The thalamic midline nucleus reuniens: potential relevance for schizophrenia and epilepsy.

Anatomical, electrophysiological and behavioral studies in rodents have shown that the thalamic midline nucleus reuniens (RE) is a crucial link in the communication between hippocampal formation (HIP, i.e., CA1, subiculum) and medial prefrontal cortex (mPFC), important structures for cognitive and executive functions. A common feature in neurodevelopmental and neurodegenerative brain diseases is a dysfunctional connectivity/communication between HIP and mPFC, and disturbances in the cognitive domain. Therefore, it is assumed that aberrant functioning of RE may contribute to behavioral/cognitive impairments in brain diseases characterized by cortico-thalamo-hippocampal circuit dysfunctions. In the human brain the connections of RE are largely unknown. Yet, recent studies have found important similarities in the functional connectivity of HIP-mPFC-RE in humans and rodents, making cautious extrapolating experimental findings from animal models to humans justifiable. The focus of this review is on a potential involvement of RE in schizophrenia and epilepsy.

Interaction of nucleus reuniens and entorhinal cortex projections in hippocampal field CA1 of the rat.

The nucleus reuniens (RE) and entorhinal cortex (EC) provide monosynaptic excitatory inputs to the apical dendrites of pyramidal cells and to interneurons with dendrites in stratum lacunosum moleculare (LM) of hippocampal field CA1. However, whether the RE and EC inputs interact at the cellular level is unknown. In this electrophysiological in vivo study, low-frequency stimulation was used to selectively activate each projection at its origin; field excitatory postsynaptic potentials (fEPSPs) were recorded in CA1. We applied (1) paired pulses to RE or EC, (2) combined paired pulses to RE and EC, and (3) simultaneously paired pulses to RE/EC. The main findings are that: (a) stimulation of either RE- or EC-evoked subthreshold fEPSPs, displaying paired pulse facilitation (PPF), (b) subthreshold fEPSPs evoked by combined stimulation did not display heterosynaptic PPF, and (c) simultaneous stimulation of RE/EC resulted in enhanced subthreshold fEPSPs in proximal LM displaying a nonlinear interaction. CSD analyses of RE/EC-evoked depth profiles revealed a nonlinear enlargement of the 'LM sink-radiatum source' configuration and the appearance of an additional small sink-source pair close to stratum pyramidale, likely reflecting (peri)somatic inhibition. The nonlinear interaction between both inputs indicates that RE and EC axons form synapses, at least partly, onto the same dendritic compartments of CA1 pyramidal cells. We propose that low-frequency activation of the RE-CA1 input facilitates the entorhinal-hippocampal dialogue, and may synchronize the neocortical-hippocampal slow oscillation which is relevant for hippocampal-dependent memory consolidation.

Early differences in dorsal hippocampal metabolite levels in males but not females in a transgenic rat model of Alzheimer's disease.

McGill-R-Thy1-APP rats express the human amyloid precursor protein carrying the Swedish and Indiana mutations. We examined the neurochemical content of the dorsal hippocampus in three-months-old male and female transgenic rats and healthy age- and gender-matched controls using in vivo (1)H MRS in order to assess early metabolite alterations and whether these were similar for both genders. Whereas male and female controls had similar levels of all metabolites, differences were evident between male and female McGill-R-Thy1-APP rats. Compared with McGill-R-Thy1-APP females, McGill-R-Thy1-APP males had lower levels of myo-inositol and N-acetylaspartate (NAA). No differences in metabolite levels were evident when female control and McGill-R-Thy1-APP rats were compared, whereas McGill-R-Thy1-APP males had lower levels of glutamate, NAA and total choline compared with male controls. In addition to metabolite concentrations, metabolite ratios are reported as these are widely used. The results from this preliminary study demonstrate early metabolite alterations in the dorsal hippocampus of males in this rat model of Alzheimer's disease, and imply that very early possible neurochemical markers of the disease are different for males and females.

Distinct brain systems underlie the processing of valence and arousal of affective pictures.

