Differentiated effects of deep brain stimulation and medication on somatosensory processing in Parkinson’s disease

Accepted Manuscript Differentiated effects of deep brain stimulation and medication on somatosensory processing in Parkinson’s disease Kousik Sarathy Sridharan, Andreas Højlund, Erik Lisbjerg Johnsen, Niels Aagaard Sunde, Lars Gottfried Johansen, Sándor Beniczky, Karen Østergaard PII: DOI: Reference:

S1388-2457(17)30160-8 http://dx.doi.org/10.1016/j.clinph.2017.04.014 CLINPH 2008128

To appear in:

Clinical Neurophysiology

Accepted Date:

19 April 2017

Please cite this article as: Sarathy Sridharan, K., Højlund, A., Lisbjerg Johnsen, E., Aagaard Sunde, N., Gottfried Johansen, L., Beniczky, S., Østergaard, K., Differentiated effects of deep brain stimulation and medication on somatosensory processing in Parkinson’s disease, Clinical Neurophysiology (2017), doi: http://dx.doi.org/10.1016/ j.clinph.2017.04.014

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Differentiated effects of deep brain stimulation and medication on somatosensory processing in Parkinson’s disease Kousik Sarathy Sridharana,b,#, Andreas Højlunda,b, Erik Lisbjerg Johnsena, Niels Aagaard Sundec, Lars Gottfried Johansend, Sándor Beniczkye,f, Karen Østergaarda,b

a

DEPARTMENT OF NEUROLOGY, AARHUS UNIVERSITY HOSPITAL, NØRREBROGADE 44, 8000 AARHUS, DENMARK

b

CENTER OF FUNCTIONALLY INTEGRATIVE NEUROSCIENCE (CFIN), AARHUS UNIVERSITY, NØRREBROGADE 44, 8000 AARHUS, DENMARK

c

DEPARTMENT OF NEUROSURGERY, AARHUS UNIVERSITY HOSPITAL, NØRREBROGADE 44, 8000 AARHUS, DENMARK

d

SCHOOL OF ENGINEERING, AARHUS UNIVERSITY, INGE LEHMANNS GADE 10, 8000 AARHUS, DENMARK

e

DEPARTMENT OF CLINICAL NEUROPHYSIOLOGY, AARHUS UNIVERSITY HOSPITAL, NØRREBROGADE 44, 8000 AARHUS, DENMARK

f

DEPARTMENT OF CLINICAL NEUROPHYSIOLOGY, DANISH EPILEPSY CENTER, KOLONIVEJ 1, 4293 DIANALUND, DENMARK

#

CORRESPONDING AUTHOR:

Kousik Sarathy Sridharan E-mail: [email protected]

Abstract Objectives: Deep brain stimulation (DBS) and dopaminergic medication effectively alleviate the motor symptoms in Parkinson’s disease (PD) patients, but their effects on the sensory symptoms of PD are still not well understood. To explore early somatosensory processing in PD, we recorded magnetoencephalography (MEG) from thirteen DBS-treated PD patients and ten healthy controls during median nerve stimulation. Methods: PD patients were measured during DBS-treated, untreated and dopaminergic-medicated states. We focused on early cortical somatosensory processing as indexed by N20m, induced gamma augmentation (31-45 Hz and 55-100 Hz) and induced beta suppression (13-30 Hz). PD patients’ motor symptoms were assessed by UPDRS-III. Results: Using Bayesian statistics, we found positive evidence for differentiated effects of treatments on the induced gamma augmentation (31-45 Hz) with highest gamma in the dopaminergic-medicated state and lowest in the DBS-treated and untreated states. In contrast, UPDRSIII scores showed beneficial effects of both DBS and dopaminergic medication on the patients’ motor symptoms. Furthermore, treatments did not affect the amplitude of N20m. Conclusions: Our results suggest differentiated effects of DBS and dopaminergic medication on cortical somatosensory processing in PD patients despite consistent ameliorating effects of both treatments on PD motor symptoms. Significance: The differentiated effect suggests differences in the effect mechanisms of the two treatments.

Highlights •

MEG study in PD patients receiving median nerve stimulation during DBS ON, medication on and no treatment.

•

Differentiated effects of treatments on the induced gamma (31-45 Hz) augmentation.

•

Results suggest differences in the effect mechanisms of DBS and dopaminergic medication.

Keywords: Deep brain stimulation; Parkinson's disease; Somatosensory processing; Median nerve stimulation; Magnetoencephalography; Induced gamma augmentation.

