Dissociation between Explicit Memory and Configural Memory in the Human Medial Temporal Lobe

The essential role of the medial temporal lobe (MTL) in long-term memory for individual events is well established, yet important questions remain regarding the mnemonic functions of the component structures that constitute the region. Within the hippocampus, recent functional neuroimaging findings suggest that formation of new memories depends on the dentate gyrus and the CA(3) field, whereas the contribution of the subiculum may be limited to retrieval. During encoding, it has been further hypothesized that structures within MTL cortex contribute to encoding in a content-sensitive manner, whereas hippocampal structures may contribute to encoding in a more domain-general manner. In the current experiment, high-resolution fMRI techniques were utilized to assess novelty and subsequent memory effects in MTL subregions for two classes of stimuli--faces and scenes. During scanning, participants performed an incidental encoding (target detection) task with novel and repeated faces and scenes. Subsequent recognition memory was indexed for the novel stimuli encountered during scanning. Analyses revealed voxels sensitive to both novel faces and novel scenes in all MTL regions. However, similar percentages of voxels were sensitive to novel faces and scenes in perirhinal cortex, entorhinal cortex, and a combined region comprising the dentate gyrus, CA(2), and CA(3), whereas parahippocampal cortex, CA(1), and subiculum demonstrated greater sensitivity to novel scene stimuli. Paralleling these findings, subsequent memory effects in perirhinal cortex were observed for both faces and scenes, with the magnitude of encoding activation being related to later memory strength, as indexed by a graded response tracking recognition confidence, whereas subsequent memory effects were scene-selective in parahippocampal cortex. Within the hippocampus, encoding activation in the subiculum correlated with subsequent memory for both stimulus classes, with the magnitude of encoding activation varying in a graded manner with later memory strength. Collectively, these findings suggest a gradient of content sensitivity from posterior (parahippocampal) to anterior (perirhinal) MTL cortex, with MTL cortical regions differentially contributing to successful encoding based on event content. In contrast to recent suggestions, the present data further indicate that the subiculum may contribute to successful encoding irrespective of event content.

Recent models of episodic memory propose a division of labor among medial temporal lobe cortices comprising the parahippocampal gyrus. Specifically, perirhinal and lateral entorhinal cortices are thought to comprise an object/item information pathway, whereas parahippocampal and medial entorhinal cortices are thought to comprise a spatial/contextual information pathway. Although several studies in human subjects have demonstrated a perirhinal/parahippocampal division, such a division among subregions of the human entorhinal cortex has been elusive. Other recent work has implicated pattern separation computations in the dentate gyrus and CA3 subregions of the hippocampus as a mechanism supporting the resolution of mnemonic interference. However, the nature of contributions of medial temporal lobe cortices to downstream hippocampal computations is largely unknown. We used high-resolution fMRI during a task selectively taxing mnemonic discrimination of object identity or spatial location, designed to differentially engage the two information pathways in the medial temporal lobes. Consistent with animal models, we demonstrate novel evidence for a domain-selective dissociation between lateral and medial entorhinal cortex in humans, and between perirhinal and parahippocampal cortex as a function of information content. Conversely, hippocampal dentate gyrus/CA3 demonstrated signals consistent with resolution of mnemonic interference across domains. These results provide insight into the information processing capacities and hierarchical interference resolution throughout the human medial temporal lobe.

