The posterior parahippocampal gyrus (PPHG) of the non-human primate brain has a distinct dual role in cortical neural systems. On the one hand, it is a critical link in providing the entorhinal cortex and hippocampal formation with cortical input, while on the other hand it receives output from these structures and projects widely by disseminating the medial temporal lobe output to the cortex. Layer III of TF and TH areas largely mediate the former (input) while layer V mediates the latter (output). We have examined areas TF and TH in the normal human brain and in Alzheimer's disease (AD) using pathological stains (Nissl, Thioflavin S) and phenotype specific stains non-phosphorylated neurofilament protein (SMI32) and parvalbumin (PV). Seven clinically and pathologically confirmed AD cases have been studied along with six age-compatible normal cases. Our observations reveal that neurofibrillary tangles (NFTs) heavily invest the area TF and TH neurons that form layers III and V. In both cortical areas, the large pyramids that form layer V contain a greater number of NFTs. These changes, and possibly, pyramidal cell loss, greatly alter the cytoarchitectural picture and diminish SMI32 staining patterns. Layer III of area TH loses the majority of SMI32 immunoreactivity, whereas this change is more conspicuous in layer V of area TF. PV-staining in both areas is largely unaffected. Normal cases contained no evidence of pathology or altered cytoarchitecture. These observations reveal a further disruption of memory-related temporal neural systems in AD where pathology selectively alters both the input to the hippocampal formation and its output to the cortex.

Alzheimer's disease (AD) is the most common form of dementia worldwide, with a projection of 151 million cases by 2050. Previous genetic studies have identified three main genes associated with early-onset familial Alzheimer's disease, however this subtype accounts for less than 5% of total cases. Next-generation sequencing has been well established and holds great promise to assist in the development of novel therapeutics as well as biomarkers to prevent or slow the progression of this devastating disease. Here we present a public resource of functional genomic data from the parahippocampal gyrus of 201 postmortem control, mild cognitively impaired (MCI) and AD individuals from the Mount Sinai brain bank, of which whole-genome sequencing (WGS), and bulk RNA sequencing (RNA-seq) were previously published. The genomic data include bulk proteomics and DNA methylation, as well as cell-type-specific RNA-seq and assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) data. We have performed extensive preprocessing and quality control, allowing the research community to access and utilize this public resource available on the Synapse platform at https://doi.org/10.7303/syn51180043.2 .

It has been proposed that behavior is influenced by representations of different types of knowledge: action representations, event knowledge, attitudes and stereotypes. Attitudes (representations of a concept or object and its emotional evaluation) allow us to respond quickly to a given stimulus. In this study, we explored the representation and inhibition of attitudes. We show that right dorsolateral prefrontal cortex mediates negative attitudes whereas left ventrolateral prefrontal cortex mediates positive attitudes. Parahippocampal regions and amygdala mediate evaluative processing. Furthermore, anxiety modulates right dorsolateral prefrontal activation during negative attitude processing. Inhibition of negative attitudes activates left orbitofrontal cortex: a region that when damaged is associated with socially inappropriate behavior in patients. Inhibition of positive attitudes activates a brain system involving right inferior frontal gyrus and bilateral anterior cingulate. Thus, we show that there are dissociable networks for the representation and inhibition of attitudes.

Atrophy in the medial temporal lobe is generally considered to be highly associated with age-related memory decline. Volume loss in the hippocampus and entorhinal cortex has extensively been investigated, but the posterior parts of the parahippocampal gyrus have received little attention. The present MRI study investigated whether volume differences in medial temporal lobe areas are differentially related to age-related memory decline. Thirty-nine subjects from a longitudinal study on cognitive aging (the Maastricht Aging Study) have been examined: 20 participants (mean age=67 years, range 52-80) with memory decline over a period of 12 years were matched to 19 participants without memory decline. Manual tracing was performed on 3T MR images to measure the volumes of the anterior, middle and posterior parts of the hippocampus and parahippocampal gyrus. A robust group difference and a significant association with memory decline were observed only in the posterior part of the parahippocampal gyrus. Our results may suggest that the posterior parahippocampal gyrus plays a key role in age-related memory decline.

