The origin, course, and termination of the hippocampothalamic projections in the macaque

The projections from the hippocampal formation to the thalamus were investigated with both anterograde and retrograde tracers. Horseradish peroxidase was injected into medial and midline thalamic sites in six cases, and tritiated amino acids were injected into the hippocampal formation in nine others, five of which had prior transections of the fornix. Only the subicular and entorhinal cortices were found to project to the thalamus. From the subicular cortex, dense bilateral projections were traced through the fornix to the anterior nuclei, while lighter fornical projections terminated in other rostral midline sites, including the nuclei reuniens, centralis latocellularis, and paraventricularis. These projections arose predominantly from the polymorphic cells which are located in the deepest cellular layers of the subiculum and prosubiculum. In addition, the subicular cortex was found to project to the nucleus lateralis dorsalis. The latter projection, which showed evidence of a crude topographic organization, ran either through the fornix or, unlike the other subicular efferents, through the sublenticular limb of the internal capsule to form part of the temporopulvinar bundle of Arnold. The nonfornical projection to the nucleus lateralis dorsalis passed through the medial pulvinar, where there was some additional termination. Few, if any, projections from the entorhinal cortex to the thalamus travelled in the fornix. Rather, the entorhinal efferents were carried in the inferior thalamic peduncle to the magnocellular portion of the nucleus medialis dorsalis, and in the internal capsule and bundle of Arnold to the medial pulvinar and the nucleus lateralis dorsalis.     

Perirhinal and postrhinal cortices of the rat: Interconnectivity and connections with the entorhinal cortex

The cortical regions dorsally adjacent to the posterior rhinal sulcus in the rat can be divided into a rostral region, the perirhinal cortex, which shares features of the monkey perirhinal cortex, and a caudal region, the postrhinal cortex, which has connectional attributes similar to the monkey parahippocampal cortex. We examined the connectivity among the rat perirhinal (areas 35 and 36), postrhinal, and entorhinal cortices by placing anterograde and retrograde tracers in all three regions. There is a dorsal-to-ventral cascade of connections in the perirhinal and entorhinal cortices. Dorsal area 36 projects strongly to ventral area 36, and ventral area 36 projects strongly to area 35. The return projections are substantially weaker. The cascade continues with the perirhinal to entorhinal connections. Area 35 is more strongly interconnected with the entorhinal cortex, ventral area 36 somewhat less strongly, and dorsal area 36 projects only weakly to the entorhinal cortex. The postrhinal-to-perirhinal connections also follow this general pattern. The postrhinal cortex is more heavily connected with dorsal area 36 than with ventral area 36 and is more heavily connected with area 36 than with area 35. The rostral portion of the postrhinal cortex has the strongest connections with the perirhinal cortex. Like in the monkey, the perirhinal and postrhinal cortices have different patterns of projections to the entorhinal cortex. The perirhinal cortex is preferentially connected with the rostrolateral portion of the entorhinal cortex. The postrhinal cortex projects to a part of this same region but is also connected to caudal and medial portions of the entorhinal cortex. The perirhinal and postrhinal projections to the entorhinal cortex originate in layers III and V and terminate preferentially in layers II and III. J. Comp. Neurol. 391:293–321, 1998. © 1998 Wiley-Liss, Inc.     

Non-hippocampal cortical projections from the entorhinal cortex in the rat and rhesus monkey

The entorhinal cortices are known to give rise to powerful projections that terminate in the hippocampus and dentate gyrus. Collectively, these link the hippocampal formation to many parts of the cortex and to subcortical structures like the amygdala. Non-hippocampal projections from the entorhinal cortices are understood poorly. Such projections to neighboring temporal areas in the rat and rhesus monkey have been investigated using the autoradiographic and horseradish peroxidase (HRP) tracing procedures. In the rat, HRP-labeled neurons were observed in the intermediate and lateral fields of the entorhinal cortices after injections of temporal cortical areas 20, 35, 36 and 41. They were located predominantly in layers II, III and IV. In the monkey , HRP-labeled neurons were observed in the entorhinal cortices after injections of the rostral superior temporal gyrus (area TA or 22); the temporal polar cortex (area TG or 38); the inferior temporal cortex (area TE or 20); the perirhinal cortex (area 35) and the posterior parahippocampal cortices (areas TF and TH). Unlike the rat, labeled entorhinal neurons in the monkey were located in layer IV. Autoradiographic experiments in the monkey yielded complimentary results. In view of the fact that layer IV of the entorhinal cortex in both the rat and monkey receives a powerful projection from the subicular-CA1 fields of the hippocampal formation, the results imply that this layer mediates an indirect non-fornical connection between the hippocampal formation and the temporal cortex.     

