Organization and Detailed Parcellation of Human Hippocampal Head and Body Regions Based on a Combined Analysis of Cyto- and Chemoarchitecture.

The hippocampal formation (HF) is one of the hottest regions in neuroscience because it is critical to learning, memory, and cognition, while being vulnerable to many neurological and mental disorders. With increasing high-resolution imaging techniques, many scientists have started to use distinct landmarks along the anterior-posterior axis of HF to allow segmentation into individual subfields in order to identify specific functions in both normal and diseased conditions. These studies urgently call for more reliable and accurate segmentation of the HF subfields DG, CA3, CA2, CA1, prosubiculum, subiculum, presubiculum, and parasubiculum. Unfortunately, very limited data are available on detailed parcellation of the HF subfields, especially in the complex, curved hippocampal head region. In this study we revealed detailed organization and parcellation of all subfields of the hippocampal head and body regions on the base of a combined analysis of multiple cyto- and chemoarchitectural stains and dense sequential section sampling. We also correlated these subfields to macro-anatomical landmarks, which are visible on magnetic resonance imaging (MRI) scans. Furthermore, we created three versions of the detailed anatomic atlas for the hippocampal head region to account for brains with four, three, or two hippocampal digitations. These results will provide a fundamental basis for understanding the organization, parcellation, and anterior-posterior difference of human HF, facilitating accurate segmentation and measurement of HF subfields in the human brain on MRI scans.

In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease.

Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid-rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD. We used diffusion tensor imaging (DTI) to assess the integrity of the parahippocampal white matter in mild cognitive impairment (MCI) and AD, as a first step in developing a noninvasive tool for early diagnosis. Subjects with AD (N = 9), MCI (N = 8), or no cognitive impairment (NCI; N = 20) underwent DTI-MRI. Fractional anisotropy (FA) and mean (MD) and radial (RD) diffusivity measured from the parahippocampal white matter in AD and NCI subjects differed greatly. Discriminant analysis in the MCI cases assigned statistical membership of 38% of MCI subjects to the AD group. Preliminary data 1 year later showed that all MCI cases assigned to the AD group either met the diagnostic criteria for probable AD or showed significant cognitive decline. Voxelwise analysis in the parahippocampal white matter revealed a progressive change in the DTI patterns in MCI and AD subjects: whereas converted MCI cases showed structural changes restricted to the anterior portions of this region, in AD the pathology was generalized along the entire anterior-posterior axis. The use of DTI for in vivo assessment of the parahippocampal white matter may be useful for identifying individuals with MCI at highest risk for conversion to AD and for assessing disease progression.

Stratum radiatum of CA2 is an additional target of the perforant path in humans and monkeys.

The perforant path (PP) connects two key components of the medial temporal memory system, the entorhinal cortex and hippocampus. Entorhinal layer II projects densely to the outer portion of the molecular layer of the dentate gyrus and the stratum lacunosum-moleculare of CA2 and CA3 of the hippocampus. This study for the first time reports that the PP terminal zone originated from entorhinal layer II extends from the stratum lacunosum-moleculare into the stratum radiatum in CA2 but not in CA3 in both human and nonhuman primates. This result indicates that CA2 probably receives additional innervation from the PP compared with CA3 and thus may play a unique role in hippocampal memory networks.

Borders, extent, and topography of human perirhinal cortex as revealed using multiple modern neuroanatomical and pathological markers.

Despite rapidly increasing interests in specific contributions of different components of human medial temporal lobe (MTL) to memory and memory impairments in normal aging and in many abnormal conditions such as Alzheimer's disease and Pick's disease, few modern neuroanatomical studies are available about the borders, extent, and topography of human perirhinal areas 35 and 36, which are important components of the MTL memory system. By a combined use of several cellular, neurochemical, and pathological markers, which mainly include neuronal nuclear antigen, calcium-binding proteins (parvalbumin and calbindin-D28k), nonphosphorylated neurofilament protein (SMI-32), Wisteria floribunda agglutinin, and abnormally phosphorylated tau (AT8), this study has revealed that the borders of human perirhinal areas 35 and 36 are significantly different from those defined with conventional Nissl staining. In general, areas 35 and 36 occupy the ventromedial temporopolar and rhinal sulcal regions, the collateral sulcal region, and the anterior two-thirds of fusiform gyrus or occipitotemporal gyrus. Furthermore, the precise borders, extent, and topography of human areas 35 and 36 and adjoining entorhinal cortex were marked at different anteroposterior levels of the MTL with reference to variations of rhinal and collateral sulci and other useful landmarks. These findings would provide reliable neuroanatomical base for the great and yet rapidly increasing number of neuroimaging studies of the human MTL structures in healthy and many abnormal conditions.

