Perirhinal circuits for memory processing.

The perirhinal cortex (PRC) serves as the gateway to the hippocampus for episodic memory formation and plays a part in retrieval through its backward connectivity to various neocortical areas. First, I present the evidence suggesting that PRC neurons encode both experientially acquired object features and their associative relations. Recent studies have revealed circuit mechanisms in the PRC for the retrieval of cue-associated information, and have demonstrated that, in monkeys, PRC neuron-encoded information can be behaviourally read out. These studies, among others, support the theory that the PRC converts visual representations of an object into those of its associated features and initiates backward-propagating, interareal signalling for retrieval of nested associations of object features that, combined, extensionally represent the object meaning. I propose that the PRC works as the ventromedial hub of a 'two-hub model' at an apex of the hierarchy of a distributed memory network and integrates signals encoded in other downstream cortical areas that support diverse aspects of knowledge about an object.

Perirhinal Cortex is Involved in the Resolution of Learned Approach-Avoidance Conflict Associated with Discrete Objects.

The rodent ventral and primate anterior hippocampus have been implicated in approach-avoidance (AA) conflict processing. It is unclear, however, whether this structure contributes to AA conflict detection and/or resolution, and if its involvement extends to conditions of AA conflict devoid of spatial/contextual information. To investigate this, neurologically healthy human participants first learned to approach or avoid single novel visual objects with the goal of maximizing earned points. Approaching led to point gain and loss for positive and negative objects, respectively, whereas avoidance had no impact on score. Pairs of these objects, each possessing nonconflicting (positive-positive/negative-negative) or conflicting (positive-negative) valences, were then presented during functional magnetic resonance imaging. Participants either made an AA decision to score points (Decision task), indicated whether the objects had identical or differing valences (Memory task), or followed a visual instruction to approach or avoid (Action task). Converging multivariate and univariate results revealed that within the medial temporal lobe, perirhinal cortex, rather than the anterior hippocampus, was predominantly associated with object-based AA conflict resolution. We suggest the anterior hippocampus may not contribute equally to all learned AA conflict scenarios and that stimulus information type may be a critical and overlooked determinant of the neural mechanisms underlying AA conflict behavior.

Thalamic-Medial Temporal Lobe Connectivity Underpins Familiarity Memory.

The neural basis of memory is highly distributed, but the thalamus is known to play a particularly critical role. However, exactly how the different thalamic nuclei contribute to different kinds of memory is unclear. Moreover, whether thalamic connectivity with the medial temporal lobe (MTL), arguably the most fundamental memory structure, is critical for memory remains unknown. We explore these questions using an fMRI recognition memory paradigm that taps familiarity and recollection (i.e., the two types of memory that support recognition) for objects, faces, and scenes. We show that the mediodorsal thalamus (MDt) plays a material-general role in familiarity, while the anterior thalamus plays a material-general role in recollection. Material-specific regions were found for scene familiarity (ventral posteromedial and pulvinar thalamic nuclei) and face familiarity (left ventrolateral thalamus). Critically, increased functional connectivity between the MDt and the parahippocampal (PHC) and perirhinal cortices (PRC) of the MTL underpinned increases in reported familiarity confidence. These findings suggest that familiarity signals are generated through the dynamic interaction of functionally connected MTL-thalamic structures.

Longitudinal atrophy in early Braak regions in preclinical Alzheimer's disease.

