Popular Stimulation Method May Not 'Enhance' Brain Activity After All

Pauline Anderson

November 13, 2017

New research questions the accepted mechanism by which transcranial alternating-current stimulation (tACS), a popular form of noninvasive brain stimulation, may improve memory.

Over the last 15 or so years, several studies have reported that tACS enhances memory. It's widely believed that the stimulation entrains and enhances neural rhythms related to memory.

But the new study, which measured endogenous brain activity intracranially in patients with epilepsy while applying tACS, showed no enhanced brain activity during non–rapid eye  movement (NREM) sleep or during restful wakefulness.

The researchers did not "set out to discredit" these previous studies, Anli Liu, MD, assistant professor of neurology at NYU School of Medicine and neurologist at NYU Langone Health's Comprehensive Epilepsy Center in New York City, told Medscape Medical News.

"We don't want to discourage the entire field of transcranial electrical stimulation because, I think, everyone who does this kind of research wants to develop noninvasive therapies to enhance memory or for some other therapeutic benefit."

What's important, said Dr Liu, is to explore other potential mechanisms for how tACS may work.

The study was published October 31 in Nature Communications.

No Changes in Brain Activity

The analysis included adult patients with medication-refractory focal-onset epilepsy undergoing invasive evaluation for seizure localization.

Researchers applied low-frequency tACS to 13 patients with implanted subdual and depth electrodes while measuring brain activity directly from the cortical surface.

Intracranial electroencephalography (EEG) provides superior signal quality compared with scalp EEG. It allows for the direct measurement of induced electrical fields and their acute effect on mesoscopic brain activity, the authors note.  

The tACS protocol involves stimulation alternating between high (up to 1 to 2 milliamps [mA]) and low (close to 0 mA) intensities. The pulses are administered at a frequency of 1 or 0.75 Hz.

Seven of the 13 patients were stimulated during NREM sleep (4 during daytime NREM sleep and  3 during nocturnal NREM sleep). Six patients were stimulated during waking rest.

All patients who were stimulated during night-time sleep, and most patients who were stimulated during an afternoon nap, were able to sleep through the stimulation.

The researchers recorded and analyzed signals from 1700 electrodes (mean of 131 per patient). There were no complications from stimulation and no induced electrographic seizures.

Investigators expected to see enhanced brain activity that could potentially boost sleep-dependent memory function, said Dr Liu.

Instead, they found that tACS, applied during NREM sleep at common stimulation intensities, did not reliably entrain spindle oscillations during NREM sleep. They note that spindle activity or events refer to brain rhythms during sleep that are thought to be associated with learning and memory.

The tACS applied during waking rest did not modulate theta, alpha, or gamma frequency activity.

"Essentially, we didn't find anything," said Dr Liu. "There were no changes in brain activity during sleep or wakefulness when we applied the stimulation in a manner that was similar to the way it was applied in previous studies. So our conclusion is that this very common and influential protocol doesn't affect brain activity."

Dr Liu pointed out that with this protocol, only about 20% of the electric current actually reaches the brain surface, with about 80% being "shunted away" by the skin and skull.

"It could be that with tACS, the current that reaches the brain surface is too weak to enhance brain activity."

DIY Brain Stimulation

Promising earlier findings generated enthusiasm for this noninvasive approach and led to a public zeal for do-it-yourself (DIY) transcranial stimulation devices, which are frequently marketed over the Internet.

As reported by Medscape Medical News, experts have previously warned about the dangers of DIY brain stimulation.

These findings, Dr. Liu noted, should give the public further pause when considering a DIY approach to memory enhancement.

A potential direction for future research, said Dr Liu, is to discover ways to deliver a higher-intensity current that would influence brain activity. However, she noted that once the current strength gets beyond 2 mA, patients can start to experience discomfort or pain.

The negative results in this study are not due to patients with epilepsy having abnormal brains, said Dr Liu.

She pointed out that the sleep physiology of these patients "was by and large normal," even if they were receiving antiseizure drugs, and that the kind of epilepsy they had affects only a part of the brain.

"The fact that they have focal epilepsy as well as the fact that they were on medications doesn't mean that we wouldn't be able to see the sleep rhythms we were looking for."

Addressing concerns that the researchers didn't exactly replicate previous sleep studies that used tACS because they couldn't put stimulating electrodes over the frontal-central region of the brain in the epileptic patients (as a result of the surgical site bandage), the investigators performed a "precise replication experiment of prior protocols" in another patient without epilepsy.

During epilepsy monitoring, it was discovered that this patient, initially believed to have epilepsy, actually had "pseudo seizures." Although these events looked like seizures, there was no abnormal electrical activity.

"Even in this patient, with a healthy brain and totally normal sleep, using the exact same replication experiment, we couldn't find any enhancement or change in brain activity," said Dr Liu

The researchers also investigated acoustic stimulation — sound pulses. In previous studies, this type of stimulation had shown enhanced brain activity during sleep that is associated with memory improvement.

Exploring Other Mechanisms

In four patients with epilepsy, the researchers applied the acoustic stimulation during sleep at a similar frequency as with tACS.

"We were able to enhance sleep activity, particularly spindles and slow waves, with this acoustic protocol," said Dr Liu.

This, she added, "essentially refutes," again, the idea that the brains of patients with epilepsy are too abnormal for stimulation to have an effect.

The null results of the study regarding the ability of tACS to boost brain activity don't necessarily contradict the reported behavioral effects of this stimulation, said Dr Liu.

Noninvasive stimulation could affect brain activity in multiple indirect ways. For example, it may activate supportive neural tissue or have a sensory effect or maybe even a placebo effect, she said

"There may be other physiological mechanisms at play that could explain why some studies show a memory benefit, but it's not by directly affecting the brain," said Dr Liu

"One of the lessons I've learned from this research is that the way we think about how this kind of stimulation works is simplistic, especially in relation to how complex the brain is," she added.

Dr Liu said she hopes the negative finding "pushes researchers to think past the simple and incorrect ideas of what tACS does to produce these behavioral effects when it does, and begin to explore other potential mechanisms for how tACS may work."

Once researchers have a more refined understanding of how tACS works, they may be better able to tap into those mechanisms "to then produce more reliable and robust behavioral results," added Dr Liu.

This work was supported by R01 MH107396-01, R44 NS092144, R01 MH-092926, NS095123, R41 NS076123, NYU Program Project Grant Development Initiative; the  NYU Clinical and Translational Science Institute; NYU Finding a Cure for Epilepsy; and the Zimin Foundation. Dr Liu has disclosed no relevant financial relations hips.

Nat Commun. Published online October 31 2017. Full text

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