Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 µm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.

Comparative anatomy of the middle cerebral artery, rhinal and endorhinal sulci, piriform lobe, entorhinal cortex, olfactory tubercule, anterior perforate substance, and hippocampus: A dissection study.

The literature describing the complex anatomy of the middle cerebral artery (MCA), lenticulostriate arteries, and recurrent artery of Heubner, does not discuss the comparative anatomy of the cerebrum, MCA, the recurrent artery of Heubner, and the relationship of the MCA with the rhinal sulci. The entorhinal literature does not detail the comparative anatomic modification of the rhinal and endorhinal sulci, piriform lobe and the hippocampus's compressed positional change in the temporal lobe. This investigation's objectives were to analyze the comparative anatomic modifications of the cerebrum, the MCA, lenticulostriate arteries, recurrent artery of Heubner, olfactory tubercule, anterior perforate substance, rhinal sulcus, endorhinal sulcus, piriform lobe, entorhinal cortex, and hippocampus. Brain dissections of adult iguana, rabbit, sheep, cat, dog, macaque, human and human fetal specimens were analyzed. The MCA branches enter the striate nuclei via the endorhinal sulcus, with few branches present in the rhinal sulcus. Modifications of the cerebrum, with the development of gyri and sulci and opercula covering the insula, changes the linear surface configuration of the MCA into a tridimensional one. Similar changes are present in human fetal specimens. The cerebral neocortical expansion changes the position of the rhinal and endorhinal sulci, their relationship with the MCA, the size of the olfactory tubercule, the position and size of the piriform lobe, and the diagonal course of the lenticulostriates and recurrent artery of Heubner. The hippocampus becomes compressed in the inferomedial region of the human temporal lobe. The lenticulostriate arteries are likely the first developed component of the MCA.

Functional network topography of the medial entorhinal cortex.

The medial entorhinal cortex (MEC) creates a map of local space, based on the firing patterns of grid, head-direction (HD), border, and object-vector (OV) cells. How these cell types are organized anatomically is debated. In-depth analysis of this question requires collection of precise anatomical and activity data across large populations of neurons during unrestrained behavior, which neither electrophysiological nor previous imaging methods fully afford. Here, we examined the topographic arrangement of spatially modulated neurons in the superficial layers of MEC and adjacent parasubiculum using miniaturized, portable two-photon microscopes, which allow mice to roam freely in open fields. Grid cells exhibited low levels of co-occurrence with OV cells and clustered anatomically, while border, HD, and OV cells tended to intermingle. These data suggest that grid cell networks might be largely distinct from those of border, HD, and OV cells and that grid cells exhibit strong coupling among themselves but weaker links to other cell types.

Toroidal topology of population activity in grid cells.

The medial entorhinal cortex is part of a neural system for mapping the position of an individual within a physical environment1. Grid cells, a key component of this system, fire in a characteristic hexagonal pattern of locations2, and are organized in modules3 that collectively form a population code for the animal's allocentric position1. The invariance of the correlation structure of this population code across environments4,5 and behavioural states6,7, independent of specific sensory inputs, has pointed to intrinsic, recurrently connected continuous attractor networks (CANs) as a possible substrate of the grid pattern1,8-11. However, whether grid cell networks show continuous attractor dynamics, and how they interface with inputs from the environment, has remained unclear owing to the small samples of cells obtained so far. Here, using simultaneous recordings from many hundreds of grid cells and subsequent topological data analysis, we show that the joint activity of grid cells from an individual module resides on a toroidal manifold, as expected in a two-dimensional CAN. Positions on the torus correspond to positions of the moving animal in the environment. Individual cells are preferentially active at singular positions on the torus. Their positions are maintained between environments and from wakefulness to sleep, as predicted by CAN models for grid cells but not by alternative feedforward models12. This demonstration of network dynamics on a toroidal manifold provides a population-level visualization of CAN dynamics in grid cells.

A comparative study of pre-alpha islands in the entorhinal cortex from selected primates and in lissencephaly.