Introduction Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopaminergic neurons in ventral mesencephalon and it is cardinally characterized by motor symptoms (Deuschl et al., 2006; Lang and Lozano, 1998; Limousin et al., 1998; Rodriguez-Oroz et al., 2009; Zgaljardic et al., 2003). Deep brain stimulation (DBS) of the subthalamic nucleus (STN) alleviates the motor symptoms when medication is no longer a viable treatment and leads to an overall improvement in quality of life (Deuschl et al., 2006; Follett et al., 2010; Johnsen et al., 2009, 2010; Just and Østergaard, 2002; Limousin et al., 1998; Okun, 2012; Østergaard et al., 2002; Østergaard and Sunde, 2006; Weaver et al., 2012). Apart from motor symptoms, non-motor symptoms are well documented in PD (Jankovic, 2008; Patel et al., 2014). Within the sensory domain, PD patients show abnormal sensory perception (Ciampi De Andrade et al., 2012; Gierthmühlen et al., 2010; Shin et al., 2005), as well as decreased tactile spatial acuity (Conte et al., 2010, 2013; Lyoo et al., 2012; Sathian et al., 1997) and haptic precision (Aman et al., 2014; Konczak et al., 2012). It is, however, not clear how DBS and dopaminergic medication affect sensory processing in PD patients. Electrophysiological studies using median nerve stimulation to investigate the effects of PD treatments on cortical sensory processing in PD patients have shown mixed results. Focusing on the earliest cortical component, the N20(m), some studies show decreased N20 amplitudes during DBS ON (Conte et al., 2010; Priori et al., 2001) while others do not show any significant effects of DBS (or dopaminergic medication) on the N20(m) (Airaksinen et al., 2011; Pierantozzi et al., 1999). A few studies have investigated the effects of treatments on the subsequent evoked components (Conte et al., 2010; Pierantozzi et al., 1999), but the latencies and amplitudes of these components can also be influenced by differences in paradigm settings and other medications (Huttunen et al., 2003; Huttunen and Lauronen, 2012; Tiihonen et al., 1989; Wikström et al., 1996), and the results are therefore difficult to compare between studies. Furthermore, to date there are no electrophysiological studies of the effects of PD treatments on cortical somatosensory processing as evidenced by oscillatory activity.

This study addresses these unresolved issues by investigating the early cortical somatosensory processing in PD patients and the effect of dissociated application of DBS and dopaminergic medication. To this end, we recorded magnetoencephalography (MEG) from PD patients and healthy controls during median nerve stimulation. The PD patients were measured during DBS ON, DBS OFF, and on dopaminergic medication alone; healthy controls were measured over a similar time scale but without any treatment interventions. Based on the literature, we focused our analyses a priori on the earliest cortical evoked component, the N20m, and the early induced gamma augmentation (31-45 and 55-100 Hz) from 20-60 ms and subsequent beta suppression (13-30 Hz; 80-200ms) as stable and well-defined indices of the earliest cortical somatosensory processing (Fukuda et al., 2010; Hari and Forss, 1999; Huttunen et al., 2006; Ihara et al., 2003). N20(m) signals the arrival of the gated afferent sensory input to somatosensory cortex (Hari and Forss, 1999; Huttunen et al., 2006; Ikeda et al., 2005). Gamma oscillations (>30 Hz) arise in both the primary and secondary somatosensory cortices in direct response to somatosensory stimulus (Fukuda et al., 2008, 2010; Hagiwara et al., 2010; Hirata et al., 2002; Ihara et al., 2003). Both rat models and human studies have shown that early somatosensory gamma oscillations synchronize intra-cortical circuitry (Hagiwara et al., 2010; Jones and Barth, 1997; MacDonald and Barth, 1995), and gamma oscillations have also more generally been hypothesized to subserve cortical computation by modulating synchrony in local and distant neuronal assemblies (Fries, 2009; Jones and Barth, 1997; Tallon-Baudry and Bertrand, 1999). Induced beta suppression following the earliest gamma oscillations are known to reflect a cortical response to afferent stimulation and is localized to the somatosensory cortex (Bauer et al., 2006; Crone et al., 1998b). Hence, the N20m, the subsequent early induced changes in gamma and beta oscillations reflect the earliest somatosensory processing at the cortical level. Based on studies showing altered blood flow and metabolism of the sensory cortical areas during DBS (Boecker et al., 1999; Knight et al., 2015), but no changes in the N20m between DBS ON and DBS OFF (Airaksinen et al., 2011), as well as effects of both treatments on sensory discrimination (Artieda et al., 1992; Conte et al., 2010; Lee et al., 2005; Lyoo et al., 2012), we hypothesized that the early cortical sensory processing (induced gamma augmentation) would show effects of both DBS and dopaminergic medication, whereas the gated afference (N20m) would not be affected by the treatments. To our knowledge, this is the first study to address the potential effects of both DBS and dopaminergic medication on early cortical somatosensory processing in PD patients.

Methods Participants Eighteen PD patients were recruited from the population of STN-DBS treated patients at the Aarhus University Hospital along with ten agematched healthy controls (age: 58±4, 7 male). Based on our exclusion criteria and data quality standards, 13 of the 18 patients were assigned to the final data analysis (age: 60±4, 10 male). The details of the resulting patient cohort are listed in Tab. 1. Informed consent was obtained from each participant. The study was approved by the local ethics committee (The Central Denmark Region Committees on Health Research Ethics). Inclusion criterion for the PD patients was at least six months of bilateral STN-DBS. Exclusion criteria for both groups were concurrent sensory neurological deficits, MMSE (Mini-Mental State Examination) below 25, clinically significant depression as defined by MDI (Major Depression Inventory), as well as the absence of a clear N20m in any of the conditions. Five patients were excluded: in two patients N20m could not be clearly identified in one or more conditions. A third patient could not tolerate the OFF state, and two other patients did not have a Unified Parkinson’s Disease Rating Scale part III (UDPRS-III score) for the last condition (medication ON). *** Insert Tab. 1 around here ***

