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Anterior cingulate cortex (ACC) and von Economo neurons (VENs) in the brain of a control individual. a Medial view of the ACC (Brodmann's area 24) located dorsally to the corpus callosum (cc) and ventrally to area 32 shows the level of investigated sections bordered by black lines. b Coronal section stained for cresyl violet displays the subdivisions of area 24 in a-c. The extension of layer Vb used for counting is marked by dotted lines. c Cresyl violet-stained section of the ACC displays layer II, III, Va, Vb and VI. Several VENs (arrows) are dispersed in layer Vb. d A cluster of VENs (arrows) in layer Vb is clearly distinguished from the large triangular-shaped pyramidal cells in layer Va. e A VEN shows an elongated soma, bipolar dendrites (arrows) and an axon tapering laterally (arrowhead). Scale bars in b 1 mm; in c 0.2 mm; in d 50 lm; in e 10 lm
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The anterior cingulate cortex (ACC) represents a phylogenetically ancient region of the mammalian brain that has undergone recent adaptive changes in humans. It contains a large spindle-shaped cell type, referred to as von Economo neuron (VEN) that has been shown to be involved in the pathophysiology of various neuropsychiatric disorders. Schizophr...
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... examined four sections per brain, each of which located at the same level in each individual according to the section number by the SFNT. All sections investigated were 2.5 mm apart from one another, with the most rostral full-face section available just behind the genu of the corpus callosum (Fig. 1a), where VENs are more frequent than at posterior levels [29]. To control the rostro-caudal gradient of VEN density, we compared the density of all four sections within and between the ...
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... subareas of the ACC 24a, b and c were identified by cytoarchitectonic criteria [42]. Within these areas, layer Vb was further delineated as the region of interest (ROI) for VEN counting by outlining the layer using low power (209) magnification (Fig. 1b). Layer Vb could be identified in the cresyl violet-stained sections adjacent to the layer Va, which is characterised by prominent triangular-shaped pyramidal cells (Fig. 1c, d). Throughout the entire delineated ROI, all VENs were counted in every section investigated. Cell counting was performed at 200 or 4009 magnification, all target ...
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... criteria [42]. Within these areas, layer Vb was further delineated as the region of interest (ROI) for VEN counting by outlining the layer using low power (209) magnification (Fig. 1b). Layer Vb could be identified in the cresyl violet-stained sections adjacent to the layer Va, which is characterised by prominent triangular-shaped pyramidal cells (Fig. 1c, d). Throughout the entire delineated ROI, all VENs were counted in every section investigated. Cell counting was performed at 200 or 4009 magnification, all target cells had to be localised within the delineated ROI. The VEN could easily be distinguished from the triangular- shaped large pyramidal cells of the adjacent layer Va at higher ...
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... the entire delineated ROI, all VENs were counted in every section investigated. Cell counting was performed at 200 or 4009 magnification, all target cells had to be localised within the delineated ROI. The VEN could easily be distinguished from the triangular- shaped large pyramidal cells of the adjacent layer Va at higher magnification (Fig. 1d). Although VENs may slightly vary in morphology, they had to fulfil strict criteria for counting [37,39,47]. The well-defined elongated somata (Fig. 1e) were always orientated perpendicular to the pial surface. All cells counted had a distinct nucleus, a visible nucleolus and displayed the characteristic bipolar dendritic orientation ...
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... target cells had to be localised within the delineated ROI. The VEN could easily be distinguished from the triangular- shaped large pyramidal cells of the adjacent layer Va at higher magnification (Fig. 1d). Although VENs may slightly vary in morphology, they had to fulfil strict criteria for counting [37,39,47]. The well-defined elongated somata (Fig. 1e) were always orientated perpendicular to the pial surface. All cells counted had a distinct nucleus, a visible nucleolus and displayed the characteristic bipolar dendritic orientation with a smooth single apical and a single basal dendrite both of which similar in size in the proximal part (Fig. 1e). Single VENs, which were rarely ...
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... [37,39,47]. The well-defined elongated somata (Fig. 1e) were always orientated perpendicular to the pial surface. All cells counted had a distinct nucleus, a visible nucleolus and displayed the characteristic bipolar dendritic orientation with a smooth single apical and a single basal dendrite both of which similar in size in the proximal part (Fig. 1e). Single VENs, which were rarely dispersed in layer Va or in layer VI were ...
