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1.  Evolutionary appearance of von Economo’s neurons in the mammalian cerebral cortex 
von Economo’s neurons (VENs) are large, spindle-shaped projection neurons in layer V of the frontoinsular (FI) cortex, and the anterior cingulate cortex. During human ontogenesis, the VENs can first be differentiated at late stages of gestation, and increase in number during the first eight postnatal months. VENs have been identified in humans, chimpanzee, bonobos, gorillas, orangutan and, more recently, in the macaque. Their distribution in great apes seems to correlate with human-like social cognitive abilities and self-awareness. VENs are also found in whales, in a number of different cetaceans, and in the elephant. This phylogenetic distribution may suggest a correlation among the VENs, brain size and the “social brain.” VENs may be involved in the pathogenesis of specific neurological and psychiatric diseases, such as autism, callosal agenesis and schizophrenia. VENs are selectively affected in a behavioral variant of frontotemporal dementia in which empathy, social awareness and self-control are seriously compromised, thus associating VENs with the social brain. However, the presence of VENs has also been related to special functions such as mirror self-recognition. Areas containing VENs have been related to motor awareness or sense-of-knowing, discrimination between self and other, and between self and the external environment. Along this line, VENs have been related to the “global Workspace” architecture: in accordance the VENs have been correlated to emotional and interoceptive signals by providing fast connections (large axons = fast communication) between salience-related insular and cingulate and other widely separated brain areas. Nevertheless, the lack of a characterization of their physiology and anatomical connectivity allowed only to infer their functional role based on their location and on the functional magnetic resonance imaging data. The recent finding of VENs in the anterior insula of the macaque opens the way to new insights and experimental investigations.
PMCID: PMC3953677  PMID: 24672457
insula; cingulate cortex; salience network; self-awareness; prediction; development
2.  Biochemical specificity of von Economo neurons in hominoids 
Von Economo neurons (VENs) are defined by their thin, elongated cell body and long dendrites projecting from apical and basal ends. These distinctive neurons are mostly present in anterior cingulate (ACC) and fronto-insular (FI) cortex, with particularly high densities in cetaceans, elephants, and hominoid primates (i.e., humans and apes). This distribution suggests that VENs contribute to specializations of neural circuits in species that share both large brain size and complex social cognition, possibly representing an adaptation to rapidly relay socially-relevant information over long distances across the brain. Recent evidence indicates that unique patterns of protein expression may also characterize VENs, particularly involving molecules that are known to regulate gut and immune function. In this study, we used quantitative stereologic methods to examine the expression of three such proteins that are localized in VENs – activating-transcription factor 3 (ATF3), interleukin 4 receptor (IL4Rα) and neuromedin B (NMB). We quantified immunoreactivity against these proteins in different morphological classes of ACC layer V neurons of hominoids. Among the different neuron types analyzed (pyramidal, VEN, fork, enveloping, and other multipolar), VENs showed the greatest percentage that displayed immunostaining. Additionally, a higher proportion of VENs in humans were immunoreactive to ATF3, IL4Rα, and NMB than in other apes. No other ACC layer V neuron type displayed a significant species difference in the percentage of immunoreactive neurons. These findings demonstrate that phylogenetic variation exists in the protein expression profile of VENs, suggesting that humans might have evolved biochemical specializations for enhanced interoceptive sensitivity.
PMCID: PMC3004764  PMID: 21140465
brain; evolution; ape; human; neuron
3.  Neuroanatomical Correlates of Suicide in Psychosis: The Possible Role of von Economo Neurons 
PLoS ONE  2011;6(6):e20936.
Suicide is the most important incident in psychiatric disorders. Psychological pain and empathy to pain involves a neural network that involves the anterior cingulate cortex (ACC) and the anterior insula (AI). At the neuronal level, little is known about how complex emotions such as shame, guilt, self-derogation and social isolation, all of which feature suicidal behavior, are represented in the brain. Based on the observation that the ACC and the AI contain a large spindle-shaped cell type, referred to as von Economo neuron (VEN), which has dramatically increased in density during human evolution, and on growing evidence that VENs play a role in the pathophysiology of various neuropsychiatric disorders, including autism, psychosis and dementia, we examined the density of VENs in the ACC of suicide victims. The density of VENs was determined using cresyl violet-stained sections of the ACC of 39 individuals with psychosis (20 cases with schizophrenia, 19 with bipolar disorder). Nine subjects had died from suicide. Twenty specimen were available from the right, 19 from the left ACC. The density of VENs was significantly greater in the ACC of suicide victims with psychotic disorders compared with psychotic individuals who died from other causes. This effect was restricted to the right ACC. VEN density in the ACC seems to be increased in suicide victims with psychosis. This finding may support the assumption that VEN have a special role in emotion processing and self-evaluation, including negative self-appraisal.
