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.

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.

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.

Scene Perception in the Human Brain.

Humans are remarkably adept at perceiving and understanding complex real-world scenes. Uncovering the neural basis of this ability is an important goal of vision science. Neuroimaging studies have identified three cortical regions that respond selectively to scenes: parahippocampal place area, retrosplenial complex/medial place area, and occipital place area. Here, we review what is known about the visual and functional properties of these brain areas. Scene-selective regions exhibit retinotopic properties and sensitivity to low-level visual features that are characteristic of scenes. They also mediate higher-level representations of layout, objects, and surface properties that allow individual scenes to be recognized and their spatial structure ascertained. Challenges for the future include developing computational models of information processing in scene regions, investigating how these regions support scene perception under ecologically realistic conditions, and understanding how they operate in the context of larger brain networks.

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.

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.

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.

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.

Organizational connectivity among the CA1, subiculum, presubiculum, and entorhinal cortex in the rabbit.

The laminar and topographical organization of connections between the hippocampal formation and parahippocampal regions was investigated in the rabbit following in vivo injection of cholera toxin B subunit as a retro- and antero-grade tracer and biotinylated dextran amine as an anterograde tracer. We confirmed several connectional features different from those of the rat, that is, the rabbit presubiculum received abundant afferents from CA1 and had many reciprocal connections with the entorhinal cortex. On the other hand, we identified many similarities with the rat: both the CA1 and subicular afferents that originated from the entorhinal cortex were abundant; moreover, the presubiculum received many inputs from the subiculum and sent massive projections to the entorhinal cortex. By plotting retrograde and anterograde labels in two-dimensional unfolded maps of the entire hippocampal and parahippocampal regions, we found that each group of entorhinal cells that project to CA1, subiculum, and presubiculum, and also the termination of the presubiculo-entorhinal projection, was distributed in band-like zones in layers II-III, extending across the medial and lateral entorhinal cortex. Our results suggest that the rabbit has a basic connectivity that is common with that of the rat, and also has additional hippocampal-presubicular and entorhino-presubicular connections that may reflect functional evolution in learning and memory.

Local morphology informs location of activation during navigation within the parahippocampal region of the human brain.

The relationship between the local morphological features that define the entorhinal and parahippocampal cortex in the medial temporal region of the human brain and activation as measured during a navigation task with functional magnetic resonance imaging was examined individually in healthy participants. Two functional activation clusters were identified one within the caudal end of the collateral sulcus proper and the other in the parahippocampal extension of the collateral sulcus, clearly establishing the activation in the posterior parahippocampal cortex. A third activation cluster was identified where the anterior segment of the collateral sulcus proper gives way to the posterior segment, demonstrating also activation within the middle parahippocampal cortex. No activation was observed in the entorhinal cortex that lies medial to the rhinal sulcus or in the anterior part of the parahippocampal cortex along the anterior branch of the collateral sulcus proper. The activations could also be clearly differentiated from the cortex of the fusiform and lingual gyri that lie laterally and posteriorly. These findings demonstrated specific activation in the middle and posterior part of the parahippocampal cortex when information necessary for navigation was retrieved from a previously established cognitive map and demonstrate that the sulci that comprise the collateral sulcal complex represent important landmarks that can provide an accurate localization of activation foci along the parahippocampal cortex and allow identification of subdivisions involved in the processing of spatial information.

Direct and indirect parieto-medial temporal pathways for spatial navigation in humans: evidence from resting-state functional connectivity.

Anatomical and functional findings in primates suggest the existence of a dedicated parieto-medial temporal pathway for spatial navigation, consisting of both direct and indirect projections from the caudal inferior parietal lobe (cIPL) to the hippocampus and the parahippocampal cortex, with indirect projections relaying through the posterior cingulate and retrosplenial cortex. This neural network is largely unexplored in humans. This study aimed at testing the existence of a parieto-medial temporal pathway for spatial navigation in humans. We explored the cortical connectivity patterns of the parahippocampal place area (PPA), the retrosplenial cortex (RSC), and the hippocampus (HC) using resting-state functional connectivity MRI. Our results demonstrate the existence of connections between the medial temporal lobe structures, i.e., PPA and HC, and the angular gyrus (AG), the human homologue of cIPL, as well as between RSC and AG. These connectivity patterns seem to reflect the direct and the indirect projections found in primates from cIPL to the medial temporal lobe. Such a result deserves feasible considerations to better understand the brain networks underpinning human spatial navigation.