A major focus of Alzheimer's disease (AD) research has been finding sensitive outcome measures to disease progression in preclinical AD, as intervention studies begin to target this population. We hypothesize that tailored measures of longitudinal change of the medial temporal lobe (MTL) subregions (the sites of earliest cortical tangle pathology) are more sensitive to disease progression in preclinical AD compared to standard cognitive and plasma NfL measures. Longitudinal T1-weighted MRI of 337 participants were included, divided into amyloid-ß negative (Aß-) controls, cerebral spinal fluid p-tau positive (T+) and negative (T-) preclinical AD (Aß+ controls), and early prodromal AD. Anterior/posterior hippocampus, entorhinal cortex, Brodmann areas (BA) 35 and 36, and parahippocampal cortex were segmented in baseline MRI using a novel pipeline. Unbiased change rates of subregions were estimated using MRI scans within a 2-year-follow-up period. Experimental results showed that longitudinal atrophy rates of all MTL subregions were significantly higher for T+ preclinical AD and early prodromal AD than controls, but not for T- preclinical AD. Posterior hippocampus and BA35 demonstrated the largest group differences among hippocampus and MTL cortex respectively. None of the cross-sectional MTL measures, longitudinal cognitive measures (PACC, ADAS-Cog) and cross-sectional or longitudinal plasma NfL reached significance in preclinical AD. In conclusion, longitudinal atrophy measurements reflect active neurodegeneration and thus are more directly linked to active disease progression than cross-sectional measurements. Moreover, accelerated atrophy in preclinical AD seems to occur only in the presence of concomitant tau pathology. The proposed longitudinal measurements may serve as efficient outcome measures in clinical trials.

Associative memory for conceptually unitized word pairs in mild cognitive impairment is related to the volume of the perirhinal cortex.

Unitization, that is, the encoding of an association as one integrated entity, has been shown to improve associative memory in populations presenting with associative memory deficit due to hippocampal dysfunction, such as amnesic patients with focal hippocampal lesions and healthy older adults. One reason for this benefit is that encoding of unitized associations would rely on the perirhinal cortex (PrC) and thus minimize the need for hippocampal recruitment. Mild cognitive impairment (MCI) is accompanied by a deficit in associative memory. However, unitization has never been studied to explore the potential benefit in associative memory in MCI, maybe because MCI is characterized by PrC pathology. However, the PrC may potentially still function sufficiently to allow for the successful adoption of unitization. In this study, we aimed at assessing whether unitization could attenuate MCI patients' associative memory deficit, and whether the ability to remember unitized associations would be modulated by the integrity of the PrC in MCI patients. Unitization was manipulated at a conceptual level, by encouraging participants to encode unrelated word pairs as new compound words. Participants also underwent a structural MRI exam, and measures of PrC were extracted (Brodmann Areas [BA] 35 and 36). Results showed that, contrary to healthy controls, MCI patients did not benefit from unitization. Moreover, their memory performance for unitized associations was related to the measure of PrC integrity (BA35), while it was not the case in controls. This finding thus suggests that unitization does not help to attenuate the associative deficit in MCI patients, and brings support to the literature linking unitization to the PrC function.

Animacy and real-world size shape object representations in the human medial temporal lobes.

Identifying what an object is, and whether an object has been encountered before, is a crucial aspect of human behavior. Despite this importance, we do not yet have a complete understanding of the neural basis of these abilities. Investigations into the neural organization of human object representations have revealed category specific organization in the ventral visual stream in perceptual tasks. Interestingly, these categories fall within broader domains of organization, with reported distinctions between animate, inanimate large, and inanimate small objects. While there is some evidence for category specific effects in the medial temporal lobe (MTL), in particular in perirhinal and parahippocampal cortex, it is currently unclear whether domain level organization is also present across these structures. To this end, we used fMRI with a continuous recognition memory task. Stimuli were images of objects from several different categories, which were either animate or inanimate, or large or small within the inanimate domain. We employed representational similarity analysis (RSA) to test the hypothesis that object-evoked responses in MTL structures during recognition-memory judgments also show evidence for domain-level organization along both dimensions. Our data support this hypothesis. Specifically, object representations were shaped by either animacy, real-world size, or both, in perirhinal and parahippocampal cortex, and the hippocampus. While sensitivity to these dimensions differed across structures when probed individually, hinting at interesting links to functional differentiation, similarities in organization across MTL structures were more prominent overall. These results argue for continuity in the organization of object representations in the ventral visual stream and the MTL.

[The 461th case: fever, hematuria, and right lumbar pain].

