Spatial navigation depends on spatial memory. Most common tasks of daily living, such as finding one’s car in a parking lot, are critically dependent on the medial temporal lobe. 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. Indeed, stimulation of the entorhinal region while subjects were learning was associated with improvement in memory performance, as measured by speed and choice of route.
The subjects in this study had epilepsy, a neurologic disease that may affect memory function. It is not clear that our findings can be generalized to patients 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 (e.g., Alzheimer’s disease).
Whether other types of learning and memory (such as verbal or autobiographical) can be similarly enhanced awaits future study, as does the determination of the existence of laterality effects. Neuropsychological data suggest that the left medial temporal lobe is better suited to verbal learning32
and that the right medial temporal lobe is better suited to nonverbal (e.g., visuospatial) learning.33
Although two subjects in our study had stimulation in the left entorhinal area, our study is too small to support conclusions about laterality effects. Much more work is required to determine whether electrical modulation of memory circuits could be used as a therapeutic strategy to enhance function in patients with memory disturbances.
Improvement of memory performance has been observed in a single case study in which deep-brain stimulation of the hypothalamus and fornix to treat morbid obesity improved verbal recall.34
Continuous stimulation of this region over a period of 12 months has also been shown to activate the circuitry of the medial temporal lobe, as measured with EEG and positron-emission tomography in five patients with early Alzheimer’s disease,35
although memory enhancement was not shown in this group. Our findings suggest that the perforant pathway, the major source of cortical afferent input into the hippocampus, may be preferable as the site of deep-brain stimulation for memory enhancement. In fact, this is further supported by a study in rodents that was published after the completion of the present study.36
An important aspect of the memory-enhancing stimulation in this study was its application during the learning phase. This suggests that with the use of neuroprosthetic devices aimed at cognitive enhancement, stimulation may not need to be applied continuously but only when patients are attempting to learn important information. Future studies are needed to determine whether stimulation during the act of recall would also have beneficial effects.
The theta rhythm (3 to 8 Hz) is a large EEG potential recorded from the hippocampus in rodents and humans29,37
and is thought to aid formation of memories.37
It has been suggested that resetting of the phase of the theta rhythm improves memory performance by allowing the best possible encoding of novel stimuli.38
Stimulation of the perforant pathway in rodents induces resetting of the theta phase and produces favorable conditions for long-term potentiation.9,39
In four subjects in our study who had contacts implanted in the entorhinal region and ipsilateral hippocampus, we observed theta-phase resetting in the hippocampus during stimulation of the entorhinal region. In a study that used functional MRI in humans, learned information that was associated with increased spontaneous activity in the entorhinal cortex was subsequently remembered better40
than learned information with no such associated activity, suggesting that increased entorhinal input to the hippocampus can improve learning. Our preliminary results support the hypothesis that stimulation that enhances memory also induces theta-phase resetting and provide evidence supporting a possible mechanism for stimulation-induced memory enhancement in humans.