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Hippocampal formation: In Paxinos G (cd): The Human Nervous System. New York
... The term hippocampal formation encompasses the DG, the hippocampus proper and the subicular complex (subiculum, presubiculum, and parasubiculum). However, other authors also consider the entorhinal cortex (EC) as part of the hippocampal formation (Insausti and Amaral, 2012). The hippocampus proper is commonly subdivided according to the nomenclature of Lorente De Nó (1934) into the CA1, CA2, CA3, and CA4 fields. ...
... The first are normally labeled as hilar cells, while the latter are frequently labeled as CA4 following Lorente De Nó, 1934. Some authors, however, consider that there are no clear differences in cytoarchitecture or connectivity in humans to distinguish CA4 from CA3 pyramidal cells, and therefore do not differentiate a CA4 field in humans (Insausti and Amaral, 2012). Other authors defined the dentate hilus "as including the entire region between the blades of the DG" containing the polymorphic layer of the DG and the CA3 pyramidal neurons which would constitute the CA3 hilar neurons (subfield CA3h; Lim et al., 1997). ...
... This scheme is mostly based on studies performed in rats, cats, monkeys and -most recently-in mice: Amaral and Cowan (1980), Mesulam et al. (1983), Amaral and Witter (1989), Witter and Amaral (1991), Gloor (1997), Witter et al. (2000), Kondo et al. (2009), Insausti andAmaral (2012), Rowland et al. (2013), Dudek et al. (2016), Liu et al. (2018), Marks et al. (2021), Witter and Amaral (2021). As previously discussed (e.g., Insausti and Amaral, 2012), although similar connectivity appears to exist in all species studied, there are also species-specific variations. ...
Temporal lobe epilepsy (TLE) is the most common form of focal epilepsy and is associated with a variety of structural and psychological alterations. Recently, there has been renewed interest in using brain tissue resected during epilepsy surgery, in particular ‘non-epileptic’ brain samples with normal histology that can be found alongside epileptic tissue in the same epileptic patients — with the aim being to study the normal human brain organization using a variety of methods. An important limitation is that different medical characteristics of the patients may modify the brain tissue. Thus, to better determine how ‘normal’ the resected tissue is, it is fundamental to know certain clinical, anatomical and psychological characteristics of the patients. Unfortunately, this information is frequently not fully available for the patient from which the resected tissue has been obtained — or is not fully appreciated by the neuroscientists analyzing the brain samples, who are not necessarily experts in epilepsy. In order to present the full picture of TLE in a way that would be accessible to multiple communities (e.g., basic researchers in neuroscience, neurologists, neurosurgeons and psychologists), we have reviewed 34 TLE patients, who were selected due to the availability of detailed clinical, anatomical, and psychological information for each of the patients. Our aim was to convey the full complexity of the disorder, its putative anatomical substrates, and the wide range of individual variability, with a view toward: (1) emphasizing the importance of considering critical patient information when using brain samples for basic research and (2) gaining a better understanding of normal and abnormal brain functioning. In agreement with a large number of previous reports, this study (1) reinforces the notion of substantial individual variability among epileptic patients, and (2) highlights the common but overlooked psychopathological alterations that occur even in patients who become “seizure-free” after surgery. The first point is based on pre- and post-surgical comparisons of patients with hippocampal sclerosis and patients with normal-looking hippocampus in neuropsychological evaluations. The second emerges from our extensive battery of personality and projective tests, in a two-way comparison of these two types of patients with regard to pre- and post-surgical performance.
... The wide range of differences in the synaptic organization of the human CA1 layers found in the present study, especially between SLM and the rest of layers, may be related to the variety of inputs arriving to these layers (Figure 7). Unfortunately, detailed hippocampal human connectivity is far to be known: data directly obtained from human brains are very scarce and most data are inferred from rodents and primates (Insausti and Amaral, 2012;Spruston and McBain, 2007). In the primate brain, the CA1 field receives a wide variety of inputs from multiple subcortical and cortical brain regions (Insausti and Amaral, 2012;Spruston and McBain, 2007), being the major input to CA1 originated in the EC. ...
... Unfortunately, detailed hippocampal human connectivity is far to be known: data directly obtained from human brains are very scarce and most data are inferred from rodents and primates (Insausti and Amaral, 2012;Spruston and McBain, 2007). In the primate brain, the CA1 field receives a wide variety of inputs from multiple subcortical and cortical brain regions (Insausti and Amaral, 2012;Spruston and McBain, 2007), being the major input to CA1 originated in the EC. Specifically, neurons located in layer III (and layer V) of the EC project directly to SLM, whereas neurons in layer II project to the rest of CA1 layers indirectly via the DG and CA3 field (Insausti and Amaral, 2012;Kondo et al., 2009). ...
... In the primate brain, the CA1 field receives a wide variety of inputs from multiple subcortical and cortical brain regions (Insausti and Amaral, 2012;Spruston and McBain, 2007), being the major input to CA1 originated in the EC. Specifically, neurons located in layer III (and layer V) of the EC project directly to SLM, whereas neurons in layer II project to the rest of CA1 layers indirectly via the DG and CA3 field (Insausti and Amaral, 2012;Kondo et al., 2009). Considering both the synaptic data obtained in the present study and the connectivity knowledge in monkeys, it may seem that the synaptic organization in the layers receiving CA3 Schaffer collateral inputs (i.e. ...
The hippocampal CA1 field integrates a wide variety of subcortical and cortical inputs, but its synaptic organization in humans is still unknown due to the difficulties involved studying the human brain via electron microscope techniques. However, we have shown that the 3D reconstruction method using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) can be applied to study in detail the synaptic organization of the human brain obtained from autopsies, yielding excellent results. Using this technology, 24,752 synapses were fully reconstructed in CA1, revealing that most of them were excitatory, targeting dendritic spines and displaying a macular shape, regardless of the layer examined. However, remarkable differences were observed between layers. These data constitute the first extensive description of the synaptic organization of the neuropil of the human CA1 region.
... The wide range of differences in the synaptic organization of the human CA1 layers found in the present study, especially between SLM and the rest of layers, may be related to the variety of inputs arriving to these layers (Figure 7). Unfortunately, detailed hippocampal human connectivity is far to be known: data directly obtained from human brains are very scarce and most data are inferred from rodents and primates (Insausti and Amaral, 2012;Spruston and McBain, 2007). In the primate brain, the CA1 field receives a wide variety of inputs from multiple subcortical and cortical brain regions (Insausti and Amaral, 2012;Spruston and McBain, 2007), being the major input to CA1 originated in the EC. ...
... Unfortunately, detailed hippocampal human connectivity is far to be known: data directly obtained from human brains are very scarce and most data are inferred from rodents and primates (Insausti and Amaral, 2012;Spruston and McBain, 2007). In the primate brain, the CA1 field receives a wide variety of inputs from multiple subcortical and cortical brain regions (Insausti and Amaral, 2012;Spruston and McBain, 2007), being the major input to CA1 originated in the EC. Specifically, neurons located in layer III (and layer V) of the EC project directly to SLM, whereas neurons in layer II project to the rest of CA1 layers indirectly via the DG and CA3 field (Insausti and Amaral, 2012;Kondo et al., 2009). ...
... In the primate brain, the CA1 field receives a wide variety of inputs from multiple subcortical and cortical brain regions (Insausti and Amaral, 2012;Spruston and McBain, 2007), being the major input to CA1 originated in the EC. Specifically, neurons located in layer III (and layer V) of the EC project directly to SLM, whereas neurons in layer II project to the rest of CA1 layers indirectly via the DG and CA3 field (Insausti and Amaral, 2012;Kondo et al., 2009). Considering both the synaptic data obtained in the present study and the connectivity knowledge in monkeys, it may seem that the synaptic organization in the layers receiving CA3 Schaffer collateral inputs (i.e. ...
The hippocampal CA1 field integrates a wide variety of subcortical and cortical inputs, but its synaptic organization in humans is still unknown due to the difficulties involved studying the human brain via electron microscope techniques. However, we have shown that the 3D reconstruction method using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) can be applied to study in detail the synaptic organization of the human brain obtained from autopsies, yielding excellent results. Using this technology, 24,752 synapses were fully reconstructed in CA1, revealing that most of them were excitatory, targeting dendritic spines and displaying a macular shape, regardless of the layer examined. However, remarkable differences were observed between layers. These data constitute the first extensive description of the synaptic organization of the neuropil of the human CA1 region.
... The wide range of differences in the synaptic organization of the human CA1 layers found in the present study, especially between SLM and the rest of layers, may be related to the variety of inputs arriving to these layers (Figure 7). Unfortunately, detailed hippocampal human connectivity is far to be known: data directly obtained from human brains are very scarce and most data are inferred from rodents and primates (Insausti and Amaral, 2012;Spruston and McBain, 2007). In the primate brain, the CA1 field receives a wide variety of inputs from multiple subcortical and cortical brain regions (Insausti and Amaral, 2012;Spruston and McBain, 2007), being the major input to CA1 originated in the EC. ...
... Unfortunately, detailed hippocampal human connectivity is far to be known: data directly obtained from human brains are very scarce and most data are inferred from rodents and primates (Insausti and Amaral, 2012;Spruston and McBain, 2007). In the primate brain, the CA1 field receives a wide variety of inputs from multiple subcortical and cortical brain regions (Insausti and Amaral, 2012;Spruston and McBain, 2007), being the major input to CA1 originated in the EC. Specifically, neurons located in layer III (and layer V) of the EC project directly to SLM, whereas neurons in layer II project to the rest of CA1 layers indirectly via the DG and CA3 field (Insausti and Amaral, 2012;Kondo et al., 2009). ...
... In the primate brain, the CA1 field receives a wide variety of inputs from multiple subcortical and cortical brain regions (Insausti and Amaral, 2012;Spruston and McBain, 2007), being the major input to CA1 originated in the EC. Specifically, neurons located in layer III (and layer V) of the EC project directly to SLM, whereas neurons in layer II project to the rest of CA1 layers indirectly via the DG and CA3 field (Insausti and Amaral, 2012;Kondo et al., 2009). Considering both the synaptic data obtained in the present study and the connectivity knowledge in monkeys, it may seem that the synaptic organization in the layers receiving CA3 Schaffer collateral inputs (i.e. ...
The hippocampal CA1 field integrates a wide variety of subcortical and cortical inputs, but its synaptic organization in humans is still unknown due to the difficulties involved studying the human brain via electron microscope techniques. However, we have shown that the 3D reconstruction method using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) can be applied to study in detail the synaptic organization of the human brain obtained from autopsies, yielding excellent results. Using this technology, 24,752 synapses were fully reconstructed in CA1, revealing that most of them were excitatory, targeting dendritic spines and displaying a macular shape, regardless of the layer examined. However, remarkable differences were observed between layers. These data constitute the first extensive description of the synaptic organization of the neuropil of the human CA1 region.
