Subthalamic deep brain stimulation improves auditory sensory gating deficit in Parkinson’s disease

Clinical Neurophysiology 126 (2015) 565–574

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Subthalamic deep brain stimulation improves auditory sensory gating deficit in Parkinson’s disease A. Gulberti a,⇑, W. Hamel b, C. Buhmann c, K. Boelmans c,d, S. Zittel c,e, C. Gerloff c, M. Westphal b, A.K. Engel a, T.R. Schneider a,1, C.K.E. Moll a,1 a

Department of Neurophysiology and Pathophysiology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany Department of Neurology, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany d Department of Psychiatry, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany e Department of Paediatric and Adult Movement Disorders and Neuropsychiatry, Institute of Neurogenetics, University of Lübeck, Lübeck, Germany b c

a r t i c l e

i n f o

Article history: Accepted 27 June 2014 Available online 11 July 2014 Keywords: Parkinson’s disease Auditory evoked potentials Sensory gating Subthalamic nucleus Deep brain stimulation

h i g h l i g h t s  Stimulus rate-dependent amplitude suppression of the auditory P1/N1-complex is impaired in

patients with advanced Parkinson’s disease.  Dopaminergic treatment has no effect on these auditory sensory gating characteristics.  Deep brain stimulation of the subthalamic nucleus restores a physiological P1/N1-amplitude attenu-

ation profile and may improve early attentive filtering processes possibly at the level of the frontal cortex.

a b s t r a c t Objective: While motor effects of dopaminergic medication and subthalamic nucleus deep brain stimulation (STN-DBS) in Parkinson’s disease (PD) patients are well explored, their effects on sensory processing are less well understood. Here, we studied the impact of levodopa and STN-DBS on auditory processing. Methods: Rhythmic auditory stimulation (RAS) was presented at frequencies between 1 and 6 Hz in a passive listening paradigm. High-density EEG-recordings were obtained before (levodopa ON/OFF) and 5 months following STN-surgery (ON/OFF STN-DBS). We compared auditory evoked potentials (AEPs) elicited by RAS in 12 PD patients to those in age-matched controls. Tempo-dependent amplitude suppression of the auditory P1/N1-complex was used as an indicator of auditory gating. Results: Parkinsonian patients showed significantly larger AEP-amplitudes (P1, N1) and longer AEP-latencies (N1) compared to controls. Neither interruption of dopaminergic medication nor of STN-DBS had an immediate effect on these AEPs. However, chronic STN-DBS had a significant effect on abnormal auditory gating characteristics of parkinsonian patients and restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. Conclusions: This differential treatment effect suggests a divergent mode of action of levodopa and STNDBS on auditory processing. Significance: STN-DBS may improve early attentive filtering processes of redundant auditory stimuli, possibly at the level of the frontal cortex. Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

1. Introduction ⇑ Corresponding author. Tel.: +49 40 7410 55622; fax: +49 40 7410 57752. 1

E-mail address: [email protected] (A. Gulberti). Co-senior authors.

Alterations in sensory information processing and related perceptual impairments are commonly encountered in patients with basal ganglia disorders (Boecker et al., 1999; Kaji, 2001; Patel

http://dx.doi.org/10.1016/j.clinph.2014.06.046 1388-2457/Ó 2014 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

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et al., 2014). As an example, dysfunction of proprioception/kinaesthesia and abnormalities of pain processing are clinically relevant impairments of somatosensation in patients with Parkinson’s disease (PD) that probably contribute to motor disturbances and result in sensory complaints in these patients, respectively (Schneider et al., 1986; Chudler and Dong, 1995; Konczak et al., 2009; Conte et al., 2013). Although not clinically obvious, a number of studies have also provided evidence for impairments in the representation and utilization of the ‘remote’ (visual and auditory) senses in PD. In the auditory domain, several electrophysiological measurements in PD patients have revealed a number of abnormalities of earlier (Pekkonen et al., 1998) and later (Ebmeier et al., 1992) auditory evoked potentials (AEPs), indicating central auditory processing deficits. On the other hand, auditory inputs can effectively be utilized by PD patients to overcome motor control deficits (Martin, 1967). Therefore, the study of sensory gating may be of particular interest in parkinsonian patients. Rhythmic auditory stimulation (RAS) is a good example for a functionally relevant sensory gating mechanism which has a facilitatory influence upon initiation and control of locomotion and which has been successfully applied to PD patients with gait disturbances (McIntosh et al., 1997). Sensory gating describes the automatic process of responsesuppression to redundant and irrelevant sensory information and can be considered a multi-component process operating at multiple temporal scales, involving a large-scale network between brainstem and cortex (Erwin and Buchwald, 1986; Cromwell et al., 2008). The basal ganglia are strategically positioned gateway hubs in-between cortical and lower-level brain networks (Reiner et al., 1998; McHaffie et al., 2005), that receive information from multiple sensory modalities (Juri et al., 2011) and that have traditionally been attributed a role in the gating of motor actions (Graybiel et al., 1994; Mink, 1996; Kaji, 2001). Moreover—through selective gating of sensory input into several different systems— the basal ganglia are also thought to affect other brain functions and behavioral activities, such as attention, perception and cognition (Brown et al., 1997; Kimura et al., 2004; Hazy et al., 2007; van Schouwenburg et al., 2010). However, the precise role of the basal ganglia in sensory gating remains elusive, partly due to their closed loop connectivity with downstream brain structures (Alexander et al., 1986; McHaffie et al., 2005) and their remote position from peripheral sensory transduction. Response decrement of AEPs to stimulus repetition is considered an index marker of sensory gating in the auditory domain and thought to reflect basic neurophysiologic processes such as habituation or refractoriness (Budd et al., 1998). Investigations of auditory sensory gating have mostly focused on early processing components such as the P1 (or P50, latency 40–70 ms), which is the earliest AEP component in the long-latency time domain showing response suppression upon repeated exposure to auditory stimuli (Picton et al., 1974). Another major early AEP exhibiting systematic amplitude reduction in repetition suppression paradigms is the auditory N1 component (latency around 100 ms). Patients with disorders of the basal ganglia such as Huntington’s disease (Uc et al., 2003) or focal dystonia (Lim et al., 2005) exhibit abnormalities of these early AEPs. PD patients show a markedly decreased P1-habituation in response to rapidly succeeding auditory stimuli (Teo et al., 1997), suggesting an influence of dopamine denervated basal ganglia circuitries on early auditory processing. However, while some aspects of later occurring AEPs (N1/P2) may be influenced by dopamine levels (Lukhanina et al., 2009), the influence of dopaminergic medication on preattentive auditory gating in PD patients is less clear. While there have been reports of a normalizing effect of ablative pallidal surgery in PD on characteristics and habituation properties of AEPs (Mohamed et al., 1996;

