Posterior Entorhinal Cortex Research Articles

Entorhinal vessel density correlates with phosphorylated tau and TDP-43 pathology.

The entorhinal cortex (EC) and perirhinal cortex (PC) are vulnerable to Alzheimer's disease. A triggering factor may be the interaction of vascular dysfunction and tau pathology. We imaged post mortem human tissue at 100 μm3 with 7 T magnetic resonance imaging and manually labeled individual blood vessels (mean=270 slices/case). Vessel density was quantified and compared perEC subfield, between EC and PC, and in relation to tau and TAR DNA-binding protein 43 (TDP-43) semiquantitative scores. PC was more vascularized than EC and vessel densities were higher in posterior EC subfields. Tau and TDP-43 strongly correlated with vasculature density and subregions with severe tau at the preclinical stage had significantly greater vessel density than those with low tau burden. These data impact cerebrovascular maps, quantification of subfield vasculature, and correlation of vasculature and pathology at early stages. The ordered association of vessel density, and tau or TDP-43 pathology, may be exploited in a predictive context. Vessel density correlates with phosphorylated tau (p-tau) burden in entorhinal and perirhinal cortices. Perirhinal area 35 and posterior entorhinal cortex showed greatest p-tau burden but also the highest vessel density in the preclinical phase of Alzheimer's disease. We combined an ex vivo magnetic resonance imaging model and histopathology to demonstrate the 3D reconstruction of intracortical vessels and its spatial relationship to the pathology.

Evidence for allocentric boundary and goal direction information in the human entorhinal cortex and subiculum

In rodents, cells in the medial entorhinal cortex (EC) and subiculum code for the allocentric direction to environment boundaries, which is an important prerequisite for accurate positional coding. Although in humans boundary-related signals have been reported, there is no evidence that they contain allocentric direction information. Furthermore, it has not been possible to separate boundary versus goal direction signals in the EC/subiculum. Here, to address these questions, we had participants learn a virtual environment containing four unique boundaries. Participants then underwent fMRI scanning where they made judgements about the allocentric direction of a cue object. Using multivariate decoding, we found information regarding allocentric boundary direction in posterior EC and subiculum, whereas allocentric goal direction was decodable from anterior EC and subiculum. These data provide the first evidence of allocentric boundary coding in humans, and are consistent with recent conceptualisations of a division of labour within the EC.

Cerebral perfusion mapping during retrieval of spatial memory in rats

Studies of brain functional activation during spatial navigation using electrophysiology and immediate-early gene responses have typically targeted a limited number of brain regions. Our study provides the first whole brain analysis of cerebral activation during retrieval of spatial memory in the freely-moving rat. Rats (LEARNERS) were trained in the Barnes maze, an allocentric spatial navigation task, while CONTROLS received passive exposure. After 19 days, functional brain mapping was performed during recall by bolus intravenous injection of [14C]-iodoantipyrine using a novel subcutaneous minipump triggered by remote activation. Regional cerebral blood flow (rCBF)-related tissue radioactivity was analyzed by statistical parametric mapping from autoradiographic images of the three-dimensionally reconstructed brains. Functional connectivity was examined between regions of the spatial navigation circuit through interregional correlation analysis.Significant rCBF increases were noted in LEARNERS compared to CONTROLS broadly across the spatial navigation circuit, including the hippocampus (anterior dorsal CA1, posterior ventral CA1-3), subiculum, thalamus, striatum, medial septum, cerebral cortex, with decreases noted in the mammillary nucleus, amygdala and insula. LEARNERS showed a significantly greater positive correlation of rCBF of the ventral hippocampus with retrosplenial, lateral orbital, parietal and primary visual cortex, and a significantly more negative correlation with the mammillary nucleus, amygdala, posterior entorhinal cortex, and anterior thalamic nucleus. The complex sensory component of the spatial navigation task was underscored by broad activation across visual, somatosensory, olfactory, auditory and vestibular circuits which was enhanced in LEARNERS. Brain mapping facilitated by an implantable minipump represents a powerful tool for evaluation of mammalian behaviors dependent on locomotion.

Clock drawing test in mild cognitive impairment: Correlation with cerebral perfusion in single-photon emission computed tomography.

