Local entrainment of oscillatory activity induced by direct brain stimulation in humans

Abstract

In a quest for direct evidence of oscillation entrainment, we analyzed intracerebral electroencephalographic recordings obtained during intracranial electrical stimulation in a cohort of three medication-resistant epilepsy patients tested pre-surgically. Spectral analyses of non-epileptogenic cerebral sites stimulated directly with high frequency electrical bursts yielded episodic local enhancements of frequency-specific rhythmic activity, phase-locked to each individual pulse. These outcomes reveal an entrainment of physiological oscillatory activity within a frequency band dictated by the rhythm of the stimulation source. Our results support future uses of rhythmic stimulation to elucidate the causal contributions of synchrony to specific aspects of human cognition and to further develop the therapeutic manipulation of dysfunctional rhythmic activity subtending the symptoms of some neuropsychiatric conditions.

Figure 1. Multielectrode implantations and intracranial stimulation procedures.

(A) Image of an 8-contact intracranial multielectrode employed for stimulation and iEEG recordings. (B) Diagram of the implantation sites of every individual multielectrode in the brain of the three patients considered in the analyses. (C) Detailed caption of a single multielectrode implanted in the frontal lobe of one of these patients, displayed on a T1 MRI scan (coronal view) recorded following implantation. Blue dots represent pairs of electrode contacts delivering 5 seconds long 50 Hz electrical bursts (blue iEEG trace). White dots signal the location of remaining contacts within the same electrode, recording brain iEEG activity concurrently with electrical stimulation patterns.

Figure 2. Enhancement of gamma oscilations time-locked to the stimulation input.

(A) Representative iEEG trace from patient 2 displaying activity recorded from a multielectrode’s contact (multi-electrode 3, contact 2 located in the left superior frontal region) during a single 50 Hz stimulation burst delivered by a pair of contacts (contacts no. 5 and 6) hosted in the same multielectrode. The 0 ms time set corresponds to the onset of electrical stimulation. The black dotted line below depicts the duration of the stimulation burst. (B) Time-frequency analyses on this same single iEEG time-series reveal either increases (warm hues) or decreases (cold hues) of synchronization at each frequency bin, as compared to a baseline epoch, i.e., [−300 to −100 ms] recorded prior to the onset of electrical stimulation bursts. Note the increases of gamma synchronization (45–55 Hz) during the 50 Hz stimulation patterns. (C) (Top) Time series displaying fluctuations of the relative phase between the 50 Hz component of the iEEG time series plotted in (A) and the stimulator output signal. Angle phase histograms represent the distribution of relative phase values calculated during three two-second long epochs (red dotted boxes).

Figure 3. Time-Frequency activity maps for each individual patient included in the study.

Representation of the time-frequency maps corresponding to the activity evoked by 3 different stimulations (one for each patient delivered through two adjacent contacts (shown in gray on the schematic representation of an intracranial multielectrode) and recorded by each of the remaining contacts (shown in black). The map shows increases (warm hues) or decreases (cold hues) of power for each frequency bin as compared to a baseline epoch, i.e., [−300 to −100 ms] recorded prior to the onset of electrical stimulation. Note increases in gamma synchronization (45–55 Hz) and associated harmonics (100 Hz) during 50 Hz stimulation patterns. The “0” ms time set corresponds to the onset of electrical stimulation. The dotted line shown above the top panel signals the duration of the 50 Hz stimulation burst.

Figure 4. Increases of gamma power and phase-locking value during the stimulation period.

Quantification of the individual single trial 50 Hz power (A) and phase-locking values (S-PLV) at this frequency band (B) for each of the three subjects of the study and group average values for these measures across stimulation trials and patients (white boxes) before, during and after the delivery of 50 Hz stimulation patterns. Power is here calculated as percent change relative to its value during the pre-stimulation period ([−300 to −100 ms]). The S-PLV index measures the stability of the phase difference (see Fig. 2C) ranging from 0 (random behavior) to 1 (constant phase syncrhony). Notice individual and group average increases of gamma (~50 Hz) power and S-PLV values ocurring specifically during the delivery of the stimulation patterns, which proved significantly lower before and after stimulation, as compared to during the delivery of 50 Hz electrical bursts (**p < 0.001 vs. before or after the stimulation burst).

Figure 5. Dose-response curves for power and phase-locking value during the stimulation period.

(Top panel) Group average power (A) and stability of phase-locking values (S-PLV) (B) for the three stimulation intensities considered in our analyses (0.5 mA, 1 mA and 2 mA) (white boxes), during 50 Hz stimulation. Power is calculated as the percent change relative to its values during the pre-stimulation epoch ([−300 to −100 ms]). The S-PLV index measures the stability of the phase difference (see Fig. 2C) ranging from 0 (random behavior) to 1 (constant phase synchrony). (Bottom panel) Individual dose-response curves of each of the three patients for power and the stability of the phase-locking value (S-PLV). Note that the S-PLV values increased significatly with accruing levels of stimulation intensity (**p < 0.001 vs. prior or following the 50 Hz stimulation period).