PMCID: PMC3120769  PMID: 21731632
4.  von Economo neurones are selectively targeted in frontotemporal dementia 
von Economo neurones (VEN) are bipolar neurones located in the anterior cingulate cortex (ACC) and the frontoinsular cortex (FI), areas affected early in behavioural variant frontotemporal dementia (bvFTD), in which VEN may constitute a selectively vulnerable cellular population.
A previous study has shown a selective loss of VEN in FTD above other neurones in the ACC of FTD. The aim of this study was to confirm this finding in a larger cohort, using a different methodology, and to examine VEN loss in relation to neuropathological severity and molecular pathology.
VEN and neighbouring neurones (NN) were quantified in layers Va and Vb of the right dorsal ACC in 21 cases of bvFTD, 10 cases of Alzheimer's disease (AD) and 10 non-demented controls (NDC).
A marked VEN reduction was seen in all FTD cases. In the neuropathologically early cases of FTD (n = 13), VEN/10 000 NN was significantly reduced by 53% compared with NDC (P < 0.001) and 41% compared with AD (P = 0.019), whereas AD patients showed a non-significant 30% reduction of VEN/10 000 NN compared with NDC. VEN reduction was present in all protein pathology subgroups.
In conclusion, this study confirms selective sensitivity of VEN in FTD and suggests that VEN loss is an early event in the neurodegenerative process.
PMCID: PMC3749467  PMID: 23346995
anterior cingulate cortex; frontotemporal dementia; frontotemporal lobar degeneration; von Economo neurones
5.  Selective functional, regional, and neuronal vulnerability in frontotemporal dementia 
Current opinion in neurology  2008;21(6):701-707.
Purpose of review
The molecular neuroscience revolution has begun to rekindle interest in fundamental neuroanatomy. Blending these disciplines may prove critical to our understanding of neurodegenerative diseases, which target specific anatomical systems. Recent research on frontotemporal dementia highlights the potential value of these approaches.
Recent findings
The behavioral variant of FTD (bvFTD) leads to progressive social-emotional processing deficits accompanied by anterior cingulate and frontal insular degeneration. These sites form a discrete human neural network and feature a class of Layer 5b projection neurons, von Economo neurons (VENs), found only in large-brained, socially complex mammals. VENs have been shown to represent an early target in bvFTD but not in Alzheimer’s disease.
Integrative approaches to selective vulnerability may help clarify neurodegenerative disease pathogenesis.
PMCID: PMC2909835  PMID: 18989116
frontotemporal dementia; von Economo neuron; anterior cingulate; insula
6.  Selective Frontoinsular von Economo Neuron and Fork Cell Loss in Early Behavioral Variant Frontotemporal Dementia 
Cerebral Cortex (New York, NY)  2011;22(2):251-259.
Behavioral variant frontotemporal dementia (bvFTD) erodes complex social–emotional functions as the anterior cingulate cortex (ACC) and frontoinsula (FI) degenerate, but the early vulnerable neuron within these regions has remained uncertain. Previously, we demonstrated selective loss of ACC von Economo neurons (VENs) in bvFTD. Unlike ACC, FI contains a second conspicuous layer 5 neuronal morphotype, the fork cell, which has not been previously examined. Here, we investigated the selectivity, disease-specificity, laterality, timing, and symptom relevance of frontoinsular VEN and fork cell loss in bvFTD. Blinded, unbiased, systematic sampling was used to quantify bilateral FI VENs, fork cells, and neighboring neurons in 7 neurologically unaffected controls (NC), 5 patients with Alzheimer's disease (AD), and 9 patients with bvFTD, including 3 who died of comorbid motor neuron disease during very mild bvFTD. bvFTD showed selective FI VEN and fork cell loss compared with NC and AD, whereas in AD no significant VEN or fork cell loss was detected. Although VEN and fork cell losses in bvFTD were often asymmetric, no group-level hemispheric laterality effects were identified. Right-sided VEN and fork cell losses, however, correlated with each other and with anatomical, functional, and behavioral severity. This work identifies region-specific neuronal targets in early bvFTD.