Teo et al., 1998), hitherto there are no studies which have examined the effects of deep brain stimulation of the subthalamic nucleus (STN-DBS) on auditory sensory gating. Therefore, the present study was designed to investigate the effect of levodopa treatment and STN-DBS on auditory sensory gating in PD patients. We employed a steady-state stimulation paradigm (Regan, 1982; Erwin and Buchwald, 1986) to study the rate-dependent amplitude attenuation profile of AEPs at stimulation frequencies between 1 and 6 Hz. Clicks were presented in a constant sequence, corresponding to RAS, which is a functionally relevant sensory gating mechanism in PD patients (McIntosh et al., 1997). Each patient was tested in two conditions before (levodopa OFF and ON) and two conditions 5 months after bilateral STN-DBS surgery (ON and OFF STN-DBS, without dopaminergic medication). 2. Material and methods 2.1. Patients and control subjects We studied twelve non-demented patients suffering from advanced idiopathic PD (7 female, 5 male, mean age: 61 ± 6 years, mean school years: 13 ± 5, Hoehn & Yahr disease stage: 3 ± 1 (Hoehn and Yahr, 1967), mean disease duration: 13 ± 4 years) and twelve healthy control subjects matched in sex, age and education (8 female, 4 male, mean age: 65 ± 8 years, mean school years: 15 ± 3). All statistical values are given as mean ± SD, unless noted otherwise. All participants gave written informed consent to participate in this study, which was conducted in agreement with the Code of Ethics of the World Medical Association (Declaration of Helsinki, 1967), and was approved by the local ethics committee. All participants reported normal hearing. Patients underwent bilateral microelectrode-guided implantation of DBS electrodes in the STN. For all patients, DBS electrodes (model 3389, Medtronic, Minneapolis, MN, USA) and stimulators (Kinetra model 7428 in 7 patients and Activa PC model 37601 in 5 patients, Medtronic, Minneapolis, MN, USA) were implanted at the Department of Neurosurgery at the University Medical Center Hamburg-Eppendorf, Germany. Details concerning the surgical procedure are reported elsewhere (Hamel et al., 2003). Before surgery, all patients showed a significant improvement of the motor-subscore (III) of the Unified Parkinson’s Disease Rating Scale (UPDRS, (Fahn et al., 1987) following intake of levodopa. Mean symptom improvement was 44% (mean UPDRS-III in DOPA-OFF: 32 ± 12 vs. DOPA-ON: 18 ± 9; [t(11) = 5.54; p = 0.0002], paired t-test). The daily levodopaequivalent dose before DBS surgery was 1132 ± 420 mg (Tomlinson et al., 2010). At the time of post-operative recordings, it was reduced to 663 ± 354 mg ([t(22) = 2.96; p = 0.0073], paired t-test). Furthermore, all patients were classified as non-demented, based on their performance on the Mattis Dementia Rating Scale (Mattis, 1988) mean score: 143 ± 0.5) and the Mini-Mental Status Exam (Folstein et al., 1975); mean score: 29 ± 1). Finally, all patients fulfilled other inclusion criteria for STN-DBS, such as no structural alterations on magnetic resonance imaging (MRI) and no concomitant severe medical comorbidities. Table 1 provides further clinical details of the patient group. 2.2. Experimental protocol PD patients were tested before and following DBS surgery. Preand post-operative sessions took place 6 ± 5 days before and 5 ± 2 months after the stereotactic intervention, respectively. Preoperative sessions in either (1) DOPA-ON or (2) DOPA-OFF were carried out on two subsequent days in a randomized manner. For the DOPA-OFF condition, recordings were conducted following

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Table 1 Clinical characteristics. In column ‘‘DBS parameters’’ values reported are: stimulation frequency in Hz, active contacts, impulse amplitude in volts and impulse with in microseconds for the left and right electrode, respectively. For the left electrode, contact 0 was the most caudal and contact 3 was the most rostral. For the right electrode, contact 4 (or 8 in case of Activa PC stimulator) was the most caudal and contact 7 (or 11 in case of Activa PC stimulator) was the most rostral. Abbreviations: H&Y = Hoehn & Yahr scale. Op = operation for DBS electrodes implantation. UPDRS-III = Unified Parkinson’s Disease Rating Scale, motor-subscore (part III). LD = L-DOPA. Gender & age

Disease duration (years)