This study aimed to understand the relationship between the Clock Drawing Test (CDT) and decreased blood flow in mild cognitive impairment (MCI) patients, using single-photon emission computed tomography. We characterized regional cerebral blood flow (rCBF) and the correlation with clinical variables and future conversion to dementia in 94 amnestic MCI patients. Blood perfusion data was correlated with the CDT (quantitative and qualitative scores) in order to evaluate their relationship and usefulness in predicting conversion to dementia. MCI patients displayed reduced rCBF in brain areas including the caudate nucleus; the frontal, parietal, and temporal lobes; as well as the cerebral cortex and cerebellum. The decrease in rCBF was higher for patients who later developed dementia. At baseline, CDT scores of these patients correlated with hypoperfusion in cortical and subcortical areas typically affected in Alzheimer's disease (AD) median 3 years before developing dementia. CDT total score was significantly correlated with rCBF in the left temporal lobe and the putamen; the analysis of rCBF in Brodmann areas showed significant correlations between the several clock elements (face, numbers, and hands), underlying qualitative errors (stimulus-bound response and conceptual deficit), and rCBF, most significantly in the left inferior temporal gyrus, posterior entorhinal cortex, posterior cingulate cortex, left parahippocampal cortex, and left inferior prefrontal gyrus. This study showed that a quantitative score and a qualitative assessment of clock drawing (error analysis) corresponded to dysfunction in AD key areas at an early stage, supporting the CDT utility in the detection of prodromal AD. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Entorhinal Tau Pathology, Episodic Memory Decline, and Neurodegeneration in Aging.

The medial temporal lobe (MTL) is an early site of tau accumulation and MTL dysfunction may underlie episodic-memory decline in aging and dementia. Postmortem data indicate that tau pathology in the transentorhinal cortex is common by age 60, whereas spread to neocortical regions and worsening of cognition is associated with β-amyloid (Aβ). We used [18F]AV-1451 and [11C]PiB positron emission tomography, structural MRI, and neuropsychological assessment to investigate how in vivo tau accumulation in temporal lobe regions, Aβ, and MTL atrophy contribute to episodic memory in cognitively normal older adults (n = 83; age, 77 ± 6 years; 58% female). Stepwise regressions identified tau in MTL regions known to be affected in old age as the best predictor of episodic-memory performance independent of Aβ status. There was no interactive effect of MTL tau with Aβ on memory. Higher MTL tau was related to higher age in the subjects without evidence of Aβ. Among temporal lobe subregions, episodic memory was most strongly related to tau-tracer uptake in the parahippocampal gyrus, particularly the posterior entorhinal cortex, which in our parcellation includes the transentorhinal cortex. In subjects with longitudinal MRI and cognitive data (n = 57), entorhinal atrophy mirrored patterns of tau pathology and their relationship with memory decline. Our data are consistent with neuropathological studies and further suggest that entorhinal tau pathology underlies memory decline in old age even without Aβ.SIGNIFICANCE STATEMENT Tau tangles and β-amyloid (Aβ) plaques are key lesions in Alzheimer's disease (AD) but both pathologies also occur in cognitively normal older people. Neuropathological data indicate that tau tangles in the medial temporal lobe (MTL) underlie episodic-memory impairments in AD dementia. However, it remains unclear whether MTL tau pathology also accounts for memory impairments often seen in elderly people and how Aβ affects this relationship. Using tau-specific and Aβ-specific positron emission tomography tracers, we show that in vivo MTL tau pathology is associated with episodic-memory performance and MTL atrophy in cognitively normal adults, independent of Aβ. Our data point to MTL tau pathology, particularly in the entorhinal cortex, as a substrate of age-related episodic-memory loss.