PMCID: PMC3256403  PMID: 21653702
Alzheimer's disease; behavioral variant frontotemporal dementia; fork cell; frontoinsula; von Economo neuron
7.  A volumetric comparison of the insular cortex and its subregions in primates 
Journal of human evolution  2013;64(4):263-279.
The neuronal composition of the insula in primates displays a gradient, transitioning from granular neocortex in the posterior-dorsal insula to agranular neocortex in the anterior-ventral insula with an intermediate zone of dysgranularity. Additionally, apes and humans exhibit a distinctive subdomain in the agranular insula, the frontoinsular cortex (FI), defined by the presence of clusters of von Economo neurons (VENs). Studies in humans indicate that the ventral anterior insula, including agranular insular cortex and FI, is involved in social awareness, and that the posterodorsal insula, including granular and dysgranular cortices, produces an internal representation of the body’s homeostatic state. We examined the volumes of these cytoarchitectural areas of insular cortex in 30 primate species, including the volume of FI in apes and humans. Results indicate that the whole insula scales hyperallometrically (exponent = 1.13) relative to total brain mass, and the agranular insula (including FI) scales against total brain mass with even greater positive allometry (exponent = 1.23), providing a potential neural basis for enhancement of social cognition in association with increased brain size. The relative volumes of the subdivisions of the insular cortex, after controlling for total brain volume, are not correlated with species typical social group size. Although its size is predicted by primate-wide allometric scaling patterns, we found that the absolute volume of the left and right agranular insula and left FI are among the most differentially expanded of the human cerebral cortex compared to our closest living relative, the chimpanzee.
PMCID: PMC3756831  PMID: 23466178
Allometry; Brain; Evolution; Frontoinsular cortex; Hominoids
8.  Predictors of nonresponse to cognitive behavioural therapy or venlafaxine using glucose metabolism in major depressive disorder 
Longitudinal neuroimaging investigations of antidepressant treatment offer the opportunity to identify potential baseline biomarkers associated with poor outcome.
To explore the neural correlates of nonresponse to cognitive behavioural therapy (CBT) or venlafaxine (VEN), we compared pretreatment (18)F-fluoro-2-deoxy-d-glucose positron emission tomography scans of participants with major depressive disorder responding to either 16 weeks of CBT (n = 7) or VEN treatment (n = 9) with treatment nonresponders (n = 8).
Nonresponders to CBT or VEN, in contrast to responders, exhibited pretreatment hypermetabolism at the interface of the pregenual and subgenual cingulate cortices.
Limitations of our study include the small sample sizes and the absence of both arterial sampling to determine absolute glucose metabolism and high-resolution structural magnetic resonance imaging coregistration for region-of-interest analyses.
Our current findings are consistent with those reported in previous studies of relative hyperactivity in the ventral anterior cingulate cortex in treatment-resistant populations.
PMCID: PMC2674969  PMID: 19448846
9.  Bilateral limbic system destruction in man 
We report here a case study of a rare neurological patient with bilateral brain damage encompassing a substantial portion of the so-called “limbic system.” The patient, Roger, has been studied in our laboratory for over 14 years and the current article presents his complete neuroanatomical and neuropsychological profiles. The brain damage occurred in 1980 following an episode of herpes simplex encephalitis. The amount of destroyed neural tissue is extensive and includes bilateral damage to core limbic and paralimbic regions, including the hippocampus, amygdala, parahippocampal gyrus, temporal poles, orbitofrontal cortex, basal forebrain, anterior cingulate cortex, and insular cortex. The right hemisphere is more extensively affected than the left, although the lesions are largely bilateral. Despite the magnitude of his brain damage, Roger has a normal IQ, average to above average attention, working memory, and executive functioning skills, and very good speech and language abilities. In fact, his only obvious presenting deficits are a dense global amnesia and a severe anosmia and ageusia. Roger's case presents a rare opportunity to advance our understanding of the critical functions underlying the human limbic system, and the neuropsychological and neuroanatomical data presented here provide a critical foundation for such investigations.
PMCID: PMC2888849  PMID: 19763994
10.  Posterior parahippocampal gyrus pathology in Alzheimer’s disease 
Neuroscience  2008;154(2):667-676.