H&Y

M 66

11

4

M 60

12

2

F 57

12

2.5

F 54

20

3

F 66

14

3

F 69

12

3

M 68

6

2

M 56

20

3

F 68

13

4

M 57

15

3

F 59

11

3

F 53

11

2

DBS parameters

130 Hz, 130 Hz, 240 Hz, 240 Hz, 130 Hz, 130 Hz, 130 Hz, 130 Hz, 130 Hz, 130 Hz, 200 Hz, 200 Hz, 210 Hz, 210 Hz, 130 Hz, 130 Hz, 130 Hz, 130 Hz, 130 Hz, 130 Hz, 200 Hz, 200 Hz, 130 Hz, 130 Hz,

1-, 4.0 V, 60 ls 5-, 2.8 V, 60 ls 1+, 2-, 3-, 4.9 V, 120 ls 5+, 6-, 7-, 4.4 V, 120 ls 1-, 2-, 2.2 V, 60 ls 5-, 6-, 2.2 V, 60 ls 1-, 2-, 3.0 V, 60 ls 5-, 6-, 2.6 V, 60 ls 1-, 2-, 3.9 V, 60 ls 6-, 7-, 3.6 V, 90 ls 1-, 2-, 3.2 V, 60ls 5-, 6-, 3.0 V, 60 ls 1-, 2-, 3.2 V, 60 ls 5-, 6-, 3.2 V, 60 ls 1-, 3.2 V, 60 ls 9-, 3.5 V, 60 ls 2-, 1.9 V, 60ls 10-, 1.9 V, 60 ls 1-, 2-, 3.0 V, 60 ls 9-, 10-, 3.0 V, 60 ls 2-, 2.0 V, 60 ls 10-, 2.5 V, 60 ls 1-, 2-, 2.3 V, 60 ls 9-, 10-, 2.5 V, 60 ls

overnight withdrawal of anti-parkinsonian medication (the practically defined OFF-state). Similarly, post-operative investigations were also carried out without dopaminergic medication on two different days. The two post-operative recording conditions were: (3) during bilateral STN stimulation with clinically effective stimulation parameters that were also used for permanent stimulation (ON-DBS) and (4) with the stimulator switched off (OFF-DBS). Recordings in the OFF-DBS condition were started at least 25 min after switching off the stimulator. In line with previous reports (Temperli et al., 2003), this period was long enough to elicit a significant aggravation of motor symptoms in our patients (UPDRS-III in DOPA-OFF: ON-DBS (20 ± 8) vs. OFF-DBS (40 ± 10; [t(9) = 7.89; p < 0.0001], paired t-test). 2.3. Experimental setup and stimuli Participants were comfortably seated in a darkened, soundattenuated chamber. Participants were asked to attend passively to the presented stimuli while fixating a white cross on a computer screen. Rhythmic metronome-like clicks were delivered at 11 different stimulation rates (from 1 Hz to 6 Hz, in steps of 0.5 Hz). For each rate, stimulus trains were presented in blocks of 75 clicks. The order of the blocks was pseudo-randomized across sessions and participants. Blocks were separated by a silent pause of 6 s. Single clicks (13 ms duration, mono) were presented at 70 dB (SPL) with two loudspeakers positioned at a distance of 150 cm in front of the participant (Bose companion 2, series II, Framingham MA, USA). The participants’ vigilance was continuously monitored throughout the recording by means of EEG and electrooculogram (EOG) inspection and video/intercom observation. 2.4. EEG recordings Continuous EEG data were collected from 64 scalp sites using sintered Ag/AgCl active ring electrodes mounted on an elastic cap (EASYCAP GmbH, Herrsching, Germany). The nose tip served as

Pre-op UPDRS-III

Post-op UPDRS-III

L-DOPA

LD

DBS

LD

DBS ON

LD

ON

OFF

OFF

OFF

14

28

28

13

N/A

9

26

N/A

N/A

N/A

9

20

N/A

2

1

11

22

26

23

17

27

48

44

25

19

42

47

38

24

16

18

32

33

12

10

17

57

57

25

10

16

26

44

27

19

18

23

52

32

27

12

26

41

22

15

17

31

37

18

14

DBS

ON

reference. We used active electrodes with integrated impedance converters in order to minimize noise from the surrounding area as well as from movement artifacts. Two additional electrodes were positioned below the eyes to record the EOG. The data were recorded with an analog passband filter of 0.016–250 Hz and digitized at a sampling rate of 1000 Hz using BrainAmp amplifiers (BrainProducts, Munich, Germany). Analysis of the data was performed using Matlab 7.10 (MathWorks, Natick, MA) and two freely available open source toolboxes: (1) EEGLAB 6.03b (Delorme and Makeig, 2004) and (2) FieldTrip (Oostenveld et al., 2011). Statistical analysis of the EEG was confined to a central region of interest (ROI), where pronounced click-responses were observed, and where the influence of muscular artifacts, eye blinks, and cable movements was minimal. This ROI comprised the averaged signal of seven adjacent electrodes located around the vertex electrode Cz (see Fig. 1B). 2.5. Pre-processing Epochs containing non-stereotyped artifacts (e.g., cable movements, swallowing) were removed by visual inspection. Chronically compromised single-electrode traces (e.g., dead channels) were replaced by interpolated data. Following the reduction of the number of components to 32 by principal component analysis, extended infomax independent component analysis (ICA) was applied using a weight change < 10 6 as stop criterion. Independent components representing artifacts such as eye blinks, horizontal eye movements, electrocardiographic activity, or DBS artifacts were efficiently removed from the EEG data by back-projecting all but these components. Finally, outlier epoch-values were automatically detected and rejected using a threshold criterion of ±100 lV. For AEPs analyses the data were first low-pass filtered (30 Hz), downsampled to 500 Hz and then high-pass filtered (2 Hz) to reduce movement artifacts and slow drifts. Epochs were extracted from the continuous data starting 200 ms before and lasting