Effects of exercise on brain activity during walking in older adults: a randomized controlled trial

BackgroundPhysical activity may preserve neuronal plasticity, increase synapse formation, and cause the release of hormonal factors that promote neurogenesis and neuronal function. Previous studies have reported enhanced neurocognitive function following exercise training. However, the specific cortical regions activated during exercise training remain largely undefined. In this study, we quantitatively and objectively evaluated the effects of exercise on brain activity during walking in healthy older adults.MethodsA total of 24 elderly women (75–83 years old) were randomly allocated to either an intervention group or a control group. Those in the intervention group attended 3 months of biweekly 90-min sessions focused on aerobic exercise, strength training, and physical therapy. We monitored changes in regional cerebral glucose metabolism during walking in both groups using positron emission tomography (PET) and [18F]fluorodeoxyglucose (FDG).ResultsAll subjects completed the 3-month experiment and the adherence to the exercise program was 100%. Compared with the control group, the intervention group showed a significantly greater step length in the right foot after 3 months of physical activity. The FDG-PET assessment revealed a significant post-intervention increase in regional glucose metabolism in the left posterior entorhinal cortex, left superior temporal gyrus, and right superior temporopolar area in the intervention group. Interestingly, the control group showed a relative increase in regional glucose metabolism in the left premotor and supplemental motor areas, left and right somatosensory association cortex, and right primary visual cortex after the 3-month period. We found no significant differences in FDG uptake between the intervention and control groups before vs. after the intervention.ConclusionExercise training increased activity in specific brain regions, such as the precuneus and entorhinal cortices, which play an important role in episodic and spatial memory. Further investigation is required to confirm whether alterations in glucose metabolism within these regions during walking directly promote physical and cognitive performance.Trial registrationUMIN-CTR (UMIN000021829). Retrospectively registered 10 April 2016.

Saccade direction encoding in the primate entorhinal cortex during visual exploration

We recently demonstrated that position in visual space is represented by grid cells in the primate entorhinal cortex (EC), suggesting that visual exploration of complex scenes in primates may employ signaling mechanisms similar to those used during exploration of physical space via movement in rodents. Here, we describe a group of saccade direction (SD) cells that encode eye movement information in the monkey EC during free-viewing of complex images. Significant saccade direction encoding was found in 20% of the cells recorded in the posterior EC. SD cells were generally broadly tuned and two largely separate populations of SD cells encoded future and previous saccade direction. Some properties of these cells resemble those of head-direction cells in rodent EC, suggesting that the same neural circuitry may be capable of performing homologous spatial computations under different exploratory contexts.

From details to large scale: the representation of environmental positions follows a granularity gradient along the human hippocampal and entorhinal anterior-posterior axis.

In rodents representations of environmental positions follow a granularity gradient along the hippocampal and entorhinal anterior-posterior axis; with fine-grained representations most posteriorly. To investigate if such a gradient exists in humans, functional magnetic resonance imaging data were acquired during virtual environmental learning of the objects' positions and the association between the objects and room geometry. The Objects-room geometry binding led to increased activation throughout the hippocampus and in the posterior entorhinal cortex. Within subject comparisons related specifically to the level of spatial granularity of the object position encoding showed that activation in the posterior and intermediate hippocampus was highest for fine-grained and medium-grained representations, respectively. In addition, the level of fine granularity in the objects' positions encoded between subjects correlated with posterior hippocampal activation. For the anterior hippocampus increased activation was observed for coarse-grained representations as compared to failed encoding. Activation in anterior hippocampus correlated with the number of environments in which the objects positions were remembered when permitting a coarse representation of positions. In the entorhinal cortex, activation in the posterior part correlated with level of fine granularity for the objects' positions encoded between subjects, and activation in the posterior and intermediate entorhinal cortex increased for medium-grained representations. This demonstrates directly that positional granularity is represented in a graded manner along the anterior-posterior axis of the human hippocampus, and to some extent entorhinal cortex, with most fine-grained positional representations posteriorly.

Impact of stress and trauma on childhood brain reactivity to emotion faces

R = right side, L = left side PEC = posterior entorhinal cortex; ACC = anterior cingulate cortex; BA = Brodmann area *p<.05; **p<.01  1Luby, J.L. et al. (2006). Risk factors for preschool depression: the mediating role of early stressful life events. J Child Psychol Psychiatry, 47, 1292-1298.  2Luby, J.L. et al. (2009). Preschool depression: Homotypic continuity and course over 24 months. Arch Gen Psychiatry, 66, 897-905.  3Dannlowski, U. et al. (2012). Limbic scars: Long-term consequences of childhood maltreatment revealed by functional and structural magnetic resonance imaging. Biol Psychiatry, 71, 286-293.  4Herringa, R.J. et al. (2012). Childhood and adult trauma both correlate with dorsal anterior cingulate activation to threat in combat veterans. Psychol Med, 1-10.  5Tottenham, N. et al. (2011). Elevated amygdala response to faces following early deprivation. Dev Sci, 14, 190-204.  6Egger, H.L. et al. (1999, 2003). The preschool age psychiatric assessmernt: Version 1.4. Duke University Medical Center.  7Angold, A., & Costello, E.J. (2000). The child and adolescent psychiatric assessment (CAPA). J Am Acad Child Adolesc Psychiatry, 39, 39-48. VIII. Discussion VII. Scatterplots Illustrating Interactions