Neuropathological abnormalities in schizophrenia have been demonstrated in the parahippocampal gyrus (PHG). Only a few studies on first-episode neuroleptic-naive schizophrenia patients have been done using in vivo neuroimaging techniques. The authors examined the PHG morphology using structural MRI in neuroleptic-naive subjects with first episode psychoses. Volumetric measurements of PHG and intracranial volume (ICV) were obtained on subjects with schizophrenia and schizoaffective disorders (SCZ; n = 33), nonschizophrenia psychotic disorders (NSCZ; n = 11) and matched healthy subjects (HS; n = 43). The subjects were rated on the Brief Psychiatric Rating Scale (BPRS). Group differences and clinical correlations of ICV-adjusted PHG volumes were examined. Left PHG was significantly different across the groups consisting of SCZ, NSCZ and HS. PHG was larger in NSCZ compared to SCZ but not relative to HS. Bilaterally, PHG was no different between SCZ and HS. In pooled psychotic patients, the PHG volume negatively correlated with total positive symptom, delusion and conceptual disorganization scores on BPRS. Patients with delusions had relatively smaller PHG compared to nondelusional subjects. Observed differences in PHG volume in first-episode neuroleptic-naive patients suggest that these observations are not confounded by illness chronicity or medication effects. Significant association of PHG volume with psychotic symptoms suggests that PHG pathology plays an important role in the etiopathology of psychosis and its symptoms.

Brain entropy reveals complexity and irregularity of brain, and it has been proven to reflect brain complexity alteration in disease states. Previous studies found that bipolar disorder adolescents showed cognitive impairment. The relationship between complexity of brain neural activity and cognition of bipolar II disorder (BD-II) adolescents remains unclear.

The default-mode network (DMN) is a distributed functional-anatomic network implicated in supporting memory. Current resting-state functional connectivity studies in humans remain divided on the exact involvement of medial temporal lobe (MTL) in this network at rest. Notably, it is unclear to what extent the MTL regions involved in successful memory encoding are connected to the cortical nodes of the DMN during resting state. Our findings using functional connectivity MRI analyses of resting-state data indicate that the parahippocampal gyrus (PHG) is the primary hub of the DMN in the MTL during resting state. Also, connectivity of the PHG is distinct from connectivity of hippocampal regions identified by an associative memory-encoding task. We confirmed that several hippocampal encoding regions lack significant functional connectivity with cortical DMN nodes during resting state. Additionally, a mediation analysis showed that resting-state connectivity between the hippocampus and posterior cingulate cortex--a major hub of the DMN--is indirect and mediated by the PHG. Our findings support the hypothesis that the MTL memory system represents a functional subnetwork that relates to the cortical nodes of the DMN through parahippocampal functional connections.

Problematic mobile phone use (PMPU) is prevalent and increases the risk for a variety of health problems. However, few studies have explored the neural mechanisms that might render adolescents more or less vulnerable. Here, we aimed to identify whether PMPU is associated with depressive symptoms and whether this relationship is moderated by intrinsic functional connectivity (iFC) which is associated with PMPU.

Understanding the neural mechanisms underlying Internet gaming disorder (IGD) is essential for the condition's diagnosis and treatment. Nevertheless, the pathological mechanisms of IGD remain elusive at present. Hence, we employed multi-voxel pattern analysis (MVPA) and spectral dynamic causal modeling (spDCM) to explore this issue.

Human ventral occipital temporal cortex contains clusters of neurons that show domain-preferring responses during visual perception. Recent studies have reported that some of these clusters show surprisingly similar domain selectivity in congenitally blind participants performing nonvisual tasks. An important open question is whether these functional similarities are driven by similar innate connections in blind and sighted groups. Here we addressed this question focusing on the parahippocampal gyrus (PHG), a region that is selective for large objects and scenes. Based on the assumption that patterns of long-range connectivity shape local computation, we examined whether domain selectivity in PHG is driven by similar structural connectivity patterns in the two populations. Multiple regression models were built to predict the selectivity of PHG voxels for large human-made objects from white matter (WM) connectivity patterns in both groups. These models were then tested using independent data from participants with similar visual experience (two sighted groups) and using data from participants with different visual experience (blind and sighted groups). Strikingly, the WM-based predictions between blind and sighted groups were as successful as predictions between two independent sighted groups. That is, the functional selectivity for large objects of a PHG voxel in a blind participant could be accurately predicted by its WM pattern using the connection-to-function model built from the sighted group data, and vice versa. Regions that significantly predicted PHG selectivity were located in temporal and frontal cortices in both sighted and blind populations. These results show that the large-scale network driving domain selectivity in PHG is independent of vision.SIGNIFICANCE STATEMENT Recent studies have reported intriguingly similar domain selectivity in sighted and congenitally blind individuals in regions within the ventral visual cortex. To examine whether these similarities originate from similar innate connectional roots, we investigated whether the domain selectivity in one population could be predicted by the structural connectivity pattern of the other. We found that the selectivity for large objects of a PHG voxel in a blind participant could be predicted by its structural connectivity pattern using the connection-to-function model built from the sighted group data, and vice versa. These results reveal that the structural connectivity underlying domain selectivity in the PHG is independent of visual experience, providing evidence for nonvisual representations in this region.