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A Pre-operation DOPA-ON DOPA-OFF

Controls

P1 Controls vs DOPA-OFF DOPA-ON

6 µV 0

N1 Controls

DOPA-ON DOPA-OFF

-6

B Post-operation ON-DBS

OFF-DBS

P1 Controls vs OFF-DBS ON-DBS

+6 µV

-100 ms

+300

and two-sample t-tests for comparisons between patients and controls, respectively). AEP intervals were considered to differ significantly between the conditions if at least 9 consecutive data points (i.e. 18 ms) reached a p-value of <0.05. Following the recommendations of Guthrie and Buchwald (1991), three adjacent windows of 50 sampling points each (0–98 ms, 100–198 ms and 200–298 ms) were tested separately. To evaluate latency differences at baseline stimulus rate, individual AEP peaks were identified in the respective time intervals: P1 (30–80 ms), N1 (70–150 ms) and P2 (140– 300 ms) and t-tests (paired-sample or two-sample t-test) were then performed. Second, to assess the amplitude attenuation profile in response to increasing RAS frequencies, repeated measures ANOVAs were performed for peak-to-peak amplitudes of the P1/ N1-complex (Papanicolaou et al., 1984; Lim et al., 2005). This peak-to-peak assessment is not influenced by baseline resetting effects due to preceding AEPs and may be considered a more stable measure than absolute amplitude of individual peak components (Zhang et al., 2009). ANOVAs were performed in PASW Statistics (PASW Statistics for Mac, version 18.0, SPSS Inc., Chicago, IL, USA) in two ways: (1) with the within-subjects factors RAS (from 1 Hz to 6 Hz) and the between-subjects factor Group (controls vs. experimental conditions of the patient cohort) for differences between patients and controls; and (2) with the within-subjects factors RAS (from 1 Hz to 6 Hz) and Treatment (DOPA-ON, DOPAOFF, ON-DBS, OFF-DBS). To test the influence of chronic STN-DBS on amplitude attenuation of the P1/N1-complex, AEP amplitudes recorded in both DOPA-OFF and DOPA-ON were collapsed into a group labeled ‘‘pre-operation’’. Conversely, AEP amplitudes recorded OFF- and ON-DBS, respectively, were merged into a group labeled ‘‘post-operation’’. To disentangle interaction effects, follow-up contrast analyses were computed using Helmert contrasts with factors RAS, Group or DBS-therapy (Wendorf, 2004). For all analyses the alpha level was set at 0.05. If necessary, p-values were Greenhouse–Geisser corrected, while degrees of freedom are reported uncorrected. 3. Results

-6 µV 3.1. AEPs at baseline stimulus rate (1 Hz)

N1 ON-DBS

OFF-DBS

Fig. 1. Auditory evoked potential analysis in the condition 1 Hz rhythmic auditory stimulation. (A) Comparison between control group vs. patients’ group before the operation in DOPA-OFF and DOPA-ON. (B) Comparison between control group and patients’ group 5 months after operation with OFF-DBS and ON-DBS. Lower part in B: location of the seven averaged electrodes of the central ROI. The color-coded whole-head topographies of the corresponded components are represented. Colorcoded horizontal bars evidence significantly different intervals for the comparisons between control group vs. patients’ conditions. Note that direct comparisons between ON-DBS vs. OFF-DBS (panel B) were not significantly different, although ON-DBS values differ more from controls than OFF-DBS values.

500 ms after click onset. The interval from onset served as baseline.

100 ms to stimulus

2.6. Statistical analysis Statistical analysis of AEPs was performed in two ways. First, in order to avoid overlapping of components in case of rapidly subsequent clicks (Carver et al., 2002), statistical AEP analysis was carried out for a baseline condition consisting of RAS with 1 Hz. To test amplitude differences in all experimental conditions of the patient sample and the control group we performed running t-tests at each sampling point of the averaged AEP traces (paired t-tests for comparisons of different conditions within the patient cohort

The assessment of AEP-topography confirmed congruent scalp distributions for P1 and N1 components in healthy controls and patients before and after surgery (Fig. 1A and B). Upon baseline auditory stimulation with 1 Hz, significant differences of AEP amplitudes and latencies were found between patients and healthy subjects. PD patients had consistently larger P1, N1 and P2 amplitudes compared to controls in both pre-operative conditions. While mean P1 latencies were similar in the two groups and stable across experimental conditions, N1 latencies in patients were consistently longer than in control subjects (p < 0.05). No significant difference—neither for amplitude nor latency of any investigated AEP component—was observed when comparing the two pre-operative conditions DOPA-OFF vs. DOPA-ON. Although AEPs recorded with the stimulator being switched on (ON-DBS) apparently differ more from controls than AEPs assessed in the OFF-DBS condition (Fig. 1B), these differences were not statistically significant when performing a direct comparison ON-DBS vs. OFF-DBS. 3.2. Frequency-dependent amplitude attenuation of the P1/N1complex Repeated measures ANOVAs with between-subjects factor Group and within-subjects factors RAS and Treatment on peakto-peak amplitudes of the P1/N1-complex confirmed the abovementioned finding of significant larger AEP amplitudes in the