Experimental paradigm Patients were asked to stop taking anti-parkinsonian dopaminergic medication the evening before the experiment (any dopamine-agonists were last taken on the morning before the experiment, i.e., approximately 24 hours before the experiment). After the neurological examinations (initial UPDRS-III, MDI and MMSE), each patient underwent seven MEG measurements in combination with median nerve stimulation over the course of four to five hours: the first with DBS ON and dopaminergic medication (MED) OFF. DBS was then switched off and five MEG measurements were made approximately every 30 minutes. Finally, anti-parkinsonian medication (200 mg levodopa/50 mg carbidopa) was administered and the last (seventh) MEG measurement was performed 60 minutes later (see Fig. 1). Hence, the seven conditions were MED OFF-DBS ON, MED OFF-DBS OFF 0 min
30 min
60 min
90 min
120 min, and MED ON-DBS OFF. UPDRS-III (motor score) was performed at four time points: before MEG with DBS ON, after MEG in DBS OFF (0 min) and after MEG in DBS OFF (120 min) and before MEG in DBS OFF/MED ON conditions (see Fig. 1 for chronological time). We recorded along the DBS-washout to study its potentially deteriorating effects on the sensory processing, as is seen with the motor symptoms (Temperli et al., 2003). Three therapeutic states were defined: DBS-treated state (MED OFF-DBS ON), untreated state (the last MED OFF-DBS OFF state) and medicated (MED ON-DBS OFF) state. Patients were brought out of the MEG system for UPDRS-III scoring and all participants were given breaks between each one or two MEG measurements. Patients were continuously monitored by a movement disorders specialist throughout the experiment. Each experiment block lasted approximately 15-20 minutes. The healthy control subjects underwent the same paradigm (i.e., seven MEG recordings), but without any treatment interventions.

Median nerve stimulation We stimulated the median nerve at wrist, using electrical stimulation at an inter-stimulus interval of 350 ms with a pulse width of 150 μs for three to five minutes. Current was set at the level of an observable twitch of the thumb without being painful. The current and position of the stimulation electrodes were kept constant across conditions in each participant. *** Insert Fig. 1 around here ***

MEG data acquisition We recorded MEG with a 306-channel Elekta Neuromag TRIUX MEG system in a magnetically shielded room. Recordings were done in supine position with eyes open and cushions were inserted to hold the head and neck still and for comfort. Vertical electro-oculogram (vEOG), electromyogram (EMG, digitorum communis), and electrocardiogram (ECG) were also measured. All signals were sampled at 1 KHz with a passband of 0.03-330 Hz. Due to interference from the DBS with the measurement of the head position indicator coils (HPI), we could not obtain a satisfactory positionfit as long as the stimulator was on. After the first recording we switched off the stimulator while the patient was still situated in the MEG device. We then made a short recording (or proceeded directly with the second condition after a short rest period) and thereby obtained a set of HPI-positions that faithfully reflected the patients’ head’s position within the MEG device during the DBS ON recording.

MEG data analysis Preprocessing and artefact rejection Artefacts arising from DBS and external sources were first suppressed by using spatio-temporal signal space separation (tSSS) as implemented in MaxFilter (Taulu and Simola, 2006) with a time window of 10 seconds, a subspace correlation limit of 0.9 (Medvedovsky et al., 2009), and the default sphere origin (0, 0, 40 mm).

Subsequent preprocessing was performed using MATLAB (2012b, The MathWorks Inc., Natick, MA) and the FieldTrip toolbox (Oostenveld et al., 2011). All data were bandpass-filtered between 1-100 Hz using a twopass, second-order Butterworth filter. A discrete Fourier transform (DFT) filter was used to suppress powerline noise (50 Hz). Data were epoched with a peri-stimulus window of -150 to 200 ms.

Somatosensory evoked fields (SEFs) To calculate the amplitudes of the SEFs and more specifically of N20m, the preprocessed data were trial-averaged, and orthogonal gradiometer pairs were combined by calculating the root-mean-square of the orthogonal gradiometer values. For the subsequent statistical analyses, we defined N20m peak amplitudes as the maximum amplitude within 17 to 27 ms post-stimulus across the gradiometer pairs over left somatosensory cortex.

Time-frequency analysis Event-related induced activity was computed using Morlet wavelets. To this end, the evoked fields (i.e. the trial-averaged ERFs) were subtracted from each trial in order to obtain the non-phase-locked activity (David et al., 2006; Fukuda et al., 2008; Hauck et al., 2007; Pfurtscheller and Lopes, 1999). We computed time-frequency representations (TFRs) on single-trial induced data using Morlet wavelets of 5cycles in width in the frequency range of 2-100 Hz at 2 Hz frequency steps. Baseline correction was applied on the trial-averaged TFRs using the time window of -100 to -20 ms to obtain the percentage increase in power. We selected data from the gradiometer-pair showing maximal N20m amplitude for each participant and condition in order to spatially focus the interpretation of any potential results. From the spatially focused TFRs, we obtained summary values for the induced gamma augmentation by averaging the normalized spectral values over the frequency bands (13-30 Hz; 31-45 Hz and 55-100 Hz) and time windows of interest (80-200 ms and 20-60 ms, respectively).

