Alteration of the Functional Connectivity of the Cortical Areas Characterized by the Presence of Von Economo Neurons in Schizophrenia, a Pilot Study.

Von Economo neurons (VENs) are rod, stick, or corkscrew cells mostly located in layer V of the frontoinsular and anterior cingulate cortices. VENs are projection neurons related to human-like social cognitive abilities. Post-mortem histological studies found VEN alterations in several neuropsychiatric disorders, including schizophrenia (SZ). This pilot study aimed to evaluate the role of VEN-containing areas in shaping patterns of resting-state brain activation in patients with SZ (n = 20) compared to healthy controls (HCs; n = 20). We performed a functional connectivity analysis seeded in the cortical areas with the highest density of VENs followed by fuzzy clustering. The alterations found in the SZ group were correlated with psychopathological, cognitive, and functioning variables. We found a frontotemporal network that was shared by four clusters overlapping with the salience, superior-frontal, orbitofrontal, and central executive networks. Differences between the HC and SZ groups emerged only in the salience network. The functional connectivity of the right anterior insula and ventral tegmental area within this network were negatively correlated with experiential negative symptoms and positively correlated with functioning. This study provides some evidence to show that in vivo, VEN-enriched cortical areas are associated with an altered resting-state brain activity in people with SZ.

Von Economo neurons: Cellular specialization of human limbic cortices?

Von Economo neurons (VENs) have been mentioned in the medical literature since the second half of the 19th century; however, it was not until the second decade of the 20th century that their cytomorphology was described in detail. To date, VENs have been found in limbic sectors of the frontal, temporal and insular lobes. In humans, their density seems to decrease in the caudo-rostral and ventro-dorsal direction; that is, from the anterior regions of the cingulate and insular cortices towards the frontal pole and the superior frontal gyrus. Several studies have provided similar descriptions of the shape of the VEN soma, but the size of the soma varies from one cortical region to another. There is consensus among different authors about the selective vulnerability of VENs in certain pathologies, in which a deterioration of the capacities involved in social behaviour is observed. In this review, we propose that the restriction of VENs towards the sectors linked to limbic information processing in Homo sapiens gives them a possible functional role in relation to the structures in which they are located. However, given the divergence in characteristics such as location, density, size and biochemical profile among VENs of different cortical sectors, the activities in which they participate could allow them to partake in a wide spectrum of neurological functions, including autonomic responses and executive functions.

The behavioral variant of Alzheimer's disease does not show a selective loss of Von Economo and phylogenetically related neurons in the anterior cingulate cortex.

BACKGROUND: The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer's disease (bvAD) remain unclear. A selective loss of Von Economo neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD. METHODS: VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n = 9) and compared to typical AD (tAD, n = 6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n = 18) and controls (n = 13) using ANCOVAs adjusted for age and Bonferroni corrected. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss. RESULTS: The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0 ± 15.3, GABRQ-ir pyramidal: 260.4 ± 87.1) and tAD (VENs: 32.0 ± 18.1, p = 1.00, GABRQ-ir pyramidal: 349.8 ± 109.6, p = 0.38) and controls (VENs: 33.5 ± 20.3, p = 1.00, GABRQ-ir pyramidal: 339.4 ± 95.9, p = 0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.5 ± 82.658, p = 0.01) and no significant differences in number of VENs (bvFTD: 10.9 ± 13.8, p = 0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5. DISCUSSION: VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.

Von Economo Neurons - Primate-Specific or Commonplace in the Mammalian Brain?

The pioneering work by von Economo in 1925 on the cytoarchitectonics of the cerebral cortex revealed a specialized and unique cell type in the adult human fronto-insular (FI) and anterior cingulate cortex (ACC). In modern studies, these neurons are termed von Economo neurons (VENs). In his work, von Economo described them as stick, rod or corkscrew cells because of their extremely elongated and relatively thin cell body clearly distinguishable from common oval or spindle-shaped infragranular principal neurons. Before von Economo, in 1899 Cajal depicted the unique somato-dendritic morphology of such cells with extremely elongated soma in the FI. However, although VENs are increasingly investigated, Cajal's observation is still mainly being neglected. On Golgi staining in humans, VENs have a thick and long basal trunk with horizontally oriented terminal branching (basilar skirt) from where the axon arises. They are clearly distinguishable from a spectrum of modified pyramidal neurons found in infragranular layers, including oval or spindle-shaped principal neurons. Spindle-shaped cells with highly elongated cell body were also observed in the ACC of great apes, but despite similarities in soma shape, their dendritic and axonal morphology has still not been described in sufficient detail. Studies identifying VENs in non-human species are predominantly done on Nissl or anti-NeuN staining. In most of these studies, the dendritic and axonal morphology of the analyzed cells was not demonstrated and many of the cells found on Nissl or anti-NeuN staining had a cell body shape characteristic for common oval or spindle-shaped cells. Here we present an extensive literature overview on VENs, which demonstrates that human VENs are specialized elongated principal cells with unique somato-dendritic morphology found abundantly in the FI and ACC of the human brain. More research is needed to properly evaluate the presence of such specialized cells in other primates and non-primate species.