The posterior parahippocampal gyrus (PPHG) of the non-human primate brain has a distinct dual role in cortical neural systems. On the one hand, it is a critical link in providing the entorhinal cortex and hippocampal formation with cortical input, while on the other hand it receives output from these structures and projects widely by disseminating the medial temporal lobe output to the cortex. Layer III of TF and TH areas (temporal areas F, H of von Economo and Koskinas (1925) and von Bonin and Bailey (1947) largely mediate the former (input) while layer V mediates the latter (output). We have examined areas TF and TH in the normal human brain and in Alzheimer’s disease (AD) using pathological stains (Nissl, Thioflavin S) and phenotype specific stains non-phosphorylated neurofilament protein (SMI-32) and parvalbumin (PV). Seven clinically and pathologically confirmed AD cases have been studied along with six age-compatible normal cases. Our observations reveal that neurofibrillary tangles (NFTs) heavily invest the area TF and TH neurons that form layers III and V. In both cortical areas, the large pyramids that form layer V contain a greater number of NFTs. These changes, and possibly, pyramidal cell loss, greatly alter the cytoarchitectural picture and diminish SMI-32 staining patterns. Layer III of area TH loses the majority of SMI-32 immunoreactivity, whereas this change is more conspicuous in layer V of area TF. PV-staining in both areas is largely unaffected. Normal cases contained no evidence of pathology or altered cytoarchitecture. These observations reveal a further disruption of memory related temporal neural systems in AD where pathology selectively alters both the input to the hippocampal formation and its output to the cortex.
PMCID: PMC2517248  PMID: 18486350
Alzheimer’s disease; neurofibrillary tangles; posterior parahippocampal gyrus; hippocampal formation; memory; laminar pattern
11.  Pharmacokinetics of venlafaxine and its major metabolite o-desmethylvenlafaxine in freely moving mice using automated dosing/sampling system 
Indian Journal of Pharmacology  2012;44(1):20-25.
To assess the pharmacokinetics of venlafaxine (VEN) and its major metabolite o-desmethylvenlafaxine (ODV) in freely moving mice using automated dosing/infusion (ADI) and automated blood sampling (ABS) systems. In addition, concentration of VEN and its metabolite ODV were also measured in brain by microdialysis.
Materials and Methods:
Venlafaxine was administered directly via jugular vein or gastric catheterization and blood samples were collected through carotid artery. A series of samples with 10 μl of blood was collected from the mouse using ADI/ABS and analyzed with a validated LC-MS/MS system. Extracellular concentrations of VEN and ODV in brain were investigated by using microdialysis procedure.
The bioavailability of VEN was 11.6%. The percent AUC ratios of ODV to VEN were 18% and 39% following intravenous and intragastric administration, respectively. The terminal half-life of venlafaxine was about two hours. Extracellular concentration of VEN contributed 3.4% of the blood amount, while ODV was not detected in dialysate.
This study suggests that besides rapid absorption of VEN, the first-pass metabolism is likely to contribute for its lower bioavailability in the mouse. The proposed automated technique can be used easily to conduct pharmacokinetic studies and is applicable to high-throughput manner in mouse model.
PMCID: PMC3271533  PMID: 22345864
Pharmacokinetics; microdialysis; O-desmethylvenlafaxine; venlafaxine
12.  Youthful Memory Capacity in Old Brains: Anatomic and Genetic Clues from the Northwestern SuperAging Project 
The Northwestern University SuperAging Project recruits community dwellers over the age of 80 who have unusually high performance on tests of episodic memory. In a previous report, a small cohort of SuperAgers was found to have higher cortical thickness on structural MRI than a group of age-matched but cognitively average peers. SuperAgers also displayed a patch of ACC where cortical thickness was higher than in 50- to 60-year-old younger cognitively healthy adults. In additional analyses, some SuperAgers had unusually low densities of age-related Alzheimer pathology and unusually high numbers of von Economo neurons in the anterior cingulate gyrus. SuperAgers were also found to have a lower frequency of the ε4 allele of apolipoprotein E than the general population. These preliminary results show that above-average memory capacity can be encountered in advanced age. They also offer clues to potential biological factors that may promote resistance to age-related involutional changes in the structure and function of the brain.
PMCID: PMC3541673  PMID: 23198888
13.  Simple Method for Evaluation of Planum Temporale Pyramidal Neurons Shrinkage in Postmortem Tissue of Alzheimer Disease Patients 
BioMed Research International  2014;2014:607171.
