Deep Brain Stimulation of Entorhinal Cortex Shows Early Promise for Enhancement of Memory Function

Abstract

Memory loss and the inability to form new memories properly is a prominent and devastating feature of many widespread neurological conditions, particularly Alzheimer's disease and other forms of dementia. Memory function is supported by the limbic system, and more specifically the ability to remember recent events requires the hippocampus and associated structures including the entorhinal, perirhinal, and parahippocampal cortices. In rodent models, scientists have found that direct electrical stimulation of the perforant pathway, which arises from the entorhinal cortex in the medial temporal lobe and projects to the hippocampus, results in the cellular correlates of long term potentiation. In a new study, Suthana et al (Memory enhancement and deep-brain stimulation of the entorhinal area. N Engl J Med. 2012;366[6]:502-510.) have demonstrated enhancement of memory formation in human subjects by entorhinal stimulation during the learning process. The authors studied seven patients with intracranial depth electrodes who were undergoing monitoring for medically refractory epilepsy. These patients had magnetic resonance image- (MRI) guided stereotactic implantation of entorhinal or hippocampal depth electrodes, or in 4 of the 7 cases, ipsilateral implantation of both entorhinal and hippocampal electrodes. In these 4 cases hippocampal electroencephalography (EEG) data was collected during entorhinal stimulation. Patients were stimulated with parameters similar to those from other neuromodulation therapies and at levels below the threshold for inducing measureable after-discharges. Subjects were also unaware of the stimulation. They each completed a computerized spatial learning task in a virtual environment in which they had to learn the location of a number of stores and then drop off passengers at each store. Stimulation was applied to the depth electrodes as a subject was learning to navigate to particular stores (3 randomly selected stores out of 6 stores that were encountered in randomized order in each trial). Subjects completed 3 trials each in which stimulation was provided during navigation to the same 3 out of 6 stores. During a 4th trial, memory retention was tested. Spatial memory was quantified by calculating the excess path length, or the difference between the shortest possible route to a store and the actual route taken by a subject to that store. Latency, or the time elapsed between passenger pickup and dropoff at an assigned store was also measured. In each of 6 subjects, stimulation of the entorhinal cortex during the initial 3 trials resulted in a reduction of excess path length and latency for the corresponding navigation tasks in the 4th trial as compared to navigation tasks in which there had been no stimulation. The average reduction of excess path length was 64%. This was true despite the wide disparity in executive functioning pre-existing between the various patients. This effect was not observed with stimulation of hippocampal electrodes (Figure 1). In addition, for the 4 patients with both hippocampal and entorhinal electrodes, entorhinal stimulation induced greater theta-phase resetting as monitored in hippocampal electrodes as compared to non-stimulation. The large amplitude/low frequency hippocampal theta rhythm is thought to be a marker of active memory circuitry. These authors have demonstrated that entorhinal stimulation during learning can significantly enhance spatial memory, as demonstrated by improvements in this virtual world scenario performance. Although the study was limited to a small number of epilepsy patients these preliminary results are very exciting. It remains to be seen whether this kind of stimulation can be used to improve memory in patients who suffer from Alzheimer's disease or other forms of dementia and degenerative neurological conditions. Further study is needed and may reveal that stimulation in different hemispheres may result in differential improvement in verbal and spatial memory.Figure 1: Reduction in path length for the 2 different stimulated regions: A) entorhinal region, B) hippocampus. A 100% reduction would represent an excess path length of zero. Entorhinal stimulation showed consistent path length reduction, while hippocampal did not. From The New England Journal of Medicine, Suthana N, Haneef Z, Stern J, et al, Deep Brain Stimulation of Entorhinal Cortex Shows Early Promise for Enhancement of Memory Function, Volume No. 366, Pages 502-510. Copyright © (2012) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.