Structural changes in limbic regions are often observed in individuals with temporal lobe epilepsy (TLE) and in animal models. However, the brain structural changes during the evolution into epilepsy remain largely unknown. Therefore, the purpose of this study was to define the temporal changes in limbic structures after experimental status epilepticus (SE) during the latency period of epileptogenesis in vivo, with quantitative diffusion tensor imaging (DTI) and T2 relaxometry in an animal model of chronic TLE. A pair of fifty micron electrodes was implanted into the ventral hippocampus in twelve male adult rats. Self-sustaining SE was induced with electrical stimulation in eleven rats. Three rats served as age-matched controls. In vivo diffusion tensor and T2 magnetic resonance imaging (MRI) was performed at 11.1 Tesla, pre- and post-implantation of electrodes and 3, 5, 7, 10, 20, 40 and 60 days post-SE to assess structural changes. Spontaneous seizures were identified with continuous time-locked video-monitoring. Following imaging in vivo, fixed, excised brains were MR imaged at 17.6 Tesla. Subsequently, histological analysis was correlated with MRI results. Following SE, 8/11 injured rats developed spontaneous seizures. Unique to these 8 rats, early T2, diffusivity and anisotropy changes were observed in vivo within the parahippocampal gyrus (contralateral) and fimbria (bilateral). In excised brains, bilateral increase in anisotropy was observed in the dentate gyrus, corresponding to mossy fiber sprouting as determined by Timm staining. Using T2 relaxometry and DTI, specific transient and long-term structural changes were observed only in rats that developed spontaneous limbic seizures.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to effectively improve impaired swallowing in Parkinson's disease (PD) patients with dysphagia. However, little is known about how rTMS affects the corresponding brain regions in this patient group. In this case-control study, we examined data from 38 PD patients with dysphagia who received treatment at Beijing Rehabilitation Medicine Academy, Capital Medical University. The patients received high-frequency rTMS of the motor cortex once per day for 10 successive days. Changes in brain activation were compared via functional magnetic resonance imaging in PD patients with dysphagia and healthy controls. The results revealed that before treatment, PD patients with dysphagia showed greater activation in the precentral gyrus, supplementary motor area, and cerebellum compared with healthy controls, and this enhanced activation was weakened after treatment. Furthermore, before treatment, PD patients with dysphagia exhibited decreased activation in the parahippocampal gyrus, caudate nucleus, and left thalamus compared with healthy controls, and this activation increased after treatment. In addition, PD patients with dysphagia reported improved subjective swallowing sensations after rTMS. These findings suggest that swallowing function in PD patients with dysphagia improved after rTMS of the motor cortex. This may have been due to enhanced activation of the caudate nucleus and parahippocampal gyrus. The study protocol was approved by the Ethics Committee of Beijing Rehabilitation Hospital of Capital Medical University (approval No. 2018bkky017) on March 6, 2018 and was registered with Chinese Clinical Trial Registry (registration No. ChiCTR 1800017207) on July 18, 2018.

A large body of literature links risk of cognitive decline, mild cognitive impairment (MCI) and dementia with Type 2 Diabetes (T2D) or pre-diabetes. Accumulating evidence implicates a close relationship between the brain insulin receptor signaling pathway (IRSP) and the accumulation of amyloid beta and hyperphosphorylated and conformationally abnormal tau. We showed previously that the neuropathological features of Alzheimer's disease (AD were reduced in patients with diabetes who were treated with insulin and oral antidiabetic medications. To understand better the neurobiological substrates of T2D and T2D medications in AD, we examined IRSP and endothelial cell markers in the parahippocampal gyrus of controls (N = 30), of persons with AD (N = 19), and of persons with AD and T2D, who, in turn, had been treated with anti-diabetic drugs (insulin and or oral agents; N = 34). We studied the gene expression of selected members of the IRSP and selective endothelial cell markers in bulk postmortem tissue from the parahippocampal gyrus and in endothelial cell enriched isolates from the same brain region. The results indicated that there are considerable abnormalities and reductions in gene expression (bulk tissue homogenates and endothelial cell isolates) in the parahippocampal gyri of persons with AD that map directly to genes associated with the microvasculature and the IRSP. Our results also showed that the numbers of abnormally expressed microvasculature and IRSP associated genes in diabetic AD donors who had been treated with anti-diabetic agents were reduced significantly. These findings suggest that anti-diabetic treatments may reduce or normalize compromised microvascular and IRSP functions in AD.