... More recently, the term parahippocampal region was advocated (Witter 2002), defined as comprising the preand parasubiculum, the entorhinal and perirhinal cortices and the postrhinal (in non-primate mammals) or parahippocampal cortex (in primates including humans). In the human brain, the parahippocampal region is a cortical area that forms the temporal part of the limbic lobe, spanning the area from the retrosplenial and posterior parts of the cingulate gyrus to the temporal incisure and the limen insulae (Amaral and Insausti 1990;Insausti 1993;Duvernoy 1998;Insausti et al. 1998a;Van Hoesen 2002;Insausti and Amaral 2012). Many alterations in the parahippocampal region have been found in neurological and psychiatric diseases ranging from schizophrenia (7 Sect. ...
... Field CA4 appears to correspond most closely to the polymorph zone of the dentate gyrus and, therefore, is not a field of the hippocampus at all (Blackstad 1956;Amaral 1978Amaral , 1987. Since CA3 pyramidal cells extend far into the hilus of the dentate gyrus, Amaral and Insausti (1990) suggested the term CA3h (see also Lim et al. 1997a, b). The Roses divided the hippocampus proper into five subfields H1-H5 (M. Rose 1927a;Rose 1938). ...
... The principal layers can each be divided into three layers Pre-α, Pre-β and Pre-γ and Pri-α, Pri-β and Pri-γ. In experimental studies in monkeys, however, mostly Amaral and Insausti's (1990) subdivision into six layers is used, of which layer 1 is the molecular layer, layer 2 Pre-α, layer 3 Pre-β and Pre-γ, layer 4 the lamina dissecans, layer 5 Pri-α and layer 6 Pri-β and Pri-γ. The human entorhinal cortex has been subdivided into eight different subfields (Insausti et al. 1995; . ...
The term “limbic” was first used in 1664 by Thomas Willis to describe the cortical structures on the medial side of the cerebral hemisphere, surrounding the brain stem. Two centuries later, Paul Broca noticed that the cingulate gyrus and the parahippocampal gyrus form a border (limbus) around the corpus callosum and the brain stem. Broca subdivided his grand lobe limbique into inner (the hippocampus) and outer (the cingulate and parahippocampal gyri) rings. During the last decades of the nineteenth century and the first decades of the twentieth century, it was generally believed that most if not all structures of Broca’s limbic lobe were dominated by olfactory input and therefore form part of the rhinencephalon. In 1937, James Papez proposed that these structures are involved in a closed circuit. The circuit of Papez includes projections from the hippocampus via the fornix to the mamillary body and then via the mamillothalamic tract of Vicq d’Azyr to the anterior thalamic nucleus, from here to the cingulate gyrus, and as last step from the cingulate gyrus back to the hippocampus. Papez suggested that his circuit formed the anatomical basis for emotions. In 1952, Paul MacLean included the circuit of Papez with the amygdala and the hypothalamus into his limbic system, supposed to be responsible for emotional behaviour (the “visceral” or “emotional” brain). Lennart Heimer promoted an expanded version of the classic limbic lobe of Broca, which contains all non-isocortical parts of the cerebral hemisphere together with the laterobasal-cortical amygdaloid complex, with several output channels in the basal forebrain. Thus defined, the limbic lobe contains all of the major cortical and amygdaloid structures known to be especially important for emotional and behavioural functions. Experimental studies in the early 1970s identified the output channels of the limbic lobe in the basal forebrain as the ventral striatopallidal system, the extended amygdala and the basal nucleus of Meynert.
... However, CA2 is not always accepted as a separate region, but has been merged with CA3 by some authors (von Economo and Koskinas 1925;Stephan 1975). CA4 is not universally accepted as a distinct region either, and merged with the multiform layer of FD to form the hilus of the DG (Vogt and Vogt 1919;von Economo and Koskinas 1925;Rose 1938;Amaral and Inausti 1990). Likewise, discrepancies also exist concerning the number of subregions which can be defined within a given CA region. ...
... Classical and contemporary architectonic studies brought forth different parcellation schemes, the most common of which includes the prosubiculum (ProS), subiculum proper (Sub), presubiculum (PreS) and parasubiculum (PaS). However, ProS and PaS are not always accepted as individual regions (Stephan 1975;Braak 1980;Amaral and Inausti 1990), and discrepancies also exist concerning the number of subregions that can be defined within a given region: e.g., two or three subdivisions within PreS (von Economo and Koskinas 1925;Rose 1927). ...
... Borders were first identified according to cytoarchitectonic criteria based on previous cyto-and pigment-architectonic studies in the hippocampus (von Economo and Koskinas 1925;Lorente de Nó 1934;Rose 1927Rose , 1938Braak 1978;Rosene and Van Hoesen 1987;Duvernoy 1988;Amaral and Inausti 1990;Amunts et al. 2005) and subicular complex (von Economo and Koskinas 1925;Stephan 1975;Braak 1980;Amaral and Inausti 1990), then compared with those revealed by differences in receptor distribution patterns. Cytoarchitectonically detected borders were mirrored by changes in the expression levels of multiple receptors. ...
The human hippocampal formation is relevant for various aspects of memory and learning, and the different hippocampal regions are differentially affected by neuropsychiatric disorders. Therefore, the hippocampal formation has been subject of numerous cytoarchitectonic and other mapping studies, which resulted in divergent parcellation schemes. To understand the principles of hippocampal architecture, it is necessary to integrate different levels of hippocampal organisation, going beyond one modality. We here applied a multimodal mapping approach combining cyto- and multi-receptorarchitectonic analyses, and generated probabilistic maps in stereotaxic space of the identified regions. Cytoarchitecture in combination with the regional and laminar distribution of 15 neurotransmitter receptors visualized by in vitro receptor autoradiography were analysed in seven hemispheres from 6 unfixed shock frozen and serially sectioned brains. Cytoarchitectonic delineations for generation of probabilistic maps were carried out on histological sections from ten fixed, paraffin embedded and serially sectioned brains. Nine cyto- and receptorarchitectonically distinct regions were identified within the hippocampal formation (i.e., fascia dentata, cornu Ammonis (CA) regions 1–4, prosubiculum, subiculum proper, presubiculum and parasubiculum), as well as the hippocampal-amygdaloid transition area and the periallocortical transsubiculum. Subsequently generated probabilistic maps quantify intersubject variability in the size and extent of these cyto- and receptorarchitectonically distinct regions. The regions did not differ in their volume between the hemispheres and gender. Receptor mapping revealed additional subdivisions which could not be detected by cytoarchitectonic analysis alone. They correspond to parcellations previously found in immunohistochemical and connectivity studies. The multimodal approach enabled the definition of regions not consistently reported, e.g., CA4 region or prosubiculum. The ensuing detailed probabilistic maps of the hippocampal formation constitute the basis for future architectonically informed analyses of in vivo neuroimaging studies.
... The gross anatomical organization of the MTL has been dealt with in several reports (Amaral and Insausti, 1990;Duvernoy, 2005;Insausti and Amaral, 2012), and they all agree with the commonly accepted pattern of the series of bulges present in the medialmost aspect of the MTL. However, the pattern of sulci present in the PHG is more controversial, and reports in the literature show a disparity of names ( Heckers et al., 1990;Ono et al., 1990;Heinsen et al., 1996;Hanke, 1997;Duvernoy, 2005;Huntgeburth and Petrides, 2012). ...
... prominences (Stephan, 1975;Amaral and Insausti, 1990;Duvernoy, 2005;Insausti and Amaral, 2012;Ding and Van Hoesen, 2015) makes it possible to use its morphometry in studies on neurodegenerative diseases, such as in Alzheimer disease. ...
... Sometimes, a secondary additional sulcus could be appreciated on the surface of the PHG. Moreover, in our series of coronal sections, the end of the intrarhinal sulcus coincided with the start of the hippocampal fissure (fissura hippocampalis) (Amaral and Insausti, 1990;Insausti and Amaral, 2012). In most cases, the intrarhinal sulcus extends as far back as the GA, which corresponds to the level of the hippocampal head. ...
The Gyrus ambiens is a gross anatomical prominence in the medial temporal lobe (MTL), associated closely with Brodmann area 34 (BA34). It is formed largely by the medial intermediate subfield of the entorhinal cortex (EC) [Brodmann area 28 (BA28)]. Although the MTL has been widely studied due to its well-known role on memory and spatial information, the anatomical relationship between G. ambiens, BA34, and medial intermediate EC subfield has not been completely defined, in particular whether BA34 is part of the EC or a different type of cortex. In order to clarify this issue, we carried out a detailed analysis of 37 human MTLs, determining the exact location of medial intermediate EC subfield and its extent within the G. ambiens, its cortical thickness, and the histological–MRI correspondence of the G. ambiens with the medial intermediate EC subfield in 10 ex vivo MRI. Our results show that the G. ambiens is limited between two small sulci in the medial aspect of the MTL, which correspond almost perfectly to the extent of the medial intermediate EC subfield, although the rostral and caudal extensions of the G. ambiens may extend to the olfactory (rostrally) and intermediate (caudally) entorhinal subfields. Moreover, the cortical thickness averaged 2.5 mm (1.3 mm for layers I–III and 1 mm for layers V–VI). Moreover, distance among different landmarks visible in the MRI scans which are relevant to the identification of the G. ambiens in MRI are provided. These results suggest that BA34 is a part of the EC that fits best with the medial intermediate subfield. The histological data, together with the ex vivo MRI identification and thickness of these structures may be of use when assessing changes in MRI scans in clinical settings, such as Alzheimer disease.
... The archicortical hippocampal formations, consists of five major intrahippocampal connections (fascia, dentate gyrus; DG, hilus, cornum ammonis (CA3-2), CA1, and subiculum), are regions of the brain most sensitive to ischemic damage. The hippocampal and retrohippocampal formations (presubiculum, parasubiculum, area retrosplenialis, and entorhinalis; entorhinal cortex) along with parahippocampal [1,2] medial temporal lobe (MTL) [ 1 , 2 ] an d t h e i s l a n d s o f C a l l e j a a r e p a r t o f a neuroanatomically well-defined cerebral limbic network involved in memory and learning behavior, particularly spatial information and associative memory processes [3][4][5]. In addition, the septohippocampal network of cholinergic neurons consists of the septal region (the medial and lateral septal nuclei, dorsomedial quadrant of the septum, and the nuclei of the horizontal (HDB) and vertical (VDB) limbs of the diagonal band of Broca) and the nucleus basalis of Meynert [6]. ...
... In the present investigation, we show that a single icv bilateral injection of Aβ and unilateral intrastriatal injection of ET1 provoked substantial biochemical alterations in the cellular and vascular anatomy of the hippocampus that provides an etiology link between AD and ischemia. Largely MTL [1] (including thalamus and entorhinal cortex), intrahippocampal subdivisions, CA3-2, and DG, fornix, hippocampal commissure, and basal forebrain were affected. Conversely, the hippocampal pathogenesis/atrophy induced by ET1 or Aβ toxicity alone was not severe enough to significantly affect the entire circuit in a hippocampal network. ...
