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The history of von Economo neurons (VENs) and their possible role in neurodevelopmental/neuropsychiatric disorders: A literature review
Abstract
Background
Von Economo neurons (VENs) develop late in the gestational period, not starting to be produced until the 35th week, when only 15% of the total adult population develops. Their development, migration and synaptogenesis is then halted until the 4th postnatal month when a second generation of cells begins to develop in a process that continues until the 4th year of life. They migrate to three areas of the human brain and to date have only been found in the great apes, certain whales, elephants, bottlenose dolphins and in very small numbers in the manatee. It has been suggested that their presence in these limited species is related to the degree of encephalization and a high brain to body ratio. They are species specific in terms of numbers present, structure, location and columnar arrangement. It has been suggested that the evolution of humans was driven by the emergence of large social networks and it is possible that VENs in humans, whales, great apes, dolphins and elephants may have a vital role in the development of this social behaviour.
Objective
To draw together research being conducted into the presence of von Economo neurons, their location, number of cells present, their migration, their connections, and the neurodevelopment of the paediatric brain and discuss their possible role in neurodevelopmental/neuropsychiatric disorders.
Design
This study was a review of the available literature.
Method
The Boolean operators (von Economo cells OR spindle cells) AND anterior cingulate; von Economo cells AND (infraorbital area OR frontal pole) were used to perform a computerised literature search of MEDLINE, Science Direct, Cochrane Library, Science Citation Index, SCOPUS, CINAHL and the worldwide web. Papers chosen were limited to those concerning human studies, the great apes, cetaceans and the African and Indian elephants.
... Of these the von Economo neurons (VENs) are the best recognised and most researched. 14,15 von Economo neurons probably originated in the common ancestor to humans and the great apes, the dryopithecine ape some 15 million years ago. 16 They develop late in ontogeny as well as phylogeny with a very few cells present by the 35th week of gestation and only some 15% of the postnatal numbers being present at birth. ...
... The full adult number is not attained until about 4 years of age. 14 Reduced numbers, altered state and abnormal activity of von Economo neurons has been cited in the pathogenesis of autism -the ultimate developmental delay -learning and behavioural disorders, obsessive compulsive disorder (OCD), depression, anxiety, phobic states, akinetic mutism, psychopathy, anorexia and schizophrenia. Altered physiological activity and/or anatomy of the anterior cingulate cortex, one of the three sites where von Economo cells are found in the human brain, has been found in the major neuropsychiatric disorders and the vulnerability of von Economo neurons to stressors due to their late ontological development has been identified. ...
... 17 A 74% reduction in von Economo neurons was also found in fronto-temporal dementia with only slight losses in neighbouring layer V pyramidal cells. 18 That von Economo neurons might be an underlying cause of developmental delay in children 14 and dementia in senescence is supported by the fact that there are substantially more von Economo neurons in the right cerebral hemisphere and that fronto-temporal dementia reflects a loss of rightlateralised brain capacity and von Economo neuron function. 18 This would include reduced social and emotional self-awareness, moral reasoning, empathy and theory of mind (Table 1). ...
Paratonia and gegenhalten – the involuntary resistance to passive movement – are terms used in the field of neurology to describe a form of hypertonia often associated with dementia. It is however also found to be present in children suffering from developmental delay where it may be accompanied by signs of dyspraxia and learning disabilities. Its presence may cause an elderly patient to appear to be being deliberately difficult and the child to be misbehaving.
Objective
To bring an awareness of how common paratonia/gegenhalten are in a general patient population.
Method
An overview of the literature retrieved from searches of computerised databases, the world-wide web and authoritative texts.
Discussion
As paratonia in children and gegenhalten in the elderly population occur at significantly high rates, as has been found with many of the primitive reflexes, it is suggested that their retention and reappearance may be associated with the postnatal development of the brain and its demise associated with ageing.
Conclusion
With such a high percentage of both the juvenile and elderly population manifesting signs of resisted movement it is considered essential that practitioners dealing with either of these groups have a good working knowledge of this common neurological sign.
... The AIC contains the unique large spindle neurons known as Von Economo Neurons (VENs) [39,40]. The VENs are specially located in layer V of the AIC, ACC, and DLPFC, and are present only in hominoid primates [40]. ...
... The AIC contains the unique large spindle neurons known as Von Economo Neurons (VENs) [39,40]. The VENs are specially located in layer V of the AIC, ACC, and DLPFC, and are present only in hominoid primates [40]. Excessive survival of the spindle neurons in the AIC, a consequence of unsuccessful programmed cell death, may be an etiologically early neural substrate of neuropsychiatric conditions, notably OCD [1]. ...