To detect local cholinergic changes in human medial temporal lobe during configural working memory performance. Proton magnetic resonance spectroscopy (1 H-MRS) measurements were acquired at 3T from a 2 × 2 × 3 cm voxel in right medial temporal lobe from 36 subjects during performance of a configural visual working memory task (cWMT). In order to compensate for expected task-based blood oxygenation level-dependent (BOLD) T2 * effects, resonance signal changes of unbound choline-containing metabolites (Cho) were referenced to an internal standard of creatine + phosphocreatine metabolites (Cre) and compared between four task blocks: rest, memorization, active memory maintenance, and recognition. An unannounced memory retention test was conducted in 21 subjects. Quality assurance analyses examined task-based Cho and Cre individually as well as referenced to resonance signal from N-acetylaspartate (NAA). Increases from a resting baseline in the Cho/Cre ratio were observed during 60-second blocks of active memory maintenance across the group (P = 0.0042). Behavioral accuracy during task performance correlated with memory retention (r = 0.48, P = 0.027). Quality assurance measures showed task-based changes in Cre resonance signal both individually (P = 0.00099) and when utilized as a noncholinergic internal reference (NAA/Cre, P = 0.00079). Increases in human medial temporal lobe 1 H-MRS Cho/Cre ratio occur during the maintenance of configural working memory information. However, interpretation of these results as driven by cholinergic activity cannot be assumed, as NAA, a noncholinergic metabolite, shows similar results when utilizing Cre as a reference. Caution is advised when considering Cre as an internal standard for task-based 1 H-MRS measurements. 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;47:682-691.

AGGRO

The integrity of the hippocampal formation is necessary for the correct function of declarative memory for facts and events. Normal aging is associated with a widespread decrease in cortical volume, including the hippocampal formation and related cortical areas, although in many cases, memory is only minimally impaired. In the present study, we quantified the extent of the parahippocampal gyrus (entorhinal cortex, as well as the medial temporal lobe proisocortical areas related to memory function, such as temporopolar cortex, perirhinal cortex, and posterior parahippocampal cortex) in 42 control cases. After detailed cytoarchitectonic analysis (based on homology with the nonhuman primate medial temporal lobe), planimetric measurement (calculated area) of a two-dimensional reconstruction of the parahippocampal gyrus was performed, and cases older than 70 years were compared with cases younger than 70 years. All areas showed atrophy with aging (average, entorhinal cortex, 5%; perirhinal cortex, 4%; posterior parahippocampal cortex, 15%; temporal pole, not assessable). Both entorhinal and posterior parahippocampal cortices reached statistical significance. Our results suggest that cortical areas relevant in memory function, and anatomically linked to the hippocampus, present a small degree of atrophy with aging, thereby permitting the reciprocal flow of information between the hippocampus and the cerebral cortex necessary for memory encoding and retrieval. Microsc. Res. Tech. 43:8–15, 1998. © 1998 Wiley-Liss, Inc.

The present study compared four different structural magnetic resonance imaging (MRI) techniques used to measure gray matter atrophy in Alzheimer's disease (AD): manual and automated volumetry, cortical thickness (CT) and voxel-based morphometry (VBM)). These techniques are used interchangeably in AD research and thus far it is unclear which technique is superior in detecting abnormalities early in the disease process. We inquired whether these techniques show similar results in healthy controls (con), patients with amnestic mild cognitive impairment (MCI) and patients suffering from mild AD. In addition, we investigated whether atrophy of prefrontal cortex (PFC) or medial temporal lobe (MTL) regions is most indicative of (preclinical) AD. Three groups of older male participants were selected: 18 healthy participants without any memory impairment, 18 patients with amnestic MCI, and 18 patients with mild AD. Between-group differences were investigated in PFC and MTL regions. A manual and automatic tracing approach were applied to calculate gray matter volume. CT was furthermore calculated by Freesurfer as the average thickness of the cortical surface in each ROI. VBM was applied by using masks of atlas-based ROI's in FSL. Manually measured right parahippocampal gyrus (PHG) volumes can differentiate con and MCI. Con and AD can furthermore be distinguished by manually measured hippocampus and PHG volumes, and by automated measurements of hippocampus and entorhinal cortex (ERC). Manual segmentation techniques are also sensitive for changes in PFC areas showing abnormalities in inferior and orbital PFC (con /AD and MCI/AD). CT analysis showed differences between con and AD in ERC, right inferior prefrontal (IPFC) and left medial orbitofrontal cortex (OFC) regions. VBM-ROI analyses showed differences between con/AD and MCI/AD in hippocampus, IPFC and OPFC (Table 1). The present study demonstrates that manual volumetry and VBM are able to detect group differences in both PFC and MTL structures (con/AD and MCI/AD). Manual volumetry of the right PhG can furthermore differentiate between con and MCI. The present study confirms earlier theories that the MTL is most indicative of (preclinical) AD, showing abnormalities in all the investigated techniques.

