The parahippocampal region: basic science and clinical implications.

In recent years, it has become clear that the cortical regions adjacent to the hippocampus deserve a good deal more attention than they had traditionally been given. A recent meeting organized under the auspices of the New York Academy of Sciences by Helen Scharfman, Menno Witter, and Robert Schwarcz, “The Parahippocampal Region: Basic Science and Clinical Implications,” was a welcome step in this direction. The meeting covered a wide range of approaches, touched on a number of structures, and might even have established some consensus among workers in the field about the proper use of several oft-confused terms. It became obvious during the course of the meeting that there was considerable confusion about how best to label structures in this part of the brain. A postmeeting wrap-up discussion generated a proposal that most agreed would help, namely, that the term parahippocampal cortex be reserved just for areas TF and TH in the primate (in rodents, the likely homologue of these areas is called the postrhinal cortex), and that the term parahippocampal region be used to embrace these areas plus the entorhinal cortex, the presubiculum, the parasubiculum, and the perirhinal cortex. The logic behind this choice, outlined by Menno Witter, is that all of these areas are reciprocally connected, they are all composed of six discernible layers (in contrast to the three-layered hippocampal formation, comprising the dentate gyrus, CA fields, and subiculum), and they all project to at least some part of the hippocampal formation. It was agreed that the use of the term “region” conveys geographical proximity, and leaves the question of functional relatedness open, as it should be at this point. The meeting, held in Baltimore from September 23–26, 1999, was divided into five major content areas, starting with neuroanatomical issues, and ending with a number of presentations on the presumed cognitive functions of structures in the parahippocampal region. Along the way it touched on, among other subjects, epilepsy, Alzheimer’s disease, recognition memory, animal models of amnesia, neurogenesis and regeneration, computational models, oscillations, neuroimaging, schizophrenia, and kindling. This range of topics gives some sense of why interest in the parahippocampal region has increased so markedly in recent years, and why it is likely to continue to attract attention. Menno Witter opened the meeting with a comprehensive overview of the anatomical structure of, and interactions among, many of the components of the parahippocampal region. He pointed out that medial and lateral entorhinal areas project to the same cells in the dentate gyrus and CA3, but to different cells in CA1 and the subiculum. Whereas the entorhinal cortex projects to all subfields of the hippocampus along about 25% of its length, projections from perirhinal and parahippocampal cortices are restricted largely to the subiculum, ranging over less than about 10% of its length. On the return side, Witter noted that hippocampal projections to entorhinal cortex terminate in layer 3 as well as layer 5, and that the standard concept of layers 2/3 only providing input to hippocampus, and layer 5 being the only layer receiving hippocampal outputs, is therefore an oversimplification. Using electrophysiological methods, Fernando Lopes da Silva showed that there are direct inputs from perirhinal and postrhinal areas into the hippocampus, in addition to the indirect inputs via the entorhinal cortex. The subiculum in particular appears to receive both direct and indirect afferents of this sort, although it seems likely that these two classes of input terminate in different layers. Stan Leung described the details of entorhinal and perirhinal inputs to the hippocampus based on current source density analyses. Rebecca Burwell carried the anatomy one step further back, noting that the perirhinal area projects mostly to the lateral entorhinal cortex, whereas the postrhinal area projects mostly to the medial entorhinal cortex. The functional implications of this pattern remain to be elucidated. Burwell also pointed out the vast increase in relative size of the perirhinal area in humans, as compared to rodents and monkeys. In the mouse and rat, the entorhinal cortex is larger than the perirhinal cortex, but in monkeys this relationship is reversed, and the perirhinal cortex is about twice the size of the entorhinal cortex. In humans, this ratio increases to about six times. The parahippocampal cortex also increases somewhat in size in relation to the entorhinal cortex, but not anything like the change observed in the perirhinal cortex. Heiko Braak focused on the entorhinal cortex, pointing out the existence of a unique transitional zone between the entorhinal cortex and temporal neocortex that is only seen in primates, and is particularly large in humans. This region is sparsely myelinated, predominantly *Correspondence to: Lynn Nadel, Department of Psychology, University of Arizona, Tucson, AZ 85721. Accepted for publication 11 December 1999 HIPPOCAMPUS 10:133–135 (2000)