A 56-year-old female was admitted to the Department of Rheumatology, Peking Union Medical College Hospital with complaint of recurrent fever and acute lumbar pain. Fever was complicated with malaise, cough and occasional blood-streaked sputum. Lab tests showed elevated white blood cell count, increased serum creatinine, erythrocyte sedimentation rate and C-reactive protein. Other lab findings included severe anemia, hematuria, and proteinuria. Immunological examinations were positive for antinuclear antibodies, antineutrophil cytoplasmic antibodies and antiglomerular basement membrane antibody. Ultrasonography and CT scan detected a huge spontaneous perirenal hematoma at right side. Angiography revealed multiple microaneurysms on bilateral renal arteries and branches. A diagnosis of systemic vasculitis was suggested. Under the combination therapy of corticosteroids and cyclophosphamide, the patient presented sustained remission for one year. This case indicates that prompt and sufficient treatment of primary disease is essential to a promising outcome.

Multi-template analysis of human perirhinal cortex in brain MRI: Explicitly accounting for anatomical variability.

RATIONAL: The human perirhinal cortex (PRC) plays critical roles in episodic and semantic memory and visual perception. The PRC consists of Brodmann areas 35 and 36 (BA35, BA36). In Alzheimer's disease (AD), BA35 is the first cortical site affected by neurofibrillary tangle pathology, which is closely linked to neural injury in AD. Large anatomical variability, manifested in the form of different cortical folding and branching patterns, makes it difficult to segment the PRC in MRI scans. Pathology studies have found that in ~97% of specimens, the PRC falls into one of three discrete anatomical variants. However, current methods for PRC segmentation and morphometry in MRI are based on single-template approaches, which may not be able to accurately model these discrete variants METHODS: A multi-template analysis pipeline that explicitly accounts for anatomical variability is used to automatically label the PRC and measure its thickness in T2-weighted MRI scans. The pipeline uses multi-atlas segmentation to automatically label medial temporal lobe cortices including entorhinal cortex, PRC and the parahippocampal cortex. Pairwise registration between label maps and clustering based on residual dissimilarity after registration are used to construct separate templates for the anatomical variants of the PRC. An optimal path of deformations linking these templates is used to establish correspondences between all the subjects. Experimental evaluation focuses on the ability of single-template and multi-template analyses to detect differences in the thickness of medial temporal lobe cortices between patients with amnestic mild cognitive impairment (aMCI, n=41) and age-matched controls (n=44). RESULTS: The proposed technique is able to generate templates that recover the three dominant discrete variants of PRC and establish more meaningful correspondences between subjects than a single-template approach. The largest reduction in thickness associated with aMCI, in absolute terms, was found in left BA35 using both regional and summary thickness measures. Further, statistical maps of regional thickness difference between aMCI and controls revealed different patterns for the three anatomical variants.

Memory-guided drawing training increases Granger causal influences from the perirhinal cortex to V1 in the blind.

The perirhinal cortex (PRC) is a medial temporal lobe structure that has been implicated in not only visual memory in the sighted, but also tactile memory in the blind (Cacciamani & Likova, 2016). It has been proposed that, in the blind, the PRC may contribute to modulation of tactile memory responses that emerge in low-level "visual" area V1 as a result of training-induced cortical reorganization (Likova, 2012, 2015). While some studies in the sighted have indicated that the PRC is indeed structurally and functionally connected to the visual cortex (Clavagnier, Falchier, & Kennedy, 2004; Peterson, Cacciamani, Barense, & Scalf, 2012), the PRC's direct modulation of V1 is unknown-particularly in those who lack the visual input that typically stimulates this region. In the present study, we tested Likova's PRC modulation hypothesis; specifically, we used fMRI to assess the PRC's Granger causal influence on V1 activation in the blind during a tactile memory task. To do so, we trained congenital and acquired blind participants on a unique memory-guided drawing technique previously shown to result in V1 reorganization towards tactile memory representations (Likova, 2012). The tasks (20s each) included: tactile exploration of raised line drawings of faces and objects, tactile memory retrieval via drawing, and a scribble motor/memory control. FMRI before and after a week of the Cognitive-Kinesthetic training on these tasks revealed a significant increase in PRC-to-V1 Granger causality from pre- to post-training during the memory drawing task, but not during the motor/memory control. This increase in causal connectivity indicates that the training strengthened the top-down modulation of visual cortex from the PRC. This is the first study to demonstrate enhanced directed functional connectivity from the PRC to the visual cortex in the blind, implicating the PRC as a potential source of the reorganization towards tactile representations that occurs in V1 in the blind brain (Likova, 2012).