Reduced cortical thickness in hippocampal subregions among cognitively normal apolipoprotein E e4 carriers

BackgroundAccumulation of tau neurofibrillary tangles (NFT) in the medial temporal lobe (MTL) is an early pathological change associated with neurodegeneration in Alzheimer’s Disease (AD). Current understanding of the spread of NFTs within the MTL is based on 2‐D histological sections sampled at sparse locations. Here, using human MTL specimens from donors with diagnoses spanning the AD continuum, we examine 3‐D quantitative maps of NFT burden derived from serial histology leveraging a high‐resolution, ex vivo MRI atlas, thus enabling more granular analyses.MethodWe combined ex vivo MRI scans (0.2×0.2×0.2mm3, 9.4T) of 55 MTL specimens using a customized registration approach to construct a 3‐D atlas (Ravikumar et al., Acta Neuropathol Comm, 2021). MTL subregions in the atlas were labelled based on cytoarchitecture using serial Nissl histology (n = 17) (Fig.1). For 25 specimens with a primary diagnosis of AD or primary age‐related tauopathy (78.6±10.9 years; 16M/9F), quantitative NFT burden maps were derived from serial anti‐tau immunohistochemistry histology and registered to the atlas for group‐level analysis (Yushkevich et al., Brain, 2021). For quantitative comparisons, we computed the mean NFT burden and cortical thickness within each subregion.ResultFig.2A shows average and summary frequency maps of NFT burden, computed separately for specimens with a low Braak stage (Braak0‐II; n = 11) and high Braak stage (BraakIV‐VI), that reveal a clear anterior‐to‐posterior gradient in NFT burden. At low Braak stages, we observe high levels of NFT burden in cornu ammonis (CA)1, entorhinal cortex (EC), and Brodmann area 35 (BA35;≈transentorhinal region), particularly in the outer cortical layers. CA1 and EC also show higher NFT burden relative to BA35 (Fig.2C). At high Braak stages, overall NFT burden is visibly higher and more widespread, with significant increases found across almost all subregions (Fig.2B). Moreover, significant correlations between NFT burden and cortical thinning were found in the perforant pathway (PP; molecular layer of the subiculum), dentate gyrus, EC and Areas TE, TF and TH (Fig.3).ConclusionBuilding on earlier work, we provide a detailed characterization of the distribution of NFT burden in the MTL. Our findings of specific subregional involvement of early NFT pathology can help inform the development of improved in vivo neuroimaging biomarkers

Functional abnormalities of the medial temporal lobe memory system in mild cognitive impairment and Alzheimer's disease: Insights from functional MRI studies

BackgroundThe medial temporal lobe (MTL) is a hotspot of different neurodegenerative pathologies, and recent studies have shown associations of severity of pathology with atrophy measured on antemortem MRI. However, these studies are limited by the interval between time of scan and death and the relatively low resolution of the commonly acquired in vivo MRI scans, limiting the granularity of the regions being measured. We investigate the association of different neurodegenerative pathologies, particularly TDP‐43, and the thickness of different MTL subregions measured on high‐resolution postmortem MRI. As prior work suggests an anterior‐to‐posterior gradient of atrophy for TDP‐43 in frontotemporal dementia spectrum disorders and Limbic‐predominant Age‐related TDP‐43 Encephalopathy (LATE), we also examined differences along the long axis of the MTL.MethodTau, TDP‐43, β‐amyloid and α‐synuclein pathology were rated (0‐absent – 3‐frequent) in the hippocampus and entorhinal cortex (ERC) of 35 individuals with and without neurodegenerative diseases (Table 1). Thickness measurements were obtained from 0.2x0.2x0.2 mm3 post‐mortem MRI scans of excised MTL specimens from the contralateral hemisphere (Figure 1) in the ERC, Brodmann Area 35 and 36, parahippocampal cortex, subiculum, cornu ammonis (CA)1 and the stratum radiatum lacunosum moleculare. For each region, thickness was measured at an anterior and posterior location using a semi‐automated approach (Figure 2). Spearman’s rank correlations were performed, correcting for age, sex and hemisphere, including all four proteinopathies in the model.ResultWe find strong negative associations of TDP‐43 with thickness in all cortical MTL regions (Table 2, Figure 3) and with CA1, averaged over the two locations. We repeated the analyses for the thickness measurements separately in the anterior and posterior locations, but did not find a clear difference along the longitudinal axis. This is potentially due to the severity of the TDP‐43 pathology.ConclusionIn this unique dataset with neurodegenerative pathologies and high‐resolution scans of the MTL, preliminary results show strong associations between TDP‐43 pathology and atrophy in several MTL subregions. As this dataset continues to grow, we will be able to tease apart the effects of multiple MTL pathologies at a subregional level.

