The episodic memory system: neurocircuitry and disorders

Abstract

The ability to encode and retrieve our daily personal experiences, called episodic memory, is supported by the circuitry of the medial temporal lobe (MTL), including the hippocampus, which interacts extensively with a number of specific distributed cortical and subcortical structures. In both animals and humans, evidence from anatomical, neuropsychological, and physiological studies indicates that cortical components of this system have key functions in several aspects of perception and cognition, whereas the MTL structures mediate the organization and persistence of the network of memories whose details are stored in those cortical areas. Structures within the MTL, and particularly the hippocampus, have distinct functions in combining information from multiple cortical streams, supporting our ability to encode and retrieve details of events that compose episodic memories. Conversely, selective damage in the hippocampus, MTL, and other structures of the large-scale memory system, or deterioration of these areas in several diseases and disorders, compromises episodic memory. A growing body of evidence is converging on a functional organization of the cortical, subcortical, and MTL structures that support the fundamental features of episodic memory in humans and animals.

Figure 1

Two sections from a transverse MRI of HM's brain illustration location of surgical lesion, which involved the excision of the rostral portion of bilateral medial temporal lobes (arrows; areas of bright signal indicate cerebrospinal fluid). Figure courtesy of Professor Suzanne Corkin.

Figure 2

The anatomy of the medial temporal lobe memory system (Eichenbaum, 2000). In both monkeys and rats the origins of specific information to the hippocampus include virtually every neocortical association area. Each of these neocortical areas (blue) projects to one or more subdivisions of the parahippocampal region, which includes the perirhinal cortex (purple), the parahippocampal (or postrhinal) cortex (dark purple), and the entorhinal cortex (light purple; Burwell et al, 1995; Suzuki, 1996). The subdivisions of the parahippocampal region are interconnected and send major efferents to multiple subdivisions of the hippocampus itself (green), the dentate gyrus, the CA3 and CA1 areas, and the subiculum. Thus, the parahippocampal region serves as a convergence site for cortical input and mediates the distribution of cortical afferents to the hippocampus. Within the hippocampus, there are broadly divergent and convergent connections that could mediate a large network of associations (Amaral and Witter, 1989). The outcomes of hippocampal processing are directed back to the parahippocampal region, and the outputs of that region are directed in turn back to the same areas of the cerebral cortex that were the source of inputs to this region (Burwell et al, 1995; Suzuki, 1996). There are additional structures that have been included as components of this system, including medial diencephalic structures that connect with the hippocampus along with other subcortical areas, through a major fiber bundle called the fornix (Aggleton and Brown, 1999).

Figure 3

A proposed functional organization of the medial temporal lobe memory system (Eichenbaum et al, 2007). Neocortical input regarding the object features (‘what') converges in the perirhinal cortex (PRC) and lateral entorhinal area (LEA), whereas details about the location (‘where') of objects converge in the parahippocampal cortex (PHC) and medial entorhinal area (MEA). These streams converge in the hippocampus, which represents items in the context in which they were experienced. Reverse projections follow the same pathways back to the parahippocampal and neocortical regions. Back projections to the PHC–MEA may support recall or context, whereas back projections to the PHC–LEA may support recall of item associations.

Figure 4

Functional MRI of 70-year-old individual during the encoding of new face-name pairs. Brain image shows localization of activation, which includes hippocampus (arrow and crosshair) and other medial temporal lobe regions. Crosshair shows localization of the area from which time course of blood-oxygen-level-dependent activity is derived, showing the signal for items that are subsequently correctly recognized (green, hits) vs items that are not correctly recognized (blue, misses).

Figure 5

Functional MRI of a group of young human subjects during the encoding of novel pictures that are subsequently recalled, showing cortical regions involved in the large-scale episodic memory network and related areas. Red/yellow regions are activated (including ventrolateral prefrontal cortex (top image, arrow) and medial temporal cortex (bottom image, long arrow)) during the encoding of new pictures of objects, whereas blue regions are deactivated (including posterior cingulate/precuneus (bottom image, short arrow) below baseline.

Figure 6

Cortical areas of the ‘default mode' network, which is a set of brain regions that are deactivated below baseline level during the performance of most types of tasks (top, including inferolateral parietal (1), posterior cingulate/precuneus (2), dorsolateral prefrontal (3), medial prefrontal (4), medial temporal (5), and rostrolateral temporal (6)). These same regions are activated above baseline during the retrieval of autobiographical memories (a) and during the envisioning of specific potential future events (b).

Figure 7

Ultrahigh-resolution (380 μm in-plane voxel size) structural MRI images of the human medial temporal lobe in a 24-year-old neurologically intact individual (a) and in a 72-year-old patient with mild Alzheimer's disease (b). In the young individual, a variety of MTL subregions can be seen, including CA3/dentate gyrus (1), CA1 (2), subiculum (3), entorhinal cortex (4), perirhinal cortex (5), and amygdala (6). Hippocampal formation and other medial temporal lobe structures are atrophic in Alzheimer patient.

Figure 8

The cortical signature of regional thinning in Alzheimer's disease. Brain regions highlighted in red/yellow are thinner than age-matched cognitively intact controls in mild AD. The episodic memory network is prominently affected (including the medial temporal lobe (1), parts of the lateral parietal cortex (3), and posterior cingulate/precuneus (4)), as are nodes of several other networks (including the parts of the lateral parietal cortex (3), temporal pole (2), and dorsolateral prefrontal cortex (5)) subserving cognitive and behavioral function with relative sparing of sensorimotor regions.