In Pilot Study, Electric Therapy Improves Memory

Series - International Conference on Alzheimer's and Parkinson's Diseases 2021 (Virtual):

Can electric current spark better memory in people with mild cognitive impairment? Possibly, according to researchers—at least short-term. At the 15th International Conference on Alzheimer's and Parkinson's Diseases, held virtually March 9–14, Alberto Benussi, University of Brescia, Italy, presented results from a neuromodulation pilot study. The complete findings were published in the March 21 Brain Stimulation. He and other researchers led by Barbara Borroni at U Brescia used transcranial alternating current stimulation (tACS), a low-intensity electric current therapy set at a gamma frequency of 40 Hz. After a one-hour session, people with MCI recalled more words and matched more names to faces than people who got sham treatment. Their acetylcholine signaling was restored to levels seen in healthy people, the scientists claimed. Whether gamma entrainment occurred will be tested in a larger trial.

  • One-hour session of gamma frequency electric current therapy improved short-term memory.
  • Known as tACS, the procedure restored acetylcholine signaling to normal.
  • The effect on gamma wave entrainment to be determined.

This neurophysiological approach to therapy is similar, but not identical, to GENUS, which uses the sensory stimuli light and sound to coordinate neuronal firing via gamma entrainment (see Part 13 of this series). tACS stimulates specific brain areas with electrical current through electrodes on the scalp. Pulsing electricity at 40 Hz is thought to entrain gamma waves (reviewed by Strüber and Herrmann, 2020). Neuronal firing in the gamma band falls out of sync in people with MCI and Alzheimer’s disease (Koenig et al., 2005; Dec 2016 news). 

Previously, other researchers had used tACS in cognitively normal older people to stimulate 4–8 Hz theta waves in the frontotemporal cortex. This synchronized participants' natural theta oscillations within 25 minutes of treatment, which in turn improved their working memory for at least 50 minutes afterward (Apr 2019 news). 

For the GammAD pilot study, Benussi and colleagues recruited 20 people with mild AD from the Center for Neurodegenerative Disorders in Brescia. The researchers stuck one electrode to the top of each participant’s scalp and the other to his or her right shoulder (see image below). “Current flows from one to the other, so the second electrode guides the current from the skull through deep brain structures, such as the precuneus,” Benussi explained. They targeted the precuneus, an area in the default network, because amyloid plaques accumulate there early in AD (Aug 2009 news). 

In at Red, Out at Black. During transcranial alternating current stimulation, low-intensity 40 Hz electricity flows from one electrode (red) to the other (black). The current is believed to travel through the precuneus deeply into the brain and out to the shoulder. [Courtesy of Benussi et al., 2021.]

All participants received both active and sham treatment in a crossover design, i.e., they got one, waited a week, then got the other. “We chose a crossover design to increase statistical power to tease out differences triggered by the treatment,” Benussi said. At the clinic, participants wore the tACS device for one hour. It emitted 40 Hz electric current for the entire hour during active treatment and for one minute during sham treatment. “After one minute, people cannot feel the current anymore, so they cannot tell if they receive pulses for longer,” Benussi wrote to Alzforum. All 20 participants completed the trial; none reported significant side effects.

Benussi and colleagues relied on the Rey auditory verbal learning test (RAVLT), before and after each treatment, to test the participants’ memory (see image below). Participants treated with tACS remembered 25 percent more words immediately, and twice as many after the 20-minute delay, than did controls. While participants were completing their last 20 minutes of treatment, they completed the face-name association task. People who got active treatment also remembered almost twice as many face-name pairs. “We were astonished to see clinical and neurophysiological changes after only one hour of stimulation,” Benussi said.

Crisscross. Participants received both tACS and sham treatment, separated by a week. They were evaluated with transcranial magnetic stimulation (TMS) and took the Rey auditory verbal learning test (RAVLT) before and after each session. During the last 20 minutes of treatment, participants matched faces to names. [Courtesy of Benussi et al., 2021.]

What caused this improvement—could it be synchronized gamma waves? The researchers did not record EEGs, so they do not know. “We are currently putting together a larger study where we will record EEGs to answer this question,” Benussi told Alzforum.

Benussi initially pursued a different concept, wondering if tACS might improve cholinergic transmission. People with AD have less acetylcholine than healthy people, which is why cholinesterase inhibitors were developed to slow its breakdown. This neurotransmitter deficit can be indirectly detected using transcranial magnetic (TMS)—not electrical—stimulation to inhibit short-latency afferent currents in cholinergic circuits. In this case, the authors placed the TMS coil on the scalp above the region of the motor cortex that controls primary hand movement. The TMS signal could then be used to block motor evoked potentials in the cortex. When there’s less acetylcholine around, this TMS-induced short-latency inhibition is weaker.   