BackgroundSleep‐disordered breathing (SDB) has been associated to greater amyloid deposition and dementia risk. However, the pattern of SDB‐associated structural brain changes is unclear, especially within the medial temporal lobe (MTL). We investigated the associations between SDB severity and the volume of MTL subregions, and hypothesized that SDB would be associated with atrophy in regions early affected by Alzheimer’s disease (AD) pathology and/or sensitive to hypoxia (i.e., the perirhinal and entorhinal cortices, and CA1 hippocampal subfield), particularly in amyloid‐positive participants.MethodWe included 120 cognitively unimpaired older participants from the Age‐Well randomized controlled trial (mean age=69 ± 3,8 years; 25 Aβ+ and 95 Aβ‐ participants). They underwent a structural MRI, including a high‐resolution T2‐weighted sequence of the MTL (0.4x0.4x2.5mm3), a Florbetapir‐PET scan to measure amyloid deposition, as well as a polysomnography. The ASHS (Automatic Segmentation of Hippocampal Subfields) software was used to segment the entorhinal, perirhinal, and parahippocampal cortices, as well as hippocampal subfields (i.e., the subiculum, CA1, CA2‐3, the dentate gyrus, their sum representing total hippocampal volume) on high‐resolution MRI sequences. Bilateral volumes normalized to the total intracranial volume were used in statistical analyses. We performed linear regressions with the volume of each MTL subregion as dependent variables, the apnea‐hypopnea index (AHI, reflecting SDB severity) and amyloid status as independent variables, and age, sex, education and the ApoE4 status as covariates.ResultWe found significant interactions between the AHI and amyloid status on the volumes of the entorhinal cortex (p<0.001), whole hippocampus (p<0.001), subiculum (p<0.001), CA1 (p=0.003) and dentate gyrus (p=0.007), such that the AHI significantly predicted the volume of these MTL subregions only in amyloid‐positive participants (Figure 1).ConclusionUntreated SDB has been previously associated with increased amyloid deposition, even in the absence of cognitive or sleep symptoms. Our data complement these findings by showing that once amyloid deposition reaches positivity, greater SDB severity is related to neurodegeneration in several MTL subregions, including the entorhinal cortex and hippocampus. Thus, the presence of SDB in cognitively unimpaired older adults who are engaged in the Alzheimer’s continuum may increase the risk of developing memory impairment over time.

Associations between white matter hyperintensities, lacunes, entorhinal cortex thickness, declarative memory and leisure activity in cognitively healthy older adults: A 7-year study