Valence and arousal are thought to be the primary dimensions of human emotion. However, the degree to which valence and arousal interact in determining brain responses to emotional pictures is still elusive. This functional MRI study aimed to delineate neural systems responding to valence and arousal, and their interaction. We measured neural activation in healthy females (N=23) to affective pictures using a 2 (Valence) x 2 (Arousal) design. Results show that arousal was preferentially processed by middle temporal gyrus, hippocampus and ventrolateral prefrontal cortex. Regions responding to negative valence included visual and lateral prefrontal regions, positive valence activated middle temporal and orbitofrontal areas. Importantly, distinct arousal-by-valence interactions were present in anterior insula (negative pictures), and in occipital cortex, parahippocampal gyrus and posterior cingulate (positive pictures). These data demonstrate that the brain not only differentiates between valence and arousal but also responds to specific combinations of these two, thereby highlighting the sophisticated nature of emotion processing in (female) human subjects.

The anatomy of memory: an interactive overview of the parahippocampal-hippocampal network.

Converging evidence suggests that each parahippocampal and hippocampal subregion contributes uniquely to the encoding, consolidation and retrieval of declarative memories, but their precise roles remain elusive. Current functional thinking does not fully incorporate the intricately connected networks that link these subregions, owing to their organizational complexity; however, such detailed anatomical knowledge is of pivotal importance for comprehending the unique functional contribution of each subregion. We have therefore developed an interactive diagram with the aim to display all of the currently known anatomical connections of the rat parahippocampal-hippocampal network. In this Review, we integrate the existing anatomical knowledge into a concise description of this network and discuss the functional implications of some relatively underexposed connections.

Contacts between medial and lateral perforant pathway fibers and parvalbumin expressing neurons in the subiculum of the rat.

The entorhinal cortex (EC) projects via the perforant pathway to all subfields in the hippocampal formation. One can distinguish medial and lateral components in the pathway, originating in corresponding medial and lateral subdivisions of EC. We analyzed the innervation by medial and lateral perforant pathway fibers of parvalbumin-expressing neurons in the subiculum. A neuroanatomical tracer (biotinylated dextran amine, BDA) was stereotaxically injected in the medial or lateral entorhinal cortex, thus selectively labeling either perforant pathway component. Transport was allowed for 1 week. Transported BDA was detected with streptavidin-Alexa Fluor 488. Parvalbumin neurons were visualized via immunofluorescence histochemistry, using the fluorochrome Alexa Fluor 594. Via a random systematic sampling scheme using a two-channel, sequential-mode confocal laser scanning procedure, we obtained image series at high magnification from the molecular layer of the subiculum. Labeled entorhinal fibers and parvalbumin-expressing structures were three dimensionally (3D) reconstructed using computer software. Further computer analysis revealed that approximately 16% of the 3D objects ('boutons') of BDA-labeled fibers was engaged in contacts with parvalbumin-immunostained dendrites in the subiculum. Both medial and lateral perforant pathway fibers and their boutons formed such appositions. Contacts are suggestive for synapses. We found no significant differences between the medial and lateral components in the relative numbers of contacts. Thus, the medial and lateral subdivisions of the entorhinal cortex similarly tune the firing of principal neurons in the subiculum by way of parvalbumin positive interneurons in their respective terminal zones.

What is the mammalian dentate gyrus good for?

In the mammalian hippocampus, the dentate gyrus (DG) is characterized by sparse and powerful unidirectional projections to CA3 pyramidal cells, the so-called mossy fibers (MF). The MF form a distinct type of synapses, rich in zinc, that appear to duplicate, in terms of the information they convey, what CA3 cells already receive from entorhinal cortex layer II cells, which project both to the DG and to CA3. Computational models have hypothesized that the function of the MF is to enforce a new, well-separated pattern of activity onto CA3 cells, to represent a new memory, prevailing over the interference produced by the traces of older memories already stored on CA3 recurrent collateral connections. Although behavioral observations support the notion that the MF are crucial for decorrelating new memory representations from previous ones, a number of findings require that this view be reassessed and articulated more precisely in the spatial and temporal domains. First, neurophysiological recordings indicate that the very sparse dentate activity is concentrated on cells that display multiple but disorderly place fields, unlike both the single fields typical of CA3 and the multiple regular grid-aligned fields of medial entorhinal cortex. Second, neurogenesis is found to occur in the adult DG, leading to new cells that are functionally added to the existing circuitry, and may account for much of its ongoing activity. Third, a comparative analysis suggests that only mammals have evolved a DG, despite some of its features being present also in reptiles, whereas the avian hippocampus seems to have taken a different evolutionary path. Thus, we need to understand both how the mammalian dentate operates, in space and time, and whether evolution, in other vertebrate lineages, has offered alternative solutions to the same computational problems.