The entorhinal cortex (EC) is the main interface between the sensory association areas of the neocortex and the hippocampus. It is crucial for the evaluation and processing of sensory data for long-term memory consolidation and shows damage in many brain diseases, for example, neurodegenerative diseases, such as Alzheimer's disease and developmental disorders. The pre-alpha layer of the EC in humans (layer II) displays a remarkable distribution of neurons in islands. These cellular islands give rise to a portion of the perforant path-the major reciprocal data stream for neocortical information into the hippocampal formation. However, the functional relevance of the morphological appearance of the pre-alpha layer in cellular islands and the precise timing of their initial appearance during primate evolution are largely unknown. Here, we conducted a comparative study of the EC from 38 nonhuman primates and Homo sapiens and found a strong relationship between gyrification index (GI) and the presence of the pre-alpha cellular islands. The formation of cellular islands also correlated with brain and body weight as well as neopallial volume. In the two human lissencephalic cases, the cellular islands in the pre-alpha layer were lacking. These findings emphasize the relationship between cortical folding and island formation in the EC from an evolutionary perspective and suggest a role in the pathomechanism of developmental brain disorders.

Structural connectivity-based segmentation of the human entorhinal cortex.

The medial (MEC) and lateral entorhinal cortex (LEC), widely studied in rodents, are well defined and characterized. In humans, however, the exact locations of their homologues remain uncertain. Previous functional magnetic resonance imaging (fMRI) studies have subdivided the human EC into posteromedial (pmEC) and anterolateral (alEC) parts, but uncertainty remains about the choice of imaging modality and seed regions, in particular in light of a substantial revision of the classical model of EC connectivity based on novel insights from rodent anatomy. Here, we used structural, not functional imaging, namely diffusion tensor imaging (DTI) and probabilistic tractography to segment the human EC based on differential connectivity to other brain regions known to project selectively to MEC or LEC. We defined MEC as more strongly connected with presubiculum and retrosplenial cortex (RSC), and LEC as more strongly connected with distal CA1 and proximal subiculum (dCA1pSub) and lateral orbitofrontal cortex (OFC). Although our DTI segmentation had a larger medial-lateral component than in the previous fMRI studies, our results show that the human MEC and LEC homologues have a border oriented both towards the posterior-anterior and medial-lateral axes, supporting the differentiation between pmEC and alEC.

Distal CA1 Maintains a More Coherent Spatial Representation than Proximal CA1 When Local and Global Cues Conflict.

Entorhinal cortical projections show segregation along the transverse axis of CA1, with the medial entorhinal cortex (MEC) sending denser projections to proximal CA1 (pCA1) and the lateral entorhinal cortex (LEC) sending denser projections to distal CA1 (dCA1). Previous studies have reported functional segregation along the transverse axis of CA1 correlated with the functional differences in MEC and LEC. pCA1 shows higher spatial selectivity than dCA1 in these studies. We employ a double rotation protocol, which creates an explicit conflict between the local and the global cues, to understand the differential contributions of these reference frames to the spatial code in pCA1 and dCA1 in male Long-Evans rats. We show that pCA1 and dCA1 respond differently to this local-global cue conflict. pCA1 representation splits as predicted from the strong conflicting inputs it receives from MEC and dCA3. In contrast, dCA1 rotates more in concert with the global cues. In addition, pCA1 and dCA1 display comparable levels of spatial selectivity in this study. This finding differs from the previous studies, perhaps because of richer sensory information available in our behavior arena. Together, these observations indicate that the functional segregation along proximodistal axis of CA1 is not of the amount of spatial selectivity but that of the nature of the different inputs used to create and anchor spatial representations.SIGNIFICANCE STATEMENT Subregions of the hippocampus are thought to play different roles in spatial navigation and episodic memory. It was previously thought that the distal part of area CA1 of the hippocampus carries lesser information about space than proximal CA1 (pCA1). We report that distal CA1 (dCA1) spatial representation moves more in concert with the global cues than pCA1 when the local and the global cues conflict. We also show that spatial selectivity is comparable along the proximodistal axis in this experimental protocol. Thus, different parts of the brain receiving differential outputs from pCA1 and dCA1 receive spatial information in different spatial reference frames encoded using different sets of inputs, rather than different amounts of spatial information as thought earlier.

Cardiovascular Endurance Modifies the Link between Subjective Sleep Quality and Entorhinal Cortex Thickness in Younger Adults.

