Deep Brain Stimulation Strengthens Memory

Allison Shelley

February 09, 2012

February 9, 2012 — Deep brain stimulation of the entorhinal region, applied during learning, appears to improve memory of spatial information, report researchers.

"Our results show that spatial learning in humans can be enhanced by electrical stimulation of the entorhinal region, a specific site within the medial temporal lobe and the chief gateway into the hippocampus," the researchers, with senior author Itzhak Fried, MD, from the department of neurosurgery at the David Geffen School of Medicine, University of California at Los Angeles, conclude.

Stimulation of the entorhinal region while patients were learning a task that involved navigation of a virtual city was associated with improvement in memory performance, gauged by their speed and choice of route.

"The entorhinal cortex is the golden gate to the brain's memory mainframe," Dr. Fried said in a news release. "Every visual and sensory experience that we eventually commit to memory funnels through that doorway to the hippocampus."

The findings were published February 9 in the New England Journal of Medicine. The investigators say they hope the work will one day lead to new methods for improving memory in patients with Alzheimer's disease.

"Losing our ability to remember recent events and form new memories is one of the most dreaded afflictions of the human condition," Dr. Fried said. "Our preliminary results provide evidence supporting a possible mechanism for enhancing memory, particularly as people age or suffer from early dementia."

His team followed 7 epilepsy patients who already had electrodes implanted in their brains to pinpoint the origin of their seizures. The researchers, led by Nanthia Suthana, PhD, also at the University of California, Los Angeles, monitored the electrodes to record neuron activity as memories were being formed.

Using a video game featuring a taxi cab, virtual passengers, and a cybercity, the investigators tested whether deep-brain stimulation of the entorhinal cortex or the hippocampus altered recall.

Deep brain stimulation.

Patients played the role of taxi cab drivers who picked up passengers and traveled across town to deliver them to 1 of 6 requested stops.

"When we stimulated the nerve fibers in the patients' entorhinal cortex during learning, they later recognized landmarks and navigated the routes more quickly," Dr. Fried explained. "They even learned to take shortcuts, reflecting improved spatial memory."

Critically, it was "the stimulation at the gateway into the hippocampus — and not the hippocampus itself — that proved effective," he added. Entorhinal stimulation resulted in a resetting of the phase of the theta rhythm on the hippocampal encephalogram, they note, but direct stimulation of the hippocampus was not effective.

The benefit seen using stimulation only during the learning phase suggests that patients need not undergo continuous treatment to boost their memory, but only when they are trying to learn important information, Dr. Fried pointed out.

Subjects in the study had epilepsy, which can itself affect memory function, they note, and it is not clear if their findings can be generalized to those with other neurologic disorders.

"We did, however, observe an improvement in performance when the medial temporal lobe in persons with epilepsy was stimulated and regardless of baseline memory performance, a finding that suggests that improvement could occur in patients with other memory impairments (eg, Alzheimer’s disease)," they conclude.

Neuroprosthetic Devices

This work may eventually lead to neuroprosthetic devices that can switch on during specific stages of information processing or daily tasks, the authors speculate.

Future studies will determine whether deep-brain stimulation can enhance other types of recall, such as verbal and autobiographical memories. No adverse effects of the stimulation were reported by the 7 patients.

In an accompanying editorial, Sandra Black, MD, from the University of Toronto in Ontario, said, "The potential application of deep-brain stimulation in amnestic disorders is enticing. Finding the best structure for stimulation and the best way to evaluate its effects, such as during virtual spatial-learning tasks, through well-designed studies in the right populations appears to be warranted."

Dr. Black pointed out the researchers took their cue from research in animals showing that stimulation of the entorhinal perforant pathway improves memory.

One study published in the September issue of the Journal of Neuroscience, and reported by Medscape Medical News at the time, showed not only that stimulating targeted regions of the brain improves spatial memory, but also that neurogenesis explains, at least in part, this cognitive improvement.

Timely Advance

Dr. Black explains that advances in electrophysiology and high-resolution brain imaging have improved understanding of the neural circuitry of episodic memory, including differential contributions of the hippocampus and the rhinal cortices.

"These advances are timely: the aging of the human population makes the elucidation of memory mechanisms in aging and dementia an urgent priority for neuroscience and global health," she notes.

Traditionally, studies of episodic learning and memory have used verbal-learning to study human memory. "Verbal learning cannot, of course, be studied in rodents, the classic model for in vivo study of memory processes," Dr. Black pointed out.

"Rather, studies of memory in rodents involve spatial-learning tasks. Memory recall of drawings and of object locations and maze learning are used to probe spatial memory in humans, but these tasks lack ecologic validity," she writes. "The development of computerized virtual environments has opened up new opportunities to study spatial-navigation learning in real time while subjects are in the operating room or in a scanner."

Dr. Black acknowledges the current evidence is preliminary, is based on small samples, and requires replication. "Finding the best structure for stimulation and the best way to evaluate its effects through well-designed studies in the right populations appears to be warranted."

This study was funded by the National Institutes of Health and the Dana Foundation. The investigators have disclosed no relevant financial relationships. Editorialist Dr. Black has received funding from Bristol-Myers Squibb, Eisai, GlaxoSmithKline, Novartis, Pfizer, and Roche.

N Engl J Med. 2012;366:502-510. Abstract. Editorial.

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