Activation of the human medial temporal lobes by stereoscopic depth cues.

The perirhinal cortex (PER) is part of both the medial temporal lobe memory system (MTL) and the ventral visual stream (VVS). In the MTL, PER provides input to the hippocampal formation directly and via the entorhinal cortex (EC), whereas in the VVS, PER is considered to be at the top of the visual processing hierarchy of object information. Because of its position in both networks, PER presumably serves a role in memory and visual perception. PER's perceptual role is thought to be contingent upon the complexity of visual information, i.e., PER only becomes active in visual perception when many higher order visual cues are combined. Using high-resolution functional MRI (fMRI), we investigated the effect of varying the presence of binocular disparity, in complex visual object stimuli. Nineteen subjects were presented with movies of complex objects and a fixation cross, either with or without binocular disparity (referred to as stereo and mono condition respectively). Subjects were instructed to attentively watch the objects, but no instructions were given to memorize them. Group results showed increased activity in the MTL, among which is PER, when comparing the stereo over the mono condition (stereo > mono). Individual analysis showed dominant activation in the stereo > mono contrast in eleven out of nineteen subjects, whereas only three subjects showed dominance in the opposite contrast. We conclude that the MTL is differentially activated by the stereo and mono condition, such that activation is stronger when a complex visual object stimulus with disparity is presented.

Does assimilation into schemas involve systems or cellular consolidation? It's not just time.

A comment by Rudy and Sutherland [Rudy, J. R., & Sutherland, R. J. (2008). Is it systems or cellular consolidation? Time will tell. An alternative interpretation of the Morris Group's recent Science Paper. Neurobiology of Learning and Memory] has suggested an alternative account of recent findings concerning very rapid systems consolidation as described in a recent paper by Tse et al [Tse, D., Langston, R. F., Kakeyama, M., Bethus, I., Spooner, P. A., & Wood, E. R., et al. (2007). Schemas and memory consolidation. Science, 316, 76-82]. This is to suppose that excitotoxic lesions of the hippocampus cause transient disruptive neural activity outside the target structure that interferes with cellular consolidation in the cortex. We disagree with this alternative interpretation of our findings and cite relevant data in our original paper indicating why this proposal is unlikely. Various predictions of the two accounts are nonetheless outlined, together with the types of experiments needed to resolve the issue of whether systems consolidation can occur very rapidly when guided by activated neural schemas.

Nonlinear changes in brain activity during continuous word repetition: an event-related multiparametric functional MR imaging study.

BACKGROUND AND PURPOSE: Changes in brain activation as a function of continuous multiparametric word recognition have not been studied before by using functional MR imaging (fMRI), to our knowledge. Our aim was to identify linear changes in brain activation and, what is more interesting, nonlinear changes in brain activation as a function of extended word repetition. MATERIALS AND METHODS: Fifteen healthy young right-handed individuals participated in this study. An event-related extended continuous word-recognition task with 30 target words was used to study the parametric effect of word recognition on brain activation. Word-recognition-related brain activation was studied as a function of 9 word repetitions. fMRI data were analyzed with a general linear model with regressors for linearly changing signal intensity and nonlinearly changing signal intensity, according to group average reaction time (RT) and individual RTs. RESULTS: A network generally associated with episodic memory recognition showed either constant or linearly decreasing brain activation as a function of word repetition. Furthermore, both anterior and posterior cingulate cortices and the left middle frontal gyrus followed the nonlinear curve of the group RT, whereas the anterior cingulate cortex was also associated with individual RT. CONCLUSION: Linear alteration in brain activation as a function of word repetition explained most changes in blood oxygen level-dependent signal intensity. Using a hierarchically orthogonalized model, we found evidence for nonlinear activation associated with both group and individual RTs.