INTRODUCTION: Poor sleep is linked to impaired cognitive function, cortical brain atrophy, and lower cortical thickness. Independently, higher cardiovascular endurance has neuroprotective effects. It remains in question, however, whether cardiovascular endurance moderates the relationship between sleep and brain health. The aims of this study included the following: 1) the association between subjective sleep quality and cognitive performance, hippocampus volume, and entorhinal cortex (EC) thickness, and 2) the moderating effects of cardiovascular endurance on the associations of sleep quality with cognitive and magnetic resonance imaging measures in healthy younger adults. METHODS: A total of 1095 younger adults (28.8 ± 3.6 yr) from the Human Connectome Project were included in the analyses. The 2-min walk test was used as a proxy of cardiovascular endurance. Self-reported sleep quality was measured using the Pittsburgh Sleep Quality Index. Composite cognitive tests were used to assess global cognition, and T1-weighted structural magnetic resonance imaging data (obtained using Siemens 3T scanner) was used to assess hippocampus volume and EC thickness. Linear regression was used to examine the moderating effects of fitness on the relationships between sleep and each of these neurocognitive outcomes after controlling for age, sex, and education year. RESULTS: Poorer sleep quality was associated with both a lower crystalized intelligence score (B = -0.198, P = 0.034) and lower EC thickness (B = -0.013, P = 0.003). With greater 2-min walk test score, the association between greater Pittsburgh Sleep Quality Index score and lower EC thickness was attenuated (B = 0.0008, P = 0.028). CONCLUSIONS: Higher cardiovascular endurance may mitigate the relationship between poorer subjective sleep quality and lower EC thickness. Future longitudinal studies should examine the interactive effects of sleep and fitness on brain health among older and more vulnerable populations.

Subiculum as a generator of sharp wave-ripples in the rodent hippocampus.

Sharp wave-ripples (SWRs) represent synchronous discharges of hippocampal neurons and are believed to play a major role in memory consolidation. A large body of evidence suggests that SWRs are exclusively generated in the CA3-CA2 network. In contrast, here, we provide several lines of evidence showing that the subiculum can function as a secondary SWRs generator. SWRs with subicular origin propagate forward into the entorhinal cortex as well as backward into the hippocampus proper. Our findings suggest that the output structures of the hippocampus are not only passively facilitating the transfer of SWRs to the cortex, but they also can actively contribute to the genesis of SWRs. We hypothesize that SWRs with a subicular origin may be important for the consolidation of information conveyed to the hippocampus via the temporoammonic pathway.

Distribution and overlap of entorhinal, premotor, and amygdalar connections in the monkey anterior cingulate cortex.

The anterior cingulate cortex (ACC) is important for decision-making as it integrates motor plans with affective and contextual limbic information. Disruptions in these networks have been observed in depression, bipolar disorder, and post-traumatic stress disorder. Yet, overlap of limbic and motor connections within subdivisions of the ACC is not well understood. Hence, we administered a combination of retrograde and anterograde tracers into structures important for contextual memories (entorhinal cortex), affective processing (amygdala), and motor planning (dorsal premotor cortex) to assess overlap of labeled projection neurons from (outputs) and axon terminals to (inputs) the ACC of adult rhesus monkeys (Macaca mulatta). Our data show that entorhinal and dorsal premotor cortical (dPMC) connections are segregated across ventral (A25, A24a) and dorsal (A24b,c) subregions of the ACC, while amygdalar connections are more evenly distributed across subregions. Among all areas, the rostral ACC (A32) had the lowest relative density of connections with all three regions. In the ventral ACC, entorhinal and amygdalar connections strongly overlap across all layers, especially in A25. In the dorsal ACC, outputs to dPMC and the amygdala strongly overlap in deep layers. However, dPMC input to the dorsal ACC was densest in deep layers, while amygdalar inputs predominantly localized in upper layers. These connection patterns are consistent with diverse roles of the dorsal ACC in motor evaluation and the ventral ACC in affective and contextual memory. Further, distinct laminar circuits suggest unique interactions within specific ACC compartments that are likely important for the temporal integration of motor and limbic information during flexible goal-directed behavior.

Reproducibility of volume and asymmetry measurements of hippocampus, amygdala, and entorhinal cortex on traveling volunteers: a multisite MP2RAGE prospective study.