Parcellation of human temporal polar cortex: a combined analysis of multiple cytoarchitectonic, chemoarchitectonic, and pathological markers.

Although the human temporal polar cortex (TPC), anterior to the limen insulae, is heavily involved in high-order brain functions and many neurological diseases, few studies on the parcellation and extent of the human TPC are available that have used modern neuroanatomical techniques. The present study investigated the TPC with combined analysis of several different cellular, neurochemical, and pathological markers and found that this area is not homogenous, as at least six different areas extend into the TPC, with another area being unique to the polar region. Specifically, perirhinal area 35 extends into the posterior TPC, whereas areas 36 and TE extend more anteriorly. Dorsolaterally, an area located anterior to the typical area TA or parabelt auditory cortex is distinguishable from area TA and is defined as area TAr (rostral). The polysensory cortical area located primarily in the dorsal bank of the superior temporal sulcus, separate from area TA, extends for some distance into the TPC and is defined as the TAp (polysensory). Anterior to the limen insulae and the temporal pyriform cortex, a cortical area, characterized by its olfactory fibers in layer Ia and lack of layer IV, was defined as the temporal insular cortex and named as area TI after Beck (J. Psychol. Neurol. 1934;41:129-264). Finally, a dysgranular TPC region that capped the tip with some extension into the dorsal aspect of the TPC is defined as temporopolar area TG. Therefore, the human TPC actually includes areas TAr and TI, anterior parts of areas 35, 36, TE, and TAp, and the unique temporopolar area TG.

The abnormally phosphorylated tau lesion of early Alzheimer's disease.

The perirhinal cortex (area 35) is well-known locus for neurofibrillary tangles (NFT) in initial Alzheimer's disease (AD) and fully developed AD and may contain tau alterations in non-demented elderly. The topography and location of this vulnerable cortex, however, is difficult to appreciate because of its variable architecture and to deviations imposed by temporal sulcal patterns. We have immunostained human brains with a short duration of dementia using antibody AT8, which recognize abnormally hyperphosphorylated tau, calcium binding protein-parvalbumin and other phenotype markers to more fully appreciate the extent of area 35 before it is obscured by pathology. We have observed in the mildly affected AD tau immunoreactive lesion that extends from the temporopolar/insular region anteriorly to the posterior parahippocampal cortex. In its anterior-posterior course, it covers the medial bank of the collateral sulcus. Although the tau lesion encroaches slightly into the temporopolar cortex (area TG) anteriorly and medially and the ectorhinal cortex (area 36) laterally, area 35 is unambiguously defined. Ventromedial temporal pathology as revealed by AT8 suggests the presence of a relatively large lesion early in AD involving all of the perirhinal cortex and other non-isocortical areas. The present study demonstrated that the early stage AD patients exhibited AT8 immunoreactive cells in the temporopolar, hippocampus, perirhinal, entorhinal, and insular cortices.

Thalamic projections to the posteromedial cortex in the macaque.

The medial parietal, posterior cingulate, and retrosplenial cortices collectively constitute a region of cortex referred to as the posteromedial cortices (PMC). In an effort to shed light on the neuroanatomical organization of the PMC, we undertook a study to identify and analyze the thalamocortical connections of these cortices. Retrograde tracer injections were placed in the posterior cingulate (PCC), retrosplenial (RSC), medial parietal cortices (MPC), and posterior cingulate sulcus (PCS), and the labeling patterns within the thalamus were analyzed. Three afferent projection patterns were observed to the PMC from the thalamus: a PCC/RSC pattern that involved the anterior thalamic nuclei, an MPC pattern that involved the lateral posterior and pulvinar nuclei, and a PCS pattern that involved the ventral thalamic nuclei. Additionally, a shared pattern of projections from the anterior intralaminar nuclei (AILN) and posterior thalamic nuclei (PTN) to all cortical regions of the PMC was observed. Our findings suggest that distinct regions within the PMC are supplied by distinctive patterns of thalamic input, but also share common projections from intralaminar and posterior thalamic sources. In addition, we relate our findings to functional abnormalities in aging and dementia, and address a domain-like pattern of thalamocortical labeling of the PMC that is drawn selectively and collectively from multiple thalamic nuclei.