A. Gulberti et al. / Clinical Neurophysiology 126 (2015) 565–574

patient group in comparison to controls (see Fig. 2 and Table 2). Significant group differences were found between the control group and all four experimental conditions. The within-subjects factor RAS was significant in all groups, highlighting the effect of stimulus rate on AEP amplitudes. As is clearly recognizable in Fig. 2, the P1/N1-complex underwent a progressive amplitude diminution with increasing RAS frequencies in both control subjects and patients. Interestingly, a significant interaction between Group and RAS was found only in the comparisons between controls and both experimental conditions before surgery (DOPAOFF and DOPA-ON; see Fig. 2 and Table 2). In the comparisons across experimental conditions, there was no significant main effect of Treatment and no significant interaction with RAS. Instead, significant interactions were found between the postoperative condition OFF-DBS and both pre-operative conditions (DOPA-OFF and DOPA-ON). Justified by the lack of Group differences and interaction effects on peak-to-peak amplitude changes between DOPA-OFF vs. DOPAON and OFF-DBS vs. ON-DBS conditions, we collapsed data from patients preceding or following DBS surgery (labeled as ‘‘pre-operation’’ and ‘‘post-operation’’). Table 3 summarizes the results of the repeated measures ANOVA analyses which were performed with the between-subjects factor Group (patients vs. controls) and the

Pre-operation

A

P1

N1

+4 µV

1Hz

B 11 P1/N1 peak-to-peak amplitude (µV)

The major finding of this study was a differential effect of levodopa and STN-DBS on auditory sensory gating. We report a ratedependent auditory sensory gating deficit of the P1/N1-complex in non-demented patients with advanced PD that was not sensitive to levodopa administration, but improved significantly following chronic STN-DBS.

+500

-4 µV

3Hz

Pre-operation Post-operation

9

5Hz

DOPA-OFF DOPA-ON OFF-DBS ON-DBS Controls

7

5

3 1

within-subjects factors RAS and DBS-therapy (pre-operation and post-operation). Significant group differences were found between controls and both newly formed patient groups (pre-operation and post-operation). Additionally, significant interactions between the factors RAS and DBS-therapy and between the factors RAS and Group (preoperation vs. controls) were found. This interaction was not found for the comparison post-operation vs. controls. Follow-up analyses were then computed using Helmert contrasts for the interaction between RAS and Group (patients vs. controls) and between RAS and DBS-therapy (pre-operation vs. post-operation). The mean difference of groups at each level of the factor RAS was compared to the mean of all subsequent levels (i.e., the mean value of the remaining levels was taken as reference). Two contrasts produced significant results. The comparison across conditions of the patient group (pre-operation vs. post-operation) was significant for stimulus rates of 2.5 and 3 Hz. Furthermore, Helmert contrast analyses for comparison of the pre-operative condition with controls revealed a significant effect for 3 Hz (for 2.5 Hz p = 0.06)—indicating that interactions between patients and controls were mainly driven by differences in the magnitude of AEP-amplitude attenuation at stimulus rates of 2.5 and 3 Hz. In controls, mean P1/N1-amplitudes fell off steeply for rhythms between 1 and 2 Hz, reaching a plateau at stimulus rates > 2 Hz (Fig. 2). In contrast, the rate dependent amplitude attenuation profile between 2 and 4 Hz in PD patients was more gradual before surgery, such that AEP amplitudes reached a plateau at rhythms > 3 Hz. The amplitude attenuation profile of operated patients showed a similar course as in healthy subjects, albeit at generally higher amplitude levels (Fig. 2). 4. Discussion

Post-operation

-200 ms

569

2 3 4 5 Rhythmic auditory stimulation (Hz)

6

Fig. 2. Attenuation of peak-to-peak absolute amplitudes of P1/N1-complex to increasing RAS. (A) Comparisons between control group vs. patients’ group before the operation in DOPA-OFF and DOPA-ON (upper part) and patients’ group after operation with OFF-DBS and ON-DBS (lower part). The dotted lines represent peakto-peak amplitude measurements of the P1/N1-complex for the condition DOPAON. (B) Comparisons between control group vs. patients’ groups where DOPA-OFF and DOPA-ON amplitudes were averaged in a group defined as ‘‘pre-operation’’ and OFF-DBS and ON-DBS amplitudes in a group defined as ‘‘post-operation’’. Error bars are SEM.

4.1. Comparison with other sensory gating paradigms Most auditory gating studies investigating AEP habituation employ a paired click paradigm where a first stimulus is followed by an identical stimulus at various intervals (Fruhstorfer et al., 1970). The amplitude-suppression ratio between the first and second AEP is then taken as index marker of sensory gating—with strong amplitude decrement of the second compared to the first AEP indicating efficient gating functions (Adler et al., 1982). Sensory gating can, as in our study, also be studied using a steady-state paradigm consisting of redundant auditory information repeated at short, identical intervals (Erwin and Buchwald, 1986; Boutros and Belger, 1999; Potter et al., 2006). In this RAS paradigm, average AEP amplitudes across all trials are taken as the sensory gating index. However, it is of note that the results of this study may not directly be comparable to those obtained from paired click paradigms, as interstimulus intervals may have been too short to demonstrate full recovery of AEP amplitudes. 4.2. Reliability of the post-operative EEG recordings A serious concern about perioperative EEG recordings in patients undergoing DBS surgery is scalp topography of the recorded signals, which may be distorted by burr holes (Litvak et al., 2011). It is conceivable that skull defects—as for instance

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Table 2 Results of repeated measures ANOVA for effects of treatment on peak-to-peak amplitudes. Factors: Rhythmic auditory stimulation (RAS), Group (Gr), Treatment (Do = dopamine, Op = operation for DBS electrodes implantation, St = high frequency DBS stimulation). Significant results are reported in bold.