Von Economo Neuron Pathology in Familial Dysautonomia: Quantitative Assessment and Possible Implications.

Von Economo neurons (VENs) and fork cells are principally located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI). Both of these regions integrate inputs from the autonomic nervous system (ANS) and are involved in decision-making and perception of the emotional states of self and others. Familial dysautonomia (FD) is an orphan disorder characterized by autonomic dysfunction and behavioral abnormalities including repetitive behavior and emotional rigidity, which are also seen in autism spectrum disorder. To understand a possible link between the ANS and the cortical regions implicated in emotion regulation we studied VENs and fork cells in an autonomic disorder. We determined the densities of VENs, fork cells, and pyramidal neurons and the ratio of VENs and fork cells to pyramidal neurons in ACC and FI in 4 FD patient and 6 matched control brains using a stereologic approach. We identified alterations in densities of VENs and pyramidal neurons and their distributions in the ACC and FI in FD brains. These data suggest that alterations in migration and numbers of VENs may be involved in FD pathophysiology thereby supporting the notion of a functional link between VENs, the ANS and the peripheral nervous system in general.

Preferential tau aggregation in von Economo neurons and fork cells in frontotemporal lobar degeneration with specific MAPT variants.

Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick's disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied.

Von Economo Neurons in Behavioral Variant Frontotemporal Dementia with Underlying Alzheimer's Disease.

The selective loss of von Economo neurons has been linked to the behavioral deficits in behavioral variant frontotemporal dementia (bvFTD) but whether these neurons are affected in bvFTD patients with underlying Alzheimer's disease (AD) has yet to be established. The present study assesses the von Economo neurons in pathological AD cases clinically diagnosed with either AD or bvFTD. Our results demonstrate no significant loss of von Economo neurons in all pathological AD cases, irrespective of clinical diagnosis or co-existing Lewy body pathology. These results suggest that the behavioral deficits in patients with clinical bvFTD and underlying pathological AD are not driven by the loss of von Economo neurons.

Von Economo Neurons in the Human Medial Frontopolar Cortex.

The von Economo neurons (VEN) are characterized by a large soma, spindle-like soma, with little dendritic arborization at both, the basal and apical poles. In humans, VENs have been described in the entorhinal cortex, the hippocampal formation, the anterior cingulate cortex, the rostral portion of the insula and the dorsomedial Brodmann's area 9 (BA9). These cortical regions have been associated with cognitive functions such as social interactions, intuition and emotional processing. Previous studies that searched for the presence of these cells in the lateral frontal poles yielded negative results. The presence of VENs in other cortical areas on the medial surface of the human prefrontal cortex which share both a common functional network and similar laminar organization, led us to examine its presence in the medial portion of the frontal pole. In the present study, we used tissue samples from five postmortem subjects taken from the polar portion of BA10, on the medial surface of both hemispheres. We found VENs in the human medial BA10, although they are very scarce and dispersed. We also observed crests and walls of the gyrus to quantitatively assess: (A) interhemispheric asymmetries, (B) the VENs/pyramidal ratio, (C) the area of the soma of VENs and (D) the difference in soma area between VENs and pyramidal and fusiform cells. We found that VENs are at least seven times more abundant on the right hemisphere and at least 2.5 times more abundant in the crest than in the walls of the gyrus. The soma size of VENs in the medial frontopolar cortex is larger than that of pyramidal and fusiform cells of layer VI, and their size is larger in the walls than in the crests. Our finding might be a contribution to the understanding of the role of these neurons in the functional networks in which all the areas in which they have been found are linked. However, the particularities of VENs in the frontal pole, as their size and quantity, may also lead us to interpret the findings in the light of other positions such as van Essen's theory of tension-based brain morphogenesis.