Amygdala interconnections with the cingulate motor cortex in the rhesus monkey.

Amygdala interconnections with the cingulate motor cortices were investigated in the rhesus monkey. Using multiple tracing approaches, we found a robust projection from the lateral basal nucleus of the amygdala to Layers II, IIIa, and V of the rostral cingulate motor cortex (M3). A smaller source of amygdala input arose from the accessory basal, cortical, and lateral nuclei, which targeted only the rostral region of M3. We also found a light projection from the lateral basal nucleus to the same layers of the caudal cingulate motor cortex (M4). Experiments examining this projection to cingulate somatotopy using combined neural tracing strategies and stereology to estimate the total number of terminal-like immunoreactive particles demonstrated that the amygdala projection terminates heavily in the face representation of M3 and moderately in its arm representation. Fewer terminal profiles were found in the leg representation of M3 and the face, arm, and leg representations of M4. Anterograde tracers placed directly into M3 and M4 revealed the amygdala connection to be reciprocal and documented corticofugal projections to the facial nucleus, surrounding pontine reticular formation, and spinal cord. Clinically, such pathways would be in a position to contribute to mediating movements in the face, neck, and upper extremity accompanying medial temporal lobe seizures that have historically characterized this syndrome. Alterations within or disruption of the amygdalo-cingulate projection to the rostral part of M3 may also have an adverse effect on facial expression in patients presenting with neurological or neuropsychiatric abnormalities of medial temporal lobe involvement. Finally, the prominent amygdala projection to the face region of M3 may significantly influence the outcome of higher-order facial expressions associated with social communication and emotional constructs such as fear, anger, happiness, and sadness.

Hughlings Jackson and the role of the entorhinal cortex in temporal lobe epilepsy: from patient A to Doctor Z.

Hughlings Jackson's insightful bedside observations of patients with epilepsy paved the way for the first effective surgical epilepsy treatments. Jackson's most famous case, that of Doctor Z, concerned a medical doctor with partial complex seizures who was reported to have a discrete and circumscribed medial temporal lobe (mTL) lesion on autopsy. Although integral to Jackson's argument for mTL resection, the case remains controversial due to inadequate pathological descriptions of Doctor Z's lesion. This motivated us to describe the case of a patient, whom we call Patient A, who suffered from a form of epilepsy similar to that of Doctor Z, accompanied by a discrete and circumscribed mTL lesion in the exact same location. The lesion, a cavernous hemangioma, spared the hippocampus and was restricted to the lateral aspect of the entorhinal cortex. This finding validates Jackson's original description and suggests that the entorhinal cortex can play a role in seizure genesis.

Neural connections of the posteromedial cortex in the macaque.

The posterior cingulate and the medial parietal cortices constitute an ensemble known as the posteromedial cortex (PMC), which consists of Brodmann areas 23, 29, 30, 31, and 7m. To understand the neural relationship of the PMC with the rest of the brain, we injected its component areas with four different anterograde and retrograde tracers in the cynomolgus monkey and found that all PMC areas are interconnected with each other and with the anterior cingulate, the mid-dorsolateral prefrontal, the lateral parietal cortices, and area TPO, as well as the thalamus, where projections from some of the PMC areas traverse in an uninterrupted bar-like manner, the dorsum of this structure from the posteriormost nuclei to its rostralmost tip. All PMC regions also receive projections from the claustrum and the basal forebrain and project to the caudate, the basis pontis, and the zona incerta. Moreover, the posterior cingulate areas are interconnected with the parahippocampal regions, whereas the medial parietal cortex projects only sparsely to the presubiculum. Although local interconnections and shared remote connections of all PMC components suggest a functional relationship among them, the distinct connections of each area with different neural structures suggests that distinct functional modules may be operating within the PMC. Our study provides a large-scale map of the PMC connections with the rest of the brain, which may serve as a useful tool for future studies of this cortical region and may contribute to elucidating its intriguing pattern of activity seen in recent functional imaging studies.

