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1 Supplementary Online Content Miocinovic S, de Hemptinne C, Qasim S, Ostrem JL, Starr PA. Patterns of cortical synchronization in isolated dystonia compared with Parkinson disease. JAMA Neurol. Published online September 26, doi: /jamaneurol emethods. Signal Processing etable. Clinical Characteristics efigure 1. Phase-Amplitude Coupling at Multiple Cortical Recording Locations for the 3 Patient Groups, Presented as z Scores efigure 2. Phase-Amplitude Coupling in the Primary Motor Cortex for Individual Patients efigure 3. Temporal Stability of Phase-Amplitude Coupling efigure 4. Phase-Amplitude Coupling at M1 for the 3 Patient Groups During Rest and Movement efigure 5. PSD Before, During, and After STN DBS for 4 Dystonia Patients efigure 6. Coherence Analysis Between M1 and S1 This supplementary material has been provided by the authors to give readers additional information about their work American Medical Association. All rights reserved. 1

2 emethods. Signal Processing Power spectral density (PSD) was calculated using the Welch periodogram method (Matlab function pwelch; 512 point fast Fourier transform (for a frequency resolution of 1.95 Hz) and 50% overlap using a Hanning window). PSD data was log transformed for all statistical analyses to allow for use of parametric statistics in comparing grouped data. The Lilliefors test (MATLAB function lillietest) was used to confirm normality. Log power was averaged over multiple frequency bands: theta (4-8 Hz), alpha (8-13 Hz), beta (13 30 Hz), low gamma (30 50 Hz) and broadband gamma (50-200Hz; excluding regions around 60 Hz and its harmonics). PSD at frequencies < 4 Hz were not analyzed due to the presence of low frequency artifacts generated by the heartbeat, respirations and movement. We used 2 sec data samples to calculate PSD: for rest condition 5 sections were randomly chosen from available recordings, for move condition they started at the EMG-determined movement onset, and for stop condition they were taken from the middle of stop period. Phase amplitude coupling (PAC) within each cortical region was calculated using the Kullback Liebler (KL)-based modulation index method (Tort2008). Thirty seconds of data was used for calculations (move/stop epochs were concatenated for analysis). Our previous analysis has shown comparable results using several different PAC calculation methods (dehemptinne2013). In the KL method, the phase of the signal at low frequencies and amplitude of the same signal at high frequencies are extracted and their interaction quantified as the modulation index (MI). Specifically, ECoG potentials were bandpass-filtered at low (from 4 to 50 Hz in steps of 2 Hz; referred to as frequency for phase ) and high (10 to 200 Hz in steps of 4 Hz; referred to as frequency for amplitude ) frequency bands using a finite impulse response (FIR) filter (eegfilt function in Matlab EEGLab toolbox). The Hilbert transform was applied, and the instantaneous phase and the instantaneous amplitude were extracted from the low and high frequencyfiltered signal, respectively. The distribution of the instantaneous amplitude envelope was then computed for every 20 interval of the instantaneous phase. The coupling between the phase of low-frequency rhythm and the high-frequency amplitude was determined by computing the entropy values of this distribution and normalizing by the maximum entropy value. For each MI, a z-score was calculated using the mean and SD of a distribution of phase amplitude coupling values obtained from 100 surrogates created by combining the instantaneous phase and amplitude with varying time lags (Canolty2006). Statistical significance threshold was determined using false discovery rate (Storey2002). MI whose z-score was below significance threshold was set to zero. We also calculated the overall magnitude of beta-broadband gamma coupling for each patient by averaging MI over phases extracted from the Hz band and the amplitude extracted from the Hz band (PAC average). Coherence analysis was performed on 2 second data epochs as described in the PSD section above, using mscohere function in Matlab (1.95 Hz frequency resolution). Permutation statistics were performed by analyzing coherence for 100 surrogates with varying time lags. Coherences whose z-scores were below significance threshold using false discovery rate were set to zero. References Tort AB, Kramer MA, Thorn C, et al. Dynamic cross-frequency couplings of local field potential oscillations in rat striatum and hippocampus during performance of a T-maze task. Proc Natl Acad Sci U S A Dec 23;105(51): Canolty RT, Edwards E, Dalal SS, et al. High gamma power is phase-locked to theta oscillations in human neocortex. Science. 2006;313(5793): Storey JD. A direct approach to false discovery rates. J. R. Stat. Soc. Series B Stat. Methodol. 2002; 64: American Medical Association. All rights reserved. 2