Statistical analyses In all our statistical tests, we analyzed the two groups (PD and controls) separately. We mainly included the control group in the study in order to control for effects of fatigue and similar time-related issues since the order of the conditions in our advantageous repeated-measures design within the PD group could not be randomized. For UPDRS-III scores, N20m amplitudes and induced gamma augmentation, we used Bayesian inferencing to test for effects of treatment.

Bayesian statistics To account for evidence in favor of both the null and the alternative hypotheses, we used Bayesian statistics to evaluate our data (Dienes, 2014). The framework relies on Bayes’ rule which explains the posterior probability of a given hypothesis in relation to the prior probability of that hypothesis given the observed data. This basic rule is then extended to allow for the comparison of competing hypotheses (or models) by estimating how their posterior probabilities should be updated in light of the observed data. Commonly, Bayes factors (BF) are used to express the extent to which the data changes the prior odds ratio of any given set of hypotheses into a posterior odds ratio. BF is thus a measure of relative likelihoods of the observed data in relation to the hypotheses at test (Jarosz and Wiley, 2014; Kass and Raftery, 1995; Rouder et al., 2009, 2012). We used the BayesFactor package (Morey et al., 2015) in R (R Core Team, 2016) for our Bayesian statistical analyses (Rouder et al., 2009, 2012). We used the default settings for priors provided with the lmbf function of the package, namely r=0.5 for fixed effects, r=1 (‘nuisance’) for random effects and r=0.353 for slopes. In each cohort, we evaluated the effect of Condition by modeling a null hypothesis (H0) with just the random effects (i.e., subject-specific offsets) against an alternative (unconstrained) hypothesis (H1) with Condition as fixed effect (and again subject-specific offsets as random effect). Using the lmbf function, both hypotheses are implicitly evaluated against an intercept-only hypothesis (i.e., even without random effects). And because both are evaluated against the same hypothesis, the likelihood ratio of the data

given the two competing hypotheses of interest can be obtained by directly dividing the BFs of both hypotheses. We also framed specific hypotheses for each measure which are explained in the separate sections below (Morey and Wagenmakers, 2014). Apart from testing the overall effect of Condition (H1) for the UPDRS-III, N20m, the gamma augmentations and the beta suppression, we also framed a more constrained hypothesis (H2) where we equated conditions DBS OFF (0 min) through DBS OFF (120 min) (only DBS OFF (0 min) and DBS OFF (120 min) for UPDRS-III, henceforth not specified explicitly) in order to test the three states more directly against each other. To further elucidate the potential differences between the three states, we estimated fits of the data to specific hypotheses where first (H3) DBS ON and DBS OFF (0 min) through DBS OFF (120 min) were equated, next (H4) DBS OFF (0 min) through DBS OFF (120 min) and MED ON were equated, and (H5) DBS ON and MED ON were equated and DBS OFF (0 min) through DBS OFF (120 min) were equated. This allowed us to test whether only one of the three states differed from the other two. Finally (H6), DBS ON and MED ON were equated and conditions DBS OFF (0 min) through DBS OFF (120 min) were allowed to vary freely. This allowed us to test for any potential washout effects, especially in the UPDRSIII scores.

Results Clinical motor state (UPDRS-III) The means of the thirteen PD patients’ UPDRS-III scores are visualized in Fig. 2a, top (see Supplementary Table S1 for the summary values). To evaluate the effect of Condition (i.e., treatments) on their motor symptoms, we compared the fits of their UPDRS-III scores under the null hypothesis and under the alternative hypothesis. The estimated BF10 (alternative/null) was 1.6E16, suggesting that the data were 1.6E16 times more likely to occur under a model including treatments as a factor than one without. A BF of this magnitude is considered very strong evidence (Kass and Raftery, 1995), thus suggestive of an effect of Condition on the UPDRS-III scores. In evaluation of the more specific hypotheses (specifically, H5 and H6) about the extent of the effects of both DBS and dopaminergic medication, we found the highest estimated BF for the data under the hypothesis (H6) with DBS ON and MED ON equated, but DBS OFF (0 min) and DBS OFF (120 min) varying freely (BF61=11.9, BF65=19,971). This suggests that the observed UPDRS-III scores were 11.9 times more likely to be observed under this hypothesis than under one with all four conditions varying freely (H1), and 19,971 times more likely than under one with the two untreated states equated as well as the treatments equated (H5). This is positive evidence suggesting both treatments affected the UPDRS-III scores similarly, as well as suggesting a difference in scores between DBS OFF (0 min) and DBS OFF (120 min), which is implicit evidence of a washout effect of DBS on the patients’ motor symptoms. *** Insert Fig. 2 around here *** *** Insert Tab. 2 around here ***

Early evoked component (N20m) After the artefact rejection procedure, the PD cohort had an average of 648 (SEM ±16) and the Control cohort an average of 709 (SEM ±3) trials remaining. The differences in the number of trials in each condition and cohort is provided in the Supplementary Table S1. Visual inspection confirmed the stability of the positions of the N20m maxima over contralateral centro-parietal sensors (consistent with the underlying somatosensory cortex) across the seven conditions within each participant. Condition-wise grand-averages of SEFs using the gradiometer-pairs showing N20m maxima are visualized for both the PD and the Control cohorts in Fig. 3 (see Supplementary Table S1 for the summary values). Evaluation of the fits of the PD cohort’s N20m amplitudes under the null (H0), the alternative (H1) and the more constrained (H2) hypotheses suggested that the data were 5.4 times (BF01=1/0.1839) and 3.1 times (BF02=1/0.3243) more likely to occur under the null than the

two

alternative

hypotheses,

respectively.