... Similarly, anterior nuclei of the thalamus have direct connections to the hippocampus through fornix. Alternatively, cellular and vascular disruption observed in entorhinal cortex may also be the epicenter of damage seen in DG, CA1, and CA3, as the perforant pathway projection [1] from the entorhinal cortex directly innervates these hippocampal subdivisions [2,38]. While thalamic deterioration in early AD stages is controversial [39,40], we observed an early sign of degeneration in the thalamus of ET1 + Aβ rats with elevated astroglial expression, vascular degeneration, BBB disruption, and the presence of pyknotic neurons. ...
The hippocampus, a brain region vital for memory and learning, is sensitive to the damage caused by ischemic/hypoxic stroke and is one of the main regions affected by Alzheimer's disease. The pathological changes that might occur in the hippocampus and its connections, because of cerebral injury in a distant brain region, such as the striatum, have not been examined. Therefore, in the present study, we evaluated the combined effects of endothelin-1-induced ischemia (ET1) in the striatum and β-amyloid (Aβ) toxicity on hippocampal pathogenesis, dictated by the anatomical and functional intra- and inter-regional hippocampal connections to the striatum. The hippocampal pathogenesis induced by Aβ or ET1 alone was not severe enough to significantly affect the entire circuit of the hippocampal network. However, the combination of the two pathological states (ET1 + Aβ) led to an exacerbated increase in neuroinflammation, deposition of the amyloid precursor protein (APP) fragments with the associated appearance of degenerating cells, and blood-brain-barrier disruption. This was observed mainly in the hippocampal formation (CA2 and CA3 regions), the dentate gyrus as well as distinct regions with synaptic links to the hippocampus such as entorhinal cortex, thalamus, and basal forebrain. In addition, ET1 + Aβ-treated rats also demonstrated protracted loss of AQP4 depolarization, dissolution of β-dystroglycan, and basement membrane laminin with associated IgG and dysferlin leakage. Spatial dynamics of hippocampal injury in ET1 + Aβ rats may provide a valuable model to study new targets for clinical therapeutic applications, specifically when areas remotely connected to hippocampus are damaged.
... Given that previous modeling work has shown that the presence of fluid can affect the transmission of mechanical forces within the brain (Zhou et al., 2020a), one structure that may be associated with the hippocampal vulnerability is the temporal horn of the lateral ventricle. The temporal horn is a cavity that forms the roof of the hippocampus and is filled with cerebrospinal fluid (CSF) and occasionally choroid plexus (Insausti and Amaral, 2003). Previous studies found that the volumes of the hippocampus and temporal horn were inversely correlated in TBI patients (Gale et al., 1994;Bigler et al., 1997;Bigler et al., 2002). ...
... Several postmortem neuropathological studies (Kotapka et al., 1992;Kotapka et al., 1993;Kotapka et al., 1994;Maxwell et al., 2003) have detected overt neuronal damage/loss in the hippocampus of TBI victims with high incidence rates up to 73%-87% (although the exact loadings endured were lacking). Animal models employing custom-built pneumatic devices that deliver impulsive angular accelerations, similar to the loading mode in the current study, have shown hippocampal lesions in non-human primates (Gennarelli et al., 1982;Kotapka et al., 1991), which have a similar hippocampal morphology and spatial relationship to the temporal horn (Insausti and Amaral, 2003;Amaral et al., 2007). A version of 3 | Wilcoxon matched-pairs signed-rank test on the region-wise strain and strain rate in the hippocampal subfields and whole hippocampus (A) and nonhippocampal regions (B) (N = 6). ...
Hippocampal injury is common in traumatic brain injury (TBI) patients, but the underlying pathogenesis remains elusive. In this study, we hypothesize that the presence of the adjacent fluid-containing temporal horn exacerbates the biomechanical vulnerability of the hippocampus. Two finite element models of the human head were used to investigate this hypothesis, one with and one without the temporal horn, and both including a detailed hippocampal subfield delineation. A fluid-structure interaction coupling approach was used to simulate the brain-ventricle interface, in which the intraventricular cerebrospinal fluid was represented by an arbitrary Lagrangian-Eulerian multi-material formation to account for its fluid behavior. By comparing the response of these two models under identical loadings, the model that included the temporal horn predicted increased magnitudes of strain and strain rate in the hippocampus with respect to its counterpart without the temporal horn. This specifically affected cornu ammonis (CA) 1 (CA1), CA2/3, hippocampal tail, subiculum, and the adjacent amygdala and ventral diencephalon. These computational results suggest that the presence of the temporal horn exacerbate the vulnerability of the hippocampus, highlighting the mechanobiological dependency of the hippocampus on the temporal horn.
... Given that previous modeling work has shown that the presence of fluid can affect the transmission of mechanical forces within the brain (Zhou et al., 2020a), one structure that may be associated with the hippocampal vulnerability is the temporal horn of the lateral ventricle. The temporal horn is a cavity that forms the roof of the hippocampus and is filled with cerebrospinal fluid (CSF) and occasionally choroid plexus (Insausti and Amaral, 2003). Previous studies found that the volumes of the hippocampus and temporal horn were inversely correlated in TBI patients (Gale et al., 1994;Bigler et al., 1997;Bigler et al., 2002). ...
... Several postmortem neuropathological studies (Kotapka et al., 1992;Kotapka et al., 1993;Kotapka et al., 1994;Maxwell et al., 2003) have detected overt neuronal damage/loss in the hippocampus of TBI victims with high incidence rates up to 73%-87% (although the exact loadings endured were lacking). Animal models employing custom-built pneumatic devices that deliver impulsive angular accelerations, similar to the loading mode in the current study, have shown hippocampal lesions in non-human primates (Gennarelli et al., 1982;Kotapka et al., 1991), which have a similar hippocampal morphology and spatial relationship to the temporal horn (Insausti and Amaral, 2003;Amaral et al., 2007). A version of 3 | Wilcoxon matched-pairs signed-rank test on the region-wise strain and strain rate in the hippocampal subfields and whole hippocampus (A) and nonhippocampal regions (B) (N = 6). ...
Hippocampal injury is common in traumatic brain injury (TBI) patients, but the underlying pathogenesis remains elusive. In this study, we hypothesize that the presence of the adjacent fluid-containing temporal horn exacerbates the biomechanical vulnerability of the hippocampus. Two finite element models of the human head were used to investigate this hypothesis, one with and one without the temporal horn, and both including a detailed hippocampal subfield delineation. A fluid-structure interaction coupling approach was used to simulate the brain-ventricle interface, in which the intraventricular cerebrospinal fluid was represented by an arbitrary Lagrangian-Eulerian multi-material formation to account for its fluid behavior. By comparing the response of these two models under identical loadings, the model that included the temporal horn predicted increased magnitudes of strain and strain rate in the hippocampus with respect to its counterpart without the temporal horn. This specifically affected cornu ammonis (CA) 1 (CA1), CA2/3, hippocampal tail, subiculum, and the adjacent amygdala and ventral diencephalon. These computational results suggest that the presence of the temporal horn exacerbate the vulnerability of the hippocampus, highlighting the mechanobiological dependency of the hippocampus on the temporal horn.
... [Gumprecht et al., 1999;Schlaier et al., 2004]) and FSL FLIRT (FMRIB's Linear Registration Tool [Jenkinson et al., 2002;Jenkinson and Smith, 2001]). Medial temporal lobe regions (entorhinal, perirhinal, and parahippocampal cortices, and hippocampal subfields CA23DG [CA2, CA3, dentate gyrus], CA1, and subiculum) were delineated using the Automatic Segmentation of Hippocampal Subfields (ASHS [Pluta et al., 2012;Yushkevich et al., 2010]) software using boundaries determined from MRI visible landmarks that correlate with underlying cellular histology ( Amaral and Insausti, 1990;Duvernoy and Bourgouin, 1998). In some cases, pixels that were clearly misplaced (e.g. ...
... In no case did this modification affect the outcome of the electrode localization procedure. In a single subject, whose electrode was farther anterior than ASHS can accommodate, subfields were delineated manually, with reference to brain atlases ( Amaral and Insausti, 1990;Duvernoy and Bourgouin, 1998). White matter and cerebral spinal fluid areas were outlined using FSL FAST software ( Zhang et al., 2001). ...
The hippocampus is critical for episodic memory, and synaptic changes induced by long-term potentiation (LTP) are thought to underlie memory formation. In rodents, hippocampal LTP may be induced through electrical stimulation of the perforant path. To test whether similar techniques could improve episodic memory in humans, we implemented a microstimulation technique that allowed delivery of low-current electrical stimulation via 100 μm-diameter microelectrodes. As thirteen neurosurgical patients performed a person recognition task, microstimulation was applied in a theta-burst pattern, shown to optimally induce LTP. Microstimulation in the right entorhinal area during learning significantly improved subsequent memory specificity for novel portraits; participants were able both to recognize previously-viewed photos and reject similar lures. These results suggest that microstimulation with physiologic level currents—a radical departure from commonly used deep brain stimulation protocols—is sufficient to modulate human behavior and provides an avenue for refined interrogation of the circuits involved in human memory.
... Critically, however, the MTL is not a unitary structure. Rather, it is composed of multiple regions with differing anatomy and connectivity (see, e.g., ref. 10), including subfields of the hippocampal formation [CA1, CA2, CA3, dentate gyrus (DG), and subiculum], and the entorhinal (ERC), perirhinal (PRC), and parahippocampal (PHC) cortices (Fig. 1A). Moreover, evidence in rodents and humans suggests that these subfields are differentially affected by age, as well as by age-related disease (8,9,11). ...
... Carr et al. 10.1073/pnas.1713308114 ...
Significance
Older adults differ in the degree to which they experience memory impairments, but the underlying factors contributing to this variability remain unclear. Motivated by the essential role of the medial temporal lobe (MTL) in declarative memory, we investigated whether episodic memory differences among older adults can be explained by differences in MTL subfield structure and function. Using high-resolution magnetic resonance imaging, we demonstrated that a combination of structural and functional subfield measures significantly accounted for differences in memory performance. These findings advance understanding of how independent but converging influences of both MTL structure and function contribute to age-related impairment in episodic memory, complementing findings in the rodent and human postmortem literatures.
... Note that the ambient gyrus is made up of different subfields in an anterior-to-posterior direction. While the ambient gyrus is occupied by the ErC in more anterior slices (Insausti and Amaral, 2012), it consists of Sub and CA1 in more posterior sections (Ding and VanHoesen, 2015). Moving posteriorly, at the point where the uncal sulcus can be followed from its fundus to the medial surface, Sub becomes the new superior border (seeFig. ...
... The only exception from this rule occurs when CS is < 4 mm deep (very shallow CS); in that case the boundary between ErC and area 35 moves more lateral to the extension of the fundus of the CS. ErC disappears approximately 2 mm after the HH (Insausti and Amaral, 2012). Segmentation of the ErC stops therefore after 2.2 mm (=2 slices here) into the HB, i.e. after 2.2 mm posterior to the uncal apex (seeFig. ...