Citations
... Selective loss of von Economo neurons (VENs) has been associated with dysfunctional interoceptive awareness and bvFTD, suggesting that these neurons likely drive anosognosia. As poor illness insight is found in up to 98% patients with SCZ, characterized by gray matter loss, probably including the VENs [62][63][64][65]. Moreover, as anosognosia is a cognitive symptom, SCZ may be primarily a cognitive disorder with psychosis as a secondary manifestation, an observation made by Emil Kraepelin more than a century ago [66]. ...
The population worldwide is ageing at a rapid pace and so are forensic detainees with severe psychiatric illnesses, including schizophrenia (SCZ) and schizophrenia-like disorders (SLDs). Forensic institutions throughout the world house patients with severe psychiatric illness and history of criminal violations. The primary objective of this study is to explore novel therapies for Schizophrenia-dementia patients in forensic settings. Improved medical care, hygiene, psychiatric treatment, and nutrition led to an unmatched longevity in this population, which previously lived, on average, 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to an increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management, increasing healthcare expenditures. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who have aged on dopamine-blocking agents. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss may contribute to the development of early dementia. Taken together, increased lifespan and the subsequent cognitive deficit observed in long-term forensic institutions raise questions and dilemmas unencountered by the previous generations of clinicians. These include: does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a life-long history of schizophrenia and violent behavior? Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? Can patients with schizophrenia and dementia meet the Dusky standard to stand trial? Should neurocognitive disorders in the elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we hypothesize that gray matter loss is the core symptom of schizophrenia which leads to dementia. We hypothesize further that strategies to delay or stop gray matter depletion would not only improve schizophrenia-sustained recovery, but also avert the development of major neurocognitive disorders in people living with schizophrenia. Based on this hypothesis, we suggest the utilization of both receptor-dependent and independent therapeutics for chronic psychosis. While acute psychosis responds very well to antipsychotic drugs, chronic psychotic illnesses are much more refractory to these agents. Over the past decades, psychopharmacology has focused excessively on the receptor-dependent actions of antipsychotic drugs and put much less emphasis on the receptor-independent ones, such as antimicrobial and anticancer actions.
... Researchers have discovered a unique type of neuron called Von Economo neurons (VEN) in the ACC and frontoinsular cortex, which may shed light on their involvement in the development of schizophrenia. While the exact function of VEN is not yet clearly understood, it is known to facilitate rapid transmission of signals between brain regions that are involved in high-level functions such as emotional regulation, decision-making, motor control, and social cognition (Allman et al., 2010;Brune et al., 2010). Furthermore, studies have shown that there are ultrastructural alterations in the VENs in the ACC of people with schizophrenia (Krause et al., 2017). ...
... Furthermore, studies have shown that there are ultrastructural alterations in the VENs in the ACC of people with schizophrenia (Krause et al., 2017). Moreover, Brune et al. found that the density of VENs in the ACC is positively linked to the age at onset and inversely correlated with the duration of illness in schizophrenia (Brune et al., 2010). Our findings together suggest that ACC may play an important role in the development and progression of schizophrenia. ...
The anterior cingulate cortex (ACC) is a heterogeneous region of the brain’s limbic system that regulates cognitive and emotional processing, and is frequently implicated in schizophrenia. This study aims to characterize resting-state functional connectivity (rsFC) profiles of three subregions of ACC in patients with first-episode schizophrenia and healthy controls. Resting-state functional magnetic resonance imaging (rs-fMRI) scans were collected from 60 first-episode schizophrenia (FES) patients and 60 healthy controls (HC), and the subgenual ACC (sgACC), pregenual ACC (pgACC), and dorsal ACC (dACC) were selected as seed regions from the newest automated anatomical labeling atlas 3 (AAL3). Seed-based rsFC maps for each ACC subregion were generated and compared between the two groups. The results revealed that compared to the HC group, the FES group showed higher rsFC between the pgACC and bilateral lateral orbitofrontal cortex (lOFC), and lower rsFC between the dACC and right posterior OFC (pOFC), the medial prefrontal gyrus (MPFC), and the precuneus cortex (PCu). These findings point to a selective functional dysconnectivity of pgACC and dACC in schizophrenia and provide more accurate information about the functional role of the ACC in this disorder.
... Selective loss of von Economo neurons (VENs) has been associated with dysfunctional interoceptive awareness and bvFTD, suggesting that these neurons likely drive anosognosia. As poor illness insight is found in up to 98% patients with SCZ, a characterized by gray matter loss, probably including the VENs [62][63][64][65]. Moreover, as anosognosia is a cognitive symptom, SCZ may be primarily a cognitive disorder with psychosis as a secondary manifestation, an observation made by Emil Kraepelin more than a century ago [66]. ...