Modifications of EEG power spectra in mesial temporal lobe during n-back tasks of increasing difficulty. A sLORETA study

The n-back task is widely used to investigate the neural basis of Working Memory (WM) processes. The principal aim of this study was to explore and compare the EEG power spectra during two n-back tests with different levels of difficulty (1-back vs. 3-back). Fourteen healthy subjects were enrolled (seven men and seven women, mean age 31.21 ± 7.05 years, range: 23–48). EEG was recorded while performing the N-back test, by means of 19 surface electrodes referred to joint mastoids. EEG analysis were conducted by means of the standardized Low Resolution brain Electric Tomography (sLORETA) software. The statistical comparison between EEG power spectra in the two conditions was performed using paired t-statistics on the coherence values after Fisher's z transformation available in the LORETA program package. The frequency bands considered were: delta (0.5–4 Hz); theta (4.5–7.5 Hz); alpha (8–12.5 Hz); beta (13–30 Hz); gamma (30.5–100 Hz). Significant changes occurred in the delta band: in the 3-back condition an increased delta power was localized in a brain region corresponding to the Brodmann Area (BA) 28 in the left posterior entorhinal cortex (T = 3.112; p < 0.05) and in the BA 35 in the left perirhinal cortex in the parahippocampal gyrus (T = 2.876; p < 0.05). No significant differences were observed in the right hemisphere and in the alpha, theta, beta, and gamma frequency bands. Our results indicate that the most prominent modification induced by the increased complexity of the task occur in the mesial left temporal lobe structures.

Iterative algorithm for spatial and intensity normalization of MEMRI images. Application to tract-tracing of rat olfactory pathways

Manganese (Mn)-enhanced magnetic resonance imaging (MEMRI) is an emerging technique for visualizing neuronal pathways and mapping brain activity modulation in animal models. Spatial and intensity normalizations of MEMRI images acquired from different subjects are crucial steps as they can influence the results of groupwise analysis. However, no commonly accepted procedure has yet emerged. Here, a normalization method is proposed that performs both spatial and intensity normalizations in a single iterative process without the arbitrary choice of a reference image. Spatial and intensity normalizations benefit from this iterative process. On one hand, spatial normalization increases the accuracy of region of interest (ROI) positioning for intensity normalization. On the other hand, improving the intensity normalization of the different MEMRI images leads to a better-averaged target on which the images are spatially registered. After automatic fast brain segmentation and optimization of the normalization process, this algorithm revealed the presence of Mn up to the posterior entorhinal cortex in a tract-tracing experiment on rat olfactory pathways. Quantitative comparison of registration algorithms showed that a rigid model with anisotropic scaling is the best deformation model for intersubject registration of three-dimensional MEMRI images. Furthermore, intensity normalization errors may occur if the ROI chosen for intensity normalization intersects regions where Mn concentration differs between experimental groups. Our study suggests that cross-comparing Mn-injected animals against a Mn-free group may provide a control to avoid bias introduced by intensity normalization quality. It is essential to optimize spatial and intensity normalization as the detectability of local between-group variations in Mn concentration is directly tied to normalization quality.

Dissimilar patterns of degeneration in brain following four different addictive stimulants.

Patterns of neural degeneration were compared following continuous administration of four drugs of addiction, each of which induces model psychoses in chronic addicts. D-amphetamine (D-Amph), cocaine (Coc), or phencyclidine (PCP) were administered continuously over a 5-day period. Both D-Amph and Coc induced pronounced degeneration in fasciculus retroflexus, but only D-Amph further induced substantial degeneration in striatum. Continuous PCP produced entirely different degeneration largely confined to the posterior entorhinal cortex, ventral dentate gyrus, and cingulate cortex. Methamphetamine (Meth) administered in the very high dose but less prolonged drug regimen often employed in studies of dopamine toxicity induced pronounced degeneration in striatum, but widespread degeneration in many other regions as well. These results indicate that drugs of abuse with psychotomimetic properties induce distinctively different patterns of neural degeneration, a finding with implications for theories of addiction and psychosis. They predict two different anatomical loci for alterations in psychosis: fasciculus retroflexus and ventral parahippocampus and hippocampus.