Architectonic analysis of the auditory-related areas of the superior temporal region in human brain

Architecture of auditory areas of the superior temporal region (STR) in the human was analyzed in Nissl-stained material to see whether auditory cortex is organized according to principles that have been described in the rhesus monkey. Based on shared architectonic features, the auditory cortex in human and monkey is organized into three lines: areas in the cortex of the circular sulcus (root), areas on the supratemporal plane (core), and areas on the superior temporal gyrus (belt). The cytoarchitecture of the auditory area changes in a stepwise manner toward the koniocortical area, both from the direction of the temporal polar proisocortex as well as from the caudal temporal cortex. This architectonic dichotomy is consistent with differences in cortical and subcortical connections of STR and may be related to different functions of the rostral and caudal temporal cortices. There are some differences between rhesus monkey and human auditory anatomy. For instance, the koniocortex, root area PaI, and belt area PaA show further differentiation into subareas in the human brain. The relative volume of the core area is larger than that of the belt area in the human, but the reverse is true in the monkey. The functional significance of these differences across species is not known but may relate to speech and language functions.     

Perirhinal and parahippocampal cortices of the macaque monkey: Intrinsic projections and interconnections

We investigated the topographic and laminar organization of the intrinsic projections and interconnections of the macaque monkey perirhinal and parahippocampal cortices. Discrete anterograde tracer injections placed at various rostrocaudal and mediolateral levels in these cortices revealed extensive associational connections both within and between the perirhinal and parahippocampal cortices. Areas 35, 36rm, 36rl, 36cm, and 36cl are highly interconnected, whereas area 36d (encompassing the dorsal portion of the medial temporal pole) shares only modest connections with the rest of the perirhinal cortex. Areas TH, TFm, and TFl of the parahippocampal cortex also share an extensive network of associational connections that tend to be heaviest within a given subdivision. Area 36c of the perirhinal cortex is the main interface between the perirhinal and parahippocampal cortices. Its heaviest connections are with area 36r and the anterior aspect of area TF. The laminar organization of all these connections is typical of associational projections. Anterograde tracer experiments revealed that these projections are distributed through both deep and superficial layers, although heavier projections are directed toward the superficial layers. Results of retrograde tracer experiments suggested that the projections from caudal areas (36c or TF) to area 36r are of the feedforward type, whereas the projections from areas 36r and 36c to area TF are of the feedback type. These findings suggest that the perirhinal cortex is at a higher level than the parahippocampal cortex in the hierarchy of associational cortices. We discuss the functional implications of the organization of these extensive networks of intrinsic, associational projections.     

Preservation of topography in the connections between the subiculum,field CA1, and the entorhinal cortex in rats

In order to examine whether the entorhinal-hippocampal-entorhinal circuit is reciprocal and topographic, the connections between the subiculum, the CA1 field, and the entorhinal cortex were studied with the carbocyanine dye (Dil), which moves in both retrograde and anterograde directions. We investigated the organization of reciprocal connections revealed by injections of Dil in the entorhinal cortex along the rhinal sulcus. Anterograde fluorescent labeling showed the same pattern reported in previous studies of the dorsal hippocampus. When the injection site of DiI extended into the deep layers (IV–VI) of the same cortical column, the anterograde labeling of the perforant path was accompanied by retrograde labeling of the subicular neurons and the CA1 neurons. The distribution of labeled cells overlapped the distribution of labeled fibers, and the distribution of labeled cells paralleled that of the labeled fibers in the CA1 field. DiI injection into the medial entorhinal cortex revealed fewer retrogradely labeled subicular neurons than injection into the lateral entorhinal cortex, whereas the number of labeled CA1 neurons was not dependent on the injection site. The number of labeled CA1 neurons was always several times greater than the number of subicular neurons. Thus, the amount of information conveyed by the CA1 projection might be higher than that conveyed by the subicular projection. These results indicate that the entorhinal cortex, CA1, and the subiculum are connected reciprocally and topographically. We believe that the framework of the major hippocampal circuit proposed in previous studies should be reconsidered. We propose that the CA1 projection, rather than the subicular projection, is the main projection that feeds back information from the hippocampus to the entorhinal cortex. © 1995 Wiley-Liss, Inc.     