On Known Unknowns: Fluency and the Neural Mechanisms of Illusory Truth.

The "illusory truth" effect refers to the phenomenon whereby repetition of a statement increases its likelihood of being judged true. This phenomenon has important implications for how we come to believe oft-repeated information that may be misleading or unknown. Behavioral evidence indicates that fluency, the subjective ease experienced while processing information, underlies this effect. This suggests that illusory truth should be mediated by brain regions previously linked to fluency, such as the perirhinal cortex (PRC). To investigate this possibility, we scanned participants with fMRI while they rated the truth of unknown statements, half of which were presented earlier (i.e., repeated). The only brain region that showed an interaction between repetition and ratings of perceived truth was PRC, where activity increased with truth ratings for repeated, but not for new, statements. This finding supports the hypothesis that illusory truth is mediated by a fluency mechanism and further strengthens the link between PRC and fluency.

High-resolution investigation of memory-specific reinstatement in the hippocampus and perirhinal cortex.

Episodic memory involves remembering the details that characterize a prior experience. Successful memory recovery has been associated with the reinstatement of brain activity patterns in a number of sensory regions across the cortex. However, how the hippocampus and surrounding medial temporal lobe (MTL) cortex contribute to this process is less clear. Models of episodic memory posit that hippocampal pattern reinstatement, also referred to as pattern completion, may mediate cortical reinstatement during retrieval. Empirical evidence of this process, however, remains elusive. Here, we use high-resolution fMRI and encoding-retrieval multi-voxel pattern similarity analyses to demonstrate for the first time that the hippocampus, particularly right hippocampal subfield CA1, shows evidence of reinstating individual episodic memories. Furthermore, reinstatement in perirhinal cortex (PrC) is also evident. Critically, we identify distinct factors that may mediate the cortical reinstatement in PrC. First, we find that encoding activation in PrC is related to later reinstatement in this region, consistent with the theory that encoding strength in the regions that process the memoranda is important for later reinstatement. Conversely, retrieval activation in right CA1 was correlated with reinstatement in PrC, consistent with models of pattern completion. This dissociation is discussed in the context of the flow of information into and out of the hippocampus during encoding and retrieval, respectively. © 2016 Wiley Periodicals, Inc.

Cross-sectional and longitudinal medial temporal lobe subregional atrophy patterns in semantic variant primary progressive aphasia.

T1-magnetic resonance imaging (MRI) studies report early atrophy in the left anterior temporal lobe, especially the perirhinal cortex, in semantic variant primary progressive aphasia (svPPA). Improved segmentation protocols using high-resolution T2-MRI have enabled fine-grained medial temporal lobe (MTL) subregional measurements, which may provide novel information on the atrophy pattern and disease progression in svPPA. We aimed to investigate the MTL subregional atrophy pattern cross-sectionally and longitudinally in patients with svPPA as compared with controls and patients with Alzheimer's disease (AD). MTL subregional volumes were obtained using the Automated Segmentation for Hippocampal Subfields software from high-resolution T2-MRIs in 15 svPPA, 37 AD, and 23 healthy controls. All MTL volumes were corrected for intracranial volume and parahippocampal cortices for slice number. Longitudinal atrophy rates of all subregions were obtained using an unbiased deformation-based morphometry pipeline in 6 svPPA patients, 9 controls, and 12 AD patients. Cross-sectionally, significant volume loss was observed in svPPA compared with controls in the left MTL, right cornu ammonis 1 (CA1), Brodmann area (BA)35, and BA36 (subdivisions of the perirhinal cortex). Compared with AD patients, svPPA patients had significantly smaller left CA1, BA35, and left and right BA36 volumes. Longitudinally, svPPA patients had significantly greater atrophy rates of left and right BA36 than controls but not relative to AD patients. Fine-grained analysis of MTL atrophy patterns provides information about the evolution of atrophy in svPPA. These results indicate that MTL subregional measures might be useful markers to track disease progression or for clinical trials in svPPA.

Content Tuning in the Medial Temporal Lobe Cortex: Voxels that Perceive, Retrieve.

