Seven patients undergoing a workup for epilepsy surgery helped physicians test the effects of deep brain stimulation on memory. They agreed to step into a virtual computer environment where they were asked to shuttle people around to different landmarks. The electrodes were either on or off during the learning of a complicated task designed to test the patients' ability to navigate the spatial environment.
Itzhak Fried, MD, PhD, professor and director of the Epilepsy Surgery program at the University of California, Los Angeles, and colleagues found that people were able to navigate faster and more efficiently if the electrodes had been activated in the entorhinal cortex during the initial learning period. They performed better and an EEG showed that the deep brain stimulation (DBS) in the entorhinal cortex triggered a resetting of the phase of a theta rhythm in the hippocampus, which is thought to aid the formation of memories. Spatial learning was not enhanced when stimulating electrodes in the hippocampus.
The findings, reported Feb. 9 in The New England Journal of Medicine, suggest the possibility that DBS may be able to enhance other types of memory, said Dr. Fried, a neurosurgeon and lead author of the study. “The memory task we studied is relevant to what we do in our daily lives,” said Dr. Fried. “We asked subjects to find their way around a city. Common tasks of daily living, like finding one's car in a parking lot, are dependent on the medial temporal lobe. The hippocampus and entorhinal cortex are critical parts of the medial temporal lobe memory system.”
DR. ITZHAK FRIED sai...Image Tools
The key structure that was affected by stimulation during learning was the entorhinal region, the gateway into the hippocampus and the first area to suffer damage in Alzheimer disease. Importantly, the electrodes were stimulated during a particular stage of information processing — when the epilepsy patients were learning the [virtual] layout of the city. They had to drive a cab to drop people off at six different stores. The stimulation was turned on or off while they were navigating to landmarks. They could not feel the stimulating electrodes.
In the study, six of the seven subjects had electrodes implanted in the entorhinal cortex and five of the seven had at least one hippocampal electrode. Four of the seven had both entorhinal and hippocampal electrodes implanted ipsilaterally. They excluded the data from the electrode that fell within the seizure-onset zone.
Each of the six subjects showed enhanced performance during entorhinal stimulation (p=0.03). When the stimulation was on, the average time to reach the destination was reduced by 64 percent. Stimulating the hippocampal electrodes had no effect on performance, said Dr. Fried.
It is not known whether other types of learning and memory could be improved with deep brain stimulation, the authors noted. Other studies have shown that the left medial temporal lobe regulates verbal learning and right medial temporal lobe controls visuospatial or non-verbal learning; it should prove interesting to examine material-specific memory with stimulation of right versus left medial temporal lobe sites, they suggested.
Dr. Fried said that all patients improved with stimulation, even those who had poor memory scores based on neuropsychological tests carried out before the navigation task. It is not clear how DBS works on the memory circuit, whether it improves memory formation or retrieval, or both.
“This whole sort of cognitive enhancement is an intriguing question,” said Dr. Fried. “We have a lot to learn about stimulating memory circuits,” he added.
“Neurosurgeons and multidisciplinary scientific teams engaged in deep-brain stimulation for clinical treatment are strategically positioned to provide invaluable insight into memory networks in action,” Sandra E. Black, MD, professor and chair of neurology at the University of Toronto, wrote in an accompanying editorial. She added that replication of the study “is warranted in younger and older candidates for epilepsy surgery to investigate left-right differences in the capacity for verbal and spatial memory, encoding, and recall.”
“This is a terrific finding,” said Andres M. Lozano, MD, PhD, chairman of neurosurgery at the University of Toronto, who has studied DBS for a range of neurological and other conditions. “We don't know to what extent this approach would influence motor or verbal learning. We also don't know whether DBS in patients with specific memory problems would have an impact on their quality of life. But it's a foot in the door.”
HOW THE STUDY WAS DONE
* The spatial learning task was done at the patient's bedside via a computer and a joystick. Navigating through a virtual environment to drop people off at specific locations has been shown to recruit circuits in the medial temporal lobe.
* Six of the seven study patients were tested under the entorhinal-stimulation condition and five under the hippocampal-stimulation condition. One subject had electrodes bilaterally placed in the hippocampus and was tested on each side. In total, there were six tests of retention of memory after stimulation of each of these brain regions. Each test had four blocks of trials where they had to learn to navigate to the six stores, ending in a total of 24 navigational trials for each brain region.
* Stimulation was delivered throughout the learning but only for half of the stores. There was a two-minute interval between each of the four blocks. During these intervals, the study subjects were asked to perform a control task. There was no stimulation for the last block of the trial. They used the results from this last block to test memory retention of the subject's ability to navigate to the stores. They quantified special learning by calculating the shortest path from pickup to drop-off. This was compared to the actual path length. They also calculated the time it took to navigate to the store. (The path lengths to each store were equal.)
* They had EEG data from the hippocampus in four of the subjects who had electrodes in both the entorhinal and hippocampal regions. The data was analyzed to look for phase resetting, which produces a greater alignment of waves, said Dr. Fried.
MORE ON DBS AND MEMORY
In 2008, Andres M. Lozano, MD, PhD, chairman of neurosurgery at the University of Toronto, published an observation from a single patient undergoing DBS for obesity. Electrodes were placed in his hypothalamus. During stimulation, the patient kept having a vivid memory from early adulthood. There was also evidence that his verbal learning improved.
The finding led him to study DBS in patients with mild Alzheimer disease (AD). Dr. Lozano and his colleagues recruited six patients and implanted electrodes in the hypothalamus and fornix. Reporting in the Annals of Neurology in 2010, they found that certain patients with the mildest form of AD improved on memory tests. “It showed us that the circuits in the brain that mediate memory function are accessible. We know where they are and how to reach them.”
They also reported in this first study that PET scans showed some partial recovery in the brain's ability to take up glucose in the temporal and parietal areas following DBS.
The Canadian researchers just received FDA approval to launch a phase 2 double-blind trial in 20 patients with mild AD. They will look for changes on a number of memory and cognitive scales, as well as activities of daily living. PET scans will also be part of the study to see if their initial finding holds up. “From the PET scan studies we can see that the lights are out but someone is home,” he explained. “It may be possible to use DBS to turn the lights back on.”
Animal studies conducted in the Lozano lab and published recently in the Journal of Neuroscience showed that a one-time stimulation of circuits in the hippocampus led to a two to three fold increase in neurogenesis. “We don't know if this happens in humans, but if it does it could change the structure of damaged circuits in the brain.”
• Suthana N, Haneef Z, Fried I, et al. Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med
• Black SE. Brain stimulation, learning, and memory. N Engl J Med
• Hamani C, McAndrews MP, Lozano AM, et al. Memory enhancement induced by hypothalamic/fornix deep brain stimulation. Ann Neurol 2008;63(1):119-123.
• Laxton AW, Tang-Wai DF, Lozano AM, et al. A phase I trial of deep brain stimulation of memory circuits in Alzheimer's disease. Ann Neurol
• Stone SS, Teixeira CM, Frankland PW, et al. Stimulation of entorhinal cortex promotes adult neurogenesis and facilitates spatial memory. J Neurosci