We measured the length of the pyramidal neurons in the cortical layer III in four subregions of the planum temporale (transitions into superior temporal gyrus, Heschl's gyrus, insular cortex, and Sylvian fissure) in control group and Alzheimer disease patients. Our hypothesis was that overall length of the pyramidal neurons would be smaller in the Alzheimer disease group compared to controls and also there would be right-left asymmetry in both the control and Alzheimer disease groups. We found pyramidal neuron length asymmetry only in controls—in the transition into the Sylvian fissure—and the rest of the subregions in the control group and Alzheimer disease patients did not show size difference. However, control-Alzheimer disease group pyramidal neuron length comparison revealed (a) no length difference in superior temporal gyrus transition area, (b) reversal of asymmetry in the insular transition area with left insular transition significantly shorter in the Alzheimer disease group compared to the control group, (c) both right and left Heschl's gyrus transitions significantly shorter in the Alzheimer disease group compared to the control group, and (d) right Sylvian fissure transition significantly shorter in the Alzheimer disease group compared to the control group. This neuronal length measurement method could supplement already existing neuropathological criteria for postmortem Alzheimer disease diagnostics.
PMCID: PMC3956417  PMID: 24719875
14.  The Human Brain in Numbers: A Linearly Scaled-up Primate Brain  
The human brain has often been viewed as outstanding among mammalian brains: the most cognitively able, the largest-than-expected from body size, endowed with an overdeveloped cerebral cortex that represents over 80% of brain mass, and purportedly containing 100 billion neurons and 10× more glial cells. Such uniqueness was seemingly necessary to justify the superior cognitive abilities of humans over larger-brained mammals such as elephants and whales. However, our recent studies using a novel method to determine the cellular composition of the brain of humans and other primates as well as of rodents and insectivores show that, since different cellular scaling rules apply to the brains within these orders, brain size can no longer be considered a proxy for the number of neurons in the brain. These studies also showed that the human brain is not exceptional in its cellular composition, as it was found to contain as many neuronal and non-neuronal cells as would be expected of a primate brain of its size. Additionally, the so-called overdeveloped human cerebral cortex holds only 19% of all brain neurons, a fraction that is similar to that found in other mammals. In what regards absolute numbers of neurons, however, the human brain does have two advantages compared to other mammalian brains: compared to rodents, and probably to whales and elephants as well, it is built according to the very economical, space-saving scaling rules that apply to other primates; and, among economically built primate brains, it is the largest, hence containing the most neurons. These findings argue in favor of a view of cognitive abilities that is centered on absolute numbers of neurons, rather than on body size or encephalization, and call for a re-examination of several concepts related to the exceptionality of the human brain.
PMCID: PMC2776484  PMID: 19915731
brain scaling; number of neurons; human; encephalization
15.  A Case of Semantic Variant Primary Progressive Aphasia with Severe Insular Atrophy 
Neurocase  2011;18(6):450-456.
Insular degeneration has been linked to symptoms of frontotemporal dementia (FTD). Presented in this case is a patient exhibiting semantic variant primary progressive aphasia, behavioral disturbance. Upon autopsy, he was found to have severe insular atrophy. In addition, selective serotonin reuptake inhibitors (SSRIs) were ineffective in reducing symptoms of obsessive-compulsive behaviours or emotional blunting. This case suggests that Seeley et al.'s hypothesis that VEN and fork cell-rich brain regions, particularly in the insula, are targeted in additional subtypes of FTD beyond the behavioral variant.
PMCID: PMC3500405  PMID: 22150361
frontotemporal dementia; MRI; PET; SPECT; insula
16.  Cytoarchitectonic and chemoarchitectonic characterization of the prefrontal cortical areas in the mouse 
Brain structure & function  2010;214(4):339-353.
This study describes cytoarchitectonic criteria to define the prefrontal cortical areas in the mouse brain (C57BL/6 strain). Currently, well-illustrated mouse brain stereotaxic atlases are available, which, however, don't provide a description of the distinctive cytoarchitectonic characteristics of individual prefrontal areas. Such a description is of importance for stereological, neuronal tracing, physiological, molecular and neuroimaging studies in which a precise parcellation of the prefrontal cortex is required. The present study describes and illustrates: medial prefrontal areas, i.e., the infralimbic, prelimbic, dorsal and ventral anterior cingulate and Fr2 area; areas of the lateral prefrontal cortex, i.e., the dorsal agranular insular cortical areas, and areas of the ventral prefrontal cortex, i.e., the lateral -, ventrolateral -, ventral - and medial orbital areas. Each cytoarchitectonically defined boundary is corroborated by one or more chemoarchitectonic stainings: i.e., acetylcholine esterase, SMI32, SMI311, dopamine, parvalbumin, calbindin and myelin staining.
