A qualitative solution with quantitative potential for the mouse hippocampal cortex flatmap problem.

The hippocampal formation (HPF) is a focus of intense experimental investigation, particularly because of its roles in conscious memory consolidation, spatial navigation, emotion, and motivated behaviors. However, the HPF has a complex three-dimensional geometry resulting from extreme curvature of its layers, and this presents a challenge for investigators seeking to decipher hippocampal structure and function at cellular and molecular scales (neuronal circuitry, gene expression, and other properties). Previously, this problem was solved qualitatively for the rat by constructing a physical surface model of the HPF based on histological sections, and then deriving from the model a flatmap. Its usefulness is exemplified by previous studies that used it to display topological relationships between different components of intrahippocampal circuitry derived from experimental pathway-tracing experiments. Here the rat HPF flatmap was used as a starting point to construct an analogous flatmap for the mouse, where the great majority of experimental hippocampal research is currently performed. A detailed account of underlying knowledge and principles is provided, including for hippocampal terminology, and development from an embryonic nonfolded sheet into differentiated multiple adjacent cortical areas, giving rise to the adult shape. To demonstrate its utility, the mouse flatmap was used to display the results of pathway-tracing experiments showing the dentate gyrus mossy fiber projection, and its relationship to the intrahippocampal Purkinje cell protein 4 gene-expression pattern. Finally, requirements for constructing a computer graphics quantitative intrahippocampal flatmap, with accompanying intrahippocampal coordinate system, are presented; they should be applicable to all mammals, including human.

Multiple parietal pathways are associated with rTMS-induced hippocampal network enhancement and episodic memory changes.

Repetitive transcranial magnetic stimulation (rTMS) of the inferior parietal cortex (IPC) increases resting-state functional connectivity (rsFC) of the hippocampus with the precuneus and other posterior cortical areas and causes proportional improvement of episodic memory. The anatomical pathway(s) responsible for the propagation of these effects from the IPC is unknown and may not be direct. In order to assess the relative contributions of candidate pathways from the IPC to the MTL via the parahippocampal cortex and precuneus, to the effects of rTMS on rsFC and memory improvement, we used diffusion tensor imaging to measure the extent to which individual differences in fractional anisotropy (FA) in these pathways accounted for individual differences in response. FA in the IPC-parahippocampal pathway and several MTL pathways predicted changes in rsFC. FA in both parahippocampal and hippocampal pathways was related to changes in episodic, but not procedural, memory. These results implicate pathways to the MTL in the enhancing effect of parietal rTMS on hippocampal rsFC and memory.

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.

Development and topographical organization of projections from the hippocampus and parahippocampus to the retrosplenial cortex.

The rat hippocampal formation (HF), parahippocampal region (PHR), and retrosplenial cortex (RSC) play critical roles in spatial processing. These regions are interconnected, and functionally dependent. The neuronal networks mediating this reciprocal dependency are largely unknown. Establishing the developmental timing of network formation will help to understand the emergence of this dependency. We questioned whether the long-range outputs from HF-PHR to RSC in Long Evans rats develop during the same time periods as previously reported for the intrinsic HF-PHR connectivity and the projections from RSC to HF-PHR. The results of a series of retrograde and anterograde tracing experiments in rats of different postnatal ages show that the postnatal projections from HF-PHR to RSC display low densities around birth, but develop during the first postnatal week, reaching adult-like densities around the time of eye-opening. Developing projections display a topographical organization similar to adult projections. We conclude that the long-range projections from HF-PHR to RSC develop in parallel with the intrinsic circuitry of HF-PHR and the projections of RSC to HF-PHR.

Defining the most probable location of the parahippocampal place area using cortex-based alignment and cross-validation.