BackgroundTau pathology in the medial temporal lobe (MTL) is closely linked to neurodegeneration, and is an early pathological change associated with Alzheimer’s disease (AD). MRI measures of MTL neurodegeneration have proven to be sensitive to change during preclinical AD. Current measures are confounded by the presence of non‐AD pathologies (e.g., TDP‐43, ageing). Here, we combine ex vivo imaging with histopathological ratings of tau and TDP‐43 to identify fine‐grained MTL atrophy patterns specific to tau. Such an analysis could be used to define MTL “hotspots” where in vivo measures of neurodegeneration are expected to be strongly associated with tau, potentially enabling the development of biomarkers that are more effective during early AD clinical trials.MethodEx vivo MRI scans (0.2x0.2x0.2mm3, 9.4T) of human MTL specimens were combined using a customized registration approach to construct a 3D atlas. Using serial histology available in a subset of specimens (n = 11), MTL subregions in the atlas were labelled based on cytoarchitecture (Ravikumar et al., 2021) (Figure 1A). To perform thickness analysis, 29 specimens containing a primary diagnosis of AD or primary age‐related tauopathy were registered to the atlas (13 specimens were registered to the atlas during atlas construction, and 16 were registered to the atlas after it was constructed) (Figure 1B, Table 1). Using histopathology measures of tau and TDP‐43 pathology (based on contralateral sampling), we investigated the association between tau and thickness by fitting a linear model (with age/TDP‐43 as covariates) at each point along the MTL and SRLM surface.ResultPointwise thickness analysis reveals significant atrophy patterns in the transentorhinal region and SRLM. When excluding age from the model, stronger tau associations are observed in the SRLM, entorhinal cortex, and extending further towards Brodmann Area 35 (Figure 2).ConclusionOur findings are consistent with early Braak stages but suggest that covarying for age may be obscuring some associations due to tau since age and tau burden have a highly correlated relationship (Figure 3). In future work, quantitative maps of NFT burden will be mapped from serial pathology images into atlas space, allowing us to characterize NFT distribution in 3D (Yushkevich et al., 2021).

Tau protein neurofibrillary tangles are closely linked to neuronal/synaptic loss and cognitive decline in Alzheimer's disease and related dementias. Our knowledge of the pattern of neurofibrillary tangle progression in the human brain, critical to the development of imaging biomarkers and interpretation of in vivo imaging studies in Alzheimer's disease, is based on conventional two-dimensional histology studies that only sample the brain sparsely. To address this limitation, ex vivo MRI and dense serial histological imaging in 18 human medial temporal lobe specimens (age 75.3 ± 11.4 years, range 45 to 93) were used to construct three-dimensional quantitative maps of neurofibrillary tangle burden in the medial temporal lobe at individual and group levels. Group-level maps were obtained in the space of an in vivo brain template, and neurofibrillary tangles were measured in specific anatomical regions defined in this template. Three-dimensional maps of neurofibrillary tangle burden revealed significant variation along the anterior-posterior axis. While early neurofibrillary tangle pathology is thought to be confined to the transentorhinal region, we found similar levels of burden in this region and other medial temporal lobe subregions, including amygdala, temporopolar cortex, and subiculum/cornu ammonis 1 hippocampal subfields. Overall, the three-dimensional maps of neurofibrillary tangle burden presented here provide more complete information about the distribution of this neurodegenerative pathology in the region of the cortex where it first emerges in Alzheimer's disease, and may help inform the field about the patterns of pathology spread, as well as support development and validation of neuroimaging biomarkers.

Distinct lines of research in both humans and animals point to a specific role of the hippocampus in both spatial and episodic memory function. The discovery of concept cells in the hippocampus and surrounding medial temporal lobe (MTL) regions suggests that the MTL maps physical and semantic spaces with a similar neural architecture. Here, we studied the emergence of such maps using MTL microwire recordings from 20 patients (9 female, 11 male) navigating a virtual environment featuring salient landmarks with established semantic meaning. We present several key findings. The array of local field potentials in the MTL contains sufficient information for above-chance decoding of subjects' instantaneous location in the environment. Closer examination revealed that as subjects gain experience with the environment the field potentials come to represent both the subjects' locations in virtual space and in high-dimensional semantic space. Similarly, we observe a learning effect on temporal sequence coding. Over time, field potentials come to represent future locations, even after controlling for spatial proximity. This predictive coding of future states, more so than the strength of spatial representations per se, is linked to variability in subjects' navigation performance. Our results thus support the conceptualization of the MTL as a memory space, representing both spatial- and nonspatial information to plan future actions and predict their outcomes.SIGNIFICANCE STATEMENT Using rare microwire recordings, we studied the representation of spatial, semantic, and temporal information in the human MTL. Our findings demonstrate that subjects acquire a cognitive map that simultaneously represents the spatial and semantic relations between landmarks. We further show that the same learned representation is used to predict future states, implicating MTL cell assemblies as the building blocks of prospective memory functions.