Hippocampal shape analysis in Alzheimer's disease: a population-based study.

BACKGROUND: Hippocampal atrophy--particularly of the CA1 region--may be useful as a biomarker for Alzheimer's disease (AD) or the risk for AD. The extent to which the AD hippocampus can be distinguished in vivo from changes due to normal aging or other processes that affect the hippocampus is of clinical importance and is an area of active research. In this study, we use structural imaging techniques to model hippocampal size and regional shape differences between elderly men with incident AD and a non-demented comparison group of elderly men. METHODS: Participants are Japanese-American men from the Honolulu Asia Aging Study (HAAS). The HAAS cohort has been followed since 1965. The following analysis is based on a sub-group of men who underwent MRI examination in 1994-1996. Participants were diagnosed with incident AD (n=24: age=82.5+/-4.6) or were not demented (n=102: age=83.0+/-5.9). One reader, blinded to dementia diagnosis, manually outlined the left and right hippocampal formation using published criteria. We used 3D structural shape analysis methods developed at the Laboratory of Neuro Imaging (LONI) to compare regional variation in hippocampal diameter between the AD cases and the non-demented comparison group. RESULTS: Mean total hippocampal volume was 11.5% smaller in the AD cases than the non-demented controls (4903+/-857 mm(3) vs. 5540+/-805 mm(3)), with a similar size difference for the median left (12.0%) and median right (11.6%) hippocampus. Shape analysis showed a regional pattern of shape difference between the AD and non-demented hippocampus, more evident for the hippocampal body than the head, and the appearance of more consistent differences in the left hippocampus than the right. While assignment to a specific sub-region is not possible with this method, the surface changes primarily intersect the area of the hippocampus body containing the CA1 region (and adjacent CA2 and distal CA3), subiculum, and the dentate gyrus-hilar region.

Entorhinal projections terminate onto principal neurons and interneurons in the subiculum: a quantitative electron microscopical analysis in the rat.

The synaptic organization of projections to the subiculum from superficial layers of the lateral and medial entorhinal cortex was analyzed in the rat, using anterograde neuroanatomical tracing followed by electron microscopical quantification. Our aim was to assess the synaptic organization and whether the two projection components (lateral, medial) within the perforant pathway are qualitatively and quantitatively similar with respect to the types of synapses formed and with respect to the postsynaptic targets of these entorhinal projections. The tracer biotinylated dextran amine (BDA) was injected into the lateral and medial entorhinal cortex, respectively, and resulting anterograde labeling in the subiculum was studied. For each of the two projection components, we analyzed in four animals (2 x 2) a total of 100 synapses/animal with respect to features of the synapse type, i.e. asymmetrical or symmetrical, as well as regarding their postsynaptic target, i.e. dendritic shaft or spine. No clear differences were observed between the two pathways. The majority of the synapses were of the asymmetrical type, making contact with spines (78%) or with dendritic shafts (14%). A low percentage of symmetrical synapses targeted dendritic shafts (4.2%) or spines (1.3%). About 2.5% of the synapses remained undetermined. The findings indicate that the majority of entorhinal fibers reaching the subiculum exert an excitatory influence primarily onto principal neurons, with a much smaller feed forward inhibitory component. Only a small percentage of entorhinal fibers in the subiculum appears to be inhibitory, largely influencing interneurons.

Intrinsic connections of the cingulate cortex in the rat suggest the existence of multiple functionally segregated networks.