This

was

also

the

case

for

the

specific

hypotheses

(H3-6) where only one of the three treatment states was allowed to differ from the two others. None of the associated BFs provided sufficient evidence (all BFs<1) in favor of any of the alternative hypotheses (see Tab. 2). The Control cohort’s N20m amplitudes were 10.1 times (BF01=1/0.0986) and 4.5 times (BF01=1/0.2209) more likely to occur under the null compared to the two alternative hypotheses, H1 and H2, respectively. And again, the same pattern was reflected in the fits for the constrained hypotheses (H3-6) with only one Condition set to differ where all of the associated BFs<1 (see Tab. 2). BF-values above 3 are recognized as positive evidence (Kass and Raftery, 1995), and we thus infer from the above that there was no effect of treatments (BF01) and no washout effect of DBS (BF02) on N20m amplitudes in the PD cohort; and furthermore no differences over time in the Control cohort. It is evident from Supplementary Table S1 that there were large interindividual differences in the general level of the N20m amplitudes and their response to treatments (or time) in both groups. *** Insert Fig. 3 around here ***

Early induced gamma augmentations Visual inspection confirmed that each participant’s early increase in gamma augmentation following median nerve stimulation was localized near the contralateral centro-parietal area in sensor space and showed a spatial spread very similar to their N20m components. The group means and the grand averaged topographies of the early induced augmentation in the lower gamma band (31-45 Hz) in all conditions are shown in Fig. 2a and b (see Supplementary Table S1 for the summary values). We evaluated the effect of Condition on the early cortical somatosensory processing by comparing the fits of the observed gamma augmentations under the null (H0) and the alternative (H1) hypotheses. For the PD patients, these fits suggested that the augmentations in the lower gamma band (31-45 Hz) and in the higher gamma band (55-100 Hz) were 1.1 (BF01=1/0.99) times and 15.6 (BF01=1/0.0642) times more likely to have occurred under the null hypothesis than the alternative, respectively. However, evaluation of the more constrained hypothesis (H2) where all the untreated conditions were equated suggested that the lower gamma augmentation was 5.6 times (BF20) more likely to occur under the more constrained alternative hypothesis than the null. Furthermore, the three constrained hypotheses (H3-6) with only one Condition different from the others suggested that the augmentation in the lower gamma band was 16.4 (BF30) times more likely to arise from the hypothesis where only MED ON differed from the other conditions (H3) than from the null (H0), and this was thus the best fit to the data among any of the hypotheses (see Tab. 2).The MED ON condition showed a mean increase in gamma augmentation of 12.9% (SEM=3.3%) compared to the augmentation in the DBS OFF (120 mins) condition (Fig. 2a). The augmentation in the higher gamma band (55-100 Hz), on the other, was still more likely to have occurred under the null than under the more constrained hypothesis (BF02=3.14). And none of the specific hypotheses (H3-6) provided sufficient evidence against the null (see Tab. 2). The data thus showed positive evidence for an effect of dopaminergic medication, but not DBS, on the lower gamma band augmentations (31-45 Hz) following median nerve stimulation. For the Control cohort, the fits suggested that the lower gamma band (31-45 Hz) and the higher gamma band (55-100 Hz) augmentations were 7.3 times (BF01=1/0.1371) and 12.2 times (BF01=1/0.0819) more likely to have occurred under the null (H0) than the alternative (H1) hypothesis, respectively. Evaluation of the more constrained hypothesis (H2) also suggested that the lower gamma augmentations (31-45 Hz) were 4.5 times (BF02=1/0.2216) and the higher gamma augmentations (55-100 Hz) were 6.1 times (BF02=0.1638) more likely to have occurred under the null hypothesis than the more constrained hypothesis. Evaluation of the specific hypotheses (H3-6) revealed no evidence for these alternative hypotheses (BFs<1; see Tab. 2). These BFs thus provide positive evidence (Kass and Raftery, 1995) for the null hypothesis against the corresponding alternative hypotheses, and hence, we infer there was no effect of Condition over time on the gamma augmentations in the Control cohort.

Beta suppression Evaluation of the fits of the PD cohort’s beta suppression under the null (H0), the alternative (H1) and the more constrained hypothesis (H2) suggested that data were 10.1 times (BF01=1/0.0994) and 3.4 times (BF02=1/0.2943) more likely to be observed under the null than the two

corresponding alternative hypotheses. This was also the case with the specific hypothesis (H3-6). The control cohort’s beta suppression were 12.5 times (BF01=1/0.0801) and 4.5 times (BF02=1/0.1753) more likely to occur under the null hypothesis than the corresponding alternative hypotheses. Inspection of the specific hypotheses (H3-6) did not reveal any evidence for those alternative hypotheses either. *** Insert Fig. 4 around here ***