BACKGROUND: Multisite studies can considerably increase the pool of normally aging individuals with neurodegenerative disorders and thereby expedite the associated research. Understanding the reproducibility of the parameters of related brain structures-including the hippocampus, amygdala, and entorhinal cortex-in multisite studies is crucial in determining the impact of healthy aging or neurodegenerative diseases. PURPOSE: To estimate the reproducibility of the fascinating structures by automatic (FreeSurfer) and manual segmentation methods in a well-controlled multisite dataset. MATERIAL AND METHODS: Three traveling individuals were scanned at 10 sites, which were equipped with the same equipment (3T Prisma Siemens). They used the same scan protocol (two inversion-contrast magnetization-prepared rapid gradient echo sequences) and operators. Validity coefficients (intraclass correlations coefficient [ICC]) and spatial overlap measures (Dice Similarity Coefficient [DSC]) were used to estimate the reproducibility of multisite data. RESULTS: ICC and DSC values varied substantially among structures and segmentation methods, and values of manual tracing were relatively higher than the automated method. ICC and DSC values of structural parameters were greater than 0.80 and 0.60 across sites, as determined by manual tracing. Low reproducibility was observed in the amygdala parameters by automatic segmentation method (ICC = 0.349-0.529, DSC = 0.380-0.873). However, ICC and DSC scores of the hippocampus were higher than 0.60 and 0.65 by two segmentation methods. CONCLUSION: This study suggests that a well-controlled multisite study could provide a reliable MRI dataset. Manual tracing of volume assessments is recommended for low reproducibility structures that require high levels of precision in multisite studies.

Homotopic Commissural Projections of Area Prostriata in Rat and Mouse: Comparison With Presubiculum and Parasubiculum.

Area prostriata in primates has recently been found to play important roles in rapid detection and processing of peripheral visual, especially fast-moving visual information. The prostriata in rodents was not discovered until recently and its connectivity is largely unknown. As a part of our efforts to reveal brain-wide connections of the prostriata in rat and mouse, this study focuses on its commissural projections in order to understand the mechanisms underlying interhemispheric integration of information, especially from peripheral visual field. Using anterograde, retrograde and Cre-dependent tracing techniques, we find a unique commissural connection pattern of the prostriata: its layers 2-3 in both hemispheres form strong homotopic commissural connections with few heterotopic projections to bilateral medial entorhinal cortex. This projection pattern is in sharp contrast to that of the presubiculum and parasubiculum, two neighbor regions of the prostriata. The latter two structures project very strongly to bilateral medial entorhinal cortex and to their contralateral counterparts. Our results also suggest the prostriata is a distinct anatomical structure from the presubiculum and parasubiculum and probably plays differential roles in interhemispheric integration and the balancing of spatial information between two hemispheres.

Effects of visual inputs on neural dynamics for coding of location and running speed in medial entorhinal cortex.

Neuronal representations of spatial location and movement speed in the medial entorhinal cortex during the 'active' theta state of the brain are important for memory-guided navigation and rely on visual inputs. However, little is known about how visual inputs change neural dynamics as a function of running speed and time. By manipulating visual inputs in mice, we demonstrate that changes in spatial stability of grid cell firing correlate with changes in a proposed speed signal by local field potential theta frequency. In contrast, visual inputs do not alter the running speed-dependent gain in neuronal firing rates. Moreover, we provide evidence that sensory inputs other than visual inputs can support grid cell firing, though less accurately, in complete darkness. Finally, changes in spatial accuracy of grid cell firing on a 10 s time scale suggest that grid cell firing is a function of velocity signals integrated over past time.

Anatomy and Function of the Primate Entorhinal Cortex.

The entorhinal cortex (EC) is a critical element of the hippocampal formation located within the medial temporal lobe (MTL) in primates. The EC has historically received attention for being the primary mediator of cortical information going into and coming from the hippocampus proper. In this review, we highlight the significance of the EC as a major player in memory processing, along with other associated structures in the primate MTL. The complex, convergent topographies of cortical and subcortical input to the EC, combined with short-range intrinsic connectivity and the selective targeting of EC efferents to the hippocampus, provide evidence for subregional specialization and integration of information beyond what would be expected if this structure were a simple conduit of information for the hippocampus. Lesion studies of the EC provide evidence implicating this region as critical for memory and the flexible use of complex relational associations between experienced events. The physiology of this structure's constituent principal cells mirrors the complexity of its anatomy. EC neurons respond preferentially to aspects of memory-dependent paradigms including object, place, and time. EC neurons also show striking spatial representations as primates explore visual space, similar to those identified in rodents navigating physical space. In this review, we highlight the great strides that have been made toward furthering our understanding of the primate EC, and we identify paths forward for future experiments to provide additional insight into the role of this structure in learning and memory.

Links between autobiographical memory richness and temporal discounting in older adults.

