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Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease

Abstract

Deep brain stimulation (DBS) is increasingly applied for the treatment of brain disorders, but its mechanism of action remains unknown. Here we evaluate the effect of basal ganglia DBS on cortical function using invasive cortical recordings in Parkinson's disease (PD) patients undergoing DBS implantation surgery. In the primary motor cortex of PD patients, neuronal population spiking is excessively synchronized to the phase of network oscillations. This manifests in brain surface recordings as exaggerated coupling between the phase of the beta rhythm and the amplitude of broadband activity. We show that acute therapeutic DBS reversibly reduces phase-amplitude interactions over a similar time course as that of the reduction in parkinsonian motor signs. We propose that DBS of the basal ganglia improves cortical function by alleviating excessive beta phase locking of motor cortex neurons.

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Figure 1: Electrodes localization, task, and timeline of recordings.
Figure 2: Example M1 recordings and their spectral characteristics, before filtering the stimulation artifact, in a single patient.
Figure 3: Acute therapeutic STN stimulation reduces PAC in the resting state.
Figure 4: DBS does not affect resting state power spectral density.
Figure 5: Examples of M1 LFP and PAC during the arm movement task in one patient.
Figure 6: Both DBS and movement reduce PAC during the arm movement task.
Figure 7: Movement-related cortical changes before, during and after DBS.

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Acknowledgements

Thanks to our patients who participated in this study, to R. Steiner for programming the iPad task, to A. Kreitzer for critical review of the manuscript, to S. Miocinovic for symptom assessment, and to N. Ziman and S. Qasim for helping to collect data. This study was supported by a grant from the Michael J. Fox foundation and by US National Institutes of Health grant R01 NS069779.

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Authors and Affiliations

Authors

Contributions

Conceived and designed the experiments: C.d.H., P.A.S. Performed the experiments: C.d.H., N.C.S., E.S.R.-W., P.A.S. Analyzed the data: C.d.H. Obtained consent from patients: C.d.H., N.C.S., E.S.R.-W. Recruited patients and characterized patients symptoms: J.L.O., M.S.L., N.B.G. Wrote the paper: C.d.H., P.A.S. Performed surgical procedures and supervised the project: P.A.S.

Corresponding author

Correspondence to Coralie de Hemptinne.

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The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Physiologic characteristic of STN and cortex at rest.

a. STN and M1 are coherent in the β band. Left panel shows a typical example of STN and M1 coherence. Peak coherence and its frequency were determined for each patient (18 patients, STN LFP was not recorded or noisy in 5 patients). The distribution of these frequencies of peak coherence is shown on the right panel. Coherence was computed using mscohere matlab function with a 512 window and 50% overlap. b. Reduction of STN β power during DBS (red curves) compared to baseline without stimulation (blue curves). STN LFPs were recorded before and during DBS using contact 0 and 2 surrounding the contact used for stimulation, in five patients (table S6). Each panel shows the STN LFPs recorded in each patient. Monopolar DBS was delivered using contact 1 as the active and a grounding pad as the reference contact. For these recordings, signals were sampled at 3000, amplified 7000 fold and an online low pass filter (100Hz) was applied to avoid saturation of the STN LFP by stimulation artifact. For each patient, log PSD was averaged in the beta band (13-30Hz). The mean log β observed during DBS is plotted versus that observed before DBS. Each dot represents one patient. c. Strong PAC, and a reduction in PAC induced by DBS, is found in the primary motor cortex but not in the primary sensory cortex. PAC was computed using an ECoG contact pair covering the motor cortex and another contact pair covering the sensory cortex (S1) in 20 patients (3 patients did not have sensory cortex coverage), using the same method as the one used in the main manuscript (Tort 2008). Boxplot of the mean PAC averaged across β (13-30Hz) and broadband activity (50-200Hz) before and during DBS is shown for M1 (left panel) and S1 (right panel).

Source data

Supplementary Figure 2 DBS effects are insensitive to the presence of stimulation artifact and to the method used to compute PAC.