Discussion In this study, we show differentiated effects of medication and DBS on early cortical somatosensory processing in PD patients, as indexed by differences in augmentation in the lower gamma band (31-45 Hz) (Cardin et al., 2009; Ihara et al., 2003; Jones and Barth, 1997). We saw the highest gamma augmentations during MED ON and the lowest during DBS ON and the untreated states (DBS OFF (0 min) through DBS OFF (120 min)). In contrast, the observed UPDRS-III scores during the different conditions showed ameliorating effects to similar extents of both treatments (i.e., DBS ON and MED ON) on the patients’ motor symptoms. Thus, we report differentiated effects of treatments on somatosensory processing, but not on motor behavior. We interpret these effects to reflect differences in the effect-mechanisms of DBS and dopaminergic medication in PD patients. We also show positive evidence for null effects of PD treatments on N20m amplitudes, beta suppression (13-30 Hz) and augmentation in the higher gamma band (55-100 Hz) following median nerve stimulation. Furthermore, we observed clear evoked and induced patterns in all conditions similar to those reported in comparable studies (Fukuda et al., 2008, 2010; Hagiwara et al., 2010). The early induced somatosensory gamma oscillations (>30 Hz) are known to play a role in sensory processing (Cardin et al., 2009; Ihara et al., 2003; Suffczynski et al., 2014) and aid in intra-cortical synchronization (Jones and Barth, 1997; MacDonald and Barth, 1995). Increases in these gamma augmentations might reflect recruitment of additional pyramidal neuronal populations or increased precision in synchronization within these pyramidal neuronal populations (Srinivasan et al., 1999). Hence, gamma band augmentation reflects an aspect of early cortical somatosensory processing. We show effects of treatments in the lower gamma band (31-45 Hz), but not in the higher gamma band (55-100 Hz). Even though the precise difference in physiological underpinnings are not yet known, both bands have been co-localized to the sensory areas and suggested to be involved in sensory processing (Crone et al., 1998a; Ihara et al., 2003; Jones and Barth, 1997; MacDonald and Barth, 1995). In the remainder of this discussion, we will thus refer to the lower gamma band augmentation as gamma augmentation. In relation to plausible mechanisms for the observed effects of treatments, the increased gamma augmentation during dopaminergic medication could be mediated through modulation of the excitability of the ventro-basal complex (VB) (ventral posterior medial and ventral posterior lateral nuclei) of the thalamus, which plays an important role in relaying sensory information to S1 (Felleman and Van Essen, 1991). Dopaminergic innervation of the thalamic sensory relay nuclei has been mapped in both humans and non-human primates (García-Cabezas et al., 2009, 2007; Sanchez-Gonzalez, 2005), and dopamine is known to increase excitability of the VB neurons and their excitatory output in rats (Govindaiah et al., 2010). Hence, we speculate that dopamine could alter excitability of the thalamo-cortical sensory projection in humans. The more detailed mechanism of such a systemic drive on early sensory processing remains to be investigated. The lack of effect of DBS on the induced gamma augmentation, on the other hand, suggests similarity with the untreated state, and hence, DBS’ effect-mechanism does not seem to involve somatosensory projections. Another plausible explanation for the dopaminergic effect could be that dopamine influences sensory processing via the nigro-striatal dopaminergic pathway. It has been shown that somatosensory and motor cortico-striatal afferents synapse with parvalbumin-positive (PV+) GABAergic interneurons in striatum which may transmit this information to spiny projection neurons in synaptic contact with nigro-striatal axons (Flaherty and Graybiel, 1991; Juri et al., 2010; Ramanathan et al., 2002). Hence, we speculate that dopamine may affect the

sensorimotor integration in striatum through the nigro-striatal dopaminergic projections and thus influence cortical somatosensory processing at a systemic level. The more detailed mechanism of such a systemic drive on early sensory processing remains to be investigated. In relation to sensory perception, the sparse literature seems to suggest that impaired behavior on sensory tasks involving discrimination (e.g., grating orientation and somatosensory-temporal discrimination) can be improved by dopaminergic medication (Artieda et al., 1992; Conte et al., 2010; Lyoo et al., 2012; Shin et al., 2005), whereas DBS seems to worsen such sensory symptoms (Conte et al., 2010). This pattern of results could seem partly in line with the differentiated effects of DBS and dopaminergic medication on the induced gamma augmentation in the present study. Our experimental paradigm did not allow for a behavioral measure of sensory perception. Further studies combining neuromagnetic and behavioral measures are needed to help discern whether such an elevated level of gamma augmentation during dopaminergic medication is beneficial or detrimental to the patients’ sensory perception. Finally regarding SEFs, the results from previous electrophysiological studies on treatment effects on N20m are mixed (Airaksinen et al., 2011; Conte et al., 2010; Pierantozzi et al., 1999; Priori et al., 2001), which may be due to both differences in referencing and lack of full dissociation between the treatments investigated. Our results are in line with Airaksinen et al.’s (2011) findings with no significant difference between DBS ON and DBS OFF on the N20m (despite the authors reporting subtle non-significant numerical differences between the two conditions). In Airaksinen et al. (2011), the PD patients were on dopaminergic medication during both DBS ON and OFF conditions. We hereby expand their original findings and show positive evidence for no effects of PD treatments (DBS and dopaminergic medication) on N20m amplitudes with full dissociation between the treatments and using MEG which cannot be influenced by different practices in electrode referencing (as can be the case with EEG). However, the present study also has a few limitations. We acknowledge the relatively small sample sizes (13 PD patients and 10 Controls) and that the observed effects arise from relatively focal analyses of induced oscillatory activity. Furthermore, when analyzing induced activity, possible leakage of evoked activity into the computed induced activity due to trial-to-trial jitter in the latency of the evoked activity, in particular, is a potential confound (David et al., 2006; Truccolo et al., 2002). Hence, if our observed effect of dopaminergic medication on induced gamma augmentation were to be confounded by changes in the temporal precision of the evoked activity, we would expect this to be evident in correlations between the evoked components and the induced gamma augmentation or between the changes in these measures between conditions. We therefore calculated Spearman’s rank correlations between the induced low-gamma augmentations and the evoked components (N20m, N30m and P60m) in the MED ON condition and for the differences in those measures between the DBS OFF (120 min) and MED ON conditions. None of these revealed any significant correlations (see Supplementary Figure S1 for more details). Finally, the moderate evidence of an effect of treatment in the current study calls for further studies investigating cortical sensory processing in PD using induced oscillatory activity to confirm the reproducibility of the reported effects. And future studies should take care in combining behavioral and neuromagnetic recordings of sensory perception to better inform the interpretation of effects of treatments on cortical processing. In conclusion, we have shown differentiated effects of DBS and dopaminergic medication on early cortical somatosensory processing in PD patients as evidenced by increased gamma augmentation during dopaminergic medication, but not DBS, following median nerve stimulation. This study thus lends support to the notion of different mechanistic effects of DBS and medication possibly driven by distinct anatomofunctional pathways.