Recent advances in MRI and increasing knowledge on the characterization and anatomical variability of medial temporal lobe (MTL) anatomy have paved the way for more specific subdivisions of the MTL in humans. In addition, recent studies suggest that early changes in many neurodegenerative and neuropsychiatric diseases are better detected in smaller subregions of the MTL rather than with whole structure analyses. Here, we developed a new protocol using 7 Tesla (T) MRI incorporating novel anatomical findings for the manual segmentation of entorhinal cortex (ErC), perirhinal cortex (PrC; divided into area 35 and 36), parahippocampal cortex (PhC), and hippocampus; which includes the subfields subiculum (Sub), CA1, CA2, as well as CA3 and dentate gyrus (DG) which are separated by the endfolial pathway covering most of the long axis of the hippocampus. We provide detailed instructions alongside slice-by-slice segmentations to ease learning for the untrained but also more experienced raters. Twenty-two subjects were scanned (19–32 yrs, mean age = 26 years, 12 females) with a turbo spin echo (TSE) T2-weighted MRI sequence with high-resolution oblique coronal slices oriented orthogonal to the long axis of the hippocampus (in-plane resolution 0.44×0.44 mm²) and 1.0 mm slice thickness. The scans were manually delineated by two experienced raters, to assess intra- and inter-rater reliability. The Dice Similarity Index (DSI) was above 0.78 for all regions and the Intraclass Correlation Coefficients (ICC) were between 0.76 to 0.99 both for intra- and inter-rater reliability. In conclusion, this study presents a fine-grained and comprehensive segmentation protocol for MTL structures at 7T MRI that closely follows recent knowledge from anatomical studies. More specific subdivisions (e.g. area 35 and 36 in PrC, and the separation of DG and CA3) may pave the way for more precise delineations thereby enabling the detection of early volumetric changes in dementia and neuropsychiatric diseases.
... Layers II and III of the entorhinal cortex provide the main cortical input to the hippocampal formation, while layers V and VI receive information from the hippocampal formation and transmit it to the neocortex and other brain structures (Witter and Amaral, 1991;Insausti et al., 1997;van Groen et al., 2003;Kerr et al., 2007;Witter, 2007Witter, , 2012Insausti and Amaral, 2012;Cappaert Van Strien and Witter, 2015;Witter et al., 2017). Our results indicate that calciumbinding protein neurons in the dolphin entorhinal cortex are located in the interface between entorhinal input and output pathways. ...
Introduction: The entorhinal cortex has been shown to be involved in high-level cognitive functions in terrestrial mammals. It can be divided into two main areas: the lateral entorhinal area (LEA) and the medial entorhinal area (MEA). Understanding of its structural organization in cetaceans is particularly important given the extensive evidence for their cognitive abilities. The present study describes the cytoarchitectural and immunohistochemical properties of the entorhinal cortex of the bottlenose dolphin (Tursiops truncatus, Montagu, 1821), perhaps the most studied cetacean species and a paradigm for dolphins and other small cetaceans. Methods: Four bottlenose dolphins' entorhinal cortices were processed. To obtain a precise overview of the organization of the entorhinal cortex we used thionin staining to study its laminar and regional organization, and immunoperoxidase technique to investigate the immunohistochemical distribution of three most commonly used calcium-binding proteins (CBPs), calbindin D-28k (CB), calretinin (CR) and parvalbumin (PV). Entorhinal cortex layers thickness were measured, morphological and morphometric analysis for each layer were conducted and statistically compared. Results: Six layers in both the LEA and MEA were identified. The main difference between the LEA and the MEA is observed in layers II and III: the neurons in layer II of the LEA were denser and larger than the neurons in layer II of MEA. In addition, a relatively cell-free zone between layers II and III in LEA, but not in MEA, was observed. The immunohistochemical distribution of the three CBPs, CB, CR and PV were distinct in each layer. The immunostaining pattern of CR, on one side, and CB/PV, on the other side, appeared to be distributed in a complementary manner. PV and CB immunostaining was particularly evident in layers II and III, whereas CR immunoreactive neurons were distributed throughout all layers, especially in layers V and VI. Immunoreactivity was expressed by neurons belonging to different morphological classes: All CBPs were expressed in non-pyramidal neurons, but CB and CR were also found in pyramidal neurons. Discussion: The morphological characteristics of pyramidal and non-pyramidal neurons in the dolphin entorhinal cortex are similar to those described in the entorhinal cortex of other species, including primates and rodents. Interestingly, in primates, rodents, and dolphins, most of the CBP-containing neurons are found in the superficial layers, but the large CR-ir neurons are also abundant in the deep layers. Layers II and III of the entorhinal cortex contain neurons that give rise to the perforant pathway, which conveys most of the cortical information to the hippocampal formation. From the hippocampal formation,
... Another important function of the HC is to track the current location in either physical (Derdikman and Moser 2010) or non-physical spaces (i.e. the structure of a cognitive task) (Stachenfeld et al. 2017). In addition, the parahippocampus (PHC), which is anatomically and functionally related to the HC (Insausti and Amaral 2012), is involved in encoding map-like representations. The PHC was related to the reorientation using landmarks when navigating in a physical space with map-like representation (Sutton et al. 2012). ...
The hippocampus (HC) and the orbitofrontal cortex (OFC) jointly encode a map-like representation of a task space to guide behavior. It remains unclear how the OFC and HC interact in encoding this map-like representation, though previous studies indicated that both regions have different functions. We acquired the functional magnetic resonance imaging data under a social navigation task in which participants interacted with characters in a two-dimensional "social space." We calculate the social relationships between the participants and characters and used a drift-diffusion model to capture the inner process of social interaction. Then we used multivoxel pattern analysis to explore the brain-behavior relationship. We found that (i) both the HC and the OFC showed higher activations during the selective trial than the narrative trial; (ii) the neural pattern of the right HC was associated with evidence accumulation during social interaction, and the pattern of the right lateral OFC was associated with the social relationship; (iii) the neural pattern of the HC can decode the participants choices, while the neural pattern of the OFC can decode the task information about trials. The study provided evidence for distinct roles of the HC and the OFC in encoding different information when representing social space.
... Briefly, 47 coronal T1 sections of the whole brain with an individual thickness of 4 mm were used to determine individual lesion size. The extent of each lesion was determined from rostral to caudal using previously proposed landmarks [74][75][76][77] . ...
Efficient navigation is supported by a cognitive map of space. The hippocampus plays a key role for this map by linking multimodal sensory information with spatial memory representations. However, in human navigation studies, the full range of sensory information is often unavailable due to the stationarity of experimental setups. We investigated the contribution of multisensory information to memory-guided spatial navigation by presenting a virtual version of the Morris water maze on a screen and in an immersive mobile virtual reality setup. Patients with hippocampal lesions and matched controls navigated to memorized object locations in relation to surrounding landmarks. Our results show that availability of multisensory input improves memory-guided spatial navigation in both groups. It has distinct effects on navigational behaviour, with greater improvement in spatial memory performance in patients. We conclude that congruent multisensory information shifts computations to extrahippocampal areas that support spatial navigation and compensates for spatial navigation deficits.
... Future approaches might investigate the application of deep learning to quantify pyramidal neurons in 3D. Fourth, our study adhered to common practice and assessed the hippocampus at the coronal plane, which is in plane with the orientation of human hippocampal pyramidal neurons 7,8,[62][63][64] . A small fraction of neurons may be oriented nonparallel to the plane and might consequently be excluded as neuron profiles. ...
Hippocampal subregions differ in specialization and vulnerability to cell death. Neuron death and hippocampal atrophy have been a marker for the progression of Alzheimer’s disease. Relatively few studies have examined neuronal loss in the human brain using stereology. We characterize an automated high-throughput deep learning pipeline to segment hippocampal pyramidal neurons, generate pyramidal neuron estimates within the human hippocampal subfields, and relate our results to stereology neuron counts. Based on seven cases and 168 partitions, we vet deep learning parameters to segment hippocampal pyramidal neurons from the background using the open-source CellPose algorithm, and show the automated removal of false-positive segmentations. There was no difference in Dice scores between neurons segmented by the deep learning pipeline and manual segmentations (Independent Samples t-Test: t(28) = 0.33, p = 0.742). Deep-learning neuron estimates strongly correlate with manual stereological counts per subregion (Spearman’s correlation (n = 9): r(7) = 0.97, p < 0.001), and for each partition individually (Spearman’s correlation (n = 168): r(166) = 0.90, p <0 .001). The high-throughput deep-learning pipeline provides validation to existing standards. This deep learning approach may benefit future studies in tracking baseline and resilient healthy aging to the earliest disease progression.
... The hippocampus is a complex structure composed of multiple subfields (cornu ammonis [CA] areas 1 to 4, dentate gyrus, and subiculum) that are distributed disproportionately along its longitudinal axis (head, body, tail) (45,46). These regions show protracted development as a result of prolonged neurogenesis, synaptic growth, dendritic arborization, pruning, vascularization, and myelination (47)(48)(49). ...
The transition from multiple sleep bouts each day to a single overnight sleep bout (i.e., nap transition) is a universal process in human development. Naps are important during infancy and early childhood as they enhance learning through memory consolidation. However, a normal part of development is the transition out of naps. Understanding nap transitions is essential in order to maximize early learning and promote positive long-term cognitive outcomes. Here, we propose a novel hypothesis regarding the cognitive, physiological, and neural changes that accompany nap transitions. Specifically, we posit that maturation of the hippocampal-dependent memory network results in more efficient memory storage, which reduces the buildup of homeostatic sleep pressure across the cortex (as reflected by slow-wave activity), and eventually, contributes to nap transitions. This hypothesis synthesizes evidence of bioregulatory mechanisms underlying nap transitions and sheds new light on an important window of change in development. This framework can be used to evaluate multiple untested predictions from the field of sleep science and ultimately, yield science-based guidelines and policies regarding napping in childcare and early education settings.
... First, hippocampal sections were manually segmented by a trained investigator (SA) into individual subfields in the hematoxylin channel, blinded to density of tau immunoreactivity and clinical group, in the QuPath software using anatomically defined boundaries [1] as described previously [10]. Briefly, hippocampal subfields of interest segmented included dentate gyrus (DG); cornu ammonis (CA) subfields CA4, CA3, CA2, and CA1; subiculum; and entorhinal cortex (ERC) based on the cytoarchitectural features of the layers and anatomical landmarks [12,24]. The general features used for the segmentations were as follow: DG segmentation represented the granular layer of dentate gyrus. ...