How do we recall vivid details from our past based only on sparse cues? Research suggests that the phenomenological reinstatement of past experiences is accompanied by neural reinstatement of the original percept. This process critically depends on the medial temporal lobe (MTL). Within the MTL, perirhinal cortex (PRC) and parahippocampal cortex (PHC) are thought to support encoding and recall of objects and scenes, respectively, with the hippocampus (HC) serving as a content-independent hub. If the fidelity of recall indeed arises from neural reinstatement of perceptual activity, then successful recall should preferentially draw upon those neural populations within content-sensitive MTL cortex that are tuned to the same content during perception. We tested this hypothesis by having eighteen human participants undergo functional MRI (fMRI) while they encoded and recalled objects and scenes paired with words. Critically, recall was cued with the words only. While HC distinguished successful from unsuccessful recall of both objects and scenes, PRC and PHC were preferentially engaged during successful versus unsuccessful object and scene recall, respectively. Importantly, within PRC and PHC, this content-sensitive recall was predicted by content tuning during perception: Across PRC voxels, we observed a positive relationship between object tuning during perception and successful object recall, while across PHC voxels, we observed a positive relationship between scene tuning during perception and successful scene recall. Our results thus highlight content-based roles of MTL cortical regions for episodic memory and reveal a direct mapping between content-specific tuning during perception and successful recall.

Impaired perceptual integration and memory for unitized representations are associated with perirhinal cortex atrophy in Alzheimer's disease.

Unitization, the capacity to encode associations as one integrated entity, can enhance associative memory in populations with an associative memory deficit by promoting familiarity-based associative recognition. Patients with Alzheimer's disease (AD) are typically impaired in associative memory compared with healthy controls but do not benefit from unitization strategies. Using fragmented pictures of objects, this study aimed at assessing which of the cognitive processes that compose unitization is actually affected in AD: the retrieval of unitized representations itself, or some earlier stages of processing, such as the integration process at a perceptual or conceptual stage of representation. We also intended to relate patients' object unitization capacity to the integrity of their perirhinal cortex (PrC), as the PrC is thought to underlie unitization and is also one of the first affected regions in AD. We evaluated perceptual integration capacity and subsequent memory for those items that have supposedly been unitized in 23 mild AD patients and 20 controls. We systematically manipulated the level of perceptual integration during encoding by presenting object pictures that were either left intact, separated into 2 fragments, or separated into 4 fragments. Subjects were instructed to unitize the fragments into a single representation. Success of integration was assessed by a question requiring the identification of the object. Participants also underwent a structural magnetic resonance imaging examination, and measures of PrC, posterior cingulate cortex volume and thickness, and hippocampal volume, were extracted. The results showed that patients' perceptual integration performance decreased with the increased fragmentation level and that their memory for unitized representations was impaired whatever the demands in terms of perceptual integration at encoding. Both perceptual integration and memory for unitized representations were related to the integrity of the PrC, and memory for unitized representations was also related to the volume of the hippocampus. We argue that, globally, this supports representational theories of memory that hold that the role of the PrC is not only perceptual nor mnemonic but instead underlies complex object representation.

Beyond episodic memory: Semantic processing as independent predictor of hippocampal/perirhinal volume in aging and mild cognitive impairment due to Alzheimer's disease.

OBJECTIVE: Given that lexical-semantic decline precedes episodic memory deficits in the Alzheimer's disease (AD) timeline, it is expected that performance on a lexical-semantic task would be associated with mediotemporal volumes independently of the association this region has with episodic memory in the early stage of AD. METHOD: Fifty patients with mild cognitive impairment due to AD and 50 healthy adults completed tests of lexical-semantic skills (category fluency test), episodic memory for semantically relevant material (prose memory test), episodic memory for non semantically relevant material (Rey-Osterrieth Figure test), lexical-executive abilities (letter fluency test), and a neurostructural MRI. Hippocampal, perirhinal, entorhinal, temporopolar, and orbitofrontal volumes were extracted. The association between test performance and volume of each region was tested using partial correlations (age-education corrected). The improvement (ΔR2) in predicting volumetric indices offered by episodic-memory/lexical-semantic processing, once accounting for their counterpart, was tested using hierarchical regressions. RESULTS: There were no significant findings for control indices. Prose memory accounted for independent portions of volumetric variability within almost all regions. Category fluency accounted for independent portions of volumetric variability of left and right hippocampus and left perirhinal cortex in addition to the predictive strength of the Rey-Osterrieth Figure, and for an independent portion of volumetric variability in the left hippocampus in addition to the predictive strength of prose memory. CONCLUSIONS: There was an association between hippocampal and perirhinal volume and lexical-semantic processing in addition to the contribution given by episodic memory. This statistical separation supports the importance of lexical-semantic processing as independent indicator of AD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Integrated deep visual and semantic attractor neural networks predict fMRI pattern-information along the ventral object processing pathway.