a. Typical example of log power spectral density computed on M1 ECoG potential, filtered at the stimulation artifact and noise harmonic (red curve) and without any filter (blue curve). b. Example of PAC computed with unfiltered and filtered data is shown on the left and right panels, respectively. Same patient as in a. c. Boxplot showing the significant reduction of mean β PAC during STN DBS when PAC is computed using unfiltered ECoG potentials. Note the similarity of these results and these presented in figure 3 C suggesting that stimulation artifact does not affect the results. d. Five PAC characteristics were evaluated using filtered and unfiltered data and represented in a scatterplot. From left to right, mean β PAC is the modulation index averaged across β (13-30Hz) and the all broad band power (50-200Hz), PAC mean 70-110 is the modulation index averaged across β and frequencies unaffected by any artifact (70-110), max PAC is the maximum coupling, max frequency for phase and amplitude are the frequency at which the maximum coupling occurs. Each dot represents a patient. A highly significant correlation was observed (red line is the regression) for each PAC variable suggesting that stimulation artifact does not alter PAC.e. Broadband activity is not modulated during DBS even in the presence of stimulation artifact. Log PSDs were computed from unfiltered ECoG potentials, averaged across the all broadband activity (50-200Hz) and compared between stimulation conditions. DBS did not significantly modulate this variable similar to what was observed with filtered data (Fig 4). f. Mean β PAC was reduced during DBS using two alternative methods of analyzing phase-amplitude interactions, the phase-locking value (PVL, left panel, see penny et al. 2008 for methods ) and coherence-cross-frequency coupling (CFC, right pane, see Osipova et al. 2008 for methods). Same convention as in fig 3d

Source data

Supplementary Figure 3 Time course of beta PAC and log PSD at the DBS transitions

Time course of β PAC and log PSD at the transitions at which DBS is turned OFF (a,c,d) or ON (b) studied in four patients. Periods of stimulation are indicated by a red bar above PAC plot. PAC was computed over a 3s sliding window of 100ms using Tort method (as in the manuscript), with the β phase estimated in small steps (13-30Hz with step of 2 Hz) but extracting the amplitude signal between 50-110 Hz in order to compute PAC over time. Signal was filtered between 50 and 110 Hz to avoid the stimulation artifact. PAC decreased or increased gradually once DBS was turned ON and OFF, respectively. These transitions take 2-4s suggesting that the reduction of PAC during DBS is not due to the stimulation artifact. (In this figure, in some of the examples, a correlation between β power and β PAC can be observed).

Supplementary Figure 4 M1 PAC correlates with symptoms as assessed by a blinded neurologist in a randomized stimulation paradigm.

a. ECoG potentials were recorded while DBS was turned OFF or ON using therapeutic and sub-optimal stimulation settings in a single subject. PAC was evaluated during the 30s without movement in each condition sub-optimal stimulation using low voltage (1-2+, 0.5V, 160Hz, upper left panel), therapeutic stimulation (1-2+, 4V, 160Hz, upper right panel), no stimulation (lower left panel), sub-optimal stimulation using low frequency (1-2+, 4V, 70Hz, lower right panel). For each condition the patient was instructed to stay quiet with eyes open for 30s then a neurologist blinded to stimulation settings was asked to assessed rigidity, tremor (rest and postural) and bradykinesia (finger tapping and hand opening and closing). b. Corresponding PSD on which the artifact of stimulation and β power can be observed. c. shows the correlation between symptoms severity (rigidity score + tremor score + bradykinesia) and mean β PAC. This result, using a within-subjects design and a blinded movement disorders neurologist, suggest that DBS reduced PAC in a manner that correlate with symptoms.

Source data

Supplementary Figure 5 Inconsistent effect of DBS on beta power

DBS does not significantly reduce β power even when this frequency band was subdivided into β power in low (12-20 Hz, left panel) and high β (20-30Hz, right panel). Mean log PSD during DBS is plotted versus that observed before DBS for low and high β power in the left and right panels, respectively. Each dot represents a patient. Diagonal is shown in dashed line.

Source data

Supplementary Figure 6 DBS reduces PAC significantly irrespective of the direction of change in spectral power.

a. Patients were divided into those with an increase in β power (10 patients, left top panel), and those with a decrease (13 patients, right top panel) and the effect of DBS on phase-amplitude coupling was then evaluated for these 2 groups. A significant decrease of PAC in both groups of patients was observed. b. Patients were also divided into those with an increase in broadband power (12 patients, left lower panel) and those with a decrease in that frequency band (11 patients, right lower panel). Both groups of patients show a significant reduction of PAC during stimulation. These results suggest that DBS-induced reductions in PAC are not related solely to alterations in cortical β or broadband activity, although both, PAC and β power, are correlated..Same convention as in fig 3d

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Supplementary Figures 1–6 and Supplementary Tables 1–6 (PDF 861 kb)

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de Hemptinne, C., Swann, N., Ostrem, J. et al. Therapeutic deep brain stimulation reduces cortical phase-amplitude coupling in Parkinson's disease. Nat Neurosci 18, 779–786 (2015). https://doi.org/10.1038/nn.3997

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