Alzheimer’s disease neuropathologic change (ADNC) is clinically heterogenous and can present with a classic multidomain amnestic syndrome or focal non-amnestic syndromes. Here, we investigated the distribution and burden of phosphorylated and C-terminally cleaved tau pathologies across hippocampal subfields and cortical regions among phenotypic variants of Alzheimer’s disease (AD). In this study, autopsy-confirmed patients with ADNC, were classified into amnestic (aAD, N = 40) and non-amnestic (naAD, N = 39) groups based on clinical criteria. We performed digital assessment of tissue sections immunostained for phosphorylated-tau (AT8 detects pretangles and mature tangles), D⁴²¹-truncated tau (TauC3, a marker for mature tangles and ghost tangles), and E³⁹¹-truncated tau (MN423, a marker that primarily detects ghost tangles), in hippocampal subfields and three cortical regions. Linear mixed-effect models were used to test regional and group differences while adjusting for demographics. Both groups showed AT8-reactivity across hippocampal subfields that mirrored traditional Braak staging with higher burden of phosphorylated-tau in subregions implicated as affected early in Braak staging. The burden of phosphorylated-tau and TauC3-immunoreactive tau in the hippocampus was largely similar between the aAD and naAD groups. In contrast, the naAD group had lower relative distribution of MN423-reactive tangles in CA1 (β = − 0.2, SE = 0.09, p = 0.001) and CA2 (β = − 0.25, SE = 0.09, p = 0.005) compared to the aAD. While the two groups had similar levels of phosphorylated-tau pathology in cortical regions, there was higher burden of TauC3 reactivity in sup/mid temporal cortex (β = 0.16, SE = 0.07, p = 0.02) and MN423 reactivity in all cortical regions (β = 0.4–0.43, SE = 0.09, p < 0.001) in the naAD compared to aAD. In conclusion, AD clinical variants may have a signature distribution of overall phosphorylated-tau pathology within the hippocampus reflecting traditional Braak staging; however, non-amnestic AD has greater relative mature tangle pathology in the neocortex compared to patients with clinical amnestic AD, where the hippocampus had greatest relative burden of C-terminally cleaved tau reactivity. Thus, varying neuronal susceptibility to tau-mediated neurodegeneration may influence the clinical expression of ADNC.
... These ROIs are flattened into two-dimensional space based on metric multidimensional scaling after the manual masking of cerebrospinal fluid (CSF) and white matter. Before their mathematical projection to the flattened cortical maps, regional boundaries are specified using histological and MRI atlases [35,36]. Mean thickness in each subregion was computed by averaging the thickness across all 2-D voxels within each ROI. ...
Background:
The olfactory system is affected early in Alzheimer's disease and olfactory loss can already be observed in patients with mild cognitive impairment (MCI). Olfactory training is effective for improving olfactory and cognitive function by stimulating the olfactory pathway, but its effect on patients with MCI remains unclear.
Objective:
The aim of this randomized, prospective, controlled, blinded study was to assess whether a 4-month period of olfactory training (frequent short-term sniffing various odors) may have an effect on olfactory function, cognitive function, and morphology of medial temporal lobe (MTL) subregions and olfactory bulb in MCI patients.
Methods:
A total of thirty-seven MCI patients were randomly assigned to the training group or a placebo group, which were performed twice a day for 4 months. Olfactory assessments, cognitive tests and magnetic resonance imaging were performed at the baseline and follow-up period.
Results:
After the training, there was an increase in odor discrimination, and increased cortical thickness of bilateral hippocampus (CA23DG and CA1) and mean MTL. Additionally, the change of olfactory score was positively associated with change of volume of olfactory bulb and hippocampus; the change of global cognition was positively associated with change of cortical thickness of hippocampus, entorhinal cortex and mean MTL; the change of cortical thickness of entorhinal cortex was positively associated with change of executive function.
Conclusion:
Olfactory training was associated with an increase in cortical thickness of the hippocampus but not olfactory bulb volume in patients with MCI. Olfactory training may serve as an early intervention of preventing hippocampal atrophy.
... To establish a multiregional pattern of developmental and age-and AD-associated changes, 14 brain regions were examined, including structures found to be involved in intellectual deficits, memory loss, and a broad spectrum of functional declines. The study of the memory system included early and severely affected EC (all layers), and most affected islands of stellate neurons in the second layer delineated by using Amaral and Insausti anatomical criteria [2]. To compare patterns of pathology in different cytoarchitectural subdivisions of the hippocampus, cornu Ammonis (CA) sectors CA1, 2, 3, and 4 and the subiculum were examined by using the anatomical criteria of Rosene and van Hoesen [71] and Duvernoy [19]. ...
The increased life expectancy of individuals with Down syndrome (DS) is associated with increased prevalence of trisomy 21–linked early-onset Alzheimer’s disease (EOAD) and dementia. The aims of this study of 14 brain regions including the entorhinal cortex, hippocampus, basal ganglia, and cerebellum in 33 adults with DS 26–72 years of age were to identify the magnitude of brain region–specific developmental neuronal deficits contributing to intellectual deficits, to apply this baseline to identification of the topography and magnitude of neurodegeneration and neuronal and volume losses caused by EOAD, and to establish age-based staging of the pattern of genetically driven neuropathology in DS. Both DS subject age and stage of dementia, themselves very strongly correlated, were strong predictors of an AD-associated decrease of the number of neurons, considered a major contributor to dementia. The DS cohort was subclassified by age as pre-AD stage, with 26–41-year-old subjects with a full spectrum of developmental deficit but with very limited incipient AD pathology, and 43–49, 51–59, and 61–72-year-old groups with predominant prevalence of mild, moderately severe, and severe dementia respectively. This multiregional study revealed a 28.1% developmental neuronal deficit in DS subjects 26–41 years of age and 11.9% AD-associated neuronal loss in DS subjects 43–49 years of age; a 28.0% maximum neuronal loss at 51–59 years of age; and a 11.0% minimum neuronal loss at 61–72 years of age. A total developmental neuronal deficit of 40.8 million neurons and AD-associated neuronal loss of 41.6 million neurons reflect a comparable magnitude of developmental neuronal deficit contributing to intellectual deficits, and AD-associated neuronal loss contributing to dementia. This highly predictable pattern of pathology indicates that successful treatment of DS subjects in the fourth decade of life may prevent AD pathology and functional decline.
... The hippocampal formation t the Cornu Ammonis (CA1, CA2, CA3 and CA4), the Dentate Gyrus (DG) and the Subiculum (SUB) subfields. These subfields are relatively small (in humans ∼1 mm in cross section; Insausti & Amaral, 2003), and furthermore, they show an intricate pattern of folding that is preserved along the long-axis of the hippocampus (see Figure 1). The differences in cell morphology and connectivity of these subfields have motivated proposals regarding their functional differences (Marr, 1971;McClelland et al., 1995;Yassa et al., 2011). ...
Many neuro‐imaging studies have shown that the hippocampus participates in a resting‐state network called the default mode network. However, how the hippocampus connects to the default mode network, whether the hippocampus connects to any other resting‐state network, and how the different hippocampal subfields take part in resting‐state networks remains poorly understood. Here we examined these issues using the high spatial‐resolution 7T resting‐state fMRI dataset from the Human Connectome Project. We used data‐driven techniques that relied on spatially‐restricted Independent Component Analysis, Dual Regression, and linear mixed‐effect group‐analyses based on participant‐specific brain morphology. The results revealed two main activity hotspots inside the hippocampus. The first hotspot was located in an anterior location and was correlated with the somatomotor network. This network was subserved by co‐activity in the CA1, CA3, CA4 and Dentate Gyrus fields. In addition, there was an activity hotspot that extended from middle to posterior locations along the hippocampal long‐axis and correlated with the default mode network. This network reflected activity in the Subiculum, CA4 and Dentate Gyrus fields. These results show how different sections of the hippocampus participate in two known resting‐state networks, and how these two resting‐state networks depend on different configurations of hippocampal subfield co‐activity.
... The word hippocampus meaning seahorse, was first coined by Arantius in 1587 to describe the arch-shaped, 4-4.5cm long, grey matter structure lying bilaterally in the medial temporal lobe of the brain. The hippocampal formation comprises two cortical laminae rolled up, one inside the other, the dentate gyrus and the cornu ammonis or ■ general three-dimensional appearance of the hippocampus is similar to a seahorse (Duvemoy, 1988;Amaral & Insausti, 1990). It is arched around the mesencephalon and bulges in to the temporal horn of the lateral ventricle. ...
The GABAA/central benzodiazepine receptor (cBZR) complex is a major inhibitory receptor in the vertebrate CNS. A functional impairment of GABAergic inhibition has been proposed as one mechanism which may underlie increased seizure susceptibility in human temporal lobe epilepsy (TLE). The objective of this study was to characterise abnormalities of the GABAA/cBZR in TLE with a correlative autoradiography, in-situ hybridisation, immunohistochemistry and quantitative neuropathology study. Hippocampal tissue was obtained at surgery from patients with intractable TLE due to hippocampal sclerosis (HS) and autopsies of neurologically normal controls. Neuronal densities were obtained using a 3-D counting method in paraffin-embedded sections. Saturation autoradiographic studies were performed on cryostat sections using [3H]-flumazenil and expression of mRNA encoding the α1-α6, β3 and γ2 subunits of the GABAA receptor was assessed using in-situ hybridisation histochemistry. Distribution of the receptor protein was also determined using immunohistochemistry with antibodies to the GABAA α1 and β2/3 subunits. A significant decrease in central benzodiazepine binding sites was demonstrated in all subfields of the human hippocampus in HS. This loss of cBZR binding sites would appear to be due primarily to changes in neuronal density characteristic of this pathology. However, in the CA 1 subfield, a reduced BZ receptor concentration was evident on surviving neurones in the HS group (p<0.05). Expression of mRNA encoding GABAA receptor subunits α1, α2, α4, α5, and γ2, was upregulated in surviving neurones of the granule cell layer of the dentate gyrus in HS. In addition, epilepsy-associated increases in the expression of mRNA encoding the α1 subunit were observed in the hilus and CA2 and α2 mRNA in the hilus and CA1. In contrast, an apparent decrease in expression of β3 mRNA per neurone was detected in CA1 in HS (p<0.07) and of γ2 in the CA2 in HS (p<0.10). These findings imply a functional abnormality of the GABAA/CBZR complex that may have a role in the pathophysiology of epileptogenicity in HS.
... U brojnim studijama u kojima je korišteno funkcionalno oslikavanje mozga potvrđena je uloga medijalnog temporalnog režnja u leksičko-semantičkoj obradi, preciznije rečeno, to se pokazalo u zadacima određivanja značenja pojma (Martin i sur. , 1999;Chao i sur., 1999;Perani i sur., 1999) i ventralne okcipitotemporalne regije ( Murtha i sur., 1999;Ricci i sur., 1999;Ishai i sur., 2000) kao i medijalni temporalni režanj (Amaral i Insausti, 1990). Psiholingvistička istraživanja pokazuju da epileptička izbijanja mogu dovesti do disfunkcije neuralne komunikacije i oštećenja semantičkog sustava zbog smanjene funkcionalne povezanosti između jezičnih regija. ...