Anatomical organization of presubicular head-direction circuits.

Neurons coding for head-direction are crucial for spatial navigation. Here we explored the cellular basis of head-direction coding in the rat dorsal presubiculum (PreS). We found that layer2 is composed of two principal cell populations (calbindin-positive and calbindin-negative neurons) which targeted the contralateral PreS and retrosplenial cortex, respectively. Layer3 pyramidal neurons projected to the medial entorhinal cortex (MEC). By juxtacellularly recording PreS neurons in awake rats during passive-rotation, we found that head-direction responses were preferentially contributed by layer3 pyramidal cells, whose long-range axons branched within layer3 of the MEC. In contrast, layer2 neurons displayed distinct spike-shapes, were not modulated by head-direction but rhythmically-entrained by theta-oscillations. Fast-spiking interneurons showed only weak directionality and theta-rhythmicity, but were significantly modulated by angular velocity. Our data thus indicate that PreS neurons differentially contribute to head-direction coding, and point to a cell-type- and layer-specific routing of directional and non-directional information to downstream cortical targets.

Three-dimensional probability maps of the rhinal and the collateral sulci in the human brain.

The sulcal segments of the collateral sulcal complex on the medial part of the temporal lobe delineate the parahippocampal gyrus involved in memory processing from the laterally adjacent fusiform gyrus. The rhinal sulcus delineates the entorhinal cortex on the anterior portion of the parahippocampal gyrus. Posterior to the rhinal sulcus lies the collateral sulcus proper which delineates the parahippocampal cortex that occupies the posterior part of the parahippocampal gyrus. A small sulcus, the parahippocampal extension of the collateral sulcus, runs transversely within the parahippocampal gyrus. The rhinal sulcus, the collateral sulcus proper, and the parahippocampal extension of the collateral sulcus were identified on magnetic resonance images of 40 healthy human brains and probability maps were created to provide quantification of the location variability within standard stereotaxic space. These probability maps can act as a reference frame for the accurate identification of key components of the parahippocampal region and assist in the interpretation of structural and functional changes obtained in neuroimaging studies.

Focal attenuation of specific electroencephalographic power over the right parahippocampal region during transcerebral copper screening in living subjects and hemispheric asymmetric voltages in fixed brain tissue.

Covering the heads of human volunteers with a toque lined with copper mesh compared to no mesh resulted in significant diminishments in quantitative electroencephalographic power within theta and beta-gamma bands over the right caudal hemisphere. The effect was most evident in women compared to men. The significant attenuation of power was verified by LORETA (low resolution electromagnetic tomography) within the parahippocampal region of the right hemisphere. Direct measurements of frequency-dependent voltages of coronal section preserved in ethanol-formalin-acetic acid from our human brain collection revealed consistently elevated power (0.2µV(2)Hz(-1)) in right hemispheric structures compared to left. The discrepancy was most pronounced in the grey (cortical) matter of the right parahippocampal region. Probing the superficial convexities of the cerebrum in an unsectioned human brain demonstrated rostrocaudal differences in hemispheric spectral power density asymmetries, particularly over caudal and parahippocampal regions, which were altered as a function of the chemical and spatial contexts imposed upon the tissue. These results indicate that the heterogeneous response of the human cerebrum to covering of the head by a thin conductor could reflect an intrinsic structure and unique electrical property of the (entorhinal) cortices of the right caudal hemisphere that persists in fixed tissue.

Myelination of the right parahippocampal cingulum is associated with physical activity in young healthy adults.

Recent evidence suggests that individual differences in physical activity (PA) may be associated with individual differences in white matter microstructure and with grey matter volume of the hippocampus. Therefore, this study investigated the association between PA and white matter microstructure of pathways connecting to the hippocampus. A total of 33 young, healthy adults underwent magnetic resonance imaging (MRI). High angular resolution diffusion-weighted imaging and multi-component relaxometry MRI scans (multi-component driven equilibrium pulse observation of T1 and T2) were acquired for each participant. Activity levels (AL) of participants were calculated from 72-h actigraphy recordings. Tractography using the damped Richardson Lucy algorithm was used to reconstruct the fornix and bilateral parahippocampal cinguli (PHC). The mean fractional anisotropy (FA) and the myelin water fraction (MWF), a putative marker of myelination, were determined for each pathway. A positive correlation between both AL and FA and between AL and MWF were hypothesized for the three pathways. There was a selective positive correlation between AL and MWF in the right PHC (r = 0.482, p = 0.007). Thus, our results provide initial in vivo evidence for an association between myelination of the right PHC and PA in young healthy adults. Our results suggest that MWF may not only be more specific, but also more sensitive than FA to detect white matter microstructural alterations. If PA was to induce structural plasticity of the right PHC this may contribute to reverse structural alterations of the right PHC in neuropsychiatric disorder with hippocampal pathologies.

