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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., (© 2024 The Authors. Hippocampus published by Wiley Periodicals LLC.)

The hippocampus and parahippocampal gyrus have been implicated as part of a tinnitus network by a number of studies. These structures are usually considered in the context of a "limbic system," a concept typically invoked to explain the emotional response to tinnitus. Despite this common framing, it is not apparent from current literature that this is necessarily the main functional role of these structures in persistent tinnitus. Here, we highlight a different role that encompasses their most commonly implicated functional position within the brain-that is, as a memory system. We consider tinnitus as an auditory object that is held in memory, which may be made persistent by associated activity from the hippocampus and parahippocampal gyrus. Evidence from animal and human studies implicating these structures in tinnitus is reviewed and used as an anchor for this hypothesis. We highlight the potential for the hippocampus/parahippocampal gyrus to facilitate maintenance of the memory of the tinnitus percept via communication with auditory cortex, rather than (or in addition to) mediating emotional responses to this percept., (© 2024 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Parahippocampal cortex (PHC) is a vital neural bases in spatial navigation. However, its functional role is still unclear. "Contextual hypothesis," which assumes that the PHC participates in processing the spatial association between the landmark and destination, provides a potential answer to the question. Nevertheless, the hypothesis was previously tested using the picture categorization task, which is indirectly related to spatial navigation. By now, study is still needed for testing the hypothesis with a navigation-related paradigm. In the current study, we tested the hypothesis by an fMRI experiment in which participants performed a distance estimation task in a virtual environment under three different conditions: landmark free (LF), stable landmark (SL), and ambiguous landmark (AL). By analyzing the behavioral data, we found that the presence of an SL improved the participants' performance in distance estimation. Comparing the brain activity in SL-versus-LF contrast as well as AL-versus-LF contrast, we found that the PHC was activated by the SL rather than by AL when encoding the distance. This indicates that the PHC is elicited by strongly associated context and encodes the landmark reference for distance perception. Furthermore, accessing the representational similarity with the activity of the PHC across conditions, we observed a high similarity within the same condition but low similarity between conditions. This result indicated that the PHC sustains the contextual information for discriminating between scenes. Our findings provided insights into the neural correlates of the landmark information processing from the perspective of contextual hypothesis., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Obstructive sleep apnea (OSA) is associated with abnormal cerebral perfusion at wakefulness, but whether these anomalies evolve over time is unknown. Here, we examined longitudinal changes in regional cerebral blood flow (rCBF) distribution in late middle-aged and older adults with treated or untreated OSA. Twelve controls (64.8 ± 8.0 years) and 23 participants with newly diagnosed OSA (67.8 ± 6.2 years) were evaluated with polysomnography and cerebral 99m Tc-HMPAO single-photon emission computed tomography during wakeful rest. OSA participants were referred to a sleep apnea clinic and 13 of them decided to start continuous positive airway pressure (CPAP). Participants were tested again after 18 months. Voxel-based analysis and extracted relative rCBF values were used to assess longitudinal changes. Untreated OSA participants showed decreased relative rCBF in the left hippocampus and the right parahippocampal gyrus over time, while treated participants showed trends for increased relative rCBF in the left hippocampus and the right parahippocampal gyrus. No changes were found over time in controls. Untreated OSA is associated with worsening relative rCBF in specific brain areas over time, while treated OSA shows the opposite. Considering that OSA possibly accelerates cognitive decline in older adults, CPAP treatment could help reduce risk for cognitive impairment., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Confidence in our retrieved memories, that is, retrospective confidence, is a metamemory process we perform daily. There is an abundance of applied research focusing on the metamemory judgments and very diverse studies including a wide range of clinical populations. However, the neural correlates that support its functioning are not well defined impeding the implementation of noninvasive