Lesions of the hippocampal formation but not lesions of the fornix or the mammillary nuclei produce long-lasting memory impairment in monkeys

A group of tasks sensitive to human amnesia were used to characterize the severity and duration of memory impairment in monkeys following bilateral damage to the hippocampal formation, fornix, or mammillary nuclei. Monkeys with hippocampal formation lesions (which included the hippocampus proper, dentate gyrus, subiculum, posterior entorhinal cortex, and much of the parahippocampal gyrus) exhibited a substantial and lasting memory impairment. Monkeys with fornix transection or bilateral damage to the mammillary nuclei were impaired on the first task administered after surgery (delayed nonmatching to sample). However, they performed all the other tasks normally and were unimpaired when the delayed nonmatching to sample task was re-administered 18 months after surgery. The findings are consistent with reports that damage limited to the human hippocampus can produce a clinically significant and permanent amnesia. Because fornix transection or mammillary lesions produced only transient memory impairment, it seems unlikely that similar damage in humans can cause a severe or permanent amnesia.

Regional and laminar density of the dopamine innervation in adult rat cerebral cortex

The topographie distribution and density of the dopamine innervation in adult rat cerebral cortex were investigated by means of a recently improved radioautographic procedure for the light microscopic visualization and counting of monoamine axonal varicosities. Dopamine terminals were specifically labeled by high-affinity uptake in whole cerebral hemisphere slices incubated for 15 min at 35°C with 10 −6M tritiated dopamine in the presence of 10 −4M pargyline and 5 × 10 −6M desipramine. The slices were subsequently fixed, embedded in Epon and processed for light microscope radioautography as large 4-μm-thick (whole hemisphere) or smaller, semi-thin sections (selected areas). In radioautographs of serial semi-thin sections exposed for various periods of time, the number of labeled axonal varicosities reached a plateau after 12–14 days of exposure. Counts on such sections of increasing thickness allowed to calculate a correcting factor to transform numbers obtained from 4-μm-thick sections into their equivalent for a tissue thickness of 0.5 μm from which all varicosities were detected. The number of labeled varicosities could then be expressed per mm 3 of tissue after measuring their mean caliper diameter in electron microscope radioautographs. As visualized at 3 transverse levels representing most of the major cytoarchitectonic divisions of cerebral cortex, two novel aspects were recognized in the topographic distribution of dopamine terminals: (1) the presence of a dopamine innervation in layer VIb of the frontal, parietal, temporal and occipital neocortex, and (2) a significant contingent of dopamine varicosities within the deep and not only upper layers of supragenual cingulate cortex. A fair number of dopamine varicosities were also detected in the upper layers of the dorsomedial frontal area, in the retrosplenial and adjacent occipital cortex as well as in the ventral subiculum and field CA1 of the hippocampus. As measured in 10 sectors representing different cortical regions, the highest density of dopamine innervation was found in the supragenual cingulate cortex (1.7 × 10 6) and particularly in its layers II and III (3.1 × 10 6). A slightly lower density was measured in the anteromedian “prefrontal” cortex (1.0 × 10 6). The rostrorhinal and the perirhinal cortex showed moderate dopamine innervation (3.0 and 5.5 × 10 5) with varicosities in every layer. The piriform and the posterior entorhinal cortex were also moderately and ubiquitously innervated (2.5 and 3.0 × 10 5). In the dorsofrontal, parietal and temporal neocortex, overall dopamine innervation was of low density (5.0−6.0 × 10 4) and concentrated in layer VI(2 × 10 5 varicosities/mm 3). The primary visual and the lateral occipital neocortex had the lowest density, with terminals also confined to layer VI(4.0 × 10 4). Together with recent immunocytochemical observations on developing or adult rat cortex, these results justify some revision of current views regarding the organizational features of the mesocortical dopamine system.