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Deep Brain Stimulation Impairs Memory, Researchers Report

Hurley, Dan

doi: 10.1097/01.NT.0000512166.27006.27
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Deep brain stimulation of the entorhinal region and hippocampus impaired memory, refuting earlier findings, a new study found.

Deep brain stimulation (DBS) of the entorhinal region and hippocampus impaired memory in a new human trial, contradicting previous findings and setting off a debate on the technical details of the approach.

The study, which was published in the December 7, 2016, issue of Neuron, included 49 people undergoing surgical electrode implantation to identify the anatomic source of drug-resistant epilepsy. The subjects were asked to perform spatial and verbal-episodic memory tasks while receiving either electrical stimulation at 50 Hz during memory encoding or no stimulation. They were blinded and unable to discern whether or not stimulation was being applied.

Across all patients and both tasks, entorhinal stimulation impaired memory accuracy by an average of 9 percent (p< 0.02). Entorhinal stimulation in 12 patients impaired memory in both the spatial (p=0.03) and verbal tasks (p=0.09). Even in the subset of seven patients who had stimulation in the entorhinal white matter, considered by some investigators to be the most promising region for stimulation, memory impairment remained robust (p< 0.02).

By contrast, a paper published in the New England Journal of Medicine (NEJM) in 2012 found that entorhinal stimulation significantly enhanced performance on a spatial memory task in six patients, by an average of 64 percent.

“We wanted to improve memory, so we thought the best place to start was to replicate the earlier experiment, but with a larger group of patients,” said the first author of the new study, Joshua Jacobs, PhD, assistant professor of biomedical engineering at Columbia University's School of Engineering and Applied Science. “Our experiment was not exactly the same as the earlier one. Methods move forward over time. Our spatial memory task had more statistical power and more measurements per session.”



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The earlier paper also used a different spatial learning task, consisting of navigation through a virtual environment to deliver passengers to stores. The task in the new paper is more similar to the Morris water maze, using an open arena with distant landmarks, hidden target locations, and randomized starting positions.

Moreover, Dr. Jacobs's study applied stimulation for exactly 10 seconds per trial, divided over two five-second intervals, whereas the earlier trial applied stimulation for varying durations depending on the length of time patients spent navigating each task. As a result, patients in the earlier trial were likely stimulated for a longer total duration, the Neuron paper concluded.

Despite those differences, Dr. Jacobs told Neurology Today, it is unlikely that such technical differences explain why his results contradict those of the earlier study. “Our effects went reliably in the opposite direction” from those reported in the earlier study, he said.

Yet Dr. Jacobs said he remains convinced that, properly targeted, DBS will still likely be shown to have benefits on memory. “We're working on trying to make it successful,” he said. “I don't think our findings mean it will never work. It just shows that this is a difficult task. It's a lot easier to impair brain function than to improve it. But I bet it will be successful one day.”

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Nanthia Suthana, PhD, assistant professor in the department of psychiatry and biobehavioral sciences and associate director of the neuromodulation division in the Semel Institute for Neuroscience and Human Behavior at the UCLA Brain Research Institute, was the first author of the 2012 paper in the NEJM. In addition to the differences between the two studies described by Dr. Jacobs, she identified other differences which, she said, could have played a critical role.

“They had completely different implantation routes than we had,” she said, adding: “The precise location of the electrodes is extremely important. Even if you're two millimeters off, it doesn't work the same way.”

Itzhak Fried, MD, PhD, professor in the department of neurosurgery at the UCLA Brain Research Institute, who was a senior author of the 2012 NEJM paper, noted that on the spatial task, only five patients in Dr. Jacobs's trial were stimulated in the same entorhinal region in which he and Dr. Suthana stimulated six patients.

“Based on what we have done since the NEJM paper, it appears that the critical issue is the location and parameters of this stimulus,” Dr. Fried said. “One key issue we find — and we now have quite a larger number of patients, some of whom we have presented at Society for Neuroscience and will present in a paper — is the placement of the electrode in the white matter of the entorhinal region. We do not want contact with the gray area.”

Andres Lozano, MD, PhD, chair of neurosurgery at the University of Toronto School of Medicine, who first reported on the use of DBS to enhance memory in 2008, pointed out that the study authors did not perform a dose-finding study to optimize stimulation parameters and identify settings that could have possibly enhanced memory. “It's a question of optimizing the dose and the location of stimulation for each patient,” he said.

Dr. Jacobs pointed out that the locations of the electrodes used in his study were chosen not by him but by the neurosurgeons seeking to treat drug-resistant epilepsy. For Dr. Lozano's study of patients with AD, however, implantation sites were chosen specifically to enhance memory.

The take-away, Dr. Jacobs said, is broader than the details of any particular study. “Doing brain stimulation for memory enhancement is a hard thing to do,” he said. “That does not mean it's impossible.”

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•. Jacobs J, Miller J, Lee SA, et al. Direct electrical stimulation of the human entorhinal region and hippocampus impairs memory http:// Neuron 2016; 92 (5): 983–990.
    •. Suthana N, Haneef Z, Stern J, et al. Memory enhancement and deep-brain stimulation of the entorhinal area http:// N Engl J Med 2012; 366 (6): 502–510.
      •. Hamani C, McAndrews MP, Cohn M, et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation Ann Neurol 2008; 63 (1): 119–123.
        •. Lozano AM, Fosdick L, Chakravarty MM, et al. A phase II study of fornix deep brain stimulation in mild Alzheimer's disease J Alzheimers Dis 2016; 54 (2): 777–787.
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