Current treatments for Alzheimer's disease are only symptomatic and limited to reduce the progression rate of the mental deterioration. Mild Cognitive Impairment, a transitional stage in which the patient is not cognitively normal but do not meet the criteria for specific dementia, is associated with high risk for development of Alzheimer's disease. Thus, non-invasive techniques to predict the individual's risk to develop Alzheimer's disease can be very helpful, considering the possibility of early treatment. Diffusion Tensor Imaging, as an indicator of cerebral white matter integrity, may detect and track earlier evidence of white matter abnormalities in patients developing Alzheimer's disease. Here we performed a voxel-based analysis of fractional anisotropy in three classes of subjects: Alzheimer's disease patients, Mild Cognitive Impairment patients, and healthy controls. We performed Support Vector Machine classification between the three groups, using Fisher Score feature selection and Leave-one-out cross-validation. Bilateral intersection of hippocampal cingulum and parahippocampal gyrus (referred as parahippocampal cingulum) is the region that best discriminates Alzheimer's disease fractional anisotropy values, resulting in an accuracy of 93% for discriminating between Alzheimer's disease and controls, and 90% between Alzheimer's disease and Mild Cognitive Impairment. These results suggest that pattern classification of Diffusion Tensor Imaging can help diagnosis of Alzheimer's disease, specially when focusing on the parahippocampal cingulum.

Neuropathology suggests an important role for the locus coeruleus (LC) in Alzheimer's disease (AD) pathophysiology. Neuropathology and structural damage in the LC appears to be one of the earliest changes. We hypothesize that reduced functional integration of the LC reflected by lower brain functional connectivity contributes to early memory dysfunction. To test this, we examined resting-state functional connectivity from the LC in 18 healthy older individuals and 18 mildly cognitively impaired patients with possible AD. Connectivity measures were correlated with memory scores. The left LC showed strong connectivity to the left parahippocampal gyrus that correlated with memory performance in healthy persons. This connectivity was reduced in aMCI patients. Lateralization of connectivity-memory correlations was altered in less impaired aMCI patients: greater right LC-left parahippocampal gyrus connectivity was associated with better memory performance, in particular for encoding. Our results provide new evidence that the LC, in interaction with the parahippocampal gyrus, may contribute to episodic memory formation. They suggest functional impairment and the possibility that associated compensatory changes contribute to preserved memory functions in early AD. Structural and functional LC-related measures may provide early AD markers.

There is evidence that brain cholesterol metabolism modulates the vulnerability for Alzheimer's disease (AD). Previous data showed that brain β-amyloid load in elderly subjects with the CYP46 (cholesterol 24S-hydroxylase) TT-positive genotype was higher than in CYP46 TT-negative elderly subjects. We investigated effects of the CYP46 T/C polymorphism on parahippocampal and hippocampal grey matter (GM) morphology in 81 young subjects using structural magnetic resonance imaging based morphometry. We found that young TT-homozygotes exhibited smallest and CC-homozygotes largest parahippocampal and hippocampal GM volumes with the volumes of the CT-heterozygotes ranging in between. Parahippocampal and hippocampal volumes were positively correlated with delayed memory performance in C-carriers and negatively with immediate memory performance in TT-homozygotes. It has been shown that the brain cholesterol metabolism in general modulates dendrite outgrowth, synaptogenesis, and neuron survival, and it was suggested that CYP46 indirectly influences β-amyloid metabolism. CYP46 C-carriers are privileged both in terms of β-amyloid metabolism and in terms of brain reserve due to their larger parahippocampal and hippocampal structures. The exact cellular mechanisms that translate the CYP46 allelic variation into volumetric brain differences in the parahippocampal gyrus and hippocampus are still unknown and need to be further investigated.