Multiple anatomical systems embedded within the primate medial temporal lobe: implications for hippocampal function

A review of medial temporal lobe connections reveals three distinct groupings of hippocampal efferents. These efferent systems and their putative memory functions are: (1) The 'extended-hippocampal system' for episodic memory, which involves the anterior thalamic nuclei, mammillary bodies and retrosplenial cortex, originates in the subicular cortices, and has a largely laminar organisation; (2) The 'rostral hippocampal system' for affective and social learning, which involves prefrontal cortex, amygdala and nucleus accumbens, has a columnar organisation, and originates from rostral CA1 and subiculum; (3) The 'reciprocal hippocampal-parahippocampal system' for sensory processing and integration, which originates from the length of CA1 and the subiculum, and is characterised by columnar, connections with reciprocal topographies. A fourth system, the 'parahippocampal-prefrontal system' that supports familiarity signalling and retrieval processing, has more widespread prefrontal connections than those of the hippocampus, along with different thalamic inputs. Despite many interactions between these four systems, they may retain different roles in memory which when combined explain the importance of the medial temporal lobe for the formation of declarative memories.     

Tracing of axonal connections by rhodamine-dextran-amine in the rat hippocampal-entorhinal cortex slice preparation.

In order to demonstrate axonal connections preserved in rat temporal cortex slices the authors used rhodamine-dextran-amine as a tracer. The slices contained the neocortical areas Te2 and Te3, the medial and lateral entorhinal cortices (MEC and LEC), the subicular regions, and the dentate gyrus and hippocampus proper. Rhodamine-dextran-amine crystals were placed by microinjection into a given area. Following this local lesioning the dye was permitted to diffuse and migrate intraaxonally in antero- and retrograde directions for about 8 hours. The slices were then formaldehyde-fixed and analyzed by fluorescence microscopy. Most of the known connections within and between the entorhinal cortex and the hippocampus and dentate gyrus were preserved in the slice preparation, provided that the slices were cut with a near horizontal orientation corresponding to plates 99-108 in Paxinos and Watson (1986). Only the lateral perforant path between the LEC and the hippocampus could not be followed to its full extent. The authors conclude that most aspects of the intrinsic synaptic organization of the temporal lobe can be reliably studied in hippocampal-entorhinal cortex slice preparations.     

Distribution,morphological features,and synaptic connections of parvalbumin- and calbindin D28k-immunoreactive neurons in the human hippocampal formation

Calcium binding proteins calbindin D_28k (CaBP) and parvalbumin (PV) are known to form distinct subpopulations of gamma-aminobutyric acid (GABA)ergic neurons in the rodent hippocampal formation. Light and electron microscopic morphology and connections of these protein-containing neurons are only partly known in the primate hippocampus. In this study, CaBP and PV were localized in neurons of the human hippocampal formation including the subicular complex (prosubiculum, subiculum, and presubiculum) in order to explore to what extent these subpopulations of hippocampal neurons differ in phylogenetically distant species. CaBP immunoreactivity was present in virtually all granule cells of the dentate gyrus and in a proportion of pyramidal neurons in the CA1 and CA2 regions. A distinct population of CaBP-positive local circuit neurons was found in all layers of the dentate gyrus and Ammon's horn. Most frequently they were located in the molecular layer of the dentate gyrus and the pyramidal layer of Ammon's horn. In the subicular complex pyramidal neurons were not immunoreactive for CaBP. In the prosubiculum and subiculum immunoreactive nonpyramidal neurons were equally distributed in all layers, whereas in the presubiculum they occurred mainly in the superficial layers. Electron microscopy showed typical somatic and dendritic features of the granule, pyramidal, and local circuit neurons. CaBP-positive mossy fiber terminals in the hilus of the dentate gyrus and terminals of presumed pyramidal neurons of Ammon's horn formed asymmetric synapses with dendrites and spines. CaBP-positive terminals of nonprincipal neurons formed symmetric synapses with dendrites and dendritic spines, but never with somata or axon initial segments. PV was exclusively present in local circuit neurons in both the hippocampal formation and subicular complex. Most of the PV-positive cell bodies were located among or close to the principal cell layers. However, large numbers of immunoreactive neurons were also found in the molecular layer of the dentate gyrus and in strata oriens of Ammon's horn. PV-positive cells were equally distributed in all layers of the subicular complex. Electron microscopy showed the characteristic somatic and dendritic features of local circuit neurons. PV-positive axon terminals formed exclusively symmetric synapses with somata, axon initial segments and dendritic shafts, and in a few cases with dendritic spines. The CaBP- and PV-containing neurons formed similar subpopulations in rodents, monkeys, and humans, although the human hippocampus displayed the largest variability of these immunoreactive neurons in their morphology and location. Calcium binding protein-containing neurons frequently occurred in the molecular layer of the human dentate gyrus and in the stratum lacunosum-moleculare of Ammon's horn. The corresponding areas of the rat or monkey hippocampus were devoid of such neurons. In both rodents and primates similar populations of principal neurons contained CaBP. In addition, CaBP and PV were localized in distinct and nonoverlapping populations of nonprincipal cells. Their target selectivity did not change during phylogeny (e.g., PV-positive cells mainly innervate the perisomatic region and CaBP-positive cells the distal dendritic region of principal cells). © 1993 Wiley-Liss,Inc.     