3 etable. Clinical Characteristics Patient Age (years) Gender Handedness Side of ECoG strip DBS target Disease duration (years) Dystonia phenotype a Motor score total b Arm subscore contralateral to ECoG c Medications, daily total (mg) Dyst-noArm1 67 M R R GPi 14 Bleph, lorazepam 2 oromandib Dyst-noArm2 d 40 F R L STN 9 Cervical 8 0 clonazepam 1 Dyst-noArm3 34 M R R GPi 4 Cervical 8 0 clonazepam 1, baclofen 20 Dyst-noArm4 57 F R L ViM 24 Cervical, head 6 0 baclofen 40 tremor Dyst-noArm5 46 F R R GPi 14 Cervical 9 0 clonazepam 1 Dyst-noArm6 56 F R R GPi 2 Cervical, bleph 7 0 none Dyst-noArm7 59 F R R GPi 10 Bleph, mandibular, cervical Dyst-noArm8 65 F R L STN 6 Bleph, oromandib, cervical 11 0 methylphenidate lorazepam 6 Dyst-noArm9 d 55 F L R STN 3 Bleph, cervical 13 0 carbamazepine 400 Dyst-noArm10 d 71 M R L STN 30 Cervical, bleph, 13 0 lorazepam 6 oromandib Dyst-noArm11 d 66 M L R STN 3 Cervical, oromandib, bleph, truncal 23 0 lorazepam 6, baclofen 40, hydrocodone 60 Dyst-noArm12 56 F R R GPi 22 Bleph, oromandib, 28 0 baclofen 20, clonazepam American Medical Association. All rights reserved. 3

4 dysphonia, cervical Dyst-noArm13 64 M L R STN 15 Oromandib, cervical, bleph, right writer s cramp Dyst-noArm14 47 M R R GPi 5 Cervical, truncal (pectoralis) Dys-Arm1 d 45 F R R STN 2 Cervical, truncal, oromandib, bilateral hands; DYT1 negative Dys-Arm2 d 63 M R R STN 15 Cervical, oromandib, bleph, writer s cramp, postural tremor Dys-Arm3 53 M R L STN 28 Cervical, writer s cramp, rest/postural tremor; DYT1 negative Dys-Arm4 57 F L R GPi 40 Generalized (cervical) Dys-Arm5 51 F R R STN 30 Generalized (arms, rest/postural tremor); DYT1 positive Dys-Arm6 47 F R L GPi 37 Generalized (right hemibody, rest/postural tremor); DYT1 positive Dys-Arm7 53 F R L GPi 11 Generalized (craniocervical) clonazepam lorazepam Intrathecal baclofen 545 mcg, tizanidine clonazepam alprazolam 3, clonazepam clonazepam 1.5, diazepam alprazolam trihexyphenidyl diazepam American Medical Association. All rights reserved. 4