Cilj ovog rada bio je istražiti neuralne korelate leksičko-semantičke obrade odabranih leksičkosemantičkih odnosa apstraktnosti i konkretnosti. U ovom je istraživanju epilepsija medijalnog temporalnog režnja uzeta kao model leksičko-semantičkih deficita zbog anatomske i funkcionalne specifičnosti lezije. Testiranjem se istraživala specifična leksičko-semantička reorganizacija s obzirom na hemisferne razlike. U istraživanju je sudjelovalo četrdeset osoba s dijagnosticiranom lateraliziranom epilepsijom medijalnog temporalnog režnja i usporedna skupina koja je izjednačena s pacijentima po dobi, spolu te dominantnoj hemisferi. Primjenom E-prime programa testirana je točnost i vrijeme leksičko-semantičke obrade apstraktnosti, odnosno konkretnosti. Za potrebe eksperimenta konstruirana je lista od ukupno 92 riječi, 46 parova od kojih je bilo 46 konkretnih i 46 apstraktnih riječi. Ispitni materijal sastojao se od konkretnih riječi s povezanim leksičko-semantičkim kategorijama i s nepovezanim leksičkosemantičkim kategorijama te apstraktne riječi s povezanim leksičko-semantičkim kategorijama i s nepovezanim leksičko-semantičkim kategorijama. Rezultati su pokazali specifičnosti odabranih leksičko-semantičkih kategorija te potvrdili da lezija dominantnog i dominantnog medijalnog temporalnog režnja utječe na leksičko-semantičku obradu apstraktnih i konkretnih riječi. Također, može se zaključiti da epileptička izbijanja mogu dovesti do disfunkcije neuralne komunikacije i oštećenja semantičkog sustava zbog smanjene funkcionalne povezanosti između jezičnih regija.
... The study of the hippocampus volume is of great interest as it is a valuable tool for follow-up and treatment adjustment (Jack et al., 2000;Jack et al., 2005;Dickerson and Sperling, 2005). However, the HC anatomy is complex and variable, and the limits between different subfields have been described in the neuroanatomy literature using cytoarchitectonic features that require histological staining and microscopic resolution to visualize (Insausti and Amaral, 2004). ...
The importance of the hippocampus in the study of several neurodegenerative diseases such as Alzheimer's disease makes it a structure of great interest in neuroimaging. However, few segmentation methods have been proposed to measure its subfields due to its complex structure and the lack of high resolution magnetic resonance (MR) data. In this work, we present a new pipeline for automatic hippocampus subfield segmentation using two available hippocampus subfield delineation protocols that can work with both high and standard resolution data. The proposed method is based on multi-atlas label fusion technology that benefits from a novel multi-contrast patch match search process (using high resolution T1-weighted and T2-weighted images). The proposed method also includes as post-processing a new neural network-based error correction step to minimize systematic segmentation errors. The method has been evaluated on both high and standard resolution images and compared to other state-of-the-art methods showing better results in terms of accuracy and execution time.
... The perirhinal cortex (PRC), lying in the anteromedial temporal lobe, corresponds to Brodmann areas (BA) 35 and 36. Medially, it borders the ERC (BA 28) and anterolaterally, the temporopolar cortex (TPC) (Amaral & Insausti, 1990;Insausti et al., 1998). Although traditionally referred to as BA 38, the ventromedial aspect of the temporal pole has come to be regarded as an extension of BA 36 (Suzuki & Amaral, 1994a,b;Saleem & Tanaka, 1996), and hence part of the 'total perirhinal cortex' (Insausti et al., 1998). ...
Studies in macaque monkeys indicate that the perirhinal cortex in the temporal lobe participates in object memory. This function may be analogous to aspects of human semantic memory (knowledge of objects, concepts, faces and words). To date, the status of perirhinal cortex has not specifically been investigated in patients with semantic deficits as seen in semantic dementia, the temporal lobe variant of frontotemporal dementia. High-resolution three-dimensional magnetic resonance imaging was performed in subjects with semantic dementia and Alzheimer's disease (characterized in its early stages by selective episodic memory impairment) and in healthy age-matched controls. Hippocampal, perirhinal, temporopolar and entorhinal cortex volumes were measured by outlining areas on successive scan slices according to recognized landmarks. The entorhinal and hippocampal regions were further subdivided into anterior and posterior parts. In keeping with the hypothesized contribution of the perirhinal cortex to semantic memory function, we found greater involvement of this region, together with the temporopolar and anterior entorhinal cortices, in semantic dementia than in either Alzheimer's disease patients or control subjects. Performance on a range of semantic tests also correlated with perirhinal volume. Bilateral reduction in hippocampal volume compared with controls was seen in Alzheimer's disease. In conclusion, atrophy of the human perirhinal cortex, and of directly connected areas, was associated with semantic memory impairment but not episodic memory impairment, as predicted from the primate work.
... The perirhinal cortex, in particular, has a complex anatomy in that it occupies a strip extending from the medial temporal pole rostrally along the banks of the collateral sulcus, making it particularly difficult to delineate. 52,54 Second, it is possible that the voxel-by-voxel method used here may not offer the resolution to settle these issues. Although the technique seems ideal for mapping the distribution of definite abnormality and for correlating such regions with the extent of cognitive deficit, it is clearly much more difficult to conclude that certain regions are normal, especially if these are small with complex anatomy. ...
The cortical anatomy of 6 patients with semantic dementia (the temporal lobe variant of frontotemporal dementia) was contrasted with that of a group of age-matched normal subjects by using voxel-based morphometry, a technique that identifies changes in gray matter volume on a voxel-by-voxel basis. Among the circumscribed regions of neuronal loss, the left temporal pole (Brodmann area 38) was the most significantly and consistently affected region. Cortical atrophy in the left hemisphere also involved the inferolateral temporal lobe (Brodmann area 20/21) and fusiform gyrus. In addition, the right temporal pole (Brodmann area 38), the ventromedial frontal cortex (Brodmann area 11/32) bilaterally , and the amygdaloid complex were affected, but no significant atrophy was measured in the hippocampus, entorhi-nal, or caudal perirhinal cortex. The degree of semantic memory impairment across the 6 cases correlated significantly with the extent of atrophy of the left anterior temporal lobe but not with atrophy in the adjacent ventromedial frontal cortex. These results confirm that the anterior temporal lobe is critically involved in semantic processing, and dissociate its function from that of the adjacent frontal region. Mummery CJ, Patterson K, Price CJ, Ashburner J, Frackowiak RSJ, Hodges JR. A voxel-based morphometry study of semantic dementia: relationship between temporal lobe atrophy and semantic memory.
... One explanation for these counterintuitive findings is that given that the hippocampus is a large structure , stimulation delivered to one part of it would not have striking effects on memory as hippocampal lesions do. Indeed, each hippocampal anatomical subfield (i.e., dentate gyrus, CA23, CA1, and subiculum) may have distinct subfunctions in memory (Amaral & Insausti, 1990; Hoge & Kesner, 2007; Stokes, Kyle, & Ekstrom, 2014). Thus, depending on which subfield (and which layer, or the anterior vs. posterior hippocampus) is stimulated, the observed effects may differ. ...
... The layer VI contains neurons of various sizes and shape. 4 It is generally accepted that PC consists of rostral part or perirhinal cortex (PRh), middle portion or entorinal cortex (EC) and caudal portion or posterior parahippocampal cortex (PPC). External morphology of MTR is characterized by rhinal groove anterolaterally and collateral groove posterolaterally. ...
Introduction/Aim: Aging of the parahippocampal cortex is accompanied by atrophy. The most common changes include cell number reduction, formation of corpora amylacea in astrocytes, which may represent the basis for the development of cognitive dysfunction. The aim of this study was to detect presence and distribution of corpora amylacea in subpial and subcortical region of parahippocampal cortex during aging process using histochemical analysis as well as to carry out quantification of structural changes in different cortical layers using histochemical and immunohistochemical methods. Material and Methods: Material represents tissue of uncus of parahippocampal gyrus of right cerebral hemisphere of 30 cadavers taken from autopsies carried out at the Forensic Medicine Institute of the Niš Faculty of Medicine. Upon tissue preparation using standard histological procedures, 10 μm thick sections were made and stained with hematoxylin eosin and periodically with acid Schiff's method. The total number of 30 samples, 16 to 93 years of age, was analyzed. Results: During the normal aging process in parahippocampal cortex the number of corpora amylacea localized in subpial region increases, and it is even greater in subcortical white matter, with no significant change in size and shape. Positive reaction to neuron specific enolase, determined by immunohistochemical methods suggests the presence of neural components, while a weaker reaction to glial acid protein and positive one to S100 protein suggests the possibility that the corpora amylacea are astrocyte inclusion. Conclusion: The obtained results indicates that the presence of these structural changes may lead to damage of those brain structures responsible for normal memory function and thus responsible for cognitive changes present in healthy elderly individuals.
... The slides were covered and examined under a light microscope. The subdivisions of the hippocampus are in accordance with the work of Lorente de Nó (Lorente de Nó, 1934) with the modifications suggested by Amaral and Insausti (Amaral and Insausti, 1990). In brief, the hippocampus is divided into (a) the subiculum, (b) the Ammon's horn (hippocampus proper), which comprises fields CA1-3, and (c) the dentate gyrus, which includes the molecular layer, granule cell layer, and polymorphic layer of the hilus. ...
Loss of glutamine synthetase (GS) in hippocampal astrocytes has been implicated in the causation of human mesial temporal lobe epilepsy (MTLE). However, the mechanism by which the deficiency in GS leads to epilepsy is incompletely understood. Here we ask how hippocampal GS inhibition affects seizure phenotype and neuronal activation during epilepsy development (epileptogenesis). Epileptogenesis was induced by infusing the irreversible GS blocker methionine sulfoximine (MSO) unilaterally into the hippocampal formation of rats. We then used continuous video-intracranial electroencephalogram (EEG) monitoring and c-Fos immunohistochemistry to determine the type of seizures and spatial distribution of neuronal activation early (1–5 days postinfusion) and late (16–43 days postinfusion) in epileptogenesis. Early in epileptogenesis, seizures were preferentially mild (stage 1–2), activating neurons in the entorhinal-hippocampal area, the basolateral amygdala, the piriform cortex, the midline thalamus, and the anterior olfactory area. Late in epileptogenesis, the seizures were generally more severe (stages 4–5) with neuronal activation extending to the neocortex, the bed nucleus of the stria terminalis, the mediodorsal thalamus, and the central nucleus of the amygdala. Our findings demonstrate that inhibition of GS focally in the hippocampal formation triggers a process of epileptogenesis characterized by gradual worsening of seizure severity and involvement of progressively larger neuronal populations over a period of several weeks. Knowledge about the underlying mechanism of epileptogenesis is important because such knowledge may result in more specific and efficacious treatments of MTLE by moving away from large and poorly specific surgical resections to highly targeted surgical or pharmacological interventions of the epileptogenic process.
... It is known that the HF has two main pathways: the polysynaptic pathway and the direct pathway (see Duvernoy et al. (2013) for review). Briefly, the polysynaptic pathway originates in the entorhinal cortex (Amaral and Insausti, 1990) and perforates the subiculum in order to synapse on the DG. From here, axons from the DG then synapse on those present in the CA4 and CA3. ...
... The fornix is a heavily myelinated tract, which connects the hippocampal formation with the septum, anterior thalamus, and hypothalamus. The precommissural fibers connect to interstitial nucleus of stria teminalis, accumbens, anterior olfactory nucleus, nucleus of the diagonal band, and preoptic areas, while postcommissural fibers connect to thalamus, hypothalamus, and midbrain (Insausti and Amaral, 2004). Lesions of the fornix have disruptive effects on the connectivity of the hippocampus, and result in deficits in memory formation ( Gupta et al., 2014;Dumont et al., 2015). ...