Recognising an object involves rapid visual processing and activation of semantic knowledge about the object, but how visual processing activates and interacts with semantic representations remains unclear. Cognitive neuroscience research has shown that while visual processing involves posterior regions along the ventral stream, object meaning involves more anterior regions, especially perirhinal cortex. Here we investigate visuo-semantic processing by combining a deep neural network model of vision with an attractor network model of semantics, such that visual information maps onto object meanings represented as activation patterns across features. In the combined model, concept activation is driven by visual input and co-occurrence of semantic features, consistent with neurocognitive accounts. We tested the model's ability to explain fMRI data where participants named objects. Visual layers explained activation patterns in early visual cortex, whereas pattern-information in perirhinal cortex was best explained by later stages of the attractor network, when detailed semantic representations are activated. Posterior ventral temporal cortex was best explained by intermediate stages corresponding to initial semantic processing, when visual information has the greatest influence on the emerging semantic representation. These results provide proof of principle of how a mechanistic model of combined visuo-semantic processing can account for pattern-information in the ventral stream.

Age-related functional changes in domain-specific medial temporal lobe pathways.

There is now converging evidence from studies in animals and humans that the medial temporal lobes (MTLs) harbor anatomically distinct processing pathways for object and scene information. Recent functional magnetic resonance imaging studies in humans suggest that this domain-specific organization may be associated with a functional preference of the anterior-lateral part of the entorhinal cortex (alErC) for objects and the posterior-medial entorhinal cortex (pmErC) for scenes. As MTL subregions are differentially affected by aging and neurodegenerative diseases, the question was raised whether aging may affect the 2 pathways differentially. To address this possibility, we developed a paradigm that allows the investigation of object memory and scene memory in a mnemonic discrimination task. A group of young (n = 43) and healthy older subjects (n = 44) underwent functional magnetic resonance imaging recordings during this novel task, while they were asked to discriminate exact repetitions of object and scene stimuli from novel stimuli that were similar but modified versions of the original stimuli ("lures"). We used structural magnetic resonance images to manually segment anatomical components of the MTL including alErC and pmErC and used these segmented regions to analyze domain specificity of functional activity. Across the entire sample, object processing was associated with activation of the perirhinal cortex (PrC) and alErC, whereas for scene processing, activation was more predominant in the parahippocampal cortex and pmErC. Functional activity related to mnemonic discrimination of object and scene lures from exact repetitions was found to overlap between processing pathways and suggests that while the PrC-alErC pathway was more involved in object discrimination, both pathways were involved in the discrimination of similar scenes. Older adults were behaviorally less accurate than young adults in discriminating similar lures from exact repetitions, but this reduction was equivalent in both domains. However, this was accompanied by significantly reduced domain-specific activity in PrC in older adults compared to what was observed in the young. Furthermore, this reduced domain-specific activity was associated to worse performance in object mnemonic discrimination in older adults. Taken together, we show the fine-grained functional organization of the MTL into domain-specific pathways for objects and scenes and their mnemonic discrimination and further provide evidence that aging might affect these pathways in a differential fashion. Future experiments will elucidate whether the 2 pathways are differentially affected in early stages of Alzheimer's disease in relation to amyloid or tau pathology.

Perirhinal cortex tracks degree of recent as well as cumulative lifetime experience with object concepts.

