Promoting Sleep Oscillations and Their Functional Coupling by Transcranial Stimulation Enhances Memory Consolidation in Mild Cognitive Impairment

Abstract

Alzheimer's disease (AD) not only involves loss of memory functions, but also prominent deterioration of sleep physiology, which is already evident at the stage of mild cognitive impairment (MCI). Cortical slow oscillations (SO; 0.5-1 Hz) and thalamocortical spindle activity (12-15 Hz) during sleep, and their temporal coordination, are considered critical for memory formation. We investigated the potential of slow oscillatory transcranial direct current stimulation (so-tDCS), applied during a daytime nap in a sleep-state-dependent manner, to modulate these activity patterns and sleep-related memory consolidation in nine male and seven female human patients with MCI. Stimulation significantly increased overall SO and spindle power, amplified spindle power during SO up-phases, and led to stronger synchronization between SO and spindle power fluctuations in EEG recordings. Moreover, visual declarative memory was improved by so-tDCS compared with sham stimulation and was associated with stronger synchronization. These findings indicate a well-tolerated therapeutic approach for disordered sleep physiology and memory deficits in MCI patients and advance our understanding of offline memory consolidation.SIGNIFICANCE STATEMENT In the light of increasing evidence that sleep disruption is crucially involved in the progression of Alzheimer's disease (AD), sleep appears as a promising treatment target in this pathology, particularly to counteract memory decline. This study demonstrates the potential of a noninvasive brain stimulation method during sleep in patients with mild cognitive impairment (MCI), a precursor of AD, and advances our understanding of its mechanism. We provide first time evidence that slow oscillatory transcranial stimulation amplifies the functional cross-frequency coupling between memory-relevant brain oscillations and improves visual memory consolidation in patients with MCI.

Keywords: declarative memory; mild cognitive impairment; phase-amplitude coupling; sleep; transcranial electrical stimulation.

Conflict of interest statement

The authors declare no competing financial interests.

Copyright © 2017 the authors 0270-6474/17/377111-14$15.00/0.

Figures

Figure 1.

Study design. a, Subjects learned a verbal, a visuospatial, and a procedural task in the indicated order after psychometric control tests. During a subsequent 90 min nap (2:00 P.M. to 3:30 P.M.), EEG was recorded and either slow oscillatory transcranial direct current stimulation (so-tDCS) or sham stimulation was applied (within-subject design, randomized order) in up to five 5 min blocks that started after sleep stage 2 onset. According to the example hypnogram stimulation, blocks are discontinued as the subject moves from sleep stage 2 to stage 1, and resumed after the subject again enters sleep stage 2 (or lower). Thick line in the hypnogram is REM. S1–S4, Sleep stages 1–4. Recordings from electrodes Fz, FC1, and FC2 (frontal ROI), and Cz, CP1, and CP2 (centroparietal ROI) during 1 min stimulation-free intervals starting 40 s after each so-tDCS/sham block were used for spectral and phase amplitude coupling analyses. Memory retrieval and psychometric control tests were performed 30 min after the nap. b, Example encoding and recognition trials of the visuospatial memory task. For encoding, a gray rectangle was presented at one of the quadrants of the screen after a fixation cross and followed by a neutral picture within the gray region for 2 s. For recognition, a picture was displayed in the center of the screen for 3 s after a fixation cross. Within this time period, subjects were asked to indicate whether they believed they had seen the picture earlier. If subjects recognized an item, then they also indicated in which quadrant they believed the item had been presented.

Figure 2.

so-tDCS enhances EEG power in the SO and fast spindle frequency ranges. EEG power in the SO (0.5–1 Hz, top) and fast spindle (12–15 Hz, bottom) frequency ranges for the five 1 min stimulation-free intervals, for so-tDCS (red) and sham (gray) condition, and considering the frontal (left) and centroparietal (right) ROI. Mean estimates ± SEM (shaded regions) from the LMM are included. To the right, individual mean power changes (mean over all intervals for each subject) from sham (gray squares) to so-tDCS (red circles) are indicated for each frequency band and ROI.

Figure 3.

Phase amplitude coupling between SO and spindle power. a, Grand average EEG trace (mean ± SEM across participants) of a total of 860 events for so-tDCS (red) and 765 events for sham (black) condition aligned to the SO trough (time 0) from the centroparietal ROI and all 1 min stimulation-free intervals. b, TFRs locked to the SO events (from a) and averaged per condition: so-tDCS (top) and sham (center). Shown are the differences from the pre-event baseline power values (−2.5 s to −1.2 s). Bottom, Difference of these TFRs masked by significance (p < 0.05, corrected). c, Time course of event-locked average power from the TFRs in b filtered in the range of the modulating SO for the fast spindle (12–15 Hz, top) and slow spindle (8–12 Hz, bottom) frequency ranges (mean ± SEM across participants). d, Histogram of SI angles indicating the phase difference between SO and the fast spindle power fluctuation (cf. a and c) for the conditions so-tDCS (top, n = 860) and sham (bottom, n = 765). An angle value of 0 indicates synchrony, whereas 180 deg indicates an anti-phase relationship. A value just below 0 (close to 360 deg) indicates that spindle power tended to peak shortly before the SO peak. Note that the SI angle distribution for so-tDCS indicates that the spindle power peak preferably occurred during the late rising phase of SO. e, SIs averaged per subject (thin lines) and across subjects (thick lines) for the two conditions. Note that the angle of the SI indicates the phase of SO at which spindles tend to occur, whereas its radius indicates the strength of locking (coupling) between SO and the oscillatory spindle power fluctuations.

Figure 4.

Retention performance in declarative memory tasks in the so-tDCS versus sham condition. a, b, Recognition performance (percentage correct: proportion of hits and correct rejections) in the picture memory subtask (a) and cued recall performance (percentage correct) in the verbal memory task (b) for so-tDCS (red) and sham condition (gray) measured before (pre-nap) and after (post-nap) the nap. Dots indicate individual performances, a white line represents the mean per condition and time point, violin plots show the distributions across subjects. A significant stimulation effect emerged for picture memory, with higher picture recognition performance after so-tDCS compared with sham condition. *p < 0.05. c, Picture recognition performance of individuals before and after napping for so-tDCS (left) and sham (right) condition. Note the separate scale for the outlier (subject 15, gray) in sham.

Figure 5.

Relationship between SO-to-fast spindle phase amplitude coupling and visual memory task performance. a, Subject-averaged SI values from the centroparietal ROI (cf. Fig. 4b) colored according to the change in visual task performance (post-nap − pre-nap) for so-tDCS (left) and sham (right) condition. Warm color indicates an improvement after the nap. b, Subject-wise difference of SI radii between conditions (indicating the change in locking strength) versus difference of absolute SI angles (reflecting the change in “preferred” SO phase at which fast spindles tend to occur) colored according to the difference of visual task performance change (“so-tDCS − sham”). Warm color indicates an improvement due to so-tDCS.