The parahippocampal place area (PPA) is a widely studied high-level visual region in the human brain involved in place and scene processing. The goal of the present study was to identify the most probable location of place-selective voxels in medial ventral temporal cortex. To achieve this goal, we first used cortex-based alignment (CBA) to create a probabilistic place-selective region of interest (ROI) from one group of 12 participants. We then tested how well this ROI could predict place selectivity in each hemisphere within a new group of 12 participants. Our results reveal that a probabilistic ROI (pROI) generated from one group of 12 participants accurately predicts the location and functional selectivity in individual brains from a new group of 12 participants, despite between subject variability in the exact location of place-selective voxels relative to the folding of parahippocampal cortex. Additionally, the prediction accuracy of our pROI is significantly higher than that achieved by volume-based Talairach alignment. Comparing the location of the pROI of the PPA relative to published data from over 500 participants, including data from the Human Connectome Project, shows a striking convergence of the predicted location of the PPA and the cortical location of voxels exhibiting the highest place selectivity across studies using various methods and stimuli. Specifically, the most predictive anatomical location of voxels exhibiting the highest place selectivity in medial ventral temporal cortex is the junction of the collateral and anterior lingual sulci. Methodologically, we make this pROI freely available (vpnl.stanford.edu/PlaceSelectivity), which provides a means to accurately identify a functional region from anatomical MRI data when fMRI data are not available (for example, in patient populations). Theoretically, we consider different anatomical and functional factors that may contribute to the consistent anatomical location of place selectivity relative to the folding of high-level visual cortex.

Cellular components and circuitry of the presubiculum and its functional role in the head direction system.

Orientation in space is a fundamental cognitive process relying on brain-wide neuronal circuits. Many neurons in the presubiculum in the parahippocampal region encode head direction and each head direction cell selectively discharges when the animal faces a specific direction. Here, we attempt to link the current knowledge of afferent and efferent connectivity of the presubiculum to the processing of the head direction signal. We describe the cytoarchitecture of the presubicular six-layered cortex and the morphological and electrophysiological intrinsic properties of principal neurons and interneurons. While the presubicular head direction signal depends on synaptic input from thalamus, the intra- and interlaminar information flow in the microcircuit of the presubiculum may contribute to refine directional tuning. The interaction of a specific interneuron type, the Martinotti cells, with the excitatory pyramidal cells may maintain the head direction signal in the presubiculum with attractor-like properties.

Unfolding the cognitive map: The role of hippocampal and extra-hippocampal substrates based on a systems analysis of spatial processing.

What has been long absent in understanding the neural circuit that supports spatial processing is a thorough description and rigorous study of the distributed neural networks associated with spatial processing-both in the human as well as in rodents. Most of our understanding regarding the elucidation of a spatial neural circuit has been based on rodents and therefore the present manuscript will concentrate on that literature. There is a trend emerging in research to expand beyond the hippocampus for evaluating spatial memory, but the thrust of the research still focuses on the role of the hippocampus as essential and other neural substrates as performing sub-servient roles to support hippocampus-dependent spatial processing. This review will describe spatial memory in terms of a system model incorporating partially overlapping and interacting event-based, knowledge-based and rule-based memory systems that are composed of different component processes or attributes associated with spatial processing which are mapped onto the corresponding neural substrates and larger networks. In particular, the interactions among brain systems that process spatial information will be emphasized. We propose that these interactions among brain regions are essential for spatial memory.

Quantitative comparison of 21 protocols for labeling hippocampal subfields and parahippocampal subregions in in vivo MRI: towards a harmonized segmentation protocol.

OBJECTIVE: An increasing number of human in vivo magnetic resonance imaging (MRI) studies have focused on examining the structure and function of the subfields of the hippocampal formation (the dentate gyrus, CA fields 1-3, and the subiculum) and subregions of the parahippocampal gyrus (entorhinal, perirhinal, and parahippocampal cortices). The ability to interpret the results of such studies and to relate them to each other would be improved if a common standard existed for labeling hippocampal subfields and parahippocampal subregions. Currently, research groups label different subsets of structures and use different rules, landmarks, and cues to define their anatomical extents. This paper characterizes, both qualitatively and quantitatively, the variability in the existing manual segmentation protocols for labeling hippocampal and parahippocampal substructures in MRI, with the goal of guiding subsequent work on developing a harmonized substructure segmentation protocol. METHOD: MRI scans of a single healthy adult human subject were acquired both at 3 T and 7 T. Representatives from 21 research groups applied their respective manual segmentation protocols to the MRI modalities of their choice. The resulting set of 21 segmentations was analyzed in a common anatomical space to quantify similarity and identify areas of agreement. RESULTS: The differences between the 21 protocols include the region within which segmentation is performed, the set of anatomical labels used, and the extents of specific anatomical labels. The greatest overall disagreement among the protocols is at the CA1/subiculum boundary, and disagreement across all structures is greatest in the anterior portion of the hippocampal formation relative to the body and tail. CONCLUSIONS: The combined examination of the 21 protocols in the same dataset suggests possible strategies towards developing a harmonized subfield segmentation protocol and facilitates comparison between published studies.