DOPA-OFF

DOPA-ON

DOPA-ON

OFF-DBS

ON-DBS

Controls

RAS [F(10,110) = 11.21; p < .001] Do [F(1,11) = .01; p = .928] Do⁄RAS [F(10,110) = .50; p = .768]

RAS [F(10,110) = 9.39; p < .001] Op [F(1,11) = 2.42; p = .148] Op⁄RAS [F(10,110) = 2.06; p = .033]

RAS [F(10,110) = 14.00; p < .001] Op [F(1,11) = 2.84; p = .120] Op⁄RAS [F(10,110) = 1.30; p = .240]

RAS [F(10,220) = 11.11; p < .001] Gr [F(1,22) = 10.54; p = .004] RAS⁄Gr [F(10,220) = 2.36; p = .041]

RAS [F(10,110) = 8.55; p < .001] Op [F(1,11) = 2.93; p = .115] Op⁄RAS [F(10,110) = 2.37; p = .014]

RAS [F(10,110) = 10.74; p < .001] Op [F(1,11) = 3.83; p = .076] Op⁄RAS [F(10,110) = 1.75; p = .140]

RAS [F(10,220) = 10.71; p < .001] Gr [F(1,22) = 12.61; p = .002] RAS⁄Gr [F(10,220) = 2.36; p = .042]

RAS [F(10,110) = 10.34; p < .001] St [F(1,11) = .00; p = .976 St⁄RAS [F(10,110) = .97; p = .470]

RAS [F(10,220) = 8.33; p < .001] Gr [F(1,22) = 10.33; p = .004] RAS⁄Gr [F(10,220) = 1.00; p = .424]

OFF-DBS

ON-DBS

incompletely sealed burr holes—may have resulted in topographic changes and/or increased power of EEG signals (Oostenveld and Oostendorp, 2002). However, the finding of consistent postoperative AEP topographies before and after surgery—as well as in comparison with the control group (Fig. 1A and B)—argues against a significant impact of previous trephine openings in our study. Supporting this notion, we did not observe globally or locally enhanced signal amplitudes in our dataset (Niedermeyer and da Silva, 2012). Another source of concerns about perioperative EEG recordings may be related to the ‘‘stun’’ effect, a temporary post-operative amelioration of parkinsonian symptoms due to microlesions as a consequence of DBS-electrode implantation (Eusebio and Brown, 2009). Significant stun-related effects are of short duration and typically disappear within one month following DBS surgery (Jech et al., 2012). Post-operative UPDRS-III scores of our patients—assessed in the OFF-DBS/DOPA-OFF condition at the time of the EEG-recordings—were not significantly different from baseline pre-operative UPDRS-III scores (Pre: 34 ± 12 vs. Post: 40 ± 10; [t(9) = 1.66; p = 0.13], paired t-test), providing further arguments against residual effects of surgery-related microlesions. 4.3. Chronic STN-DBS modulates auditory sensory gating In the current study, we capitalized on the advantages of DBS as a reversible neuromodulatory technique to probe possible contributions of the basal ganglia to auditory processing in PD patients. To exclude possible confounding effects of antiparkinsonian pharmacotherapy, both post-operative experimental conditions (DBSOFF vs. DBS-ON) were also studied following overnight withdrawal of dopaminergic medication. Similar to ablative techniques in the GPi (Mohamed et al., 1996; Teo et al., 1998), chronic subthalamic DBS restored a physiological amplitude attenuation profile of the auditory P1/N1-complex. Contrary to our expectation, STN-DBS had no influence on P1/N1 sensory gating compared to the OFF STN-DBS condition. This failure may result from long-term carry-over effects of therapeutic STN-DBS—exceeding our washout-time of 30 min—which could have masked differential effects of STIM ON vs. OFF. In the present study, a washout-time of 30 min was long enough to elicit a significant aggravation of motor symptoms in our patient group. In accordance with previous descriptions (Temperli et al., 2003), a sequential pattern of return of PD symptoms was observed, with first an immediate reappearance of tremor in 4 patients, followed by a significant worsening of bradykinesia and rigidity in all patients. In line with a differential time course of the axial response to DBS, a worsening of these symptoms was not observed. We consider that a distinctive effect on P1/N1 sensory gating may in fact be obtainable with longer washout-intervals, however,

RAS [F(10,220) = 11.51; p < .001] Gr [F(1,22) = 13.40; p = .001] RAS⁄Gr [F(10,220) = 1.02; p = .412]

discomfort resulting from intensified parkinsonian symptoms may limit the patient’s compliance, especially if investigations are carried out without dopaminergic medication (as in our study). 4.4. Downstream effects of STN-DBS In this study, we took the average P1/N1 peak-to-peak amplitude as an indicator of auditory sensory gating. Both P1 and N1 belong to an obligatory sequence of positive and negative peaks, that are elicited by simple auditory stimuli (Davis et al., 1966). Both components are thought to reflect early sensory processing stages of auditory stimuli. Source analyses of auditory AEPs converge on cortical generator sites for both P1 (Wood and Wolpaw, 1982; Lee et al., 1984; Liegeois-Chauvel et al., 1994) and N1 (Naatanen and Picton, 1987). While the P1 response is thought to reflect a pre-attentive or bottom-up stage of sensory gating that is largely insensitive to attentional modulation (Jerger et al., 1992; Kho et al., 2003), repetition suppression of the N1 is sensitive to top-down modulations indexing early attentive processes (Hillyard et al., 1973; Naatanen and Picton, 1987). How could subthalamic DBS then influence auditory sensory gating at a cortical level, given that anatomical projections between auditory cortex and STN are sparse or absent (Canteras et al., 1990; Kolomiets et al., 2001)? Evidence from intracranial recordings in patients undergoing stereotactic surgery indicates that the human basal ganglia and thalamus participate in information processing of different sensory modalities (Bares and Rektor, 2001; Rektor et al., 2001; Bares et al., 2003). As an example, auditory evoked potentials can be recorded from the human subthalamic area (Velasco et al., 1986; Minks et al., 2014). It is of note that a number of studies investigating the neural circuitry involved in auditory sensory gating (i.e., tempo-dependent P1/N1 suppression) converge on demonstrating a prominent involvement of the prefrontal cortex (Knight et al., 1989; Weisser et al., 2001; Grunwald et al., 2003; Korzyukov et al., 2007; Garcia-Rill et al., 2008; Mayer et al., 2009; Boutros et al., 2011; Boutros et al., 2013). In apparent contrast to the sparse interconnection between (auditory) temporal cortex and STN, frontal cortical areas have intimate relations with the STN (Monakow et al., 1978; Nambu et al., 1996; Haynes and Haber, 2013). Interestingly, the inferior frontal cortex—a candidate target structure for functional STN-DBS effects (Aron and Poldrack, 2006)—exhibits maximal gating of P1 (Boutros et al., 2013) and N1 (Boutros et al., 2011), respectively. Taking this anatomical information into consideration, it may be postulated that STN-DBS exerts an influence on sensory gating functions of the frontal cortex—either through modulation of pallido-thalamic output or through retrograde

