia in animal models after DBS-STN have shown varied results [48]. High frequency stimulation of STN in a rat model does lead to increase in extracellular glutamate in substantia nigra and globus pallidum and it also leads to increase in GABA in substantia nigra [48,49]. Yet, the exact neurotransmitter mechanism responsible for decreased BP in DBS ON-2/ DRUGS ON state needs to be explored. To compare the effect of DBSSTN ON and OFF we fixed the interval of fifteen minutes based on a pilot study; this study design limitation may have been insufficient for DBS ON-2/DRUGS ON i.e. re-switching stimulation ON to provide beneficial effect on motor planning. However, we do not conclude on the changes seen in BP waveform as permanent, as we have not studied the potentials beyond 15 min. In this study we have recorded BP for right wrist movements and found equivocal responses in BP at bilateral motor hemispheres viz. C3 and C4. The late component of BP arises principally from the contralateral cortex, but studies also show ipsilateral motor cortex contribution in this phase of motor planning [5]. Future studies should also include left wrist/arm movement and calculate lateralized readiness potentials (LRP) [50], which would help in evaluating the asymmetrical components of the BP [4]. Such inclusion will help in understanding effects of DBS-STN on unilateral vs. bilateral motor hemispheres. Bilateral deep brain stimulation of subthalamic nucleus along with medications improves premovement cortical activity in Parkinson’s disease. The improved BP after stimulation is probably due to both antidromic and orthodromic stimulation of the cortex as well as by changing the abnormal firing pattern within the basal-ganglia circuitry. Acute effect of switching DBS-STN OFF was observed as reduction in later part of motor planning as reflected by decreased BP amplitude and late slope. On the other hand, re-switching DBS-STN ON did not return BP to normal even after 15 min implying that apart from stimulation of motor cortical areas, DBS-STN acts via basal ganglia circuitry probably involving time consuming mechanisms. These findings must be considered in future research queries by the scientific world to study the structural and neurotransmitter changes after DBS-STN. It is worthwhile to note for the physicians that, the chronic effects and acute effects of switching DBS-STN ON or OFF do have different time lags for beneficial improvement in motor planning. These findings might also be helpful while devising newer DBS strategies in PD, like the closed loop stimulation [51] or brain computer interface controlled [52], which are aimed at providing personalized stimulation.
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Acknowledgements No other financial disclosures or potential conflicts of interest related to this article are reported.
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