Tunes stuck in your brain: The frequency and affective evaluation of involuntary musical imagery correlate with cortical structure.

Recent years have seen a growing interest in the neuroscience of spontaneous cognition. One form of such cognition is involuntary musical imagery (INMI), the non-pathological and everyday experience of having music in one's head, in the absence of an external stimulus. In this study, aspects of INMI, including frequency and affective evaluation, were measured by self-report in 44 subjects and related to variation in brain structure in these individuals. Frequency of INMI was related to cortical thickness in regions of right frontal and temporal cortices as well as the anterior cingulate and left angular gyrus. Affective aspects of INMI, namely the extent to which subjects wished to suppress INMI or considered them helpful, were related to gray matter volume in right temporopolar and parahippocampal cortices respectively. These results provide the first evidence that INMI is a common internal experience recruiting brain networks involved in perception, emotions, memory and spontaneous thoughts.

Distinct contributions of the amygdala and parahippocampal gyrus to suspicion in a repeated bargaining game.

Humans assess the credibility of information gained from others on a daily basis; this ongoing assessment is especially crucial for avoiding exploitation by others. We used a repeated, two-person bargaining game and a cognitive hierarchy model to test how subjects judge the information sent asymmetrically from one player to the other. The weight that they give to this information is the result of two distinct factors: their baseline suspicion given the situation and the suspicion generated by the other person's behavior. We hypothesized that human brains maintain an ongoing estimate of the credibility of the other player and sought to uncover neural correlates of this process. In the game, sellers were forced to infer the value of an object based on signals sent from a prospective buyer. We found that amygdala activity correlated with baseline suspicion, whereas activations in bilateral parahippocampus correlated with trial-by-trial uncertainty induced by the buyer's sequence of suggestions. In addition, the less credible buyers that appeared, the more sensitive parahippocampal activation was to trial-by-trial uncertainty. Although both of these neural structures have previously been implicated in trustworthiness judgments, these results suggest that they have distinct and separable roles that correspond to their theorized roles in learning and memory.

Simple line drawings suffice for functional MRI decoding of natural scene categories.

Humans are remarkably efficient at categorizing natural scenes. In fact, scene categories can be decoded from functional MRI (fMRI) data throughout the ventral visual cortex, including the primary visual cortex, the parahippocampal place area (PPA), and the retrosplenial cortex (RSC). Here we ask whether, and where, we can still decode scene category if we reduce the scenes to mere lines. We collected fMRI data while participants viewed photographs and line drawings of beaches, city streets, forests, highways, mountains, and offices. Despite the marked difference in scene statistics, we were able to decode scene category from fMRI data for line drawings just as well as from activity for color photographs, in primary visual cortex through PPA and RSC. Even more remarkably, in PPA and RSC, error patterns for decoding from line drawings were very similar to those from color photographs. These data suggest that, in these regions, the information used to distinguish scene category is similar for line drawings and photographs. To determine the relative contributions of local and global structure to the human ability to categorize scenes, we selectively removed long or short contours from the line drawings. In a category-matching task, participants performed significantly worse when long contours were removed than when short contours were removed. We conclude that global scene structure, which is preserved in line drawings, plays an integral part in representing scene categories.

Presubiculum layer III conveys retrosplenial input to the medial entorhinal cortex.

Navigation is mediated by a network of brain areas, and research has focused on the head-direction system in the presubiculum (PrS), the grid cell containing medial entorhinal cortex (EC) (MEC) and place cells in the hippocampus. Less research addressed the interactions of the retrosplenial cortex (RSC) and the navigational system, although it is well established that damage to the RSC leads to navigational deficits. We previously showed that RSC provides a dense input to deep layers of MEC and to superficial layers of PrS. In this study we use confocal microscopical analysis and show that the dense projection from the caudal part of the ventral retrosplenial granular cortex targets neurons in Layer III of PrS, which provide input to superficial layers of MEC. Our high resolution anatomical data indicate that sparsely spiny pyramidal neurons in Layer III of PrS that originate projections to Layer III of MEC are the main target of these retrosplenial projections. Retrosplenial axonal boutons were found to equally contact spines and shafts of basal dendrites in Layer III, but contacts on shafts are more prominent close to the soma, indicating the potential for efficient synaptic transfer. These observations suggest that neurons in Layer III of PrS have an important role in mediating RSC contributions to navigation.