Forensic institutions throughout the world house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, psychiatric treatment, and nutrition led to an unmatched longevity in this population, which previously lived, on average, 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management, increasing healthcare expenditures. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who have aged on dopamine-blocking agents. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss may contribute to the development of early dementia. Taken together, increased lifespan and the subsequent cognitive deficit observed in long-term forensic institutions raise questions and dilemmas unencountered by the previous generations of clinicians. These include: does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a lifelong history of schizophrenia and violent behavior? Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? Can patients with schizophrenia and dementia meet the Dusky standard to stand trial? Should neurocognitive disorders in the elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we hypothesize that gray matter loss is the core symptom of schizophrenia which leads to dementia. We hypothesize further that strategies to delay or stop gray matter depletion would not only improve the schizophrenia sustained recovery, but also avert the development of major neurocognitive disorders in people living with schizophrenia. Based on this hypothesis, we suggest utilization of both receptor-dependent and independent therapeutics for chronic psychosis.
... The homeostasis of intestinal barrier is maintained by interleukin 22 (IL-22), a cytokine regulated by aryl hydrocarbon receptor (AhR), a gut barrier protein responding to exogenous and endogenous ligands (63). In this regard, VENs-rich IC was demonstrated to keep the record of gut inflammations, emphasizing the tight link between the GI tract and insula (147)(148). ...
Forensic institutions throughout the country house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, and nutrition led to unmatched longevity in this population which previously lived on average 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who had aged on dopamine blockers. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss, may contribute to the development of early dementia. Taken together, increased lifespan and subsequent cognitive deficit observed in long-term psychiatric institutions brought forth questions and dilemmas unencountered by the previous generations of clinicians, such as: 1. Does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a lifelong history of schizophrenia and violent behavior? 2. Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? 3. Can patients with schizophrenia and dementia meet the Dusky standard and stand trial? 4. Should neurocognitive disorders in elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we describe strategies for potentially slowing the development of neurocognitive disorders in forensic patients with chronic mental illness by adopting a three-prong strategy: 1. Approaching lifelong psychosis from microbial and immunological perspective. 2. Identify modifiable risk factors for age-related diseases in forensic institutions. 3. Utilizing novel receptor-independent treatments for chronic psychosis.
... In addition to NRG1 50,51 , this included ZNF804B 52 , CDH12 53 , CLSTN2 54,55 , RIT2 56 , and MCTP1 57 . This pattern is somewhat reminiscent of so-called Von Economo neurons (VENs) that are known to be altered in diseases such as Alzheimer, autism, and schizophrenia [58][59][60] . VENs are found in humans and great apes (but not other primates), cetaceans, and elephants, and may have evolved for the rapid transmission of crucial social information in very large brains 61 . ...
Brain disorders are leading causes of disability worldwide. Gene expression studies provide promising opportunities to better understand their etiology but it is critical that expression is studied on a cell-type level. Cell-type specific association studies can be performed with bulk expression data using statistical methods that capitalize on cell-type proportions estimated with the help of a reference panel. To create a fine-grained reference panel for the human prefrontal cortex, we performed an integrated analysis of the seven largest single nucleus RNA-seq studies. Our panel included 17 cell-types that were robustly detected across all studies, subregions of the prefrontal cortex, and sex and age groups. To estimate the cell-type proportions, we used an empirical Bayes estimator that substantially outperformed three estimators recommended previously after a comprehensive evaluation of methods to estimate cell-type proportions from brain transcriptome data. This is important as being able to precisely estimate the cell-type proportions may avoid unreliable results in downstream analyses particularly for the multiple cell-types that had low abundances. Transcriptome-wide association studies performed with permuted bulk expression data showed that it is possible to perform transcriptome-wide association studies for even the rarest cell-types without an increased risk of false positives.
... In addition, the hypoactivity of the anterior cingulate cortex (ACC), which is often considered a functional extension of the vmPFC, was associated with the presence of negative symptoms (27)(28)(29). Alterations to von Economo neurons, a highly specialized class of projection neurons located in the ACC, have also been described (30)(31)(32). ...