Topographic organization of connections between the hypothalamus and prefrontal cortex in the rhesus monkey

Prefrontal cortices have been implicated in autonomic function, but their role in this activity is not well understood. Orbital and medial prefrontal cortices receive input from cortical and subcortical structures associated with emotions. Thus, the prefrontal cortex may be an essential link for autonomic responses driven by emotions. Classic studies have demonstrated the existence of projections between prefrontal cortex and the hypothalamus, a central autonomic structure, but the topographic organization of these connections in the monkey has not been clearly established. We investigated the organization of bidirectional connections between these areas in the rhesus monkey by using tracer injections in orbital, medial, and lateral prefrontal areas. All prefrontal areas investigated received projections from the hypothalamus, originating mainly in the posterior hypothalamus. Differences in the topography of hypothalamic projection neurons were related to both the location and type of the target cortical area. Injections in lateral eulaminate prefrontal areas primarily labeled neurons in the posterior hypothalamus that were equally distributed in the lateral and medial hypothalamus. In contrast, injections in orbitofrontal and medial limbic cortices labeled neurons in the anterior and tuberal regions of the hypothalamus and in the posterior region. Projection neurons targeting orbital limbic cortices were more prevalent in the lateral part of the hypothalamus, whereas those targeting medial limbic cortices were more prevalent in the medial hypothalamus. In comparison to the ascending projections, descending projections from prefrontal cortex to the hypothalamus were highly specific, originating mostly from orbital and medial prefrontal cortices. The ascending and descending connections overlapped in the hypothalamus in areas that have autonomic functions. These results suggest that specific orbitofrontal and medial prefrontal areas exert a direct influence on the hypothalamus and may be important for the autonomic responses evoked by complex emotional situations. J. Comp. Neurol. 398:393–419, 1998. © 1998 Wiley-Liss, Inc.     

Frontal and temporal functional connections of the living human brain

Connections between human temporal and frontal cortices were investigated by intracranial electroencephalographic responses to electrical stimulation with 1-ms single pulses in 51 patients assessed for surgery for treatment of epilepsy. The areas studied were medial temporal, entorhinal, lateral temporal, medial frontal, lateral frontal and orbital frontal cortices. Findings were assumed to be representative of human brain as no differences were found between epileptogenic and non-epileptogenic hemispheres. Connections between intralobar temporal and frontal regions were common (43-95%). Connections from temporal to ipsilateral frontal regions were relatively uncommon (seen in 0-25% of hemispheres). Connections from frontal to ipsilateral temporal cortices were more common, particularly from orbital to ipsilateral medial temporal regions (40%). Contralateral temporal connections were rare (< 9%) whereas contralateral frontal connections were frequent and faster, particularly from medial frontal to contralateral medial frontal (61%) and orbital frontal cortices (57%), and between both orbital cortices (67%). Orbital cortex receives profuse connections from the ipsilateral medial (78%) and lateral (88%) frontal cortices, and from the contralateral medial (57%) and orbital (67%) frontal cortices. The high incidence of intralobar temporal connections supports the presence of temporal reverberating circuits. Frontal cortex projects within the lobe and beyond, to ipsilateral and contralateral structures.     