... The VENs integrate representations of emotional moments and behavior [2] and possibly underlie the exaggeration of interoception or conscious awareness of visceral activity in OCD [39]. This altered interoception may be attributable to the rapid transmission of signals to adjacent nerve cells from VENs [39,40]. The mismatch between current and anticipated body states may lead to a prediction-error signal that acts as a strong impulse for immediate changes in behavioral responses until the error is eliminated [41]. ...
Recent studies have reported that the insular cortex is involved in the pathophysiology of obsessive-compulsive disorder (OCD). However, specific morphometric abnormalities of the insular subregions remain unclear. In this study, we examined insular cortical volume to determine whether the volume of the anterior and posterior insular cortices of unmedicated OCD patients differed according to different symptom dimensions.
Using magnetic resonance imaging, we measured the gray matter volumes of the insular cortex and its subregions (anterior and posterior divisions) in 41 patients with OCD (31 drug-naïve and 10 non-medicated) and 53 healthy controls. Volumetric measures of the insular cortex were compared according to different OC symptoms. Enlarged anterior and reduced posterior insular cortices were observed in OCD patients. The insular volumetric alterations were more significant in OCD patients with predominant checking rather than cleaning symptoms when compared with healthy controls.
Our results suggest the presence of unbalanced anterior and posterior insular volumetric abnormalities in unmedicated OCD patients and emphasize the distinct role of the insular cortex in different OC symptoms. We propose that the insular morphometric alterations may influence the modulation of interoceptive processing, the insular functional role, in OCD patients with different symptoms.
... 13 The anterior cingulate gyrus contains populations of von Economo neurons 85% of which do not begin to migrate until 4 months after birth and continue doing so until the fourth year of life. 14 The adult (mature) control of reflexive and volitional eye movements is dependent upon two cortical networks. 15 The reflexive network involves a ventrolateral frontoparietal system situated in the parietal cortex, while the dorsolateral frontoparietal system is situated in the frontal lobe. ...
... If as has been suggested the right hemisphere is potentially more vulnerable to developmental delay and the right magnocellular region is the site of lateralised peripheral monitoring, then its under functioning and/or delayed maturation might help explain why so many children find it all but impossible to ignore non-threatening stimuli within either visual field. 14,19 Consequently, without knowledge of a possibly retained primitive visual reflex, it may be wrongly thought that a child that is constantly distracted may be suffering from aspects of attention deficit disorder. ...
Objective
To consider if poor (immature) visual fixation in children aged 4–15 years could contribute to aspects of attention deficit disorder within a triad of symptoms – dyslexia, dyspraxia and attention deficit – of developmental delay.
Background
Although visual fixation and developmental delay have been widely researched the link between a possible retained visual reflex and attention deficit has not been established.
Methods
A prospective epidemiological study of 100 children.
Discussion
Within a group of children that constituted Group 1 of a case series of children with a primary diagnosis of dyslexia, dyspraxia, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD) and Tourette's syndrome of childhood a significant number of children (57%) demonstrated, on testing, aspects of convergence insufficiency/failure. On revisiting the original data it was found that a significant number of children demonstrated poor visual fixation as measured by an inability to maintain gaze on a fixed target during standard confrontational testing for the peripheral visual fields. This new data was then related to patterns of comorbidity and the presence of convergence insufficiency.
Conclusion
It is suggested that a retained primitive visual reflex may contribute to aspects of inattention in children which, as a consequence, may be wrongly considered as a behavioural issue and may also impact upon the child's ability to learn.
Design
A prospective epidemiological study.
... Functional properties of VENs have been associated with intuitive decision making [37] in complex situations that are often characteristic of social situations [38]. VENs are located in the ACC and FI, which constitute key regions of the salience network [39] and regulate higher order social emotions like guilt, embarrassment, and empathy as well as the subjective experience of pain and the need for autonomic activity [40], acting as a gateway between soma and psyche [41]. ...
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.
... 20 Also, with increasing knowledge of the postnatal development of the brain and the negative impact stressors may have upon it, the likelihood of the epigenome as the prime factor in developmental delay seems probable and would go a long way towards explaining why the geneticists to date have not found a purely genetic underlying cause for these common conditions. 21,22 Conclusion As dyspraxia is thought to affect up to eight per cent of the adult population in varying degrees and sometimes runs in families, an increased awareness and a better understanding of its various presentations are essential to anyone working with children with learning and behavioural disorders but also to those addressing conditions of the musculoskeletal system. It is known to have profound effects upon learning ability but it may also present as a latent/underlying predisposing factor in many common complaints, and it is suggested, may cause the treatment of such conditions to respond poorly or potentially lead to recurring relapses. ...