The hippocampus has a unique microarchitecture, is situated at the nexus of multiple macroscale functional networks, contributes to numerous cognitive as well as affective processes, and is highly susceptible to brain pathology across common disorders. These features make the hippocampus a model to understand how brain structure covaries with function, in both health and disease. Here, we introduce HippoMaps, an open access toolbox and online data warehouse for the mapping and contextualization of hippocampal data in the human brain (http://hippomaps.readthedocs.io). HippoMaps capitalizes on a novel hippocampal unfolding approach as well as shape intrinsic registration capabilities to allow for cross-subject and cross-modal data aggregation. We initialize this repository with data spanning 3D post-mortem histology, ex-vivo 9.4 Tesla MRI, as well as in-vivo structural MRI and resting-state functional MRI (rsfMRI) obtained at 3 and 7 Tesla, together with intracranial encephalography (iEEG) recordings in epilepsy patients. HippoMaps also contains validated tools for spatial map association analysis in the hippocampus that correct for autocorrelation. All code and data are compliant with community standards, and comprehensive online tutorials facilitate broad adoption. Applications of this work span methodologies and modalities, spatial scales, as well as clinical and basic research contexts, and we encourage community feedback and contributions in the spirit of open and iterative scientific resource development.
The hippocampus has a unique microarchitecture, is situated at the nexus of multiple macroscale functional networks, contributes to numerous cognitive as well as affective processes, and is highly susceptible to brain pathology across common disorders. These features make the hippocampus a model to understand how brain structure covaries with function, in both health and disease. Here, we introduce HippoMaps, an open access toolbox and online data warehouse for the mapping and contextualization of hippocampal data in the human brain (http://hippomaps.readthedocs.io). HippoMaps capitalizes on a novel hippocampal unfolding approach as well as shape intrinsic registration capabilities to allow for cross-subject and cross-modal data aggregation. We initialize this repository with data spanning 3D post-mortem histology, ex-vivo 9.4 Tesla MRI, as well as in-vivo structural MRI and resting-state functional MRI (rsfMRI) obtained at 3 and 7 Tesla, together with intracranial encephalography (iEEG) recordings in epilepsy patients. HippoMaps also contains validated tools for spatial map association analysis in the hippocampus that correct for autocorrelation. All code and data are compliant with community standards, and comprehensive online tutorials facilitate broad adoption. Applications of this work span methodologies and modalities, spatial scales, as well as clinical and basic research contexts, and we encourage community feedback and contributions in the spirit of open and iterative scientific resource development.
Dendritic spine features in human neurons follow the up-to-date knowledge presented in the previous chapters of this book. Human dendrites are notable for their heterogeneity in branching patterns and spatial distribution. These data relate to circuits and specialized functions. Spines enhance neuronal connectivity, modulate and integrate synaptic inputs, and provide additional plastic functions to microcircuits and large-scale networks. Spines present a continuum of shapes and sizes, whose number and distribution along the dendritic length are diverse in neurons and different areas. Indeed, human neurons vary from aspiny or “relatively aspiny” cells to neurons covered with a high density of intermingled pleomorphic spines on very long dendrites. In this chapter, we discuss the phylogenetic and ontogenetic development of human spines and describe the heterogeneous features of human spiny neurons along the spinal cord, brainstem, cerebellum, thalamus, basal ganglia, amygdala, hippocampal regions, and neocortical areas. Three-dimensional reconstructions of Golgi-impregnated dendritic spines and data from fluorescence microscopy are reviewed with ultrastructural findings to address the complex possibilities for synaptic processing and integration in humans. Pathological changes are also presented, for example, in Alzheimer’s disease and schizophrenia. Basic morphological data can be linked to current techniques, and perspectives in this research field include the characterization of spines in human neurons with specific transcriptome features, molecular classification of cellular diversity, and electrophysiological identification of coexisting subpopulations of cells. These data would enlighten how cellular attributes determine neuron type-specific connectivity and brain wiring for our diverse aptitudes and behavior.
in the series of publications, which this article opens, we consider five fundamental neuromorphological observations of our compatriot, the classic of world neuroscience, Volodymr Betz. For four of them, we demonstrate the status of discoveries for the first time, for the other one — the giant pyramidal neurons of the motor cortex — despite its widespread and long-standing recognition, we reveal the limitations of modern knowledge and ideas. Two of the mentioned observations — giant fusiform, or spindle-shaped neurons of the cingulate and insular cortex and islands of the entorhinal cortex — are currently known only to a narrow circle of specialists; to the others two, islands of Calleja and signs of the columnar cortex organization, we pay attention for the first time. In this, the initial part of the series, exposing modern apprehensions about the structure and functions of the entorhinal cortex, we demonstrate the weight of Betz's pioneering observation of extraordinary neuron clusters, which are nowadays known as entorhinal islands, and prove the fact of recognizing his historical priority in the description of these amazing brain structures.
Neurodegeneration in Alzheimer's disease continuum (ADC) starts from the transentorhinal cortex and progresses within hippocampal circuitry following the connectivity of its subfields transsynaptically. We aimed to track volumet-ric changes of the hippocampal subfields by comparing three stages of the ADC. MRI data of 15 patients diagnosed with Alzheimer's disease dementia (ADD), 15 patients with amnestic mild cognitive impairment (MCI), and 15 individuals with subjective cognitive impairment (SCI) were analyzed. The hippocampal formation was subdivided into CA1, CA3, subiculum (SUB), and dentate gyrus (DG) using FreeSurfer and volumetric values were obtained. The volumetric values were analyzed with ANCOVA and intracranial volume was selected as a covariate. ANCOVA results of the hippocampal subfields displayed statistically significant differences among the three groups in bilateral CA1, SUB, and DG volumes (Right CA1: F = 7.316, p = 0.002; left CA1: F = 6.768, p = 0.003; right SUB: F = 9.390, p < 0.001; left SUB: F = 5.925, p = 0.005; right DG: F = 9.469, p < 0.001; left DG: F = 9.354, p < 0.001), while CA3 volumes were not significantly different among the groups. Post hoc comparisons revealed that volume reductions in bilateral CA1, DG, and SUB were present in ADD compared to both MCI and SCI groups. No significant volumetric changes were found between the SCI and MCI groups. While our results are generally consistent with the literature in terms of the CA1 and SUB findings, they additionally point to the importance of the significant volume loss in DG and the resilience of the CA3 sector.
Emotions are valenced mental responses and associated physiological reactions that occur spontaneously and automatically in response to internal or external stimuli, and can influence our behavior, and can themselves be modulated to a certain degree voluntarily or by external stimuli. They are subserved by large-scale integrated neuronal networks with epicenters in the amygdala and the hippocampus, and which overlap in the anterior cingulate cortex. Although emotion processing is accepted as being lateralized, the specific role of each hemisphere remains an issue of controversy, and two major hypotheses have been proposed. In the right-hemispheric dominance hypothesis, all emotions are thought to be processed in the right hemisphere, independent of their valence or of the emotional feeling being processed. In the valence lateralization hypothesis, the left is thought to be dominant for the processing of positively valenced stimuli, or of stimuli inducing approach behaviors, whereas negatively valenced stimuli, or stimuli inducing withdrawal behaviors, would be processed in the right hemisphere. More recent research points at the existence of multiple interrelated networks, each associated with the processing of a specific component of emotion generation, i.e., its generation, perception, and regulation. It has thus been proposed to move from hypotheses supporting an overall hemispheric specialization for emotion processing toward dynamic models incorporating multiple interrelated networks which do not necessarily share the same lateralization patterns.
The entorhinal cortex (EC) is especially vulnerable in the early stages of Alzheimer's disease (AD). In particular, cognitive deficits have been linked to alterations in the upper layers of EC. In the present report, we examined layers II and III from eight human brain autopsies (four subjects with no recorded neurological alterations and four AD cases). We used stereological methods to assess cortical atrophy of the EC, and possible changes in the volume occupied by different cortical elements (neuronal and glial cell bodies; blood vessels; and neuropil). We performed 3D ultrastructural analyses of synapses using Focused Ion Beam/Scanning Electron Microscopy (FIB/SEM) to examine possible alterations related to AD.At the light microscope level, we found a significantly lower volume fraction occupied by neuronal bodies in layer III and a higher volume fraction occupied by glial cell bodies in layer II in AD cases. At the ultrastructural level we observed that (i) there was a significantly lower synaptic density in both layers in AD cases; (ii) synapses were larger and more complex in layer II in AD cases; and (iii) there was a greater proportion of small and simple synapses in layer III in AD cases than in control individuals. These structural differences may play a role in the anatomical basis for the impairment of cognitive functions in AD.Significant StatementAnalysis of the synaptic characteristics provides critical data on synaptic organization. Using 3D electron microscopy, the present study shows the synaptic organization of the neuropil of the human entorhinal cortex (EC) at the ultrastructural level. The EC is especially vulnerable in the early stages of Alzheimer's disease (AD). Our present results show structural differences that may contribute as anatomical basis for the impairment of cognitive functions in AD. Thus, these results may help to understand the relationship between alterations of the synaptic circuits and the cognitive deterioration in AD.
In a large series of 413 epilepsy surgical resections from the National Hospital, hippocampal sclerosis was the commonest pathology identified in 60% of cases. Microdysgenesis is a complex microscopic cortical malformation recognised in association with hippocampal sclerosis in epilepsy, but its incidence, relationship to hippocampal sclerosis and functional relevance to epileptogenesis remain unknown. This is largely due to a lack of well-defined diagnostic criteria. To address this a stereological quantitative analysis of several components of microdysgenesis was carried out. White matter, cortical and layer I neuronal densities (ND) were measured in 31 surgical temporal lobectomies using immunohistochemistry for neuronal marker NeuN. Patients with seizure-free postoperative outcomes showed significantly more microdysgenetic features, including high white matter ND (P 0.05) or layer I ND (P 0.05). Mean white matter ND of 2164/mm3 were observed in epilepsy patients. There was no correlation between layer I and white matter ND suggesting that they may represent separate developmental abnormalities. Abnormal patterns of cortical myelination were also identified in microdysgenesis. Cyto-architectural abnormalities in analysis of 206 hippocampal specimens included disorganisation of dentate granule cells in 40% and cytoskeletal abnormalities in residual hilar cells in 55%. Granule cell disorganisation correlated with the degree of hippocampal neuronal loss suggesting an acquired rather than developmental lesion. Stereological quantitation of granule cells showed an overall cell loss, but greater numbers in regions of disorganisation, which may indicate enhanced neurogenesis. Quantitation of Cajal- Retzius cells showed increased numbers in hippocampal sclerosis and microdysgenesis compared to controls. Abnormalities in the cyto-architectural distribution of inhibitory interneurones were observed in microdysgenesis and focal cortical dysplasia in epilepsy, which may represent adaptive changes. In summary, the findings suggest that microdysgenesis may be a significant lesion in temporal lobe epilepsy in terms of post-surgical prognosis and quantitation allows a more precise definition. Increased Cajal-Retzius cells in hippocampal sclerosis and microdysgenesis may indicate a common developmental process involving the reelin pathway.