Benussi and colleagues previously used this strategy to detect transmission deficits in people with MCI that were not found in healthy people (Benussi et al., 2021). 

Would tACS stimulation counter TMS-driven inhibitor of cholinergic circuits? Benussi reported that, in this pilot trial population, tACS stimulation restored short-latency afferent inhibition to levels seen in healthy people, suggesting there was more acetylcholine transmission (see image below). “Increasing cholinergic transmission could be one way this stimulation works,” Benussi wrote to Alzforum.

Back to Normal? In this pilot trial, people had less short-latency afferent inhibition of cholinergic circuits (right) after treatment (green bars) than after a placebo (blue bars). Inhibition was restored from baseline (left) to healthy control levels (blue line) as compared to levels typically seen in AD (red line). [Courtesy of Benussi et al., 2021.]

For next steps, Benussi and his colleagues want to define how much electric current is reaching the precuneus and if repeated treatment extends the benefit. They plan to see if ApoE status and baseline cognitive reserve affect treatment response. They will also study how long the short-term memory improvements last, since they only measured memory immediately after tACS in this pilot study.

To that point, another pilot study recently investigated longer-term effects of multiple sessions of gamma tACS in combination with cognitive training. Seventeen older adults with mild to moderate dementia performed cognitive training tasks in the lab for one hour daily, five days a week for four weeks; 11 also received simultaneous tACS. Participants sat for Wechsler Memory Scale (WMS-IV) testing at baseline, after four weeks of treatment, and one month after treatment ended. Both groups improved their scores after treatment, but the tACS recipients better sustained their improvement one month after treatment than did participants who did not receive tACS (Kehler et al., 2020). 

TMS itself was being developed to treat AD by Neuronix, a company based in Yokneam, Israel. Their neuroAD chair apparatus paired repetitive TMS with simultaneous cognitive training (Apr 2017 conference news). In 2019, an FDA panel advised against its approval (Mar 2019 news). The company’s website is no longer active. Benussi’s group is not using TMS as a treatment, but rather as an indirect way to measure acetylcholine signaling.—Chelsea Weidman Burke

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References

News Citations

  1. Does Synchronizing Brain Waves Bring Harmony?
  2. Flashy Treatment Synchronizes Neurons, Lowers Aβ in Mice
  3. Resetting Brain Rhythms Gives Working Memory a Brief Boost
  4. BOLD New Look—Aβ Linked to Default Network Dysfunction
  5. Transcranial Magnetic Stimulation for AD Boasts Success in Phase 3
  6. FDA Panel Rejects Neuronix Brain Stimulation Device

Paper Citations

  1. Strüber D, Herrmann CS. Modulation of gamma oscillations as a possible therapeutic tool for neuropsychiatric diseases: A review and perspective. Int J Psychophysiol. 2020 Jun;152:15-25. Epub 2020 Mar 30 PubMed.
  2. Koenig T, Prichep L, Dierks T, Hubl D, Wahlund LO, John ER, Jelic V. Decreased EEG synchronization in Alzheimer's disease and mild cognitive impairment. Neurobiol Aging. 2005 Feb;26(2):165-71. PubMed.
  3. Benussi A, Grassi M, Palluzzi F, Cantoni V, Cotelli MS, Premi E, Di Lorenzo F, Pellicciari MC, Ranieri F, Musumeci G, Marra C, Manganotti P, Nardone R, Di Lazzaro V, Koch G, Borroni B. Classification accuracy of TMS for the diagnosis of mild cognitive impairment. Brain Stimul. 2021 Mar-Apr;14(2):241-249. Epub 2021 Jan 13 PubMed.
  4. Kehler L, Francisco CO, Uehara MA, Moussavi Z. The effect of transcranial alternating current stimulation (tACS) on cognitive function in older adults with dementia. Annu Int Conf IEEE Eng Med Biol Soc. 2020 Jul;2020:3649-3653. PubMed.

External Citations

  1. GammAD

Further Reading

Primary Papers

  1. Benussi A, Cantoni V, Cotelli MS, Cotelli M, Brattini C, Datta A, Thomas C, Santarnecchi E, Pascual-Leone A, Borroni B. Exposure to gamma tACS in Alzheimer's disease: A randomized, double-blind, sham-controlled, crossover, pilot study. Brain Stimul. 2021 May-Jun;14(3):531-540. Epub 2021 Mar 21 PubMed.

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