5 Dys-Arm8 34 M R L STN 17 Generalized (craniocervical; DYT1 negative 52 9 trihexyphenidyl, clonazepam 3 PD1 e 64 M R L STN 8 none 11 4 LEDD 1300 PD2 d 46 M R L STN 7 none 30 6 LEDD 810 PD3 d, e 65 F R L STN 11 foot dystonia 30 8 LEDD 1025 (not in OR) PD4 d 61 M R R STN 19 none 31 7 LEDD 954 PD5 65 M R R GPi 8 none 31 8 LEDD 1370 PD6 d 67 F R L STN 19 none 32 7 LEDD 600 PD7 d,e 63 M R R STN 20 jaw and foot dystonia (foot in OR) LEDD 1674 PD8 d, e 59 M R L STN 10 foot dystonia LEDD 1924 (not in OR) PD9 63 M R R GPi 15 none LEDD 600; trihexyphenidyl 6mg PD10 55 F R R STN 14 foot dystonia (in 22 5 LEDD 1472 OR) PD11 d 54 M R L STN 6 none 31 7 LEDD 1420 PD12 52 M R L STN 8 toe dystonia (not 18 4 LEDD 1000 in OR) PD13 d 50 M R R STN 8 none LEDD 1000 PD14 30 M R R STN 7 foot dystonia (in OR) LEDD 690 a dystonia symptoms listed in approximate order of severity. For generalized dystonia, most severely affected body part is listed in the parenthesis. DYT1 status listed if known. For PD, off-period dystonia listed if present by history or during intraoperative recordings. b Motor score of the Burke Fahn Marsden (BFM) Dystonia Rating Scale (dystonia) or OFF-medication Unified Parkinson s Disease Rating Scale (UPDRS) part III (PD). c arm subscore of the BFM Scale (dystonia) or items of the UPDRS III (PD), contralateral to the side of ECoG recording. No patients had arm dystonic symptoms at rest (three patients had history of rest tremor, but none was present during relevant intraoperative recordings as confirmed by EMG, accelerometer and visual observation). d patient previously reported in Ref 5 e patient previously reported in Ref 13 Dyst-noArm = isolated dystonia without arm symptoms contralateral to ECoG side; Dyst-Arm = isolated dystonia with arm symptoms contralateral to ECoG side; PD = Parkinson s disease; LEDD = levodopa equivalent daily dose; bleph = blepharospasm; oromandib = oromandibular; OR = operating room American Medical Association. All rights reserved. 5

6 efigure 1. Phase Amplitude Coupling at Multiple Cortical Recording Locations for the 3 Patient Groups, Presented as z Scores This is the same data as in Figure 2, but instead of raw PAC scores, z scored PAC values are presented. Z scored values were obtained from the surrogate permutation testing described in emethods 5. Z score emphasizes the statistical significance of observed coupling, while raw score describes absolute strength of coupling and allows for comparison between the groups American Medical Association. All rights reserved. 6

7 efigure 2. Phase Amplitude Coupling in the Primary Motor Cortex for Individual Patients PAC axis and scale are the same for all graphs and as described in Figure 1. M1 data is shown for all patients except for PD7, PD9 and PD14 who had higher average PAC in the CS recording American Medical Association. All rights reserved. 7

8 efigure 3. Temporal Stability of Phase Amplitude Coupling Top row is from a patient from Dyst noarm group who had low coupling, and bottom row is from a patient from Dyst Arm group who had high coupling. Each plot was computed from a 30 second recording at rest. Time between the first and last plot is approximately 30 minutes for each patient. MER = microelectrode recordings performed for clinical purposes American Medical Association. All rights reserved. 8

9 efigure 4. Phase Amplitude Coupling at M1 for the 3 Patient Groups During Rest and Movement Color indicates value of PAC index. Box plots show average beta broadband gamma PAC. Horizontal lines represent medians of the individual patients average PAC, boxes represent the 25th and 75 th percentiles, whiskers extend to the most extreme data points not considered outliers, and crosses represent outliers. P values refer to rank sum test. Average PAC decreased approximately 80% during move phase (compared to stop) (14 100% in Dyst noarm group, % in Dyst Arm group, and % for PD group). Eight patients did not have movement data American Medical Association. All rights reserved. 9

10 efigure 5. PSD Before, During, and After STN DBS for 4 Dystonia Patients Mean beta power was decreased in two Dyst noarm patients and one Dyst Arm patient, and remained unchanged in the other Dyst Arm patient. Mean gamma power ( Hz, to avoid stimulation artifact) was increased in one Dyst noarm patient and decreased in the other three. Dip around 60 Hz was created by notch filtering of power line noise American Medical Association. All rights reserved. 10

11 efigure 6. Coherence Analysis Between M1 and S1 Top. Boxplots for average beta band (13 30 Hz) coherence. There was no difference in average coherence for any of the frequency bands (theta, alpha, beta, low gamma or gamma) for any condition (rest, move, stop) between the patient groups (Dyst Arm trended toward lowest beta coherence at rest, p val 0.05). Bottom. Boxplots for peak coherence frequency. Coherence peak increased with movement in all 3 groups (Dyst noarm group from 19.5 to 27.3 Hz, p val ; Dyst Arm group from 19.5 to 29.3 Hz, p val 0.003; PD group from 21.5 to 27.3 Hz, p val 0.04), but there was no difference between the groups American Medical Association. All rights reserved. 11