The cingulate cortex is a functionally and morphologically heterogeneous cortical area comprising a number of interconnected subregions. To date, the exact anatomy of intracingulate connections has not been studied in detail. In the present study we aimed to determine the topographical and laminar characteristics of intrinsic cingulate connections in the rat, using the anterograde tracers Phaseolus vulgaris-leucoagglutinin and biotinylated dextran amine. For assessment of these data we further refined and compared the existing cytoarchitectonic descriptions of the two major cingulate constituents, the anterior cingulate and retrosplenial cortices. The results of this study demonstrate that rostral areas, i.e. the infralimbic and prelimbic cortices and the rostral one third of the dorsal anterior cingulate cortex are primarily interconnected with each other and not with other cingulate areas. The caudal two thirds of the dorsal anterior cingulate cortex project to the caudal part of the ventral anterior cingulate cortex, whereas the entire ventral anterior cingulate cortex projects to only the mid-rostro-caudal part of the dorsal anterior cingulate cortex. Dense reciprocal connections exist between the remaining, i.e. the supracallosal parts of the anterior cingulate and retrosplenial cortices with a general rostro-caudal topography, in the sense that the rostral part of the anterior cingulate cortex and caudal part of the retrosplenial cortex are interconnected and the same holds true for the caudal part of the anterior cingulate cortex and rostral part of the retrosplenial cortex. This topographical pattern of intracingulate connections relates to the results of several functional studies, suggesting that specific cingulate functions depend on a number of interconnected cingulate subregions. Through their intricate associational connections, these subregions form functionally segregated networks.

Projections from the parahippocampal region to the prefrontal cortex in the rat: evidence of multiple pathways.

The purpose of the present study was to investigate, by means of anterograde tracing methods, the detailed organization of the parahippocampal-prefrontal projections in the rat brain. Efferents from the perirhinal cortex were found to terminate principally in both the ventromedial (prelimbic and infralimbic cortices) and lateral (agranular insular cortex) regions of the prefrontal cortex. Terminal fields were observed mainly in the superficial layers of the prefrontal cortex. Projections arising from the dorsolateral entorhinal cortex, which borders the perirhinal cortex along its ventral extent, were similarly directed to the ventromedial and lateral prefrontal cortices but also encompassed other frontal areas (dorsomedial and orbital prefrontal regions). Terminal fields of entorhinal projections were also found in the superficial layers of the prefrontal cortex. A third pathway, taking its source in the post-rhinal cortex, presented striking topographical differences with the two other output systems. Hence, post-rhinal efferences terminated only in the ventrolateral orbital area. The results indicate that two main routes originate from the parahippocampal region to reach the prefrontal cortex. One pathway involves the rostral and lateral portions of the parahippocampal region (perirhinal and dorsolateral entorhinal cortices), and the other relies on its most caudal region, the post-rhinal cortex. The presence of such different multiple parahippocampal-prefrontal pathways may have functional relevance for learning and memory processes.

Anterior medial temporal lobe activation during attempted retrieval of encoded visuospatial scenes: an event-related fMRI study.

Various studies have shown that the medial temporal lobe (MTL), which consists of the hippocampus and parahippocampal gyrus, is important for episodic memory. Earlier fMRI studies substantiated this role by showing activation upon encoding of visuospatial scenes. In this study we used event-related fMRI to study whether the cognitive process of retrieval of visuospatial scenes, tested with the use of a recognition paradigm, also activates the MTL. Nine subjects (mean age 24 years) were presented previously studied color pictures (old) and pictures they had never seen before (new) in a mixed trial design. Data analysis allowed calculation of the fMRI response of correct judgments on new pictures, old pictures, and false judgments. Since we used previously encoded color pictures as old stimuli, we also included an encoding paradigm in the current set of experiments. This allowed us to compare encoding and recognition activation in the MTL of exactly the same pictures in the same subjects. Correct judgments on new pictures showed an increased activation in the anterior parahippocampus bilaterally and the right anterior hippocampus compared to judgments on old pictures in the recognition experiment. The former judgments took significantly longer, indicating that retrieval of successfully stored information is less demanding than the effort to retrieve nonencoded information. A comparison of the two experimental data sets showed evidence for a functional segregation of encoding and retrieving color pictures. We conclude that the left posterior parahippocampal gyrus responds during encoding, while on the other hand the left anterior parahippocampal gyrus and the right anterior hippocampus were more strongly involved in retrieval.

