Literature Review

Brain Stimulation May Enhance Memory


Electrical stimulation in the lateral temporal cortex enhances verbal memory performance, according to two studies in patients with epilepsy.

“While electrical stimulation of the brain is emerging as potential therapy for a wide range of neurologic and psychiatric diseases, little is known about its effect on memory,” said Gregory Worrell, MD, PhD, Professor of Neurology at the Mayo Clinic in Rochester, Minnesota, and an author of the studies. Electrical stimulation may have the potential to treat memory deficits and cognitive dysfunction in brain disorders such as traumatic brain injury and Alzheimer’s disease, the researchers said.

Gregory Worrell, MD, PhD

The two studies were part of a multicenter project designed to assess the effects of electrical stimulation on memory-related brain function and were supported by the Defense Advanced Research Projects Agency’s Restoring Active Memory program.

Patients Were Tested During Seizure Monitoring

In the April issue of Brain, Michal T. Kucewicz, PhD, a researcher at the Mayo Clinic, and colleagues described a study of patients with epilepsy who were undergoing evaluation for resective surgery. As part of the evaluations, patients had intracranial subdural and depth electrode arrays implanted in cortical and subcortical brain regions.

After implantation, patients completed delayed free-recall memory tasks in which they learned lists of words for subsequent recall. Twelve words appeared one at a time on a laptop screen for 1.6 seconds each. Participants then solved a series of arithmetic problems. Afterward, participants had 30 seconds to verbally recall as many words as possible from the list in any order. Patients completed this procedure 25 times during each testing session. Twenty of the lists in each session were learned with stimulation (ie, with stimulation applied for two words and then turned off for two words throughout the list), and five lists were learned without stimulation. Participants completed at least two control sessions with no stimulation to reduce potential learning effects.

The investigators focused on 22 patients (nine males) who had electrodes implanted in four brain regions known to support declarative memory: the hippocampus (n = 6), the parahippocampal cortex (n = 7), the prefrontal cortex (n = 6), and the temporal cortex (n = 4). One subject received stimulation in two of the brain regions (ie, the temporal cortex and the parahippocampal cortex).

The number of sessions that patients completed was determined by the length of seizure monitoring (range, two days to 14 days) and patients’ willingness to participate in the study. The subjects were blinded to the stimulation site.

Within-Individual and Between-Group Effects

Stimulation in the lateral temporal cortex enhanced memory performance, whereas stimulation in other brain regions did not. “The positive effect of [lateral cortex] stimulation was reported in individual patients tested across multiple days of stimulation sessions, on the level of the group of patients stimulated in the temporal cortex, and between the four groups stimulated in different brain regions,” the researchers said.

Two of the four patients stimulated in the lateral temporal cortex had significantly improved recall with stimulation, and the other two patients showed a positive trend.

In the subject who received stimulation in two brain regions, stimulation in the dominant lateral temporal neocortex increased the number of remembered words above the normal range, whereas stimulation in the parahippocampal region did not.

Among the participants who received temporal cortex stimulation, memory performance within each session on the stimulated word lists was consistently higher than on the control lists without stimulation.

For the stimulated lists, memory enhancement was observed on the level of the entire list, with no difference in recall between stimulated and nonstimulated words. This finding suggests that the positive effect of stimulation lasted beyond the period of electrical current administration, the researchers said.

The study’s limitations include the small number of participants and their variable clinical characteristics (eg, epilepsy pathologies, medications, and baseline cognition). It is unclear whether electrical stimulation modulates memory processing, attention, perception, or other related processes, the researchers noted. It also is not known whether the positive effect generalizes to other verbal and nonverbal memory functions, or whether stimulation in the nondominant hemisphere would have a different effect.

The data “might provide a hint as to why some patients undergoing surgical removal of this region complain about verbal memory deficits,” Dr. Kucewicz and colleagues said.

“The next step for this project is to determine how to best apply electrical current in terms of the exact location within this area of the brain, timing, and parameters of stimulation,” said study author Brent Berry, MD, PhD, a Mayo Clinic researcher in the Department of Physiology and Biomedical Engineering.

A Closed-Loop Approach

In a study published February 6 in Nature Communications, Youssef Ezzyat, PhD, a senior data scientist at the University of Pennsylvania in Philadelphia, and colleagues found that a closed-loop stimulation system may identify periods of poor memory encoding and apply targeted stimulation to the lateral temporal cortex to compensate.

The investigators recruited 25 neurosurgical patients undergoing clinical monitoring for epilepsy to participate in sessions of a delayed free-recall memory task. Subjects completed at least three record-only sessions of free recall with which the researchers trained a system to use intracranial EEG activity during encoding to predict the likelihood of later word recall.

During subsequent sessions, if the system predicted that the probability of recall was less than 0.5, it triggered 500 ms of bipolar stimulation. The researchers found that lateral temporal cortex stimulation increased the relative probability of item recall by 15%.

“By developing patient-specific, personalized, machine-learning models, we could program our stimulator to deliver pulses only when memory was predicted to fail, giving this technology the best chance of restoring memory function,” said Michael Kahana, PhD, Professor of Psychology at the University of Pennsylvania and principal investigator of the Restoring Active Memory program. “This [approach] was important, because we knew from earlier work that stimulating the brain during periods of good function was likely to make memory worse.”

—Jake Remaly

Suggested Reading

Ezzyat Y, Wanda PA, Levy DF, et al. Closed-loop stimulation of temporal cortex rescues functional networks and improves memory. Nat Commun. 2018;9(1):365.

Hampson RE, Song D, Robinson BS, et al. Developing a hippocampal neural prosthetic to facilitate human memory encoding and recall. J Neural Eng. 2018;15(3):036014.

Inman CS, Manns JR, Bijanki KR, et al. Direct electrical stimulation of the amygdala enhances declarative memory in humans. Proc Natl Acad Sci U S A. 2018;115(1):98-103.

Kucewicz MT, Berry BM, Kremen V, et al. Electrical stimulation modulates high γ activity and human memory performance. eNeuro. 2018;5(1).

Kucewicz MT, Berry BM, Miller LR, et al. Evidence for verbal memory enhancement with electrical brain stimulation in the lateral temporal cortex. Brain. 2018;141(4):971-978.

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