Evidence from numerous sources indicates that recognition of the prior occurrence of objects requires computations of perirhinal cortex (PrC) in the medial temporal lobe (MTL). Extant research has primarily probed recognition memory based on item exposure in a recent experimental study episode. Outside the laboratory, however, familiarity for objects typically accrues gradually with learning across many different episodic contexts, which can be distributed over a lifetime of experience. It is currently unknown whether PrC also tracks this cumulative lifetime experience with object concepts. To address this issue, we conducted a functional magnetic resonance imaging (fMRI) experiment in healthy individuals in which we compared judgments of the perceived lifetime familiarity with object concepts, a task that has previously been employed in many normative studies on concept knowledge, with frequency judgments for recent laboratory exposure in a study phase. Guided by neurophysiological data showing that neurons in primate PrC signal prior object exposure at multiple time scales, we predicted that PrC responses would track perceived prior experience in both types of judgments. Left PrC and a number of cortical regions that are often co-activated as part of the default-mode network showed an increase in Blood-Oxygen-Level Dependent (BOLD) response in relation to increases in the perceived cumulative lifetime familiarity of object concepts. These regions included the left hippocampus, left mid-lateral temporal cortex, as well as anterior and posterior cortical midline structures. Critically, left PrC was found to be the only region that showed this response in combination with the typically observed decrease in signal for perceived recent exposure in the experimental study phase. These findings provide, to our knowledge, the first evidence that ties signals in human PrC to variations in cumulative lifetime experience with object concepts. They offer a new link between the role of PrC in recognition memory and its broader role in conceptual processing.

Accounting for the Confound of Meninges in Segmenting Entorhinal and Perirhinal Cortices in T1-Weighted MRI.

Quantification of medial temporal lobe (MTL) cortices, including entorhinal cortex (ERC) and perirhinal cortex (PRC), from in vivo MRI is desirable for studying the human memory system as well as in early diagnosis and monitoring of Alzheimer's disease. However, ERC and PRC are commonly over-segmented in T1-weighted (T1w) MRI because of the adjacent meninges that have similar intensity to gray matter in T1 contrast. This introduces errors in the quantification and could potentially confound imaging studies of ERC/PRC. In this paper, we propose to segment MTL cortices along with the adjacent meninges in T1w MRI using an established multi-atlas segmentation framework together with super-resolution technique. Experimental results comparing the proposed pipeline with existing pipelines support the notion that a large portion of meninges is segmented as gray matter by existing algorithms but not by our algorithm. Cross-validation experiments demonstrate promising segmentation accuracy. Further, agreement between the volume and thickness measures from the proposed pipeline and those from the manual segmentations increase dramatically as a result of accounting for the confound of meninges. Evaluated in the context of group discrimination between patients with amnestic mild cognitive impairment and normal controls, the proposed pipeline generates more biologically plausible results and improves the statistical power in discriminating groups in absolute terms comparing to other techniques using T1w MRI. Although the performance of the proposed pipeline is inferior to that using T2-weighted MRI, which is optimized to image MTL sub-structures, the proposed pipeline could still provide important utilities in analyzing many existing large datasets that only have T1w MRI available.

Neuropsychological Markers of Medial Perirhinal and Entorhinal Cortex Functioning are Impaired Twelve Years Preceding Diagnosis of Alzheimer's Dementia.

Neurofibrillary pathology in Alzheimer's dementia (AD) is associated with cognitive impairments and cortical thinning, and begins in medial perirhinal cortex (mPRC) before entering entorhinal cortex (ERC). Thus, mPRC dysfunction (e.g., semantic object memory impairments) may predate or accompany ERC (i.e., episodic memory) dysfunction in the preclinical course of typical AD. We developed formulae estimating mPRC and ERC integrity (i.e., cortical thickness) using common neuropsychological tests in 31 healthy individuals and 58 early AD patients. These formulae estimated the longitudinal courses of mPRC and ERC functioning in independent groups of 28 optimally healthy individuals who developed AD (NC-AD) over 2.8-13.4 years and 28 pairwise-matched, stable, healthy individuals (NC-NC). Mixed models demonstrated significantly worse NC-AD than NC-NC estimated mPRC and ERC functioning at the earliest observation, 12 years preceding diagnosis, and a significant decline 4 years preceding the AD diagnosis. These findings demonstrate that specific neuropsychological impairments occur early in the course of preclinical AD and that tasks measuring mPRC functioning may serve as additional, powerful markers of preclinical AD.