PMCID: PMC2862954  PMID: 20221886
cortical parcellation; infralimbic, prelimbic, anterior cingulate, Fr2, agranular insular and orbital cortical areas; Nissl; myelin; acetylcholinesterase; Dopamine; calcium binding proteins; SMI-32; SMI-311
17.  Cytoarchitectonic and chemoarchitectonic characterization of the prefrontal cortical areas in the mouse 
Brain Structure & Function  2010;214(4):339-353.
This study describes cytoarchitectonic criteria to define the prefrontal cortical areas in the mouse brain (C57BL/6 strain). Currently, well-illustrated mouse brain stereotaxic atlases are available, which, however, do not provide a description of the distinctive cytoarchitectonic characteristics of individual prefrontal areas. Such a description is of importance for stereological, neuronal tracing, and physiological, molecular and neuroimaging studies in which a precise parcellation of the prefrontal cortex (PFC) is required. The present study describes and illustrates: the medial prefrontal areas, i.e., the infralimbic, prelimbic, dorsal and ventral anterior cingulate and Fr2 area; areas of the lateral PFC, i.e., the dorsal agranular insular cortical areas and areas of the ventral PFC, i.e., the lateral, ventrolateral, ventral and medial orbital areas. Each cytoarchitectonically defined boundary is corroborated by one or more chemoarchitectonic stainings, i.e., acetylcholine esterase, SMI32, SMI311, dopamine, parvalbumin, calbindin and myelin staining.
PMCID: PMC2862954  PMID: 20221886
Cortical parcellation; Infralimbic, prelimbic, anterior cingulate, Fr2, agranular insular and orbital cortical areas; Nissl; Myelin; Acetylcholinesterase; Dopamine; Calcium binding proteins; SMI-32; SMI-311
18.  The Human Parahippocampal Region: I. Temporal Pole Cytoarchitectonic and MRI Correlation 
Cerebral Cortex (New York, NY)  2010;20(9):2198-2212.
The temporal pole (TP) is the rostralmost portion of the human temporal lobe. Characteristically, it is only present in human and nonhuman primates. TP has been implicated in different cognitive functions such as emotion, attention, behavior, and memory, based on functional studies performed in healthy controls and patients with neurodegenerative diseases through its anatomical connections (amygdala, pulvinar, orbitofrontal cortex). TP was originally described as a single uniform area by Brodmann area 38, and von Economo (area TG of von Economo and Koskinas), and little information on its cytoarchitectonics is known in humans. We hypothesize that 1) TP is not a homogenous area and we aim first at fixating the precise extent and limits of temporopolar cortex (TPC) with adjacent fields and 2) its structure can be correlated with structural magnetic resonance images. We describe here the macroscopic characteristics and cytoarchitecture as two subfields, a medial and a lateral area, that constitute TPC also noticeable in 2D and 3D reconstructions. Our findings suggest that the human TP is a heterogeneous region formed exclusively by TPC for about 7 mm of the temporal tip, and that becomes progressively restricted to the medial and ventral sides of the TP. This cortical area presents topographical and structural features in common with nonhuman primates, which suggests an evolutionary development in human species.
PMCID: PMC2923216  PMID: 20064939
cytoarchitecture; humans; MRI; temporal pole; temporopolar cortex
19.  Brain and aviation: on the 80th anniversary of Constantin von Economo’s (1876–1931) death 
Neurological Sciences  2012;34(3):387-391.
2011 marks the 80th anniversary of the death of Constantin Alexander von Economo who conducted advanced research on the cytoarchitectonics of the brain. This Austrian neurologist and the pioneer of aviation described encephalitis lethargica, discovered the spindle neurons, and postulated the existence of the sleep and wakefulness centre in the brain. What is more he realized two of the biggest dreams of humankind: conquering space and getting to know the secrets of the human brain.