Figure captions Fig. 1. Experimental paradigm: Each vertical bar reflects a MEG measurement. Median nerve stimulation was administered at each MEG measurement. Medication was withdrawn overnight before the experiment. UPDRS-III (Unified Parkinson’s Disease Rating Scale – motor score)

was performed at four time points. As shown with different background colors, we defined three therapeutic states: DBS-treated, untreated, and medicated. Cohort sizes: 13 PD patients and 10 healthy controls (with no interventions). See Methods section for more details. Fig. 2. Early somatosensory processing and motor symptoms: (a) Changes in early induced gamma (31-45 Hz, 20-60 ms after stimulus onset) augmentation following median nerve stimulation. Blue and grey lines show summary values for PD patients and controls, respectively. Group averages of the PD patients’ UPDRS-III scores for each assessment are shown as a broken blue line. The UPDRS-III scores show the progression of the motor symptoms in PD patients as an effect of treatment. Errorbars reflect ±SEM. Low-gamma augmentation in MED ON condition is marked with *. (b) Topographic plots of the early induced gamma augmentation in the group-averaged data from PD and controls. The early induced gamma power is localized across all conditions and both groups to the sensors over the contralateral sensorimotor area. Fig. 3. Somatosensory evoked fields (SEFs): Condition-wise group-averages of the SEFs in Controls (a) and PD patients (b). Group-averages were computed from the gradiometer-pair in each participant showing maximal N20m amplitude. Inset topographic plots are the grand-grand averages of the SEFs of each cohort. See Results section for more details. Fig. 4. Grand-averaged induced TFRs: Condition-wise group-averages of the induced TFRs in PD patients (top row) and Controls (bottom row). X-axis shows the time dimension while Y-axis shows the frequency dimension. Frequency bands of primary interest were high gamma (55-100 Hz; 20-60 ms), low gamma (31-45 Hz; 20-60 ms) and beta (13-30 Hz; 80-200 ms). Group-averages were computed from the gradiometer-pair in each participant showing maximal N20m amplitude.

Table Captions Tab. 1. Details of the PD and Control cohort: DBS: deep brain stimulation; MED: Levodopa medication; UPDRS-III: Unified Parkinson’s Disease Rating Scale, motor score. SR: slow release. LEDD: Levodopa equivalent daily dose. LEDD formula: 100 mg Levodopa = 130 mg controlledrelease Levodopa = 70 mg Levodopa + COMT-inhibitor = 1 mg Pramipexole = 5 mg Ropinirole (Mamikonyan et al., 2008). #UPDRS scoring was performed after the measurement block (~20 mins after the start of the block). For details on the Controls, see Participants section. Tab. 2. Bayes factors: Bayes factors for the fits of the data to the corresponding alternative hypotheses against the null. See Results section for further details. Bayes factors suggesting evidence for (> 3) or against (< 0.33) the null are highlighted in bold. ‘1’ denotes the DBS ON condition. ‘2:6’ denotes the five conditions from DBS OFF (0 min) through DBS OFF (120 min) equated (for UPDRS-III, only conditions DBS OFF (0 min) and DBS OFF (120 min)). ‘2||6’ denotes the five conditions from DBS OFF (0 min) through DBS OFF (120 min) varying freely. ‘7’ denotes the MED ON condition. From Kass and Raftery (1995): BF = 1 to 3 is evidence “barely worth a mention”; BF = 3 to 20 is “positive evidence”; BF = 20 to 150 is “strong evidence”; BF > 150 is “very strong evidence”. Supplementary Table S1. Summary values: Means and SEMs of the differences between each condition and DBS OFF (120 mins) (reference condition) for each measure. The SEMs of the values in the reference condition (i.e., not referring to the differences between conditions) are listed in parentheses after each mean value. The increases in gamma augmentation (31-45 Hz) in the MED ON condition for the PD group is highlighted in bold. Supplementary Figure S1. Correlations between evoked fields (ERFs) and low-gamma augmentations: Top row: scatter plot for the induced low-gamma augmentation and N20m, N30m and P60m in the MED ON condition. The titles list the Spearman’s rank correlation coefficients and p-values. Bottom row: scatter plot for the differences between the MED ON and DBS OFF (120 min) conditions for both induced lowgamma augmentation and the ERFs. Again, coefficients and p-values in the titles. There are no significant correlations (p>0.05) in any of the six

analyses. Any significant correlations could have suggested that the co-occurring evoked activity would have “leaked” into the computation of the induced activity due to trial-to-trial jitter (David et al., 2006; Truccolo et al., 2002). The lack of significant correlations does not support this explanation of the induced low-gamma augmentation in the MED ON condition (but as null results, they also do not conclusively rule out this explanation).