GABAergic cortical interneurons are important components of cortical microcircuits. Their alterations are associated with a number of neurological and psychiatric disorders, and are thought to be especially important in the pathogenesis of schizophrenia. Here, we reviewed neuroanatomical and histological studies that analyzed different populations of cortical interneurons in postmortem human tissue from patients with schizophrenia and adequately matched controls. The data strongly suggests that in schizophrenia only selective interneuron populations are affected, with alterations of somatostatin and parvalbumin neurons being the most convincing. The most prominent changes are found in the prefrontal cortex, which is consistent with the impairment of higher cognitive functions characteristic of schizophrenia. In contrast, calretinin neurons, the most numerous interneuron population in primates, seem to be largely unaffected. The selective alterations of cortical interneurons are in line with the neurodevelopmental model and the multiple-hit hypothesis of schizophrenia. Nevertheless, a large number of data on interneurons in schizophrenia is still inconclusive, with different studies yielding opposing findings. Furthermore, no studies found a clear link between interneuron alterations and clinical outcomes. Future research should focus on the causes of changes in the cortical microcircuitry in order to identify potential therapeutic targets.
... Within this framework, the hyper-activation of the ACC could occur if the hypoactivation of the DLPFC leads to impaired cognitive control and demands increased conflict monitoring and adjustments in control from the ACC (Carter et al., 2001). Crucially, clinical characteristics in EOS also associate with structural abnormalities in the ACC: ACC volume and neuronal density decrease with younger age of onset (Brüne et al., 2010), while aberrant white matter integrity is associated with psychotic symptoms (Tang et al., 2010).Our results enrich the evidence implicating DLPFC and ACC pathology in the pathogenesis of schizophrenia and the relationship of observed activation in these areas with clinical severity. ...
Schizophrenia, a debilitating disorder with typical manifestation of clinical symptoms in early adulthood, is characterized by cognitive impairments in executive processes such as in working memory (WM). However, there is a rare case of individuals with early-onset schizophrenia (EOS) starting before their 18th birthday, while WM and its neural substrates are still undergoing maturation. Using the WM n-back task with functional magnetic resonance imaging, we assessed the functional neurodevelopment of WM in adolescents with EOS and age- and gender-matched typically developing controls. Participants underwent neuroimaging in the same scanner twice, once at age 17 and at 21 (mean interscan interval = 4.3 years). General linear model analysis was performed to explore WM neurodevelopmental changes within and between groups. Psychopathological scores were entered in multiple regressions to detect brain regions whose longitudinal functional change was predicted by baseline symptoms in EOS. WM neurodevelopment was characterized by widespread functional reductions in frontotemporal and cingulate brain areas in patients and controls. No between-group differences were found in the trajectory of WM change. Baseline symptom scores predicted functional neurodevelopmental changes in frontal, cingulate, parietal, occipital, and cerebellar areas. The adolescent brain undergoes developmental processes such as synaptic pruning, which may underlie the refinement WM of network. Prefrontal and parietooccipital activity reduction is affected by clinical presentation of symptoms. Using longitudinal neuroimaging methods in a rare diagnostic sample of patients with EOS may help the advancement of neurodevelopmental biomarkers intended as pharmacological targets to tackle WM impairment.
... Although less unanimous, findings of perturbed ACC connectivity have been frequently reported [17][18][19]. Area 24 is the major subregion of the ACC [20] and it has been thoroughly investigated in a series of studies focusing on the neuropathology of schizophrenia [21][22][23][24][25][26][27][28] as a proxy for the ACC. Focusing on layer-specific alterations in area 24, studies reported not only increased [29] but also decreased [28] and unchanged neuron density [23,25,26,30,31]. ...
... VENs are likely specialized projection neurons [34][35][36] and occur in humans, great apes [33,37] and several other mammalian species [38]. A growing interest in the role of VENs in neuropsychiatric disorders has led to findings of VEN alterations in a number of illnesses [36,[39][40][41], including schizophrenia [21,42,43] for review, see [44]. So far, however, only alterations in the density of VENs in area 24 of patients with schizophrenia were investigated, that revealed no statistically significant differences between patients with schizophrenia and controls [21,43]. ...
... A growing interest in the role of VENs in neuropsychiatric disorders has led to findings of VEN alterations in a number of illnesses [36,[39][40][41], including schizophrenia [21,42,43] for review, see [44]. So far, however, only alterations in the density of VENs in area 24 of patients with schizophrenia were investigated, that revealed no statistically significant differences between patients with schizophrenia and controls [21,43]. However, lack of alterations of mean cell densities does not predict or imply lack of alterations of total cell numbers [45]. ...