neuromodulatory clinical interventions. To address the neural basis of metamemory judgments, we ran a meta-analysis, where we used the activation likelihood estimation method on the 19 eligible functional magnetic resonance imaging studies. The main analysis of retrospective confidence revealed concordant bilateral activation in the parahippocampal gyrus, left middle frontal gyrus, and right amygdala. We also run an analysis between the two extreme levels of confidence, namely, high and low. This additional analysis was exploratory, since the minimum amount of articles reporting these two levels was not reached. Activations for the exploratory high > low confidence subtraction analysis were the same as observed in the main analysis on retrospective confidence, whereas the exploratory low > high subtraction showed distinctive activations of the right precuneus. The involvement of the right precuneus emphasizes its role in the evaluation of low confidence memories, as suggested by previous studies. Overall, our study contributes to a better understanding of the specific brain structures involved in confidence evaluations. Better understanding of the neural basis of metamemory might eventually lead to designing more precise neuromodulatory interventions, significantly improving treatment of patients suffering from metamemory problems., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Early course schizophrenia is associated with reduced gray matter. The specific structures affected first and how deficits impact symptoms and cognition remain unresolved. We used the Human Connectome Project multimodal parcellation (HCP-MMP) to precisely identify cortical areas and investigate thickness abnormalities in discovery and replication samples of first-episode schizophrenia spectrum individuals (FESz). In the discovery sample, T1w scans were acquired from 31 FESz and 31 matched healthy controls (HC). Thickness was calculated for 360 regions in Freesurfer. In the replication sample, high-resolution T1w, T2w, and BOLD-rest scans were acquired from 23 FESz and 32 HC and processed with HCP protocols. Thickness was calculated for regions significant in the discovery sample. After FDR correction (q < .05), left and right parahippocampal area 3 (PHA3) were significantly thinner in FESz. In the replication sample, bilateral PHA3 were again thinner in FESz (q < .05). Exploratory correlation analyses revealed left PHA3 was positively associated with hallucinations and right PHA3 was positively associated with processing speed, working memory, and verbal learning. The novel use of the HCP-MMP in two independent FESz samples revealed thinner bilateral PHA3, suggesting this byway between cortical and limbic processing is a critical site of pathology near the emergence of psychosis., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Insomnia disorder is the most common sleep disorder and has drawn increasing attention. Many studies have shown that hyperarousal plays a key role in the pathophysiology of insomnia disorder. However, the specific brain mechanisms underlying insomnia disorder remain unclear. To elucidate the neuropathophysiology of insomnia disorder, we investigated the brain functional networks of patients with insomnia disorder and healthy controls across the sleep-wake cycle. EEG-fMRI data from 33 patients with insomnia disorder and 31 well-matched healthy controls during wakefulness and nonrapid eye movement sleep, including N1, N2 and N3 stages, were analyzed. A medial and anterior thalamic region was selected as the seed considering its role in sleep-wake regulation. The functional connectivity between the thalamic seed and voxels across the brain was calculated. ANOVA with factors "group" and "stage" was performed on thalamus-based functional connectivity. Correlations between the misperception index and altered functional connectivity were explored. A group-by-stage interaction was observed at widespread cortical regions. Regarding the main effect of group, patients with insomnia disorder demonstrated decreased thalamic connectivity with the left amygdala, parahippocampal gyrus, putamen, pallidum and hippocampus across wakefulness and all three nonrapid eye movement sleep stages. The thalamic connectivity in the subcortical cluster and the right temporal cluster in N1 was significantly correlated with the misperception index. This study demonstrated the brain functional basis in insomnia disorder and illustrated its relationship with sleep misperception, shedding new light on the brain mechanisms of insomnia disorder and indicating potential therapeutic targets for its treatment., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

