16 Feb 2018

Scientists have tried enhancing memory by modulating neurons in the brain, to little success. In the February 6 Nature Communications, researchers led by Michael Kahana and Daniel Rizzuto, University of Pennsylvania, Philadelphia, scored a victory by giving neurons an electrical boost in the right place at the right time. Their approach relies on “closed-loop” stimulation. This term implies activating neurons only timed to a specific event, in this case poor encoding of memories, analogous to a pacemaker that kicks in only when the heart’s rhythm becomes abnormal. The paper’s implications for treating memory disorders caught the attention of media outlets, including the New York Times. 

“I agree this approach could help researchers develop future interventions in the field of neurodegenerative disorders,” noted Lorenzo Pini, IRCCS Centro San Giovanni di Dio–Fatebenefratelli, Brescia, Italy. Pini added that the results could be especially helpful for designing noninvasive stimulation protocols (Apr 2017 news). Some strategies under consideration for boosting memory require electrodes be implanted into the brain.

Why has neuromodulation to boost memory proved so challenging (Nov 2017 news; Jacobs et al., 2016)? The authors partially blame open-loop interventions, which zap neurons continuously without taking into account their changing states. Also, most interventions have targeted the medial temporal lobes, which, though critical for spatial learning, are not the only, nor perhaps the best, target in human memory, said Rizzuto. This study targeted the lateral temporal lobes.

With these issues in mind, first author Youssef Ezzyat analyzed electrical recordings from 25 epilepsy patients. They had electrodes implanted in their brain that monitored more than 100 spots to evaluate prospects for corrective neurosurgery. Ezzyat used the electrodes to map brain activity during a memorization task. Volunteers had to remember 12 words flashed in succession on a screen and, after being distracted with math problems, recall as many words as they could. Most remembered about four. Intracranial electroencephalography (iEEG) revealed firing patterns that correlated with remembered words, as well as patterns matching words not recalled. Although each patient’s signatures were unique, in general, global rises in high-frequency activity, together with drops in low-frequency activity, correlated with successful memorization.

Ezzyat used this knowledge as a basis to improve memory. He gave the volunteers a new list of words, but this time, when he detected an iEEG pattern indicative of poor memorization, he stimulated various regions of the brain via the same implanted electrodes. The lateral temporal cortex proved to be the most effective target for this kind of prodding. A 500 millisecond pulse at a frequency and amplitude customized to each patient based on his or her iEEG data optimally disrupted the faulty encoding pattern and improved patients’ scores by 15 percent on average. “This may not sound like a lot, but for a person with Alzheimer’s disease it could make a difference,” said Rizzuto. He estimates that 15 percent better recall could delay symptom onset by 2–2.5 years.

Hoping to develop a therapeutic device, Rizzuto recently founded Nia Therapeutics, based in Philadelphia. He envisions implanting a device in people with AD, or other memory disorders, similar to those currently used for deep-brain stimulation of patients with Parkinson’s disease. The electrodes, programmable controls, and battery would all be implanted in the body. “It will be completely invisible, with no external components,” said Rizzuto. After implantation, patients would see a neurologist who would run memory tests such as the one in this study, and program the closed-loop stimulation. The device could be reprogrammed as needed.

Rizzuto plans to piggyback on previously developed technologies, such as implantable neurostimulators for epilepsy that deliver an electric jolt when they sense the beginnings of a seizure. One major challenge, says Rizzuto, is to figure out how to package the nearly 130 electrode contacts needed to get efficient firing signatures.—Marina Chicurel

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References

News Citations

1. Transcranial Magnetic Stimulation for AD Boasts Success in Phase 3 27 Apr 2017
2. Sparking the Brain May Enhance Plasticity, Memory 3 Nov 2017

Paper Citations

1. Jacobs J, Miller J, Lee SA, Coffey T, Watrous AJ, Sperling MR, Sharan A, Worrell G, Berry B, Lega B, Jobst BC, Davis K, Gross RE, Sheth SA, Ezzyat Y, Das SR, Stein J, Gorniak R, Kahana MJ, Rizzuto DS. Direct Electrical Stimulation of the Human Entorhinal Region and Hippocampus Impairs Memory. Neuron. 2016 Dec 7;92(5):983-990. PubMed.

External Citations

1. New York Times

Further Reading

Papers

1. Ezzyat Y, Kragel JE, Burke JF, Levy DF, Lyalenko A, Wanda P, O'Sullivan L, Hurley KB, Busygin S, Pedisich I, Sperling MR, Worrell GA, Kucewicz MT, Davis KA, Lucas TH, Inman CS, Lega BC, Jobst BC, Sheth SA, Zaghloul K, Jutras MJ, Stein JM, Das SR, Gorniak R, Rizzuto DS, Kahana MJ. Direct Brain Stimulation Modulates Encoding States and Memory Performance in Humans. Curr Biol. 2017 May 8;27(9):1251-1258. Epub 2017 Apr 20 PubMed.