Intrinsic connectivity of the rat subiculum: I. Dendritic morphology and patterns of axonal arborization by pyramidal neurons.

The dendritic and axonal morphology of rat subicular neurons was studied in single cells labeled with Neurobiotin. Electrophysiological classification of cells as intrinsic burst firing or regular spiking neurons was correlated with morphologic patterns and cell locations. Every cell had dendritic branches that reached the outer molecular layer, with most cells having branches that reached the hippocampal fissure. All but two pyramidal cells had axon collaterals that entered the deep white matter (alveus). Branching patterns of apical dendrites varied as a function of the cell's soma location along the fissure-alveus axis of the cell layer. The first major dendritic branch point for most cells occurred at the superficial edge of the cell layer giving deep cells long primary apical dendrites and superficial cells short or absent primary apical dendrites. In contrast, basal dendritic arbors were similar across cells regardless of cell position. Apical and basal dendrites of all cells had numerous spines. Superficial and deep cells also differed in axonal collateralization. Deep cells (mostly intrinsically bursting [IB] class) had one or more ascending axon collaterals that typically remained within the region circumscribed by their apical dendrites. Superficial cells (mostly regular spiking [RS] class) tended to have axon collaterals that reached longer distances in the cell layer. Numerous varicosities and axonal extensions were present on axon collaterals in the cell layer and in the apical dendritic region, suggesting intrinsic connectivity. Axonal varicosities and extensions were found on axons that entered presubiculum, entorhinal cortex or CA1, supporting the notion that these were projection cells. Local collaterals were distinctly thinner than collaterals that would leave the subiculum, suggesting little or no myelin on local collaterals and some myelin on efferent fibers. We conclude that both IB and RS classes of subicular principal cells make synaptic contacts in and apical to the cell layer. Based on the patterns of axonal arborization, we suggest that subiculum has at least a crude columnar and laminar architecture, with ascending collaterals of deep cells forming columns and broader axonal arbors of superficial cells serving to distribute activity across multiple columns.

Evidence for a direct projection from the postrhinal cortex to the subiculum in the rat.

Behavioral data indicate that three of the areas which form the parahippocampal region in the rat, i.e., the entorhinal, perirhinal, and postrhinal cortices, have different, although related functions that also differ from those of the hippocampal formation. These functional differences might be related to differences in connectivity, on the one hand with parts of the association cortex, and on the other with the hippocampal formation. In a previous study, we showed the existence of both a direct and an indirect projection from the perirhinal cortex to areas CA1 and subiculum of the hippocampus. Here we present the result of a second study, demonstrating a similarly organized projection from the postrhinal cortex to the subiculum, comprising both a direct and an indirect route. Electrical stimulation of the postrhinal cortex in vivo evoked field potentials throughout the subiculum and the dentate gyrus. Current source density analysis in both the subiculum and dentate gyrus revealed the presence of sink-source pairs, indicative of a synaptic termination. Based on comparison with the sink-source pairs found after stimulation of the medial entorhinal cortex, we conclude that the connection between the postrhinal cortex and the dentate gyrus most likely is formed by a polysynaptic pathway mediated via the medial entorhinal cortex, while the pathway from the postrhinal cortex to the subiculum is likely monosynaptic. In order to substantiate these findings, we carried out several tracer experiments. Anterograde tracer injections in the postrhinal cortex resulted in labeled fibers in limited parts of the subiculum, but no anatomical evidence for a projection of the postrhinal cortex to the dentate gyrus was found. Additional retrograde tracer injections in the subiculum also showed evidence for a direct postrhinal-to-subiculum projection with a strong topological organization. Based on these combined anatomical and electrophysiological data, we conclude that the postrhinal cortex indeed can reach the subiculum via both a direct and an indirect pathway.

Reciprocal connections between the entorhinal cortex and hippocampal fields CA1 and the subiculum are in register with the projections from CA1 to the subiculum.