The limbic lobe and its output channels: implications for emotional functions and adaptive behavior.

Current dissatisfaction with the limbic system concept reflects a desire to move beyond the limbic system in efforts to explain key facets of emotional functions and motivational behavior. This review promotes an anatomical viewpoint, which originated as a result of histotechnical advances. These improvements paved the way for anatomical discoveries, which in turn led to the concepts of the ventral striatopallidal system and extended amygdala. These two systems, together with the basal nucleus of Meynert and the septum-diagonal band system, serve as output channels for an expanded version of the classic limbic lobe of Broca, which contains all non-isocortical parts of the cortical mantle together with the large laterobasal-cortical amygdaloid complex. Thus defined, the limbic lobe contains all of the major cortical (e.g. orbitofrontal, cingulate and insular cortices in addition to the hippocampal formation) and cortical-like (laterobasal-cortical amygdala) structures known to be especially important for emotional and motivational functions. In their role as output channels for the limbic lobe, the basal forebrain functional-anatomical systems contribute to the establishment of a number of cortico-subcortical circuits, which provide an important part of the anatomical substrate for the elaboration of emotional functions and adaptive behavior.

Pathology of the insular cortex in Alzheimer disease depends on cortical architecture.

The insular cortex plays important roles in a variety of regulatory mechanisms ranging from visceral control and sensation to covert judgments regarding inner well-being. The dementia of Alzheimer disease (AD) often includes behavioral dyscontrol and visceral dysfunction not observed in other diseases affecting cognition. This could be related to autonomic instability and to loss of the sense of self, and pathologic changes within the insula may play essential roles. The pattern of insular pathology of 17 patients with AD was examined and the severity of pathology was compared with that of the entorhinal cortex (EC), a region involved early in AD with reciprocal connections to the insula. Thioflavin S staining and Alz-50 immunostaining revealed that the insula carries a heavy burden of pathology in AD. Neurofibrillary tangles (NFTs) were largely confined to the deep layers of the cortex, whereas neuritic plaques (NPs) were distributed throughout the cellular layers and subcortical white matter. The density of NFTs, but not NPs, was highly correlated with the degree of EC pathology. However, NFTs were not seen in the insula until EC pathology reached a relatively advanced level. The density of insular NFTs varied according to architectonic type, with agranular cortex most affected, dysgranular cortex less affected, and granular cortex least affected. Thus, the insula is often involved in AD, and some of the behavioral abnormalities in AD may reflect insular pathology.

Topography, cytoarchitecture, and cellular phenotypes of cortical areas that form the cingulo-parahippocampal isthmus and adjoining retrocalcarine areas in the monkey.

The monkey cingulo-parahippocampal isthmus was identified recently in the depths and lateral bank of the anterior calcarine fissure but was not characterized fully. Cytoarchitectonic and immunohistochemical results presented here reveal that the isthmus is composed of four cortical areas. These include the presubiculum of the isthmus (PrSi), parasubiculum of the isthmus (PaSi), area 29 of the isthmus (area 29i) and area prostriata (Pro), which has anterior (Pro-a) and posterior (Pro-p) divisions. The PrSi, characterized by dense calbindin+ (CB+) neuropil in layer III, merges with area 29i at approximately the middle portion of the isthmus; the latter lacking the CB+ neuropil. The PaSi, characterized by a cell-free lamina dissecans and light parvalbumin+ labeling, is observed in the ventral isthmus. The Pro, located posterior to area 29i and PaSi, and anterior to area 17, has an incipient layer IV, but the density of granule cells gradually increase toward area 17. Pro-a has an incipient layer IV, contains few SMI-32+ neurons, and adjoins area 30 dorsally. The latter also has an incipient layer IV but contains, in contrast, more SMI-32+ neurons. Pro-p has a clear but thin layer IV, contains a small number of SMI-32+ neurons, and adjoins both area 23 and area 18 dorsally and area 18 ventrally. Compared with Pro-p, area 23 contains many more SMI-32+ neurons, whereas area 18 contains far more SMI-32+ neurons. These findings reveal that the isthmus is a key cortical zone connecting both the cingulate and parahippocampal gyri, but also the limbic and visual cortices. Emphasizing the former only, which has been the tendency historically, underestimates the anatomic complexity of the isthmus, and likely, its functional correlates.