Objective
To bring an awareness of how common dyspraxia is and how it may impact upon the general health of patients visiting the general chiropractic practitioner.
Method
An overview of the literature retrieved from searches of computerised databases, the world-wide web and authoritative texts.
Discussion
Although generally considered in association with the learning and behavioural problems, dyspraxia can be an underlying cause of certain musculoskeletal conditions and may account for a slower than expected response to treatment or relapses.
Conclusion
Dyspraxia is said to occur in 20% of the population of children and without effective treatment will continue into adult life where it may not be recognised by the general chiropractic practitioner. It is hoped that this overview may bring to the attention of chiropractors the diverse symptoms and signs of dyspraxia and the sometimes subtle and yet debilitating effect it can have upon the patient and their treatment outcome.
... It is suggested that reduced nurturing and poor nutrition may adversely affect brain maturation and that both neurodevelopmental disorders and many neuropsychiatric disorders may originate from the medial wall of the brain that is, from an ontological perspective, particularly vulnerable to stressors be it birth interventions, lack of omega 3, or food additives. 32,33 Funding sources and potential conflicts of interest No funding sources or conflicts of interest were reported for this study. ...
The purpose of this article is to provide an overview of the current state of knowledge of poorly understood and underresearched neuroanatomy of selected pyramidal cells of the medial wall of the cingulate gyrus.
A literature review was performed; and separate computerized literature searches of PubMed, Science Direct, Cochrane Library, Science Citation Index, SCOPUS, CINAHL, and the World Wide Web were used for each cell type using individual set time scales for the discovery of each cell. A narrative overview of the literature was developed using information from searches of computerized databases and authoritative texts.
The medial walls of the cerebral hemispheres, notably the cingulate gyri, contain species-specific neuron fields that to date are not well known within the scientific community and yet have been implicated as the underlying cause of such varying conditions as dysgraphia and autism in children and obsessive-compulsive disorder and Alzheimer disease in adults. As these neurons are late to develop both phylogenetically and ontogenetically, it has been suggested that they may be particularly vulnerable to stressors that potentially could be an underlying factor in a wide range of neurodevelopmental and neuropsychiatric disorders.
It is considered that knowledge of these little-known pyramidal fields of the medial wall of the human brain is essential to the understanding of how the brain functions both in sickness and in health.
... Although Kennedy et al. [23] found normal VEN density in the insular cortex of autistic subjects, Simm et al. [39] revealed a diverse pattern with increased VEN density in the ACC in some subjects and rarefication of VENs in others [23]. In any event, despite the heterogeneity of findings, VEN comprise an interesting population of neurons that could be affected in complex diseases, such as schizophrenia in which both neurodevelopmental and neurodegenerative alterations occur [31]. ...
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. Schizophrenia is a group of disorders that is, in part, characterised by a disruption of neuronal migration in early ontogeny and presumably secondary degeneration after the first psychotic episode in some patients. Accordingly, we tested the hypothesis that the density of VENs is reduced in a neurodevelopmental subtype of schizophrenia, which we defined by an early onset of the disorder. The density of VENs was estimated in layer Vb of Brodmann's area 24 in 20 subjects diagnosed with schizophrenia. The results were compared with 19 specimens from patients with bipolar disorder as a clinical control and 22 non-psychiatric samples. The density of VENs did not differ between the three groups. However, the VEN density in the right ACC correlated with the age at onset, and inversely with the duration of the illness in schizophrenia, but not in bipolar disorder. Thus, patients with early onset schizophrenia (and longer duration of illness) had a reduced VEN density. Age, sex, postmortem interval, brain weight, and cortical thickness had no significant impact on the results. These findings suggest that VENs in the ACC are involved in neurodevelopmental and perhaps neurodegenerative processes specific to schizophrenia.