Conflict of Interest KØ: Consultancy for Metdtronic Inc.; Honororia from Medtronic Inc., UCB, Fertin Pharma and AbbVie outside the submitted work. SB: non-financial support from Elekta and EGI; personal fees from UCB Pharma outside the submitted work.

Acknowledgments We extend our special thanks to the PD patients and healthy controls that volunteered to participate in the study. We would also like to thank Jonas Kristoffer Lindeløv, Lau Møller Andersen and Mads Jensen for their helpful input on the statistical analyses. This study is based on work that has been funded by the Danish Research Council for Independent Research, the Danish Parkinson Association, Central Denmark Research Foundation, Aarhus University and Aarhus University Hospital.

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281

1-case+; 2.7V; 60μs; 140 Hz

10-case+; 3.3V; 60μs; 140 Hz

13

26

44

11

PD6

53

F

N

29

15.8

1.8

Pramipexole

0.7

>24

Stalevo

400

470

1-case+; 3.5V; 60μs; 130 Hz

10-case+; 3.5V; 60μs; 130 Hz

13

31

40

7

PD7

61

F

N

29

14.8

1.9

Ropinirole (SR)

10

>24

Madopar

375

575

1-case+; 3.2V; 60μs; 130 Hz

9-case+; 3.3V; 60μs; 130 Hz

12

16

29

14

PD8

55

M

N

27

14.5

2.3

Pramipexole (SR)

0.52

>24

Sinemet

400

452

2-case+; 3.4V; 60μs; 130 Hz

9-case+; 1.6V; 60μs; 130 Hz

12

20

38

9

PD9

59

M

N

30

19.6

1.2

-

-

-

Sinemet

450

450

3-case+; 2.1V; 60μs; 140 Hz

10-case+; 2.1V; 60μs; 140 Hz

13

30

35

19

PD10

66

M

N

29

11.6

1

Pramipexole (SR)

1.05

>24

Sinemet

200

305

1-case+; 2.3V; 60μs; 130 Hz

9-case+; 3.1V; 60μs; 130 Hz

11

21

40

15

PD11

59

M

N

30

10.4

1.3

-

-

-

Sinemet

300

300

1-case+;2.4V; 60μs; 130 Hz

9-case+; 2.7V; 60μs; 130 Hz

5

26

40

16

PD12

59

M

N

27

18.4

2.6

-

-

-

Sinemet

600

600

2-case+;3.5V; 60μs; 130 Hz

10-case+; 3.5V; 60μs; 130 Hz

14

30

38

21

PD13

60

F

N

29

12.1

1.1

Ropinirole (SR)

6

>24

Sinemet

250

400

1-case+;3.5V; 60μs; 130 Hz

9-case+; 3.5V; 60μs; 130 Hz

6

24

35

5

C1

62

F

N

30

C2

54

M

N

30

C3

58

F

N

30

C4

64

M

N

30

C5

51

M

N

29

C6

56

F

N

30

C7

55

M

N

30

C8

59

M

N

30

C9

63

M

N

28

C10

61

M

N

30

Tab 1. Details of the PD and control cohort

PD BFX0 -> alternative/null

Ctrl Specific hypotheses

All conditions (H1/H0)

1 ≠ 2:6 ≠ 7 (H2/H0)

HGamma

0.0642

LGamma

1 ≠ 2:6 ≠ 7 (H2/H0)

1:6 ≠ 7 (H3/H0)

1 ≠ 2:7 (H4/H0)

1=7 ≠ 2:6 (H5/H0)

1=7 ≠ 2||6 (H6/H0)

0.1638

0.3358

0.3177

0.2658

0.1755

0.0819

0.2216

0.4405

0.3633

0.2713

0.0831

0.1202

0.0801

0.1753

0.3189

0.3644

0.2735

0.0982

0.2563

0.0986

0.2209

0.4406

0.3212

0.3327

0.1199

1:6 ≠ 7 (H3/H0)

1 ≠ 2:7 (H4/H0)

1=7 ≠ 2:6 (H5/H0)

1=7 ≠ 2||6 (H6/H0)

0.1927

0.3185

0.4271

0.2587

0.0665

0.1371

1.0055

5.5554

16.4032

0.624

0.4693

0.114

Beta

0.0994

0.2943

0.2905

0.6252

0.4398

N20m

0.1839

0.3243

0.3215

0.6148

0.5518

UPDRS

1.60E+16 1.20E+12

56.1851

254.5299 9.51E+12

Specific hypotheses

All conditions (H1/H0)

1.90E+17