A major focus of Alzheimer's disease (AD) research has been finding sensitive outcome measures to disease progression in preclinical AD, as intervention studies begin to target this population. We hypothesize that tailored measures of longitudinal change of the medial temporal lobe (MTL) subregions (the sites of earliest cortical tangle pathology) are more sensitive to disease progression in preclinical AD compared to standard cognitive and plasma NfL measures. Longitudinal T1-weighted MRI of 337 participants were included, divided into amyloid-β negative (Aβ-) controls, cerebral spinal fluid p-tau positive (T+) and negative (T-) preclinical AD (Aβ+ controls), and early prodromal AD. Anterior/posterior hippocampus, entorhinal cortex, Brodmann areas (BA) 35 and 36, and parahippocampal cortex were segmented in baseline MRI using a novel pipeline. Unbiased change rates of subregions were estimated using MRI scans within a 2-year-follow-up period. Experimental results showed that longitudinal atrophy rates of all MTL subregions were significantly higher for T+ preclinical AD and early prodromal AD than controls, but not for T- preclinical AD. Posterior hippocampus and BA35 demonstrated the largest group differences among hippocampus and MTL cortex respectively. None of the cross-sectional MTL measures, longitudinal cognitive measures (PACC, ADAS-Cog) and cross-sectional or longitudinal plasma NfL reached significance in preclinical AD. In conclusion, longitudinal atrophy measurements reflect active neurodegeneration and thus are more directly linked to active disease progression than cross-sectional measurements. Moreover, accelerated atrophy in preclinical AD seems to occur only in the presence of concomitant tau pathology. The proposed longitudinal measurements may serve as efficient outcome measures in clinical trials., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Natural scenes are inherently structured, with meaningful objects appearing in predictable locations. Human vision is tuned to this structure: When scene structure is purposefully jumbled, perception is strongly impaired. Here, we tested how such perceptual effects are reflected in neural sensitivity to scene structure. During separate fMRI and EEG experiments, participants passively viewed scenes whose spatial structure (i.e., the position of scene parts) and categorical structure (i.e., the content of scene parts) could be intact or jumbled. Using multivariate decoding, we show that spatial (but not categorical) scene structure profoundly impacts on cortical processing: Scene-selective responses in occipital and parahippocampal cortices (fMRI) and after 255 ms (EEG) accurately differentiated between spatially intact and jumbled scenes. Importantly, this differentiation was more pronounced for upright than for inverted scenes, indicating genuine sensitivity to spatial structure rather than sensitivity to low-level attributes. Our findings suggest that visual scene analysis is tightly linked to the spatial structure of our natural environments. This link between cortical processing and scene structure may be crucial for rapidly parsing naturalistic visual inputs., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Background and Purpose: Previous magnetic resonance spectroscopy (MRS) studies have concluded that hippocampal and parahippocampal metabolite concentrations remain stable during healthy adult aging. However, these studies used short repetition times (TR ≤ 2 seconds), which lead to incomplete longitudinal magnetization recovery, and thus, heavily T 1 -weighted measurements. It is important to accurately characterize brain metabolites changes with age to enable appropriate interpretations of MRS findings in the context of neurodegenerative diseases. Our goal was to assess hippocampal brain metabolite concentrations in a large cohort of diversely aged healthy volunteers using a longer TR of 4 seconds., Methods: Left hippocampal MR spectra were collected from 38 healthy volunteers at 3T. Absolute metabolite concentrations were determined for total N-acetyl-aspartate (tNAA), total creatine (tCr), total choline (tCho), glutamate and glutamine (Glx), and myoinositol (mI). Individual partial correlations between each metabolite with age were assessed using demographic information and voxel compartmentation as confounders., Results: Hippocampal tNAA, tCr, tCho, and mI all increased with age (NAA: R 2 = .17, P = .041; tCr: R 2 = .45, P = .0002; tCho: R 2 = .37, P = .001; mI: R 2 = .44, P = .0003). There were no relationships between age and signal to noise ratio, linewidth, or scan date, indicating the correlations were not confounded by spectral quality. Furthermore, we did not observe a trend with age in the voxel tissue compartmentations., Conclusions: We observed increases in hippocampal/parahippocampal metabolite concentrations with age, a finding that is in contrast to previous literature. Our findings illustrate the importance of using a sufficiently long TR in MRS to avoid T 1 -relaxation effects influencing the measurement of absolute metabolite concentrations., (© 2019 by the American Society of Neuroimaging.)

