Disruption and rescue of interareal theta phase coupling and adaptive behavior

Abstract

Rescuing executive functions in people with neurological and neuropsychiatric disorders has been a major goal of psychology and neuroscience for decades. Innovative computer-training regimes for executive functions have made tremendous inroads, yet the positive effects of training have not always translated into improved cognitive functioning and often take many days to emerge. In the present study, we asked whether it was possible to immediately change components of executive function by directly manipulating neural activity using a stimulation technology called high-definition transcranial alternating current stimulation (HD-tACS). Twenty minutes of inphase stimulation over medial frontal cortex (MFC) and right lateral prefrontal cortex (lPFC) synchronized theta (∼6 Hz) rhythms between these regions in a frequency and spatially specific manner and rapidly improved adaptive behavior with effects lasting longer than 40 min. In contrast, antiphase stimulation in the same individuals desynchronized MFC-lPFC theta phase coupling and impaired adaptive behavior. Surprisingly, the exogenously driven impairments in performance could be instantly rescued by reversing the phase angle of alternating current. The results suggest executive functions can be rapidly up- or down-regulated by modulating theta phase coupling of distant frontal cortical areas and can contribute to the development of tools for potentially normalizing executive dysfunction in patient populations.

Keywords: adaptive control; high-definition transcranial alternating current stimulation; lateral prefrontal cortex; medial frontal cortex; phase synchronization.

Fig. 1.

Stimulation and task procedures of Experiment 1. (A) The right-lateralized eight-channel 6-Hz inphase (Top) and antiphase (Bottom) HD-tACS protocols and current-flow models are shown on 3D reconstructions of the cortical surface. The location and current intensity value of each stimulating electrode are shown. Target regions were the medial frontal cortex (MFC) and right lateral prefrontal cortex (lPFC). Each stimulation site used four electrodes in a center-surround, source-sink pattern to achieve focality. (B) The sequence of events on feedback and nonfeedback trials in the time-estimation task. (C) Schematic illustration of the experimental design. Each subject underwent three separate test days (inphase, antiphase, and sham). On each day, EEG was recorded for 60 min while subjects performed the time-estimation task. The first 20 min consisted of inphase (blue), antiphase (red), or sham (black) HD-tACS, depending on the test day, and was followed by 40 min in which no stimulation was applied. The task alternated between blocks of feedback (FB, gray) and nonfeedback (NFB, white) trials. Critically, EEG data were analyzed only after the HD-tACS during the poststimulation period to avoid stimulation-related artifacts.

Fig. 2.

Experiment 1 results. (A) Performance measures of absolute error magnitude (Top), response variability (Middle), and adjustment efficiency (Bottom) across blocks of feedback (gray) and nonfeedback (white) trials during and after antiphase (6 Hz 180°, red), sham (black), and inphase (6 Hz 0°, blue) stimulation within the same subjects. The solid green lines show data from a subset of subjects who participated in the follow-up behavioral condition in which 35-Hz inphase stimulation was administered. (B) Time-frequency representations of phase coupling between electrodes overlaying medial frontal cortex (MFC) (i.e., the frontocentral midline, FCz) and right lateral prefrontal cortex (lPFC) (i.e., F6) from error-minus-correct feedback trials recorded after antiphase (180°), sham, or inphase (0°) stimulation. Cortical source reconstruction of FCz-seeded theta (4–8 Hz) interelectrode phase coupling at peak values between 200 and 600 ms after error relative to correct feedback shown across antiphase, sham, and inphase conditions. (C) FCz-F6 (Left) and FCz-F5 (Right) phase coupling from 200 to 600 ms after correct (solid line) and error (dashed line) feedback shown across delta (1–3 Hz), theta (4–8 Hz), alpha (9–12 Hz), and beta (13–30 Hz) frequency bands, and antiphase (red), sham (black), and inphase (blue) stimulation conditions. (D) Local theta (4–8 Hz) total power, 200–600 ms after correct (solid) or error (dashed) feedback shown across stimulation conditions and electrodes of interest. (E) Aggregated individualized β-weights from bivariate regressions between error feedback-locked peak theta phase coupling and the degree of error magnitude on the trial immediately after error feedback shown across antiphase (red), sham (black), and inphase (blue) conditions. The analytic window was 4–8 Hz and 200–600 ms postfeedback. Solid bars show phase coupling measured between FCz-F6, and outlined bars show coupling from FCz-F5. Phase coupling was calculated as the percentage change from baseline (i.e., −200–0 ms before feedback onset). Error bars in A, C–E show ±1 SEM.

Fig. 3.

Experiment 3 design and results. (A) Schematic illustration of the experimental design. Each participant underwent an active test day consisting of three consecutive stimulation sessions (i.e., sham, antiphase, inphase) and an inactive test day consisting of three consecutive sham stimulation sessions. On each day, behavior was recorded for ∼120 min while subjects performed the time-estimation task in which blocks of feedback (FB, gray) and nonfeedback (NFB, white) trials were interleaved. (B) Performance measures of absolute error magnitude (Top), response variability (Middle), and adjustment efficiency (Bottom) across blocks of feedback (gray) and nonfeedback (white) trials are shown during and after the sham (solid black), antiphase (6 Hz 180°, red), and inphase (6 Hz 0°, blue) stimulation sessions on the active test day, and the three sham (dashed black) stimulation sessions on the inactive test day within the same subjects. The dotted black lines in the third session show data from the final sham session of the follow-up test in which a subset of subjects from Experiment 3 received the sequence of sham, antiphase, and sham stimulation to determine whether the deleterious effects of antiphase stimulation would continue over a more protracted time course or naturally improve and return to baseline levels without the assistance of inphase stimulation. Error bars show ±1 SEM.