Structural and functional abnormalities of the anterior cingulate cortex (ACC) have frequently been identified in schizophrenia. Alterations of von Economo neurons (VENs), a class of specialized projection neurons, have been found in different neuropsychiatric disorders and are also suspected in schizophrenia. To date, however, no definitive conclusions can be drawn about quantitative histologic changes in the ACC in schizophrenia because of a lack of rigorous, design-based stereologic studies. In the present study, the volume, total neuron number and total number of VENs in layer V of area 24 were determined in both hemispheres of postmortem brains from 12 male patients with schizophrenia and 11 age-matched male controls. To distinguish global from local effects, volume and total neuron number were also determined in the whole area 24 and whole cortical gray matter (CGM). Measurements were adjusted for hemisphere, age, postmortem interval and fixation time using an ANCOVA model. Compared to controls, patients with schizophrenia showed alterations, with lower mean total neuron number in CGM (− 14.9%, P = 0.007) and in layer V of area 24 (− 21.1%, P = 0.002), and lower mean total number of VENs (− 28.3%, P = 0.027). These data provide evidence for ACC involvement in the pathophysiology of schizophrenia, and complement neuroimaging findings of impaired ACC connectivity in schizophrenia. Furthermore, these results support the hypothesis that the clinical presentation of schizophrenia, particularly deficits in social cognition, is associated with pathology of VENs.
... Individuals with early-onset schizophrenia have been shown to have lower VEN density in the ACC than individuals with bipolar disorder and individuals without psychiatric diagnoses (36). Age, sex, postmortem interval, brain weight, and cortical thickness appear to have no significant impact on the reduction in VEN density in the ACC in individuals with early-onset schizophrenia (36). ...
... Individuals with early-onset schizophrenia have been shown to have lower VEN density in the ACC than individuals with bipolar disorder and individuals without psychiatric diagnoses (36). Age, sex, postmortem interval, brain weight, and cortical thickness appear to have no significant impact on the reduction in VEN density in the ACC in individuals with early-onset schizophrenia (36). Ultrastructural alterations in ACC VENs, including an increased number of lysosomal aggregations, have also been observed among persons with schizophrenia. ...
... Ultrastructural alterations in ACC VENs, including an increased number of lysosomal aggregations, have also been observed among persons with schizophrenia. VENs in limbic structures (i.e., the ACC and FI cortex) may be neurodevelopmentally altered in schizophrenia and possibly associated with suicide among persons with psychotic disorders (36)(37)(38). Furthermore, these pathological changes possibly explain the changes in morphology and connectivity of the ACC seen among patients at risk for developing psychosis (i.e., psychosis in 22q11.2 ...
... identified several additional populations in the deeply sampled McL cohort not captured by the broadly sampled MSSM cohort which we did not analyze in depth. These include multiple excitatory neuronal subpopulations within cortical layers V and VI, including extratelencephalic projecting von Econemo neurons reported to be selectively vulnerable in schizophrenia(106,107). Within our McL cohort, von Econemo neurons exhibited dysregulation of genes specifically enriching axonogenesis-related pathways. ...
Schizophrenia is a prevalent mental illness with a high societal burden, complex pathophysiology, and diverse genetic and environmental etiology. Its complexity, polygenicity, and heterogeneity have hindered mechanistic elucidation and the search for new therapeutics. We present a single-cell dissection of schizophrenia-associated transcriptomic changes in the human prefrontal cortex across two independent cohorts, one deeply profiling 48 subjects (361,996 cells), and the other broadly profiling 92 subjects (106,761 cells). We identified 25 cell types that we used to produce a high-resolution atlas of schizophrenia-altered genes and pathways. Excitatory neurons were the most affected cell group, with transcriptional changes converging on neurodevelopment and synapse-related molecular pathways. Differentially expressed gene sets implicate a coherently expressed module of trans-acting regulatory factors involved in neurodevelopment and genetically associated with schizophrenia risk. Transcriptional alterations significantly overlapped with known genetic risk factors, suggesting convergence of rare and common genomic variants on reproducible neuronal population specific alterations in schizophrenia. The severity of transcriptional pathology segregated two populations of schizophrenia subjects in a manner consistent with the expression of specific transcriptional patterns marked by genes involved in synaptic function and chromatin dynamics. Our results provide a high-resolution single cell atlas linking transcriptomic changes within specific cell populations to etiological genetic risk factors, contextualizing established knowledge within the cytoarchitecture of the human cortex and facilitating mechanistic understanding of schizophrenia pathophysiology and heterogeneity.