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Table 3 Results of repeated measures ANOVA and Helmert contrasts for effects of treatment on peak-to-peak amplitudes with patients’ groups averaged as ‘‘pre-operation’’ and ‘‘postoperation’’. Comparisons between control group vs. patients’ groups pre-operation (DOPA-OFF and DOPA-ON amplitudes averaged) and post-operation (OFF-DBS and ON-DBS amplitudes averaged). Factors: Rhythmic auditory stimulation (RAS), Group (Gr), Treatment (Op = operation for DBS electrodes implantation). The Helmert contrasts show the interaction effects of RAS ⁄ Group (controls vs. patients’ groups) and RAS ⁄ Treatment (comparisons between the two patients’ groups). Significant results are reported in bold. Results showing p-values 6 0.06 are reported underlined. PRE-OP

POST-OP

PRE-OP

ANOVA RAS [F(10,110) = 15.41; p < .001] Op [F(1,11) = 3.73; p = .080] Op⁄RAS [F(10,110) = 2.89; p = .003] Helmert contrasts 1 Hz vs. 1.5–6 Hz [F(1,11) = 1.78; p = .209] 1.5 Hz vs. 2–6 Hz [F(1,11) = .00; p = .962] 2Hz vs. 2.5–6Hz [F(1,11) = 4.75; p = .052] 2.5 Hz vs. 3–6 Hz [F(1,11) = 5.27; p = .042] 3 Hz vs. 3.5–6 Hz [F(1,11) = 7.97; p = .017] 3.5 Hz vs. 4–6 Hz [F(1,11) = .71; p = .417] 4 Hz vs. 4.5–6 Hz [F(1,11) = .31; p = .591] 4.5 Hz vs. 5–6 Hz [F(1,11) = .06; p = .805] 5 Hz vs. 5.5–6 Hz [F(1,11) = .00; p = .996] 5.5 Hz vs. 6 Hz [F(1,11) = 1.65; p = .226]

Controls

ANOVA RAS [F(10,220) = 14.03; p < .001] Op [F(1,22) = 11.89; p = .002] Op⁄RAS [F(10,220) = 2.92; p = .018]

ANOVA RAS [F(10,220) = 13.35; p < .001] Op [F(1,22) = 12.94; p = .002] Op⁄RAS[F(10,220) = 1.02; p = .405]

Helmert contrasts 1 Hz vs. 1.5–6 Hz [F(1,22) = 1.69; p = .207]

Helmert contrasts 1 Hz vs. 1.5–6 Hz [F(1,22) = .20; p = .660] 1.5 Hz vs. 2–6 Hz [F(1,22) = 4.53; p = .045] 2 Hz vs. 2.5–6 Hz [F(1,22) = .00; p = .976] 2.5 Hz vs. 3–6 Hz [F(1,22) = .02; p = .878] 3 Hz vs. 3.5–6 Hz [F(1,22) = .01; p = .912] 3.5 Hz vs. 4–6 Hz [F(1,22) = .23; p = .636] 4 Hz vs. 4.5–6 Hz [F(1,22) = .02; p = .879] 4.5 Hz vs. 5–6 Hz [F(1,22) = .61; p = .444] 5 Hz vs. 5.5–6 Hz [F(1,22) = .31; p = .583] 5.5 Hz vs. 6 Hz [F(1,22) = 1.18; p = .289]

1.5Hz vs. 2–6Hz [F(1,22) = 4.15; p = .054] 2 Hz vs. 2.5–6 Hz [F(1,22) = 2.88; p = .104] 2.5Hz vs. 3–6Hz [F(1,22) = 3.81; p = .064] 3 Hz vs. 3.5–6 Hz [F(1,22) = 6.30; p = .020] 3.5 Hz vs. 4–6 Hz [F(1,22) = 1.51; p = .232] 4 Hz vs. 4.5–6 Hz [F(1,22) = .30; p = .587] 4.5 Hz vs. 5–6 Hz [F(1,22) = .40; p = .531] 5 Hz vs. 5.5–6 Hz [F(1,22) = .24; p = .632] 5.5 Hz vs. 6 Hz [F(1,22) = 3.56; p = .072]