During the last decades, there have been tremendous technical developments to study the human central nervous system (CNS) and its connectivity. Modern imaging techniques such as positron emission tomography (PET) and functional magnetic resonance imaging (fMRI) have greatly improved our knowledge of the circuitry of the human CNS. New developments in MR imaging, especially diffusion MRI (“tractography”), allow the visualization of at least the major fibre connections in the human CNS. The second edition of Clinical Neuroanatomy tries to bridge the gap between neuroanatomy and clinical neurology and emphazises human and primate data in the context of the many disorders of brain circuitry so common in neurological practice. In this introductory chapter, an overview is presented of the macroscopy (► Sect. 1.2) and microscopy of the CNS and the relations of the brain to the skull, the skull base in particular (► Sect. 1.3), and of the spinal cord to the vertebral column (► Sect. 1.5). Following an introduction into a developmental ontology of the brain (► Sect. 1.4), the various structures of the brain and the spinal cord and their main fibre connections will be discussed, starting with the spinal cord (► Sect. 1.5), followed by the brain stem (► Sect. 1.6), the cerebellum (► Sect. 1.7), the diencephalon (► Sect. 1.8), the hypothalamus and the preoptic area (► Sect. 1.9) and the telencephalon (► Sect. 1.10). The English terms of the Terminologia Neuroanatomica are used throughout.
Temporal lobe epilepsy (TLE) is associated with impaired inhibitory neurotransmission. Studies in animal models suggest that GABA A receptor dysfunction contributes to epileptogenesis. To understand the mechanisms underlying TLE in humans, it is fundamental to determine whether and how GABA A receptor subtypes are altered. Furthermore, identifying novel receptor targets is a prerequisite for developing selective antiepileptic drugs. We have therefore analyzed subunit composition and distribution of the three major GABA A receptor subtypes immunohistochemically with subunit-specific antibodies (α1, α2, α3, β2,3, and γ2) in surgical specimens from TLE patients with hippocampal sclerosis ( n = 16). Profound alterations in GABA A receptor subtype expression were observed when compared with control hippocampi ( n = 10). Although decreased GABA A receptor subunit staining, reflecting cell loss, was observed in CA1, CA3, and hilus, the distinct neuron-specific expression pattern of the α-subunit variants observed in controls was markedly changed in surviving neurons. In granule cells, prominent upregulation mainly of the α2-subunit was seen on somata and apical dendrites with reduced labeling on basal dendrites. In CA2, differential rearrangement of all three α-subunits occurred. Moreover, there was layer-specific loss of α1-subunit-immunoreactive interneurons in hippocampus proper, whereas surviving interneurons exhibited extensive changes in dendritic morphology. Throughout, expression patterns of β2,3- and γ2-subunits largely followed those of α-subunit variants. These results demonstrate unique subtype-specific expression of GABA A receptors in human hippocampus. The significant reorganization of distinct receptor subtypes in surviving hippocampal neurons of TLE patients with hippocampal sclerosis underlines the potential for synaptic plasticity in the human GABA system.
The entorhinal cortex (EC) plays a crucial role as a gateway connecting the neocortex and the hippocampal formation. Layer II of the EC gives rise to the perforant pathway, the major source of the excitatory input to the hippocampus, and layer IV receives a major hippocampal efferent projection. The EC is affected severely in Alzheimer disease (AD), likely contributing to memory impairment. We applied stereological principles of neuron counting to determine whether neuronal loss occurs in the EC in the very early stages of AD. We studied 20 individuals who at death had a Clinical Dementia Rating (CDR) score of 0 (cognitively normal), 0.5 (very mild), 1 (mild), or 3 (severe cognitive impairment). Lamina-specific neuronal counts were carried out on sections representing the entire EC. In the cognitively normal (CDR = 0) individuals, there were ∼650,000 neurons in layer II, 1 million neurons in layer IV, and 7 million neurons in the entire EC. The number of neurons remained constant between 60 and 90 years of age. The group with the mildest clinically detectable dementia (CDR = 0.5), all of whom had sufficient neurofibrillary tangles (NFTs) and senile plaques for the neuropathological diagnosis of AD, had 32% fewer EC neurons than controls. Decreases in individual lamina were even more dramatic, with the number of neurons in layer II decreasing by 60% and in layer IV by 40% compared with controls. In the severe dementia cases (CDR = 3), the number of neurons in layer II decreased by ∼90%, and the number of neurons in layer IV decreased by ∼70% compared with controls. Neuronal number in AD was inversely proportional to NFT formation and neuritic plaques, but was not related significantly to diffuse plaques or to total plaques. These results support the conclusion that a marked decrement of layer II neurons distinguishes even very mild AD from nondemented aging.
The human hippocampus plays a key role in memory management and is one of the first structures affected by Alzheimer’s disease. Ultra-high magnetic resonance imaging provides access to its inner structure in vivo. However, gradient limitations on clinical systems hinder access to its inner connectivity and microstructure. A major target of this paper is the demonstration of diffusion MRI potential, using ultra-high field (11.7 T) and strong gradients (750 mT/m), to reveal the extra- and intra-hippocampal connectivity in addition to its microstructure. To this purpose, a multiple-shell diffusion-weighted acquisition protocol was developed to reach an ultra-high spatio-angular resolution with a good signal-to-noise ratio. The MRI data set was analyzed using analytical Q-Ball Imaging, Diffusion Tensor Imaging (DTI), and Neurite Orientation Dispersion and Density Imaging models. High Angular Resolution Diffusion Imaging estimates allowed us to obtain an accurate tractography resolving more complex fiber architecture than DTI models, and subsequently provided a map of the cross-regional connectivity. The neurite density was akin to that found in the histological literature, revealing the three hippocampal layers. Moreover, a gradient of connectivity and neurite density was observed between the anterior and the posterior part of the hippocampus. These results demonstrate that ex vivo ultra-high field/ultra-high gradients diffusion-weighted MRI allows the mapping of the inner connectivity of the human hippocampus, its microstructure, and to accurately reconstruct elements of the polysynaptic intra-hippocampal pathway using fiber tractography techniques at very high spatial/angular resolutions.
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Neuropathologic hallmarks of Alzheimer’s disease (AD) include the progressive deposition of virtually insoluble proteinaceous material in both extracellular and intraneuronal locations. The extracellular deposits consist mainly of Aβ-amyloid-protein (Joachim and Selkoe, 1989; Beyreuther and Masters, 1991; Selkoe, 1991, 1993, 1994); abnormally phosphorylated tau protein (PHF-tau, paired helical filament tau) dominates among the intraneuronal changes (Goedert et al., 1991, 1992; Iqbal and Grundke-Iqbal, 1991; Schmidt et al., 1991; Dickson et al., 1992; Goedert, 1993; Iqbal et al., 1993, 1994; Price and Sisodia, 1994; Trojanowski et al., 1995). A variety of other substances accompany both the Aβ-amyloid deposits and the abnormal tau protein.
Cortical and subcortical brain areas regulating behaviors
The aim of this study was to investigate the neural correlates of the lexical-semantic processing of the selected lexical-semantic relations of abstract and concrete ords. Medial temporal lobe epilepsy was chosen as a model of lexical-semantic processing deficit because of the anatomical and functional specificity of its lesion. The study examined the specific lexical-semantic reorganization considering the hemispheric differences. It was conducted on forty patients diagnosed with lateralized medial temporal lobe epilepsy with matching age, gender and dominant hemisphere controls. E-prime program was used to examine the accuracy and time needed for lexical-semantic processing of abstract/concrete words. Test material included the list of 92 words in total ( 46 word pairs; each pair included an abstract and a concrete word), pairs of words, including 46 concrete and 46 abstract words. The material included concrete words with associated lexical-semantic categories and concrete words with unrelated lexical-semantic categories, as well as abstracted words with associated lexical-semantic categories and abstract words with unrelated lexical-semantic categories. The results have shown the specificity of the selected lexical-semantic categories, and confirmed that the lesion of the dominant medial temporal lobe affects the lexical-semantic processing of abstract and concrete words. Furthermore, it can be concluded that epileptic seizures may lead to a dysfunction of neural communication and the impairment of the semantic system due to a reduced functional association between the language regions.
Recent functional imaging studies have proposed that the human entorhinal cortex (ERC) is subdivided into functionally distinct anterolateral (alERC) and posteromedial (pmERC) subregions. The alERC overlaps with regions that are affected earliest by Alzheimer’s disease pathology, yet its cognitive function remains poorly understood. Previous human fMRI studies have focused on its role in object memory, but rodent studies on the putatively homologous lateral entorhinal cortex suggest that it also plays an important role in representing spatial properties of objects. To investigate the cognitive effects of human alERC volume differences, we developed an eye-tracking-based task to evaluate intra-item configural processing (i.e., processing the arrangement of an object’s features) and used manual segmentation based on a recently developed protocol to delineate the alERC/pmERC and other medial temporal lobe (MTL) subregions. In a group of older adult men and women at varying stages of brain atrophy and cognitive decline, we found that intra-item configural processing, regardless of an object’s novelty, was strongly predicted by alERC volume, but not by the volume of any other MTL subregion. These results provide the first evidence that the human alERC plays a role in supporting a distinct aspect of object processing, namely attending to the arrangement of an object’s component features.
Creutzfeldt-Jakob disease (CJD) is a human prion disease with different etiologies. To determine the spectrum of tau pathologies in CJD we assessed phospho-Tau (pTau) immunoreactivities in 75 sporadic CJD cases including an evaluation of the entorhinal cortex and six hippocampal subregions. 12 cases (16%) showed only small tau-immunoreactive neuritic profiles. 52 (69.3%) showed additional tau pathology in the medial temporal lobe compatible with primary age related tauopathy (PART). In 22/52 cases the lower pTau immunoreactivity load in the entorhinal cortex as compared to subiculum, dentate gyrus or CA4 region of the hippocampus was significantly different from the typical distribution of the Braak staging. A further 11 cases (14.7%) showed widespread tau pathologies compatible with features of primary tauopathies or the gray matter type of ageing-related tau astrogliopathy (ARTAG). Prominent gray matter ARTAG was also observed in two out of three additionally examined V203I genetic CJD cases. Analysis of cerebrospinal fluid revealed prominent increase of total tau protein in cases with widespread tau pathology, while pTau (T181) level was increased only in four. This correlated with immunohistochemical observations showing less pathology with anti-pTau T181 antibody when compared to anti-pTau S202/T205, T212/S214, and T231. The frequency of tau pathologies is not unusually high in sporadic CJD and does not precisely relate to PrP deposition. However, the pattern of hippocampal tau pathology often deviates from the stages of Braak. Currently applied examination of cerebrospinal fluid pTau (T181) level does not reliably reflect primary tauopathies, PART, and ARTAG seen in CJD brains. This article is protected by copyright. All rights reserved.
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