The resurgent Na(+) current (I(NaR)) is a component of neuronal voltage-dependent Na(+) currents that is activated by repolarization and is believed to result from an atypical path of Na(+)-channel recovery from inactivation. So far, I(NaR) has only been identified in a small number of central neuronal populations in the cerebellum, diencephalon, and brainstem. The possible presence and roles of I(NaR) in neurons of the cerebral cortex and temporal-lobe memory system are still uncharacterized. In this study whole-cell, patch-clamp experiments were carried out in acute rat brain slices to investigate I(NaR) expression and properties in several neuronal populations of the parahippocampal region and hippocampal formation. Specifically, we examined pyramidal neurons of perirhinal cortex areas 36 and 35 (layers II and V); neurons of superficial and deep layers of medial entorhinal cortex (mEC); dentate gyrus (DG) granule cells; and pyramidal cells of the CA3 and CA1 hippocampal fields. I(NaR) was found to be thoroughly expressed in parahippocampal cortices. The most consistent and prominent I(NaR) expression was observed in mEC layer-II cells. A vast majority of areas 36 and 35 neurons (both in layers II and V) and mEC layer-III and -V neurons were also endowed with I(NaR), although at lower amplitude levels. I(NaR) was expressed by approximately 60% of DG granule cells and approximately 35% of CA1 pyramidal cells of the ventral hippocampus, whereas it was never observed in CA3 neurons (both in the ventral and dorsal hippocampus) and CA1 neurons of the dorsal hippocampus. The biophysical properties of I(NaR) were very similar in all of the neuronal types in which the current was observed, with a peak in the current-voltage relationship at -35/-40 mV. Our results show that the parahippocampal region and part of the hippocampal formation are sites of major I(NaR) expression, and provide a new basis for further studies on the molecular correlates of I(NaR).

Brain areas at the parahippocampal gyrus of the temporal-occipital transition region are involved in different functions including processing visual-spatial information and episodic memory. Results of neuroimaging experiments have revealed a differentiated functional parcellation of this region, but its microstructural correlates are less well understood. Here we provide probability maps of four new cytoarchitectonic areas, Ph1, Ph2, Ph3 and CoS1 at the parahippocampal gyrus and collateral sulcus. Areas have been identified based on an observer-independent mapping of serial, cell-body stained histological sections of ten human postmortem brains. They have been registered to two standard reference spaces, and superimposed to capture intersubject variability. The comparison of the maps with functional imaging data illustrates the different involvement of the new areas in a variety of functions. Maps are available as part of Julich-Brain atlas and can be used as anatomical references for future studies to better understand relationships between structure and function of the caudal parahippocampal cortex.

Context sometimes helps make objects more recognizable. Previous studies using functional magnetic resonance imaging (fMRI) have examined regional neural activity when objects have strong or weak associations with their contexts. Such studies have demonstrated that activity in the parahippocampal cortex (PHC) generally corresponds with strong associations between objects and their spatial contexts while retrosplenial cortex (RSC) activity is linked with episodic memory. However these studies investigated objects viewed in associated contexts, but the direct influence of scene on the perception of visual objects has not been widely investigated. We hypothesized that the PHC and RSC may only be engaged for congruent contexts in which the object could typically be found but not for neutral contexts. While in an fMRI scanner, 15 participants rated the recognizability of 152 photographic images of objects, presented within congruent and incongruent contexts. Regions of interest were created to examine PHC and RSC activity using a hypothesis-driven approach. Exploratory analyses were also performed to identify other regional activity. In line with previous studies, PHC and RSC activity emerged when objects were viewed in congruent contexts. Activity in the RSC, inferior parietal lobe (IPL) and fusiform gyrus also emerged. These findings indicate that different brain regions are employed when objects are meaningfully contextualized.

The "parahippocampal place area" (PPA) in the human ventral visual stream exhibits increased hemodynamic activity correlated with the perception of landscape photos compared to faces or objects. Here, we investigate the perception of scene-related, spatial information embedded in two naturalistic stimuli. The same 14 participants were watching a Hollywood movie and listening to its audio-description as part of the open-data resource studyforrest.org. We model hemodynamic activity based on annotations of selected stimulus features, and compare results to a block-design visual localizer. On a group level, increased activation correlating with visual spatial information occurring in the movie is overlapping with a traditionally localized PPA. Activation correlating with semantic spatial information occurring in the audio-description is more restricted to the anterior PPA. On an individual level, we find significant bilateral activity in the PPA of nine individuals and unilateral activity in one individual. Results suggest that activation in the PPA generalizes to spatial information embedded in a movie and an auditory narrative, and may call for considering a functional subdivision of the PPA.