When making choices between smaller, sooner rewards and larger, later ones, people tend to discount future outcomes. Individual differences in temporal discounting in older adults have been associated with episodic memory abilities and entorhinal cortical thickness. The cause of this association between better memory and more future-oriented choice remains unclear, however. One possibility is that people with perceptually richer recollections are more patient because they also imagine the future more vividly. Alternatively, perhaps people whose memories focus more on the meaning of events (i.e., are more "gist-based") show reduced temporal discounting, since imagining the future depends on interactions between semantic and episodic memory. We examined which categories of episodic details - perception-based or gist-based - are associated with temporal discounting in older adults. Older adults whose autobiographical memories were richer in perception-based details showed reduced temporal discounting. Furthermore, in an exploratory neuroanatomical analysis, both discount rates and perception-based details correlated with entorhinal cortical thickness. Retrieving autobiographical memories before choice did not affect temporal discounting, however, suggesting that activating episodic memory circuitry at the time of choice is insufficient to alter discounting in older adults. These findings elucidate the role of episodic memory in decision making, which will inform interventions to nudge intertemporal choices.

Interaction of APOE, cerebral blood flow, and cortical thickness in the entorhinal cortex predicts memory decline.

The ε4 allele of the apolipoprotein E (APOE) gene, a risk factor for cognitive decline, is associated with alterations in medial temporal lobe (MTL) structure and function, yet little research has been dedicated to understanding how these alterations might interact to negatively impact cognition. To bridge this gap, the present study employed linear regression models to determine the extent to which APOE genotype (ε4+, ε4-) modifies interactive effects of baseline arterial spin labeling MRI-measured cerebral blood flow (CBF) and FreeSurfer-derived cortical thickness/volume (CT/Vo) in two MTL regions of interest (entorhinal cortex, hippocampus) on memory change in 98 older adults who were cognitively normal at baseline. Baseline entorhinal CBF was positively associated with memory change, but only among ε4 carriers with lower entorhinal CT. Similarly, baseline entorhinal CT was positively associated with memory change, but only among ε4 carriers with lower entorhinal CBF. Findings suggest that APOE ε4 carriers may experience concomitant alterations in neurovascular function and morphology in the MTL that interact to negatively affect cognition prior to the onset of overt clinical symptoms. Results also suggest the presence of distinct multimodal neural signatures in the entorhinal cortex that may signal relative risk for cognitive decline among this group, perhaps reflecting different stages of cerebrovascular compensation (early effective vs. later ineffective).

Cytoarchitecture and myeloarchitecture of the entorhinal cortex of the common marmoset monkey (Callithrix jacchus).

The entorhinal cortex (EC) is associated with impaired cognitive function such as in the case of Alzheimer's disease, Parkinson's disease and Huntington's disease. The present study provides a detailed analysis of the cytoarchitectural and myeloarchitectural organization of the EC in the common marmoset Callithrix jacchus. Data were collected using Nissl and fiber stained preparations, supplemented with acetylcholinesterase and parvalbumin immunohistochemistry. The EC layers and subfields in the marmoset seem to be architectonically similar to those that have been proposed in nonhuman primates and humans to date; however, slight differences could be revealed using the present techniques. Throughout its rostrocaudal length, the entorhinal cortex presents a clear six-layered pattern. The entorhinal cortex is divided into six fields, named mainly in accordance to their rostrocaudal and mediolateral positions. At rostral levels, the neurons tend to be organized in patches that are surrounded by large, thick, radially oriented bundles of fibers, and the deep layers are poorly developed. At caudal levels, the divisions are more laminated in appearance. AChE staining at the borders of adjacent fields are consistent with the changes in layering revealed in Nissl-stained sections, of which the lateral regions of the EC display denser AChE staining than that of the medial banks. PV immunoreactivity was found in the labeled somata, dendrites, and axons in all layers and subdivisions. Additionally, we distinguished three subtypes of PV-immunoreactive neurons: multipolar, bipolar and spherical-shaped neurons, based on the shape of the somata and the disposition of the dendrites.

APOE modifies the interaction of entorhinal cerebral blood flow and cortical thickness on memory function in cognitively normal older adults.

