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Working memory revived in older adults by synchronizing rhythmic brain circuits


Understanding normal brain aging and developing methods to maintain or improve cognition in older adults are major goals of fundamental and translational neuroscience. Here we show a core feature of cognitive decline—working-memory deficits—emerges from disconnected local and long-range circuits instantiated by theta–gamma phase–amplitude coupling in temporal cortex and theta phase synchronization across frontotemporal cortex. We developed a noninvasive stimulation procedure for modulating long-range theta interactions in adults aged 60–76 years. After 25 min of stimulation, frequency-tuned to individual brain network dynamics, we observed a preferential increase in neural synchronization patterns and the return of sender–receiver relationships of information flow within and between frontotemporal regions. The end result was rapid improvement in working-memory performance that outlasted a 50 min post-stimulation period. The results provide insight into the physiological foundations of age-related cognitive impairment and contribute to groundwork for future non-pharmacological interventions targeting aspects of cognitive decline.

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Fig. 1: Experiment 1, frontotemporal HD-tACS procedure and task.
Fig. 2: Experiment 1, behavioral results.
Fig. 3: Experiment 1, PAC results.
Fig. 4: Experiment 1, phase synchronization results.
Fig. 5: Experiment 2, single-region HD-tACS procedures.
Fig. 6: Experiment 2, behavioral results.

Data availability

The data and software code that support the findings of this study are available from the corresponding author upon reasonable request.


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This work was supported by a grant from the National Institutes of Health (R01 MH 114877) awarded to R.M.G.R.

Author information




R.M.G.R. conceived the experiments. R.M.G.R. and J.A.N. conducted the experiments and analyzed the data. R.M.G.R. wrote the paper.

Corresponding author

Correspondence to Robert M. G. Reinhart.

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The authors declare no competing interests.

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Journal peer review information: Nature Neuroscience thanks Michael Nitsche and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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Integrated supplementary information

Supplementary Figure 1 Experiment 1: Age, but not HD-tACS, impacts posterior alpha power suppression.

We questioned whether improvements in maintenance-related neural interactions and working-memory behavior might be due to the stimulation having enhanced perceptual attention immediately after target onset, which could in turn boost the fidelity of the target representation stored in working memory. To test this idea, we examined alpha power suppression immediately after target presentation because this EEG signature is thought to index the release of inhibition to facilitate task-relevant processing 92. If the exogenous stimulation enhanced working memory via a gating-by-inhibition attention mechanism, we should find greater target-locked posterior alpha suppression after active relative to sham stimulation in older adults. a, Target-locked time-frequency representations of total power from occipital and parietooccipital electrodes during memory blocks following sham stimulation in younger minus older adults reveal a significant age-related deficit in alpha suppression (t82 = 3.154, P = 0.002, dz = 0.688), suggesting that older adults were unable to functionally disinhibit task-relevant areas as efficiently as younger adults during the perceptual analysis of real-world objects. b, However, this age-related deficit in alpha suppression remained significant even after older adults received active stimulation (t82 = 2.766, P = 0.007, dz = 0.604). c, No changes to alpha power were observed between sham and active stimulation in older adults (t41 = 0.733, P = 0.468, dz = 0.113). The results showing age-related dysfunction in alpha rhythms during perceptual analysis align with work on the selective attention deficits in aging 96–98. However, unlike the neural interactions of theta-gamma PAC and theta phase synchronization during memory maintenance, this earlier signal during stimulus processing was not influenced by the HD-tACS and is thus an unlikely candidate for underlying the stimulation-induced performance benefit observed in older adults. Topographies show the spatial distribution of the power responses during the 8–14 Hz, 100–400 ms post-target analytic window, indicated by the white dashed box. Between-group comparisons used independent two-tailed t-tests (n = 84). Within-group comparisons used paired sample two-tailed t-tests (n = 42).

Supplementary Figure 2 Experiment 3: Reversing the phase angle of HD-tACS impairs working-memory performance.

We interpret the findings from experiments 1 and 2 showing improved working-memory performance following in-phase stimulation as resulting from the increased temporal synchronization of large-scale cortical interactions. However, if working-memory performance is truly mediated by a phase-sensitive network mechanism, then we should find that changing the phase angle direction of alternating current applied to frontotemporal regions should change the direction of the effects on behavioral performance. Unlike experiments 1 and 2 where we sought to synchronize neural activity with in-phase stimulation and enhance working memory, experiment 3 tested whether a desynchronizing or anti-phase montage could impair working memory. We predicted that delivering theta-tuned HD-tACS simultaneously to frontal and temporal regions with a relative 180° phase difference between targeted areas would impede frontotemporal neural integration and induce impairments in working-memory performance. We tested this prediction in a new cohort of young adults using a double blind, sham-controlled, within-subjects design (Methods), in which working-memory behavior on the change-detection task was evaluated (Fig. 1b). Experiment 3 showed that by shifting the phase angle of alternating current, we could switch the direction of the causal effects on working-memory performance. Box plots of RT and accuracy in young adults from memory blocks show anti-phase stimulation significantly decreased accuracy (t17 = 3.359, P = 0.004, dz = 0.792) and increased RT (t17 = 2.928, P = 0.009, dz = 0.690), relative to sham. These results, combined with those from experiments 1 and 2, suggest that we may be able to obtain rapid, bidirectional control over phase-sensitive memory mechanisms using frequency-tuned HD-tACS. Paired sample two-tailed t-tests (n = 18). Box-plot center, median; box limits, lower and upper quartiles; whiskers, lower and upper extreme values; points, outliers. ** P < 0.01.

Supplementary Figure 3 Experiment 4: HD-tACS improves working-memory success in poor performing young adults.

We asked whether the HD-tACS behavioral improvement observed in older adults across experiments 1 and 2 could be extended to younger individuals with relatively poor working-memory performance and weak maintenance-related PAC (Fig. 3e). For experiment 4, we re-recruited the poorest performing younger adults from experiment 1 to participate in a single test day involving frequency-tuned in-phase frontotemporal HD-tACS (Methods). Subjects’ behavior on the change-detection task (Fig. 1b) was collected before, during, and after stimulation. Box plots of RT and accuracy of poor performing younger adults from memory blocks show preferential enhancement of working-memory accuracy following stimulation, relative to the pre-stimulation baseline (t13 = 3.610, P = 0.003, dz = 0.965) and relative to subjects’ sham stimulation day from experiment 1 (t13 = 3.571, P = 0.003, dz = 0.954). Consistent with previous findings from older adults, the in-phase stimulation did not affect RT in these poor performing younger subjects compared to either baseline condition (all t13 < 0.656, P > 0.523, dz < 0.175). Further analysis showed that post-stimulation accuracy gains were significant for each 4 min time bin, relative to either baseline control condition (all t13 > 3.520, P < 0.005, dz > 0.941). The results suggest that the HD-tACS improvement may be applicable to younger individuals with poor working-memory function. Paired sample two-tailed t-tests (n = 14). Box-plot center, median; box limits, lower and upper quartiles; whiskers, lower and upper extreme values; points, outliers. ** P < 0.01.

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Reinhart, R.M.G., Nguyen, J.A. Working memory revived in older adults by synchronizing rhythmic brain circuits. Nat Neurosci 22, 820–827 (2019).

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