Cortical afferents of the perirhinal,postrhinal, and entorhinal cortices of the rat

We have divided the cortical regions surrounding the rat hippocampus into three cytoarchitectonically discrete cortical regions, the perirhinal, the postrhinal, and the entorhinal cortices. These regions appear to be homologous to the monkey perirhinal, parahippocampal, and entorhinal cortices, respectively. The origin of cortical afferents to these regions is well-documented in the monkey but less is known about them in the rat. The present study investigated the origins of cortical input to the rat perirhinal (areas 35 and 36) and postrhinal cortices and the lateral and medial subdivisions of the entorhinal cortex (LEA and MEA) by placing injections of retrograde tracers at several locations within each region. For each experiment, the total numbers of retrogradely labeled cells (and cell densities) were estimated for 34 cortical regions. We found that the complement of cortical inputs differs for each of the five regions. Area 35 receives its heaviest input from entorhinal, piriform, and insular areas. Area 36 receives its heaviest projections from other temporal cortical regions such as ventral temporal association cortex. Area 36 also receives substantial input from insular and entorhinal areas. Whereas area 36 receives similar magnitudes of input from cortices subserving all sensory modalities, the heaviest projections to the postrhinal cortex originate in visual associational cortex and visuospatial areas such as the posterior parietal cortex. The cortical projections to the LEA are heavier than to the MEA and differ in origin. The LEA is primarily innervated by the perirhinal, insular, piriform, and postrhinal cortices. The MEA is primarily innervated by the piriform and postrhinal cortices, but also receives minor projections from retrosplenial, posterior parietal, and visual association areas. J. Comp. Neurol. 398:179–205, 1998. © 1998 Wiley-Liss, Inc.     

Interhemispheric connections in the visual cortex of the squirrel monkey (Saimiri sciureus)

The callosal connections within the posterior parietal and occipital cortices were studied in the squirrel monkey with horseradish peroxidase tracing techniques. The data were evaluated with particular emphasis on the relationship of major callosal connections along the 17-18 border. The overall pattern of callosal connections in the squirrel monkey also was compared with callosal patterns in other New World simians. Our results show that the dense band of callosal connections along the 17-18 border in the squirrel monkey differs from the connections observed in other New World monkeys in that it is virtually confined to area 18 and avoids area 17. In addition to a continuous band of callosal connections in area 18 that parallels the 17-18 border, rostral extensions of the band are oriented perpendicular to the 17-18 border and present an obvious periodicity. The remaining parieto-occipital cortex contains a complex pattern of callosal connections that is strikingly similar to patterns reported for other New World monkeys. Thus, it is likely that the dorsolateral extrastriate visual cortex in the squirrel monkey is organized in a manner similar to that found within other New World monkeys.     

Reduced nicotinamide adenine dinucleotide phosphate-diaphorase/nitric oxide synthase profiles in the human hippocampal formation and perirhinal cortex

Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d)-stained profiles were evaluated throughout the human hippocampal formation (i. e., dentate gyrus, Ammon's horn, subicular complex, entorhinal cortex) and perirhinal cortex. NADPH-d staining revealed pleomorphic cells, fibers, and blood vessels. Within the entorhinal and the perirhinal cortices, darkly stained (type 1) NADPH-d pyramidal, fusiform, bipolar, and multipolar neurons with extensive dendrites were scattered mainly within deep layers and subjacent white matter. Moderately stained (type 2) NADPH-d round or oval neurons were seen mainly in layers II and III of the entorhinal and perirhinal cortices, in the dentate gyrus polymorphic layer, in the CA fields stratum pyramidal and radiatum, and in the subicular complex. The distribution of type 2 cells was more abundant in the perirhinal cortex compared to the hippocampal formation. Lightly stained (type 3) NADPH-d pyramidal and oval neurons were distributed in CA4, the entorhinal cortex medial subfields, and the amygdalohippocampal transition area. Sections concurrently stained for NADPH-d and nitric oxide synthase (NOS) revealed that all type 1 neurons coexpressed NOS, whereas types 2 and 3 were NOS immunonegative. NADPH-d fibers were heterogeneously distributed within the different regions examined and were frequently in close apposition to reactive blood vessels. The greatest concentration of fibers was in layers III and V–VI of the entorhinal and perirhinal cortices, dentate gyrus polymorphic and molecular layers, and CA1 and CA4. A band of fibers coursing within CA1 divided into dorsal and ventral bundles to reach the presubiculum and entorhinal cortex, respectively. Although the distribution of NADPH-d fibers was conserved across all ages examined (28–98 years), we observed an increase in the density of fiber staining in the aged cases. These results may be relevant to our understanding of selective vulnerability of neuronal systems within the human hippocampal formation in aging and in neurodegenerative diseases. © 1995 Wiley-Liss, Inc.     