Electrophysiological and morphological properties of neurons in layer 5 of the rat postrhinal cortex.

The postrhinal (POR) cortex of the rat is homologous to the parahippocampal cortex of the primate based on connections and other criteria. POR provides the major visual and visuospatial input to the hippocampal formation, both directly to CA1 and indirectly through connections with the medial entorhinal cortex. Although the cortical and hippocampal connections of the POR cortex are well described, the physiology of POR neurons has not been studied. Here, we examined the electrical and morphological characteristics of layer 5 neurons from POR cortex of 14- to 16-day-old rats using an in vitro slice preparation. Neurons were subjectively classified as regular-spiking (RS), fast-spiking (FS), or low-threshold spiking (LTS) based on their electrophysiological properties and similarities with neurons in other regions of neocortex. Cells stained with biocytin included pyramidal cells and interneurons with bitufted or multipolar dendritic patterns. Similarity analysis using only physiological data yielded three clusters that corresponded to FS, LTS, and RS classes. The cluster corresponding to the FS class was composed entirely of multipolar nonpyramidal cells, and the cluster corresponding to the RS class was composed entirely of pyramidal cells. The third cluster, corresponding to the LTS class, was heterogeneous and included both multipolar and bitufted dendritic arbors as well as one pyramidal cell. We did not observe any intrinsically bursting pyramidal cells, which is similar to entorhinal cortex but unlike perirhinal cortex. We conclude that POR includes at least two major classes of neocortical inhibitory interneurons, but has a functionally restricted cohort of pyramidal cells.

Neural correlates of socioeconomic status in the developing human brain.

Socioeconomic disparities in childhood are associated with remarkable differences in cognitive and socio-emotional development during a time when dramatic changes are occurring in the brain. Yet, the neurobiological pathways through which socioeconomic status (SES) shapes development remain poorly understood. Behavioral evidence suggests that language, memory, social-emotional processing, and cognitive control exhibit relatively large differences across SES. Here we investigated whether volumetric differences could be observed across SES in several neural regions that support these skills. In a sample of 60 socioeconomically diverse children, highly significant SES differences in regional brain volume were observed in the hippocampus and the amygdala. In addition, SES × age interactions were observed in the left superior temporal gyrus and left inferior frontal gyrus, suggesting increasing SES differences with age in these regions. These results were not explained by differences in gender, race or IQ. Likely mechanisms include differences in the home linguistic environment and exposure to stress, which may serve as targets for intervention at a time of high neural plasticity.

The human parahippocampal region: I. Temporal pole cytoarchitectonic and MRI correlation.

The temporal pole (TP) is the rostralmost portion of the human temporal lobe. Characteristically, it is only present in human and nonhuman primates. TP has been implicated in different cognitive functions such as emotion, attention, behavior, and memory, based on functional studies performed in healthy controls and patients with neurodegenerative diseases through its anatomical connections (amygdala, pulvinar, orbitofrontal cortex). TP was originally described as a single uniform area by Brodmann area 38, and von Economo (area TG of von Economo and Koskinas), and little information on its cytoarchitectonics is known in humans. We hypothesize that 1) TP is not a homogenous area and we aim first at fixating the precise extent and limits of temporopolar cortex (TPC) with adjacent fields and 2) its structure can be correlated with structural magnetic resonance images. We describe here the macroscopic characteristics and cytoarchitecture as two subfields, a medial and a lateral area, that constitute TPC also noticeable in 2D and 3D reconstructions. Our findings suggest that the human TP is a heterogeneous region formed exclusively by TPC for about 7 mm of the temporal tip, and that becomes progressively restricted to the medial and ventral sides of the TP. This cortical area presents topographical and structural features in common with nonhuman primates, which suggests an evolutionary development in human species.