OBJECTIVE: The ε4 allele of the apolipoprotein E (APOE) gene increases risk for cognitive decline in normal and pathologic aging. However, precisely how APOE ε4 exerts its negative impact on cognition is poorly understood. The present study aimed to determine whether APOE genotype (ε4+ vs. ε4-) modifies the interaction of medial temporal lobe (MTL) resting cerebral blood flow (CBF) and brain structure (cortical thickness [CT], volume [Vo]) on verbal memory performance. METHODS: Multiple linear regression models were employed to investigate relationships between APOE genotype, arterial spin labeling MRI-measured CBF and FreeSurfer-based CT and Vo in four MTL regions of interest (left and right entorhinal cortex and hippocampus), and verbal memory performance among a sample of 117 cognitively normal older adults (41 ε4+, 76 ε4-) between the ages of 64 and 89 (mean age â€‹= â€‹73). RESULTS: Results indicated that APOE genotype modified the interaction of CBF and CT on memory in the left entorhinal cortex, such that the relationship between entorhinal CBF and memory was negative (lower CBF was associated with better memory) in non-carriers with higher entorhinal CT, positive (higher CBF was associated with better memory) in non-carriers with lower entorhinal CT, and negative (higher CBF was associated with worse memory) in ε4 carriers with lower entorhinal CT. CONCLUSIONS: Findings suggest that older adult APOE ε4 carriers may experience vascular dysregulation and concomitant morphological alterations in the MTL that interact to negatively affect memory even in the absence overt clinical symptoms, providing potential insight into the mechanistic link between APOE ε4 and detriments in cognition. Moreover, findings suggest a distinct multimodal neural signature in ε4 carriers (higher CBF and lower CT in the entorhinal cortex) that could aid in the identification of candidates for future clinical trials aimed at preventing or slowing cognitive decline. Differential findings with respect to ε4 carriers and non-carriers are discussed in the context of neurovascular compensation.

Object-in-place Memory Predicted by Anterolateral Entorhinal Cortex and Parahippocampal Cortex Volume in Older Adults.

The lateral portion of the entorhinal cortex is one of the first brain regions affected by tau pathology, an important biomarker for Alzheimer disease. Improving our understanding of this region's cognitive role may help identify better cognitive tests for early detection of Alzheimer disease. Based on its functional connections, we tested the idea that the human anterolateral entorhinal cortex (alERC) may play a role in integrating spatial information into object representations. We recently demonstrated that the volume of the alERC was related to processing the spatial relationships of the features within an object [Yeung, L. K., Olsen, R. K., Bild-Enkin, H. E. P., D'Angelo, M. C., Kacollja, A., McQuiggan, D. A., et al. Anterolateral entorhinal cortex volume predicted by altered intra-item configural processing. Journal of Neuroscience, 37, 5527-5538, 2017]. In this study, we investigated whether the human alERC might also play a role in processing the spatial relationships between an object and its environment using an eye-tracking task that assessed visual fixations to a critical object within a scene. Guided by rodent work, we measured both object-in-place memory, the association of an object with a given context [Wilson, D. I., Langston, R. F., Schlesiger, M. I., Wagner, M., Watanabe, S., & Ainge, J. A. Lateral entorhinal cortex is critical for novel object-context recognition. Hippocampus, 23, 352-366, 2013], and object-trace memory, the memory for the former location of objects [Tsao, A., Moser, M. B., & Moser, E. I. Traces of experience in the lateral entorhinal cortex. Current Biology, 23, 399-405, 2013]. In a group of older adults with varying stages of brain atrophy and cognitive decline, we found that the volume of the alERC and the volume of the parahippocampal cortex selectively predicted object-in-place memory, but not object-trace memory. These results provide support for the notion that the alERC may integrate spatial information into object representations.

Smell training improves olfactory function and alters brain structure.

Training and repeated exposure to odorants leads to enhanced olfactory sensitivity. So far, the efficacy of intensive olfactory training on olfactory function in a healthy population and its underlying neurobiological basis remain poorly known. This study investigated the effects of a 6-week intensive and well-controlled olfactory training on olfactory function and brain structure/neuroplasticity. Thirty-six healthy young individuals were recruited and randomly distributed in three groups: (1) 12 participants underwent daily intensive olfactory training of at least 20 min that included an (a) odor intensity classification task, an (b) odor quality classification task and an (c) target odor detection task, (2) 12 participants underwent an equivalent visual control training, and (3) 12 control individuals did not participate in any training. Before and after the training period, all participants performed a series of olfactory tests and those from groups 1 and 2 underwent structural magnetic resonance (MR) imaging, from which we obtained measures such as cortical thickness and tissue density. Participants improved in the respectively trained tasks throughout the 6-weeks training period. Those who underwent olfactory training improved general olfactory function compared to control participants, especially in odor identification, thus showing intramodal transfer. Further, MR imaging analysis revealed that olfactory training led to increased cortical thickness in the right inferior frontal gyrus, the bilateral fusiform gyrus and the right entorhinal cortex. This research shows that intensive olfactory training can generally improve olfactory function and that this improvement is associated with changes in the structure of olfactory processing areas of the brain.