Mental imagery and visual perception rely on the same content-dependent brain areas in the high-level visual cortex (HVC). However, little is known about dynamic mechanisms in these areas during imagery and perception. Here we disentangled local and inter-regional dynamic mechanisms underlying imagery and perception in the HVC and the hippocampus (HC), a key region for memory retrieval during imagery. Nineteen healthy participants watched or imagined a familiar scene or face during fMRI acquisition. The neural code for familiar landmarks and faces was distributed across the HVC and the HC, although with a different representational structure, and generalized across imagery and perception. However, different regional adaptation effects and inter-regional functional couplings were detected for faces and landmarks during imagery and perception. The left PPA showed opposite adaptation effects, with activity suppression following repeated observation of landmarks, but enhancement following repeated imagery of landmarks. Also, functional coupling between content-dependent brain areas of the HVC and HC changed as a function of task and content. These findings provide important information about the dynamic networks underlying imagery and perception in the HVC and shed some light upon the thin line between imagery and perception which has characterized the neuropsychological debates on mental imagery., (© 2019 Wiley Periodicals, Inc.)

Identifying what an object is, and whether an object has been encountered before, is a crucial aspect of human behavior. Despite this importance, we do not yet have a complete understanding of the neural basis of these abilities. Investigations into the neural organization of human object representations have revealed category specific organization in the ventral visual stream in perceptual tasks. Interestingly, these categories fall within broader domains of organization, with reported distinctions between animate, inanimate large, and inanimate small objects. While there is some evidence for category specific effects in the medial temporal lobe (MTL), in particular in perirhinal and parahippocampal cortex, it is currently unclear whether domain level organization is also present across these structures. To this end, we used fMRI with a continuous recognition memory task. Stimuli were images of objects from several different categories, which were either animate or inanimate, or large or small within the inanimate domain. We employed representational similarity analysis (RSA) to test the hypothesis that object-evoked responses in MTL structures during recognition-memory judgments also show evidence for domain-level organization along both dimensions. Our data support this hypothesis. Specifically, object representations were shaped by either animacy, real-world size, or both, in perirhinal and parahippocampal cortex, and the hippocampus. While sensitivity to these dimensions differed across structures when probed individually, hinting at interesting links to functional differentiation, similarities in organization across MTL structures were more prominent overall. These results argue for continuity in the organization of object representations in the ventral visual stream and the MTL., (© 2018 Wiley Periodicals, Inc.)

Navigating through space is fundamental to human nature and requires the ability to retrieve relevant information from the remote past. With the passage of time, some memories become generic, capturing only a sense of familiarity. Yet, others maintain precision, even when acquired decades ago. Understanding the dynamics of memory consolidation is a major challenge to neuroscientists. Using functional magnetic resonance imaging, we systematically examined the effects of time and spatial context on the neural representation of landmark recognition memory. An equal number of male and female subjects (males N = 10, total N = 20) watched a route through a large-scale virtual environment. Landmarks occurred at navigationally relevant and irrelevant locations along the route. Recognition memory for landmarks was tested directly following encoding, 24 h later and 30 days later. Surprisingly, changes over time in the neural representation of navigationally relevant landmarks differed between males and females. In males, relevant landmarks selectively engaged the parahippocampal gyrus (PHG) regardless of the age of the memory. In females, the response to relevant landmarks gradually diminished with time in the PHG but strengthened progressively in the inferior frontal gyrus (IFG). Based on what is known about the functioning of the PHG and IFG, the findings of this study suggest that males maintain access to the initially formed spatial representation of landmarks whereas females become strongly dependent on a verbal representation of landmarks with time. Our findings yield a clear objective for future studies. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Surprisingly little is known about how the brain combines spatial elements to form a coherent percept. Regions that may underlie this process include the hippocampus (HC) and parahippocampal place area (PPA), regions central to spatial perception but whose role in spatial coherency has not been explored. Participants were scanned with functional MRI while they judged whether Escher-like scenes were possible or impossible. Univariate analyses revealed differential HC and PPA involvement, with greater HC activity during spatial incoherency detection and more PPA activity during spatial coherency detection. Recognition and eye-tracking data ruled out long- or short-term memory confounds. Multivariate statistics demonstrated spatial coherency-dependent functional connectivity for the HC, but not PPA, with greater HC connectivity to various brain regions including lateral occipital complex during spatial incoherency detection. We suggest the PPA is preferentially involved during the perception of spatially coherent scenes, whereas the HC binds distinct features to create coherent representations. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The advent of high-resolution magnetic resonance imaging (MRI) has enabled in vivo research in a variety of populations and diseases on the structure and function of hippocampal subfields and subdivisions of the parahippocampal gyrus. Because of the many extant and highly discrepant segmentation protocols, comparing results across studies is difficult. To overcome this barrier, the Hippocampal Subfields Group was formed as an international collaboration with the aim of developing a harmonized protocol for manual segmentation of hippocampal and parahippocampal subregions on high-resolution MRI. In this commentary we discuss the goals for this protocol and the associated key challenges involved in its development. These include differences among existing anatomical reference materials, striking the right balance between reliability of measurements and anatomical validity, and the development of a versatile protocol that can be adopted for the study of populations varying in age and health. The commentary outlines these key challenges, as well as the proposed solution of each, with concrete examples from our working plan. Finally, with two examples, we illustrate how the harmonized protocol, once completed, is expected to impact the field by producing measurements that are quantitatively comparable across labs and by facilitating the synthesis of findings across different studies. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Individuals vary widely in their ability to orient and navigate within the environment. Previous neuroimaging research has shown that hippocampus (HC) and scene-responsive regions (retrosplenial complex [RSC] and parahippocampal gyrus/parahippocampal place area [PPA]) were crucial for spatial orienting and navigation. Resting-state functional connectivity and a self-reported questionnaire of navigational ability were used to examine the hypothesis that the pattern of reciprocal connections between these regions reflects individual differences in spatial navigation. It was found that the functional connectivity between the posterior HC and RSC was significantly higher in good than in poor navigators. These results confirmed the crucial role of hippocampal and extra-hippocampal regions in spatial navigation and provided new insight into how spontaneous brain activity may account for individual differences in spatial ability. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Recent studies have reported memory deficits and reduced hippocampal volumes in posttraumatic stress disorder (PTSD). The goal of the current research was to use functional neuroimaging and a validated explicit memory paradigm to examine hippocampal function in PTSD. We used positron emission tomography (PET) and a word-stem completion task to study regional cerebral blood flow (rCBF) in the hippocampus in 16 firefighters: 8 with PTSD (PTSD group) and 8 without PTSD (Control group). During PET scanning, participants viewed three-letter word stems on a computer screen and completed each stem with a word they had previously encoded either deeply (High Recall condition) or shallowly (Low Recall condition). Relative to the Control group, the PTSD group exhibited significantly smaller rCBF increases in the left hippocampus in the High vs Low Recall comparison. However, this finding reflected relatively elevated rCBF in the Low Recall condition in the PTSD group. Collapsing across High and Low Recall conditions, (1) the PTSD group had higher rCBF in bilateral hippocampus and left amygdala than the Control group, and (2) within the PTSD group, symptom severity was positively associated with rCBF in hippocampus and parahippocampal gyrus. The groups did not significantly differ with regard to accuracy scores on the word-stem completion task. The PTSD group had significantly smaller right (and a trend for smaller left) hippocampal volumes than the Control group. The results suggest an abnormal rCBF response in the hippocampus during explicit recollection of nonemotional material in firefighters with PTSD, and that this abnormal response appears to be driven by relatively elevated hippocampal rCBF in the comparison condition.

Past neuroimaging research has identified a parahippocampal place area (PPA) in the posterior medial temporal lobe (MTL), which responds preferentially to visual scenes and plays a role in episodic memory for this class of stimuli. In the present positron emission tomography study, we examined to what extent the functional characteristics of the PPA resemble those of other, more anterior MTL regions across various learning and recognition-memory tasks. We also determined whether the involvement of the PPA in recognition of previously studied scenes is specific to a particular type of scene information. We found that, like the PPA, anterior hippocampal regions showed a novelty response (higher activation for novel than repeated scenes) and a stimulus-related response (higher activation for scenes than objects) during learning, indicating that MTL structures other than the PPA contribute to the encoding of novel stimulus relationships in scenes. However, these anterior hippocampal regions showed no involvement during recognition of either spatial or nonspatial information contained in scenes. The PPA, by contrast, was consistently involved in recognition of all types of scene details, presumably through interactions with co-activated parietal and occipitotemporal cortices. We suggest that MTL contributions from the PPA are sufficient to support recognition of scenes when the task can be based on a perceptually based familiarity process.