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.

Fig.1

Electrodes localization, task paradigm, and timeline of recordings. a. Localization of subdural ECoG strip. The six contacts of the ECoG strip (white dots) relative to the central sulcus (white arrow) can be observed on this parasagital view of the iCT scan merged with the preoperative MRI scan. b. Localization of tip of the DBS electrode (arrow) at the base of STN, on an axial view of the iCT scan merged with the preoperative MRI. c. Description of the arm movement task. A single trial is represented. Each trial starts with a ‘hold phase’ period of 3-5 s during which the patient maintains gaze on a central red dot. Then, the ‘target’, a blue dot, occurs at the upper or lower edge of the screen (‘preparation phase’). Patient was instructed to touch the target with the index finger after the central dot turns green (‘movement phase’). d. Typical timeline for lead insertion, recording, and stimulation. Rectangles represent the different data collection events as follows: Green, somatosensory evoked potential (SSEP); red, rest; blue; arm movement task. The time between recordings is indicated under the horizontal arrows in minutes or hour.

Fig.2

Example M1 recordings and their spectral characteristics, prior to filtering the stimulation artifact, in a single patient. a. M1 LFPs before (left panel), during (middle panel) and after STN stimulation (right panel). b. Log power spectral density for each recording in (a). A small artifact of stimulation can be observed on the zoomed LFP (a middle panel) and the corresponding log PSD (arrow, b middle panel). A peak in the β band can be observed in each condition. Grey rectangles indicate β band and broadband activity.

Fig.3

Acute therapeutic STN stimulation reduces PAC in the resting state. a. Representative example of PAC observed in the M1 of a Parkinson's disease patient before (left panel), during (middle panel) and after STN stimulation (right panel). The warmest colors represent the strongest coupling. The white dotted box (left panel) shows the range of frequencies over which modulation indices were averaged to generate the statistical comparison between stimulation conditions. b. Average PAC observed during DBS is plotted versus that observed before DBS (left panel) and after DBS (right panel). Each dot represents one patient. Grey rectangles show the zoomed area plotted in the inserts. c. Boxplot showing the significant and partly reversible reduction of PAC during STN DBS. d. Boxplot showing the therapeutic reversible effect of DBS on patient's rigidity. The boxes represent the 25th and 75^th percentiles, and the whiskers extend to the most extreme data points not considered outliers (1.5 IQR). * indicates a significant difference with a p-value <0.05 and ** with a p-values <0.01.

Fig. 4

DBS does not affect resting state power spectral density. a. Mean β power. For each subject before versus during DBS (left), for each subject after DBS versus during DBS (middle), and grouped data represented in boxplots (right). b. Mean broadband power, represented in same manner as in a. Same conventions as in Fig. 3d

Fig. 5

Examples of M1 LFP and PAC during the arm movement task in one patient. a. M1 LFP (top panel) and accelerometry (lower panel) during two trials of the task. Vertical dashed lines indicate the three phases of the task: red; hold phase, blue; preparation, green; movement. b. PAC in the three phases (left panels, hold; middle panels, preparation; right panels, movement) and in the three conditions of stimulation (top panels, before DBS; middle panels, during DBS; lower panels, after DBS). There is reduction of PAC from hold to movement preparation to movement execution, and DBS decreases PAC in all three phases of the task.

Fig. 6

Both DBS and movement reduce PAC during the arm movement task. Medians and 25-75 percentiles are shown in the three phases of the task (hold, preparation and movement) before and during DBS stimulation. The three phases are represented in the x axis while the conditions are represented by colors. Dark grey, before DBS; black, during DBS; light grey, after DBS. A reduction of PAC is observed from hold phase to movement phase with an additional decrease of PAC during STN stimulation. Same conventions as in Fig. 3d

Fig.7

Movement related cortical changes before, during and after DBS. a. Typical example of cortical changes associated with movement preparation and initiation observed before (left panel), during (middle panel) and after DBS (right panel) in an individual patient (PD7). Time spectrograms are aligned either on the target onset (dashed vertical line; left spectrograms) or the movement onset (dashed vertical line; right spectrograms). Spectrograms were averaged across β frequency (13-30Hz) and broadband (100-200Hz), during the hold period (white rectangles), the preparation phase (grey rectangles) and the movement onset (black rectangles). b. Boxplots showing changes in β activity associated to movement preparation and execution before (left panel), during (middle panel) and after DBS (right panel). Significant p values are indicated. c. Boxplots showing changes in broadband activity associated with movement preparation and execution before (left panel), during (middle panel) and after DBS (right panel). Significant p values (after correction for multiple comparisons) are indicated. Same conventions as in Fig. 3d