Like a circle in a spiral: stimulating the windmills of your mind.

Commentary The entorhinal cortex stands out among the myriad of mysterious and elegant brain structures as a relay station between the neocortical parahippocampus and the more primal memory-encoding, seizure-producing hippocampus. It seems to have not six neocortical layers or three archicortical layers, but arguably five to eight layers with one atrophied layer (layer IV, the lamina dessicans) and a complex layer V with three distinct layered cell types (A, B, and C). Therefore, the entorhinal cortex combines a near sum of the neocortical and archicortical layers as it sorts input from the amygdala, olfactory bulb, septal nuclei, hippocampus, and parahippocampus (not a complete list) and delivers output to the dentate gyrus and hippocam-pus (1). Its proper functioning is critical for episodic memory, and it certainly mediates the formation of memories of naviga-tional landmarks, via input from the parahippocampal cortex, which itself houses the processing of spatial relationships and the contextual information of experiences (2). The entorhinal cortex is a critical hub for memory formation and is invariably one of the first areas of pathology in Alzheimer disease, showing neuronal loss and atrophy (3). If there was ever a single site important for memory functioning , this would be it. What if its function could be enhanced? The investigators of the article at hand appear to have found a way. Based on evidence that there are site-specific brain areas in which stimulation can improve neurologic and psychiatric disease, and rodent experiments in which stimulation to analogous structures produced physiologic potential changes in the dentate, including long-lasting potentiation (4), it was undertaken to stimulate the entorhinal cortex and hippocam-pus in humans in order assess the effect on memory function. A key feature of this experiment was the surrogate marker for enhanced memory encoding, the resetting of the hippo-campal theta rhythm, which was measured as an increase in hippocampal theta power associated with stimulation versus nonstimulation conditions. Intractable epilepsy patients were studied who already had hippocampal and/or entorhinal depth electrodes placed for localization of seizure onset for subsequent epilepsy surgery. The stimulation parameters used were already known to be subthreshold for afterdischarges based on pretesting of the stimulation sites. Overall, seven patients were studied: six underwent stimulation in the entorhinal cortex and five in the hippocampus. Four of the subjects were stimulated at both sites, which logically would be the only approach to determine a site-specific differential effect on memory function. It should …