Microsurgical Approaches to the Ambient Cistern Region: An Anatomic and Qualitative Study.

OBJECTIVE: We used microscopy to conduct qualitative and quantitative analysis of 4 surgical approaches commonly used in the surgery of the ambient cistern: infratentorial supracerebellar (SC), occipital interhemispheric, subtemporal (ST), and transchoroidal (TC). In addition, we performed a parahippocampal gyrus resection in the ST context. METHODS: Each approach was performed in 3 cadaveric heads (6 sides). After the microscopic anatomic dissection, the parahippocampal gyrus was resected through an ST approach. The qualitative analysis was based on anatomic observation and the quantitative analysis was based on the linear exposure of vascular structures and the area of exposure of the ambient cistern region. RESULTS: The ST approach provided good exposure of the inferior portion of the cistern and of the proximal segments of the posterior cerebral artery. After the resection of the parahippocampal gyrus, the area of exposure improved in all components, especially the superior area. A TC approach provided the best exposure of the superior area compared with the other approaches. The posterolateral approaches (SC/occipital interhemispheric) to the ambient cistern region provided similar exposure of anatomic structures. There was a significant difference (P < 0.05) in linear exposure of the posterior cerebral artery when comparing the ST/TC and ST/SC approaches. CONCLUSIONS: This study has demonstrated that surgical approaches expose dissimilarly the different regions of the ambient cistern and an approach should be selected based on the specific need of anatomic exposure.

Hippocampal size is related to short-term true and false memory, and right fusiform size is related to long-term true and false memory.

There is a keen interest in identifying specific brain regions that are related to individual differences in true and false memories. Previous functional neuroimaging studies showed that activities in the hippocampus, right fusiform gyrus, and parahippocampal gyrus were associated with true and false memories, but no study thus far has examined whether the structures of these brain regions are associated with short-term and long-term true and false memories. To address that question, the current study analyzed data from 205 healthy young adults, who had valid data from both structural brain imaging and a misinformation task. In the misinformation task, subjects saw the crime scenarios, received misinformation, and took memory tests about the crimes an hour later and again after 1.5 years. Results showed that bilateral hippocampal volume was associated with short-term true and false memories, whereas right fusiform gyrus volume and surface area were associated with long-term true and false memories. This study provides the first evidence for the structural neural bases of individual differences in short-term and long-term true and false memories.

Graph analysis of the anatomical network organization of the hippocampal formation and parahippocampal region in the rat.

Graph theory was used to analyze the anatomical network of the rat hippocampal formation and the parahippocampal region (van Strien et al., Nat Rev Neurosci 10(4):272-282, 2009). For this analysis, the full network was decomposed along the three anatomical axes, resulting in three networks that describe the connectivity within the rostrocaudal, dorsoventral and laminar dimensions. The rostrocaudal network had a connection density of 12% and a path length of 2.4. The dorsoventral network had a high cluster coefficient (0.53), a relatively high path length (1.62) and a rich club was identified. The modularity analysis revealed three modules in the dorsoventral network. The laminar network contained most information. The laminar dimension revealed a network with high clustering coefficient (0.47), a relatively high path length (2.11) and four significantly increased characteristic network building blocks (structural motifs). Thirteen rich club nodes were identified, almost all of them situated in the parahippocampal region. Six connector hubs were detected and all of them were located in the entorhinal cortex. Three large modules were revealed, indicating a close relationship between the perirhinal and postrhinal cortex as well as between the lateral and medial entorhinal cortex. These results confirmed the central position of the entorhinal cortex in the (para)hippocampal network and this possibly explains why pathology in this region has such profound impact on cognitive function, as seen in several brain diseases. The results also have implications for the idea of strict separation of the "spatial" and the "non-spatial" information stream into the hippocampus. This two-stream memory model suggests that the information influx from, respectively, the postrhinal-medial entorhinal cortex and the perirhinal-lateral entorhinal cortex is separate, but the current analysis shows that this apparent separation is not determined by anatomical constraints.

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.