The topology of the connections between the entorhinal cortex (EC), area CA1, and the subiculum is characterized by selective and restricted origin and termination along the transverse or proximodistal axis of CA1 and the subiculum. In the present study, we analyzed whether neurons in CA1 and the subiculum that receive EC projections are interconnected and give rise to return projections to EC, such that they terminate deep in the area of origin of the EC-to-CA1/subiculum projections. Both for the lateral and medial subdivision of EC, the projections to CA1/subiculum, as well as the projections from CA1 to the subiculum and back to EC, are rather divergent. Interestingly, we only rarely observed evidence for the presence of "reentry loops," i.e., cells in layer III of EC giving rise to projections to interconnected neurons in CA1 and the subiculum, while the targeted CA1 neurons also projected back to the deep layers of the area of origin of the pathway in EC. We conclude that although fibers originating from a restricted part of EC distribute extensively in a divergent way along the longitudinal axis of CA1 and the subiculum, only restricted portions of the latter two areas, receiving inputs from the same entorhinal area, are interconnected. Moreover, only a small percentage of the CA1 neurons that project to the correspondingly innervated subicular neurons give rise to projections that return to the deep layers of the originating part of EC. The present findings are taken to indicate that the EC-hippocampal circuitry functionally comprises many parallel-organized specific "reentry loops."

Functional MR imaging in Alzheimer's disease during memory encoding.

BACKGROUND AND PURPOSE: We applied functional MR imaging with a learning task in healthy elderly volunteers and in patients with Alzheimer's disease to study brain activation during memory performance. The purpose was to determine the feasibility of functional MR imaging during a learning task in healthy elderly volunteers and in patients with Alzheimer's disease and to test our hypothesis that brain activation is decreased in the medial temporal lobe (MTL) memory system in patients with Alzheimer's disease compared with control volunteers. METHODS: In 12 patients with mild to moderate forms of Alzheimer's disease and 10 elderly control volunteers, activation of the MTL memory system was studied. We used two learning tasks that required the encoding of new information into memory. After the functional MR imaging experiment, participants were tested for recognition of the encoded objects. RESULTS: In the elderly control volunteers, activation during memory encoding was observed in medial and lateral temporal lobe structures (fusiform, parietal and occipital parts, and hippocampal formation) and in the frontal cortex, as reported previously in studies of young control volunteers. Focusing on the MTL, we observed that activation was significantly decreased in patients with Alzheimer's disease compared with control volunteers in the left hippocampus and parahippocampal gyrus bilaterally during the first encoding task but not during the second (P < .05, uncorrected). CONCLUSION: Functional MR imaging with a learning task seems feasible in elderly volunteers and in patients with Alzheimer's disease. The measured functional signal decrease in MTL areas warrants further exploration of the (early) diagnostic usefulness of functional MR imaging in cases of Alzheimer's disease and other dementias.

Cortico-hippocampal communication by way of parallel parahippocampal-subicular pathways.

The hippocampal memory system, consisting of the hippocampal formation and the adjacent parahippocampal region, is known to play an important role in learning and memory processes. In recent years, evidence from a variety of experimental approaches indicates that each of the constituting fields of the hippocampal memory system may serve functionally different, yet complementary roles. Understanding the anatomical organization of cortico-parahippocampal-hippocampal connectivity may lead to a further understanding of these potential functional differences. In the present paper we present the two main conclusions of experiments in which we studied the anatomical organization of the hippocampal memory system of the rat in detail, with a focus on the pivotal position of the entorhinal cortex. We first conclude that the simple traditional view of the entorhinal cortex as simply the input and output structure of the hippocampal formation needs to be modified. Second, our data indicate the existence of two parallel pathways through the hippocampal memory system, arising from the perirhinal and postrhinal cortex. These two parallel pathways may be involved in separately processing functionally different types of sensory information. This second proposition will be subsequently evaluated on the basis of series of electrophysiological studies we carried out in rats and some preliminary functional brain imaging studies in humans.