effects on hyperdirect pathways. This explanation would be in accordance with our observation that STN-DBS did not significantly influence neural substrates responsible for P1 elicitation per se which have been predominantly localized to the temporal cortex (Yvert et al., 2001). In addition to cortical generator sites, several studies have also described subcortical contributions to the P1 response (Woods et al., 1987). In the context of our study it may be of interest to note that the pedunculopontine nucleus (PPN) as part of the reticular activating system has repeatedly been implicated in the manifestation of the P1 response and auditory sensory gating (Erwin and Buchwald, 1986; Teo et al., 1997; Garcia-Rill et al., 2011). On the one hand, the PPN is a strategic relay nucleus for auditory input (Reese et al., 1995; Schofield et al., 2011), the stimulation of which induces plastic changes in auditory cortex (Luo and Yan, 2013). On the other hand, the PPN is highly interconnected to the output nuclei of the basal ganglia and is also reciprocally coupled to the STN (Pahapill and Lozano, 2000; Mena-Segovia et al., 2004). Thus, STN-DBS may also exert a multi-synaptic influence on auditory processing through modulation of PPN activity. Taken together, we consider it possible that the observed improvements of auditory P1/N1 gating may be related to, and perhaps caused by a stimulation-induced modification of downstream neural activity at the level of frontal cortex and/or brainstem. 4.5. No effect of levodopa on P1/N1 gating A second hypothesis tested in this study was that dopaminergic medication can exert an effect on auditory processing. A recent study in PD patients suggested a significant influence of dopamine levels on the auditory N1/P2 complex (Lukhanina et al., 2009). The

lack of effect of dopaminergic medication on auditory P1/N1 gating in this study is in agreement with the failure of acute dopamine depletion to modulate P1 suppression in healthy subjects (Mann et al., 2008) and is in line with work by Teo and colleagues (Teo et al., 1997) who found no correlation between levodopa dosage and P1 habituation in parkinsonian patients. The preoperative medication history of PD patients is notoriously diverse and difficult to assess. In our study, all patients underwent a standardization of their anti-parkinsonian medication around the time of investigation (replacement of dopamine agonists by levodopa). They were tested after overnight levodopa withdrawal in a pragmatically defined OFF-medication state. Therefore, we cannot rule out the possibility that longer washout-times of dopaminergic medication would have resulted in significant AEP differences. Furthermore, little is known whether chronic anti-parkinsonian medication—beyond disease modification—also has an effect on electrophysiological measures such as AEPs. Stanzione et al. (1998) investigated the effects of sustained (2 weeks) levodopa withdrawal on long latency AEPs in both de novo and advanced PD patients. In this study, both age and disease stage were identified as important factors contributing to delayed latencies of the P300 component. Age-related changes of AEPs are well described (Woods and Clayworth, 1986). Interestingly, Laffont et al. (1989) reported a higher auditory P1/N1-amplitude in healthy elderly subjects – which, according to our results and those of other groups (Teo et al., 1997; Tanaka et al., 2000), is even more pronounced in patients with pathological dopamine deficiency. In summary, the complex interplay between age, disease course (duration and severity) and chronic drug treatment may have contributed to the AEP abnormalities found in PD patients before surgery.

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4.6. AEP abnormalities Several aspects of central auditory processing have been reported to be abnormal in PD. There is ample evidence to suggest that more endogenous AEP components such as N2 and P3 are impaired in PD patients compared with healthy subjects (Lagopoulos et al., 1998). Our investigations of transient AEP responses obtained at baseline stimulus rate confirm and partially overlap with previous reports on increased latencies (Ebmeier et al., 1992; Raudino et al., 1997; Pekkonen et al., 1998; Jiang et al., 2000) and larger AEP amplitudes (Tanaka et al., 2000) in PD patients compared to controls. Increased latencies of the N1 response have previously been reported to differentiate demented PD patients from those without cognitive deficits (Goodin and Aminoff, 1987). Although this study reports increased N1 latencies, it is important to note that all patients had adequate global intellectual capacities as assessed by formal testing and met the selection criteria for neurosurgical interventions stated by the CAPSIT-PD committee (Defer et al., 1999). Dopaminergic medication had no effect on AEPs in this study, which contrasts with a previous report of larger N1 amplitudes in PD patients without than with dopaminergic medication (Vieregge et al., 1994). This discrepancy may be attributed to differences in the experimental design and clinical characteristics of the patient cohort, respectively. Evidence on the effects of STN-DBS on AEPs is limited. While STN-DBS had no effect on late AEPs in an auditory oddball paradigm (Gerschlager et al., 2001; Kovacs et al., 2008), STN-DBS resulted in enlarged amplitudes of the N100m, the electromagnetic counterpart of the N1, in a recent magnetoencephalography study (Airaksinen et al., 2011). 5. Conclusions In summary, we observed generally increased AEP amplitudes together with latency abnormalities in parkinsonian patients compared with controls, providing further support for a central processing deficit in the auditory domain (Vieregge et al., 1994; Pekkonen et al., 1998; Tanaka et al., 2000; Vitale et al., 2012). Levodopa had no significant effect on transient AEPs and failed to normalize altered auditory gating characteristics of PD patients in this study. In contrast, STN-DBS restored a physiological P1/N1-amplitude attenuation profile in response to RAS with increasing stimulus rates. This differential treatment effect suggests a divergent mode of action of levodopa and STN-DBS on auditory processing. We conclude that chronic STN-DBS may improve early attentive filtering processes of redundant auditory stimuli, possibly mediated by alteration of top-down modulation from the frontal cortex. Funding sources This work has been funded by the EU (FP7-ICT-270212; AKE, AG). Acknowledgements We are grateful to the patients who volunteered to participate in this research and to Kriemhild Saha for help with EEG-data recording. Alessandro Gulberti and Andreas K. Engel acknowledge support by the EU (FP7-ICT-270212). Conflict of interest statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Authors A. Gulberti, W. Hamel, T.R. Schneider, C.K.E. Moll, K. Boelmans, S. Zittel, C. Gerloff, M. Westphal, and A.K. Engel declare no relevant conflicts of interest. C. Buhmann served on

the scientific advisory board for GSK and UCB Pharma and received honoraria for lectures from GSK, Medtronic, Orion Pharma, and UCB.

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