Von Economo Neurons and Fork Cells: A Neurochemical Signature Linked to Monoaminergic Function.

The human anterior cingulate and frontoinsular cortices are distinguished by 2 unique Layer 5 neuronal morphotypes, the von Economo neurons (VENs) and fork cells, whose biological identity remains mysterious. Insights could impact research on diverse neuropsychiatric diseases to which these cells have been linked. Here, we leveraged the Allen Brain Atlas to evaluate mRNA expression of 176 neurotransmitter-related genes and identified vesicular monoamine transporter 2 (VMAT2), gamma-aminobutyric acid (GABA) receptor subunit θ (GABRQ), and adrenoreceptor α-1A (ADRA1A) expression in human VENs, fork cells, and a minority of neighboring Layer 5 neurons. We confirmed these results using immunohistochemistry or in situ hybridization. VMAT2 and GABRQ expression was absent in mouse cerebral cortex. Although VMAT2 is known to package monoamines into synaptic vesicles, in VENs and fork cells its expression occurs in the absence of monoamine-synthesizing enzymes or reuptake transporters. Thus, VENs and fork cells may possess a novel, uncharacterized mode of cortical monoaminergic function that distinguishes them from most other mammalian Layer 5 neurons.

Von Economo neurons of the anterior cingulate across the lifespan and in Alzheimer's disease.

BACKGROUND: Throughout the human aging lifespan, neurons acquire an unusually high burden of wear and tear; this is likely why age is considered the strongest risk factor for the development of Alzheimer's Disease (AD). Von Economo neurons (VENs) are rare, spindle-shaped cells mostly populated in anterior cingulate cortex. In a prior study, "SuperAgers" (individuals older than 80 years of age with outstanding memory ability) showed higher VEN densities compared to elderly controls with average memory, and those with amnestic Mild Cognitive Impairment (aMCI). The intrinsic vulnerabilities of these neurons are unclear, and their contribution to neurodegeneration is unknown. The current study investigated the influence of age and the severity of Alzheimer's disease (AD) on VEN density. METHODS: VEN and total neuronal densities were quantitated using unbiased stereological methods in the anterior cingulate cortex of postmortem samples from the following subject groups: younger controls (age 20-60), SuperAgers, cognitively average elderly controls (age 65+), individuals diagnosed antemortem with aMCI, and individuals diagnosed antemortem with dementia of AD (N = 5, per group). RESULTS: The AD group showed significantly lower VEN density compared to younger and older controls (p < .05), but not compared to the aMCI group, and VENs bearing neurofibrillary tangles were discovered in AD cases. The aMCI group showed lower VEN density than elderly controls, but this was not significant. There was a significant negative correlation between VEN density and Braak stages of AD (p < .001). Consistent with prior findings, SuperAgers showed highest mean VEN density, even when compared to younger cases. CONCLUSIONS: VENs in human anterior cingulate cortex are vulnerable to AD pathology, particularly in later stages of pathogenesis. Their densities do not change throughout aging in individuals with average cognition, and they are more numerous in SuperAgers.

Ultrastructural Alterations of Von Economo Neurons in the Anterior Cingulate Cortex in Schizophrenia.

Von Economo neurons (VENs) are large bipolar projection neurons mainly located in layer Vb of anterior cingulate cortex (ACC) and anterior insula. Both regions are involved in cognitive and emotional procedures and are functionally and anatomically altered in schizophrenia. Although the detailed function of VEN remains unclear, it has been suggested that these neurons are involved in the pathomechanism of schizophrenia. Here, we were interested in the question whether or not the VEN of schizophrenia patients would show abnormalities at the ultrastructural level. Accordingly, we examined the amount of lysosomal aggregations of the VEN in post-mortem tissue of patients with schizophrenia, bipolar disorder and psychologically unaffected individuals, and compared the findings with aggregations in adjacent pyramidal cells in layer Vb of the ACC. VEN of patients with schizophrenia, and to a lesser degree individuals with bipolar disorder contained significantly more lysosomal aggregations compared with tissue from unaffected controls. Specifically, the larger amount of lysosomal aggregations in schizophrenia seemed to be selective for VEN, with no differences occurring in pyramidal cells. These findings may indicate that the VEN of schizophrenia patients are selectively vulnerable to neuronal damage. Anat Rec, 2017. © 2017 Wiley Periodicals, Inc. Anat Rec, 300:2017-2024, 2017. © 2017 Wiley Periodicals, Inc.

von Economo Neuron Density and Thalamus Volumes in Behavioral Deficits in Frontotemporal Dementia Cases with and without a C9ORF72 Repeat Expansion.

