10 Apr 2019

Groups of neurons fire in sync with each other across the brain when it performs a task; however, with age, they fall out of step. In the April 8 Nature Neuroscience, Robert Reinhart and John Nguyen of Boston University reported that out-of-sync circuits explained a decline in working memory with age. What’s more, delivering a precisely tuned, very mild electrical current through the scalp restored neural synchrony and working memory performance—at least for an hour. How long the benefits might last, or whether they could extend to people with AD, remain to be tested. The story was widely reported in the media, including the home page of The New York Times. 

Marcus Raichle of Washington University in St. Louis was impressed that the study not only pinned decoupled rhythms to memory slippage, but also achieved a bona fide behavioral effect by resynchronizing them. He thinks exploring this type of treatment further is justified, but said that much is left to learn about exactly how these stimulations affect coordinated neuronal firing across the brain.

Brain rhythms oscillate at multiple frequencies, ranging from far-reaching, infra-slow waves with frequencies below 1 Hz to fast and localized gamma waves, with a frequency of around 40 Hz. Some fall out of sync with aging or during disease, and researchers have proposed that restoring them via externally applied stimuli could reverse deficits.

Rhythm Rescue. Phase amplitude coupling in the temporal cortex perked up during a memory task in young (left) but not old (center) adults. HD-tACs treatment restored coupling in older volunteers (right). [Courtesy of Reinhart and Nguyen, Nature Neuroscience, 2019.]

In their study, Reinhart and Nguyen focused on two types of rhythmicities in the frontotemporal cortex: theta oscillations, whose frequency is 4 to 8 Hz, spanning the prefrontal and temporal cortex; and phase-amplitude coupling of theta and gamma waves within the temporal cortex (Fell and Axmacher, 2011; Roux and Uhlhaas, 2014). 

The researchers initially recruited 42 people in their 20s, and 42 cognitively normal older folks aged 60–76. They used an EEG to measure brain waves in the prefrontal (PFC) and temporal cortex (TC) as the volunteers attempted to rapidly distinguish between novel and identical objects—a typical working-memory task. The older adults were much slower and error-prone. In the young volunteers, theta oscillations, ranging from 7–9 Hz, in the PFC and TC were strikingly synchronized, and the theta-gamma phase-amplitude coupling in the TC was much stronger than in the older people. Among the young volunteers, the extent of rhythmicity correlated with their working-memory performance.

Could synching up these circuits boost working memory in the older adults? The researchers used high–definition, transcranial, alternating-current stimulation (HD-tACS)—a recently improved version of tACS that allows more precise targeting—to deliver theta-tuned electrical pulses into the prefrontal and temporal cortex. Because the exact frequency of theta oscillations varied among people, the researchers tailored their stimulations to suit each individual’s inherent rhythms. Each donned a skullcap affixed with electrodes that delivered the theta waves for 25 minutes as they took the working memory test, and they continued to do the task for another 50 minutes after the stimulus stopped. (The skullcaps also contained recording electrodes.) Remarkably, after eight to 12 minutes of stimulation, the volunteers’ performance started to improve. By 25 minutes, the older participants distinguished objects with as much speed and accuracy as the young participants did without stimulation. They maintained their working memory prowess for 50 minutes after the stimulus stopped.

As intended, the stimulation restored synchronous firing in the targeted frontotemporal circuits, an effect that lasted for the duration of the experiment. The researchers repeated these experiments, with largely the same results, in an additional 28 older volunteers. They also invited back the young volunteers who had performed poorest on the task, and found that their working memory improved when they received the stimulation. Working memory rapidly slipped in young volunteers when neuronal firing was intentionally desynchronized with an out-of-phase current.

Together, the findings suggest that synchronization of neuronal firing between frontotemporal areas underlies working memory, and that restoring the brain rhythms rescues memory deficits. To Reinhart, the findings suggest that age-related working memory loss is reversible. But for how long? He does not know if the improvement could last beyond the tested 50 minutes, or whether the benefit extends beyond the memory test into the real world. He pointed out that functionally connected circuitry controls both working and long-term memory, suggesting that the stimulation could have broader implications. He plans to study whether restoring these brain rhythms might restore memory in people with AD and other brain disorders.

Other recent studies in AD mice suggest that synchronizing brain rhythms might even remove Aβ pathology. Researchers led by Li-Huei Tsai at Massachusetts Institute of Technology in Boston recently reported that exposing AD mouse models to light or sound at a frequency of 40 Hz synched gamma oscillations, which somehow triggered microglia to mop up plaques and even restored memory (Dec 2016 news; Mar 2019 news). 

Tsai noted that Reinhart’s data mesh with her mouse findings, and also with an independent study reporting loss of theta-gamma coupling in people with AD and MCI (Goodman et al., 2018). “All together, boosting neural oscillations using noninvasive stimulation approaches could be broadly beneficial to age-related cognitive impairment,” Tsai wrote to Alzforum.

Efforts to use such approaches to treat AD are underway. An FDA panel recently rejected a device called neuroAD for use in the U.S. after a Phase 3 trial failed to show clear benefit (Mar 2019 news). 

Tsai stimulated mice with light and sound to entrain gamma waves, while Reinhart used electrical current to synchronize theta waves to boost working memory in humans. These differences in methods and entrained frequencies illustrate that more work is needed to understand how external stimuli can influence functional connectivity in the brain, Raichle said. For example, he pointed out that the BU researchers did not even measure the lower frequency infra-slow waves that orchestrate large-scale connectivity over long distances. He added that future studies could incorporate imaging measures, such as functional MRI, to more precisely investigate how these stimulations affect connectivity and plasticity.—Jessica Shugart

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References

News Citations

1. Flashy Treatment Synchronizes Neurons, Lowers Aβ in Mice 7 Dec 2016
2. Flash! Beep! Gamma Waves Stimulate Microglia, Memory 15 Mar 2019
3. FDA Panel Rejects Neuronix Brain Stimulation Device 27 Mar 2019

Paper Citations

1. Fell J, Axmacher N. The role of phase synchronization in memory processes. Nat Rev Neurosci. 2011 Feb;12(2):105-18. PubMed.
2. Roux F, Uhlhaas PJ. Working memory and neural oscillations: α-γ versus θ-γ codes for distinct WM information?. Trends Cogn Sci. 2014 Jan;18(1):16-25. Epub 2013 Nov 19 PubMed.
3. Goodman MS, Kumar S, Zomorrodi R, Ghazala Z, Cheam AS, Barr MS, Daskalakis ZJ, Blumberger DM, Fischer C, Flint A, Mah L, Herrmann N, Bowie CR, Mulsant BH, Rajji TK. Theta-Gamma Coupling and Working Memory in Alzheimer's Dementia and Mild Cognitive Impairment. Front Aging Neurosci. 2018;10:101. Epub 2018 Apr 16 PubMed.

External Citations

1. The New York Times

Further Reading

News

1. Off Key—Aβ Detunes the Theta Rhythms of the Hippocampus 25 Aug 2010
2. Deep Brain Stimulation: It’s All About the Rhythm 22 Apr 2015