The Pathology of Paraphrenia

Evidence derived from postmortem brain studies has implicated the uncal cortex in paraphrenia. In the present review, we expand on the anatomic and physiologic nuances endogenous to this region that make entorhinal cortex pathology an important clinicopathological correlate to paraphrenia. First, we summarize the anatomic landmarks and histologic features that will allow the reader to define the entorhinal region in future research studies. As cortical regions usually project to neighboring cortices, inferences will be drawn as to the function of the entorhinal region based on the surrounding cortical regions. The results will help explain why patients with paraphrenia may exhibit amnestic deficits that stand in contrast to a well-preserved thought process and personality. We also review the results of surgical ablation studies in animals. These studies suggest that some risk factors currently associated with paraphrenia (eg, social isolation) may in reality be an early manifestation of entorhinal pathology. Finally, the author provides a parallelism between the hallucinations observed in some paraphrenic patients and the results of electrical stimulation of the uncal cortex. The results will help explain why hallucinations in paraphrenia are usually limited to the patient’s surroundings.     

The Role of the Entorhinal Cortex in Paraphrenia

Evidence derived from postmortem brain studies has implicated the uncal cortex in paraphrenia. In the present review, we expand on the anatomic and physiologic nuances endogenous to this region that make entorhinal cortex pathology an important clinicopathological correlate to paraphrenia. First, we summarize the anatomic landmarks and histologic features that will allow the reader to define the entorhinal region in future research studies. As cortical regions usually project to neighboring cortices, inferences will be drawn as to the function of the entorhinal region based on the surrounding cortical regions. The results will help explain why patients with paraphrenia may exhibit amnestic deficits that stand in contrast to a well-preserved thought process and personality. We also review the results of surgical ablation studies in animals. These studies suggest that some risk factors currently associated with paraphrenia (eg, social isolation) may in reality be an early manifestation of entorhinal pathology. Finally, the author provides a parallelism between the hallucinations observed in some paraphrenic patients and the results of electrical stimulation of the uncal cortex. The results will help explain why hallucinations in paraphrenia are usually limited to the patient’s surroundings.     

Distribution of calbindin D-28k in the entorhinal,perirhinal, and parahippocampal cortices of the macaque monkey

We examined the distribution of calbindin D-28k-immunoreactive (CB-IR) neurons, fibers, and neuropil in the entorhinal (area 28), perirhinal (areas 35 and 36), and parahippocampal (areas TH and TF) cortices in the macaque monkey. Two main findings are reported. First, except for CB-IR neurogliaform cells that are only observed in the parahippocampal cortex, the morphology of CB-stained pyramidal and nonpyramidal cells were similar across the three cortical areas examined. Second, we find that the topography of CB staining differed between the three areas. The entorhinal cortex exhibits the most striking gradient of CB staining such that the most anterior and medial portions are most strongly labeled, whereas posterior and lateral areas exhibit only weak labeling. The labeling throughout the perirhinal and parahippocampal cortices is more homogeneous. Area 35 contains only lightly stained neuropil and few CB-IR cells. Area 36 and areas TH and TF of the parahippocampal cortex contain a moderate to high density of CB-IR cells and fibers throughout their full rostrocaudal extents, although each area exhibits unique laminar patterns of staining. In all areas examined, the highest density of CB-positive cells and fibers is observed in superficial layers with lower densities of CB-positive cells and fibers present in deep layers. These findings, taken together with our current understanding of the connections of these areas may have implications for understanding the circuit properties of the entorhinal, perirhinal, and parahippocampal cortices areas in both normal and disease states.