BACKGROUND: The early and selective loss of von Economo neurons in the anterior cingulate cortex has been linked to behavioral deficits in frontotemporal dementia (FTD). Importantly, whether these neurons are also targeted in patients with the C9ORF72 repeat expansion has yet to be established. This is of particular interest given the recent evidence highlighting the thalamus rather than anterior cingulate cortex as a region of significant degeneration in patients with the C9ORF72 repeat expansion. OBJECTIVE: To assess the von Economo neuron density and thalamus volumes in behavioral variant FTD (bvFTD) cases with the C9ORF72 repeat expansion, sporadic bvFTD, sporadic ALS, and controls. METHODS: Volumetric and quantitative cell counting methods were employed to assess the von Economo neuron density and thalamus volumes in 37 pathologically-confirmed cases comprised of patients with bvFTD (n = 13) cases with the C9ORF72 repeat expansion (62% with psychosis), sporadic bvFTD (n = 8), sporadic amyotrophic lateral sclerosis (n = 7) and controls (n = 9). RESULTS: von Economo neuron density was significantly reduced in sporadic bvFTD cases only. Thalamus degeneration was identified only in bvFTD cases with the C9ORF72 repeat expansion, and to a similar extent in cases with and without psychosis. No significant difference in von Economo neuron density or thalamus degeneration was seen between bvFTD cases with or without the C9ORF72 repeat expansion. CONCLUSION: The present histological findings converge with neuroimaging results to corroborate the anterior cingulate cortex as a core region involved in sporadic bvFTD, and the thalamus as a major region targeted in patients with the C9ORF72 expansion.

Reduced anterior insula, enlarged amygdala in alcoholism and associated depleted von Economo neurons.

The insula, a structure involved in higher order representation of interoceptive states, has recently been implicated in drug craving and social stress. Here, we performed brain magnetic resonance imaging to measure volumes of the insula and amygdala, a structure with reciprocal insular connections, in 26 alcohol-dependent patients and 24 healthy volunteers (aged 22-56 years, nine females in each group). We used an established morphometry method to quantify total and regional insular volumes. Volumetric measurements of the amygdala were obtained using a model-based segmentation/registration tool. In alcohol-dependent patients, anterior insula volumes were bilaterally reduced compared to healthy volunteers (left by 10%, right by 11%, normalized to total brain volumes). Furthermore, alcohol-dependent patients, compared with healthy volunteers, had bilaterally increased amygdala volumes. The left amygdala was increased by 28% and the right by 29%, normalized to total brain volumes. Post-mortem studies of the anterior insula showed that the reduced anterior insular volume may be associated with a population of von Economo neurons, which were 60% diminished in subjects with a history of alcoholism (n = 6) as compared to subjects without a history of alcoholism (n = 6) (aged 32-56 years, all males). The pattern of neuroanatomical change observed in our alcohol-dependent patients might result in a loss of top-down control of amygdala function, potentially contributing to impaired social cognition as well as an inability to control negatively reinforced alcohol seeking and use.

Greater loss of von Economo neurons than loss of layer II and III neurons in behavioral variant frontotemporal dementia.

Previous studies have shown a selective reduction of von Economo neurons (VENs) in behavioral variant frontotemporal dementia (bvFTD). However, the alleged selectivity rests on the comparison between VENs and other neurons in cortical layer V, while it has been established that neurons in the superficial cortical layers (I-III) are particularly affected in bvFTD. The purpose of this study was to examine loss the loss of VENs in comparison with that of non-VEN-neurons of superficial cortical layers. VENs and non-VEN-neurons of cortical layer V and layers II+III were quantified in the anterior cingulate cortex in 16 cases of bvFTD, 12 non-demented controls and 10 cases of Alzheimer's disease (AD). In bvFTD VENs were more depleted than non-VEN-neurons of layers V and II+III. Also, non-VEN-neurons of layer II+III showed a greater density reduction than those of layer V in bvFTD. VEN density was also reduced in AD, albeit to a lesser extent than in bvFTD, and the differences between bvFTD and AD were only significant when relating VEN loss to that of layer V neurons. Our study strengthens the view of VENs as a particularly sensitive neuronal type of bvFTD, and appears to be on a continuum with the loss of other neurons both in bvFTD and between conditions.