How reliable are visual context effects in the parahippocampal place area?

The parahippocampal place area (PPA) is a region of human cortex that responds more strongly to visual scenes (e.g., landscapes or cityscapes) than to other visual stimuli. It has been proposed that the primary function of the PPA is encoding of contextual information about object co-occurrence. Supporting this context hypothesis are reports that the PPA responds more strongly to strong-context than to weak-context objects and more strongly to famous faces (for which contextual associations are available) than to nonfamous faces. We reexamined the reliability of these 2 effects by scanning subjects with functional magnetic resonance imaging while they viewed strong- and weak-context objects, scrambled versions of these objects, and famous and nonfamous faces. "Contextual" effects for objects were observed to be reliable in the PPA at slow presentation rates but not at faster presentation rates intended to discourage scene imagery. We were unable to replicate the earlier finding of preferential PPA response to famous versus nonfamous faces. These results are difficult to reconcile with the hypothesis that the PPA encodes contextual associations but are consistent with a competing hypothesis that the PPA encodes scenic layout.

Anatomy and White Matter Connections of the Parahippocampal Gyrus.

BACKGROUND: The parahippocampal gyrus is understood to have a role in high cognitive functions including memory encoding and retrieval and visuospatial processing. A detailed understanding of the exact location and nature of associated white tracts could significantly improve postoperative morbidity related to declining capacity. Through diffusion tensor imaging-based fiber tracking validated by gross anatomic dissection as ground truth, we have characterized these connections based on relationships to other well-known structures. METHODS: Diffusion imaging from the Human Connectome Project for 10 healthy adult controls was used for tractography analysis. We evaluated the parahippocampal gyrus as a whole based on connectivity with other regions. All parahippocampal gyrus tracts were mapped in both hemispheres, and a lateralization index was calculated with resultant tract volumes. RESULTS: We identified 2 connections of the parahippocampal gyrus: inferior longitudinal fasciculus and cingulum. Lateralization of the cingulum was detected (P < 0.05). CONCLUSIONS: The parahippocampal gyrus is an important center for memory processing. Subtle differences in executive functioning following surgery for limbic tumors may be better understood in the context of the fiber-bundle anatomy highlighted by this study.

In search of recollection and familiarity signals in the hippocampus.

fMRI studies of recognition memory have often been interpreted to mean that the hippocampus selectively subserves recollection and that adjacent regions selectively subserve familiarity. Yet, many of these studies have confounded recollection and familiarity with strong and weak memories. In a source memory experiment, we compared correct source judgments (which reflect recollection) and incorrect source judgments (often thought to reflect familiarity) while equating for old-new memory strength by including only high-confidence hits in the analysis. Hippocampal activity associated with both correct source judgments and incorrect source judgments exceeded the activity associated with forgotten items and did so to a similar extent. Further, hippocampal activity was greater for high-confidence old decisions relative to forgotten items even when source decisions were at chance. These results identify a recollection signal in the hippocampus and may identify a familiarity signal as well. Similar results were obtained in the parahippocampal gyrus. Unlike in the medial temporal lobe, activation in prefrontal cortex increased differentially in association with source recollection.

High-resolution fMRI of content-sensitive subsequent memory responses in 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.

Functional connectivity of the macaque posterior parahippocampal cortex.

Neuroimaging experiments in humans suggest that regions in parietal cortex and along the posterior midline are functionally connected to the medial temporal lobe and are active during memory retrieval. It is unknown whether macaques have a similar network. We examined functional connectivity in isoflurane-anesthetized macaques to identify a network associated with posterior parahippocampal cortex (PPHC). Functional connectivity was observed between the PPHC and retrosplenial, posterior cingulate, superior temporal gyrus, and inferior parietal cortex. PPHC correlations were distinct from regions in parietal and temporal cortex activated by an oculomotor task. Comparison of macaque and human PPHC correlations revealed similarities that suggest the temporal-parietal region identified in the macaque may share a common lineage with human Brodmann area 39, a region thought to be involved in recollection. These results suggest that macaques and humans may have homologous PPHC-parietal pathways. By specifying the location of the putative macaque homologue in parietal cortex, we provide a target for future physiological exploration of this area's role in mnemonic or alternative processes.