PMCID: PMC3586395  PMID: 22569570
Constantin von Economo; History of neurology; von Economo neurons; Encephalitis lethargica; Brain
What pattern of brain damage could completely obliterate the sense of olfaction in humans? We had an opportunity to address this intriguing question in patient B., who has extensive bilateral damage to most of the limbic system, including the medial and lateral temporal lobes, orbital frontal cortex, insular cortex, anterior cingulate cortex, and basal forebrain, caused by herpes simplex encephalitis. The patient demonstrated profound impairments in odor identification and recognition. Moreover, he could not discriminate between olfactory stimuli and he had severe impairments in odor detection. Reliable stimulus detection was obtained only for solutions of the organic solvent acetone and highly concentrated solutions of ethanol. In contrast to the more circumscribed olfactory deficits demonstrated in patients with damage confined to either the temporal lobes or orbitofrontal cortex (which tend to involve odor identification but not odor detection), patient B. demonstrates a strikingly severe and complete anosmia. This contrast in olfactory abilities and deficits as a result of different anatomical pathology affords new insights into the neural substrates of olfactory processing in humans.
PMCID: PMC3269190  PMID: 22220560
21.  Gliogenesis and Glial Pathology in Depression 
Recent research has changed the perception of glia from being no more than silent supportive cells of neurons to being dynamic partners participating in brain metabolism and communication between neurons. This discovery of new glial functions coincides with growing evidence of the involvement of glia in the neuropathology of mood disorders. Unanticipated reductions in the density and number of glial cells are reported in fronto-limbic brain regions in major depression and bipolar illness. Moreover, age-dependent decreases in the density of glial fibrillary acidic protein (GFAP) - immunoreactive astrocytes and levels of GFAP protein are observed in the prefrontal cortex of younger depressed subjects. Since astrocytes participate in the uptake, metabolism and recycling of glutamate, we hypothesize that an astrocytic deficit may account for the alterations in glutamate/GABA neurotransmission in depression. Reductions in the density and ultrastructure of oligodendrocytes are also detected in the prefrontal cortex and amygdala in depression. Pathological changes in oligodendrocytes may be relevant to the disruption of white matter tracts in mood disorders reported by diffusion tensor imaging. Factors such as stress, excess of glucocorticoids, altered gene expression of neurotrophic factors and glial transporters, and changes in extracellular levels of neurotransmitters released by neurons may modify glial cell number and affect the neurophysiology of depression. Therefore, we will explore the role of these events in the possible alteration of glial number and activity, and the capacity of glia as a promising new target for therapeutic medications. Finally, we will consider the temporal relationship between glial and neuronal cell pathology in depression.
PMCID: PMC2918806  PMID: 17511618
22.  Spatial distribution and density of oligodendrocytes in the cingulum bundle are unaltered in schizophrenia 
Acta neuropathologica  2008;117(4):385-394.
It has been proposed that schizophrenia results partly from altered brain connectivity. Gene microarray analyses performed in gray matter have indicated that several myelin-related genes normally expressed in oligodendrocytes have decreased expression levels in schizophrenia. These data suggest that oligodendrocytes may be involved in the deficits of schizophrenia and may be decreased in number in the disease. The anterior cingulate cortex in particular has been demonstrated to be affected in schizophrenia, with studies reporting altered neuronal arrangement, decreased anisotropy in diffusion tensor images, and hypometabolism. We used a stereologic nearest-neighbor estimator of spatial distribution to investigate oligodendrocytes in the anterior cingulum bundle using postmortem tissue from 13 chronic schizophrenics and 13 age-matched controls. Using a spatial point pattern analysis, we measured the degree of oligodendrocyte clustering by comparing the probability of finding a nearest-neighbor at a given distance in schizophrenics and controls. At the same time, we also estimated the number and density of oligodendrocytes in the region of interest. In the present study, we found no significant differences in the oligodendrocyte distribution or density in the cingulum bundle between the two groups, in contrast to earlier data from the prefrontal subcortical white matter. These results suggest that a more subtle oligodendrocyte or myelin anomaly may underlie the structural deficits observed by brain imaging in the cingulum bundle in schizophrenia.
PMCID: PMC2656594  PMID: 18438678
schizophrenia; oligodendrocyte; cingulate gyrus; stereology
23.  Magnetic resonance spectroscopy of limbic structures displays metabolite differences in young unaffected relatives of schizophrenia probands 
Schizophrenia research  2011;131(1-3):4-10.
Imaging studies of schizophrenia patients showed fronto-temporal brain volume deficits, while magnetic resonance spectroscopy (MRS) studies of patients and unaffected biological relatives have found a decrement of the neuronal marker N-acetyl-aspartate (NAA) in the hippocampus and frontal lobes, and increased choline-containing phospholipids. Using a 3 T MR scanner, we determined the metabolite profile within limbic regions (anterior cingulate cortex (ACC) and left hippocampus) of 36 unaffected, adolescent/young adult relatives of schizophrenia probands (first-degree=16, second-degree=20) and 25 healthy controls with no family history of schizophrenia. Significant main effects of group were found on NAA/Cho ratios for both the left hippocampus (F=6.11, p≤0.02) and ACC (F=4.89, p≤0.03) as well as for the left hippocampus Cho/Cr ratio (F=5.55, p≤0.02). Compared to age and sex matched healthy controls without a family history of schizophrenia, first-degree relatives of probands had greater MRS metabolite deviations than second-degree relatives. Greater familial proximity to the schizophrenia proband (or higher schizophrenia susceptibility) among biological relatives was associated with stepwise lowering of NAA/Cho and elevations in Cho/Cr ratios. The observed limbic metabolite changes among young, nonpsychotic biological relatives are likely related to shared genetic vulnerability factors, and may assist in the early identification of schizophrenia for primary and secondary prevention.
PMCID: PMC3485075  PMID: 21705196
Adolescence; Endophenotype; Genetics; Magnetic resonance spectroscopy; Hippocampus; Anterior cingulate cortex
24.  Cumulative Adversity and Smaller Gray Matter Volume in Medial Prefrontal, Anterior Cingulate, and Insula Regions 
Biological Psychiatry  2012;72(1):57-64.
Cumulative adversity and stress are associated with risk of psychiatric disorders. While basic science studies show repeated and chronic stress effects on prefrontal and limbic neurons, human studies examining cumulative stress and effects on brain morphology are rare. Thus, we assessed whether cumulative adversity is associated with differences in gray matter volume, particularly in regions regulating emotion, self-control, and top-down processing in a community sample.
One hundred three healthy community participants, aged 18 to 48 and 68% male, completed interview assessment of cumulative adversity and a structural magnetic resonance imaging protocol. Whole-brain voxel-based-morphometry analysis was performed adjusting for age, gender, and total intracranial volume.
Cumulative adversity was associated with smaller volume in medial prefrontal cortex (PFC), insular cortex, and subgenual anterior cingulate regions (familywise error corrected, p <.001). Recent stressful life events were associated with smaller volume in two clusters: the medial PFC and the right insula. Life trauma was associated with smaller volume in the medial PFC, anterior cingulate, and subgenual regions. The interaction of greater subjective chronic stress and greater cumulative life events was associated with smaller volume in the orbitofrontal cortex, insula, and anterior and subgenual cingulate regions.
Current results demonstrate that increasing cumulative exposure to adverse life events is associated with smaller gray matter volume in key prefrontal and limbic regions involved in stress, emotion and reward regulation, and impulse control. These differences found in community participants may serve to mediate vulnerability to depression, addiction, and other stress-related psychopathology.
PMCID: PMC3391585  PMID: 22218286
Brain MRI; chronic stress; cumulative adversity; gray matter volume; life trauma; prefrontal cortex; recent adverse life events
The juxtacapsular nucleus of the anterior division of the BNST (jcBNST) receives robust glutamatergic projections from the basolateral nucleus of the amygdala (BLA), the postpiriform transition area, and the insular cortex as well as dopamine (DA) inputs from the midbrain. In turn the jcBNST sends GABAergic projections to the medial division of the central nucleus of the amygdala (CEAm) as well as other brain regions. We recently described a form of long-term potentiation of the intrinsic excitability (LTP-IE) of neurons of the juxtacapsular nucleus of BNST (jcBNST) in response to high-frequency stimulation (HFS) of the stria terminalis that was impaired during protracted withdrawal from alcohol, cocaine, and heroin and in rats chronically treated with corticotropin releasing factor (CRF) intracerebroventricularly. Here we show that DAergic neurotransmission is required for the induction of LTP-IE of jcBNTS neurons through dopamine (DA) D1 receptors. Thus, activation of the central CRF stress system and altered DAergic neurotransmission during protracted withdrawal from alcohol and drugs of abuse may contribute to the disruption of LTP-IE in the jcBNST. Impairment of this form of intrinsic neuronal plasticity in the jcBNST could result in inadequate neuronal integration and reduced inhibition of the CEA, contributing to the negative affective state that characterizes protracted abstinence in post-dependent individuals. These results provide a novel neurobiological target for vulnerability to alcohol and drug dependence.
PMCID: PMC2935256  PMID: 19683025
stress; reward; action potential threshold; neuronal integration; temporal precision

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