OBJECTIVE: The cingulate cortex is a functionally heterogeneous region involved in diverse cognitive and emotional processes. It is a region of special interest to investigate the neurological substrate of schizophrenia. The aim of this paper is to review all the studies that investigated the relation between the cingulate cortex and two of the most important and little known areas of this disease: the psychotic onset and the negative symptoms. MATERIALS AND METHODS: Relevant literature was identified through a search in PubMed, Web of Science, and Cochrane database. Search terms included negative symptoms, cingulate cortex, cingulate gyrus, schizophrenia, PET, SPECT, MRI, fMRI, BOLD, deficit schizophrenia, early-onset schizophrenia, psychotic onset, psychosis. RESULTS: 9 studies evidenced a link between negative symptoms and hypoactivity of cingulate cortex, whereas 7 studies did not. A positive relationship between anterior cingulate cortex gray matter thinning and high risk for schizophrenia is well characterized in literature. CONCLUSIONS: In a large portion of patients hypoactivity of cingulate cortex underlie the presence of negative symptoms. In particular, ACC (anterior cingulated cortex) thinning seems to be related to the increasing social withdrawal that is characteristic of the psychosis prodrome. New
therapies focused on the brain stimulation of the cingulate cortex could represent an important aid
for patients with this kind of symptoms.
The standard cranial nerve tests are well documented and form an essential part of the neurological examination conducted by practitioners on a daily basis; however, the results are not always clear cut and may be difficult to interpret in the absence of a full-blown specific disease entity. It may therefore prove necessary to evaluate the findings in terms of the functional neurology of the brain to appreciate the wider implications of the results.
Objective
To review the standard cranial nerve tests in terms of which tests should be included, how they should be performed, their validity and how widely the results should be evaluated.
Design
A review of clinical procedures taken from available literature retrieved from computerised databases, the worldwide web and authoritative texts.
Method
Information was gathered from a computerised literature search of medline, Science Direct, Cochrane library, Science Citation Index, Scopus, CINAHL and the worldwide web. The search terms used were cranial nerves, cranial tests, cranial nerve testing and the neurological examination.
We report the existence and distribution of an unusual type of projection neuron, a large, spindle-shaped cell, in layer Vb
of the anterior cingulate cortex of pongids and hominids. These spindle cells were not observed in any other primate species
or any other mammalian taxa, and their volume was correlated with brain volume residuals, a measure of encephalization in
higher primates. These observations are of particular interest when considering primate neocortical evolution, as they reveal
possible adaptive changes and functional modifications over the last 15–20 million years in the anterior cingulate cortex,
a region that plays a major role in the regulation of many aspects of autonomic function and of certain cognitive processes.
That in humans these unique neurons have been shown previously to be severely affected in the degenerative process of Alzheimer’s
disease suggests that some of the differential neuronal susceptibility that occurs in the human brain in the course of age-related
dementing illnesses may have appeared only recently during primate evolution.
We propose that the anterior cingulate cortex is a specialization of neocortex rather than a more primitive stage of cortical evolution. Functions central to intelligent behavior, that is, emotional self-control, focused problem solving, error recognition, and adaptive response to changing conditions, are juxtaposed with the emotions in this structure. Evidence of an important role for the anterior cingulate cortex in these functions has accumulated through single-neuron recording, electrical stimulation, EEG, PET, fMRI, and lesion studies. The anterior cingulate cortex contains a class of spindle-shaped neurons that are found only in humans and the great apes, and thus are a recent evolutionary specialization probably related to these functions. The spindle cells appear to be widely connected with diverse parts of the brain and may have a role in the coordination that would be essential in developing the capacity to focus on difficult problems. Furthermore, they emerge postnatally and their survival may be enhanced or reduced by environmental conditions of enrichment or stress, thus potentially influencing adult competence or dysfunction in emotional self-control and problem-solving capacity.
The division of labor by the two cerebral hemispheres—once thought to be uniquely human—predates us by half a billion years. Speech, right-handedness, facial recognition and the processing of spatial relations can be traced to brain asymmetries in early vertebrates
Caspases are essential components of the mammalian cell death machinery. Here we test the hypothesis that Caspase 9 (Casp9) is a critical upstream activator of caspases through gene targeting in mice. The majority of Casp9 knockout mice die perinatally with a markedly enlarged and malformed cerebrum caused by reduced apoptosis during brain development. Casp9 deletion prevents activation of Casp3 in embryonic brains in vivo, and Casp9-deficient thymocytes show resistance to a subset of apoptotic stimuli, including absence of Casp3-like cleavage and delayed DNA fragmentation. Moreover, the cytochrome c-mediated cleavage of Casp3 is absent in the cytosolic extracts of Casp9-deficient cells but is restored after addition of in vitro-translated Casp9. Together, these results indicate that Casp9 is a critical upstream activator of the caspase cascade in vivo.
We report the existence and distribution of an unusual type of projection neuron, a large, spindle-shaped cell, in layer Vb of the anterior cingulate cortex of pongids and hominids. These spindle cells were not observed in any other primate species or any other mammalian taxa, and their volume was correlated with brain volume residuals, a measure of encephalization in higher primates. These observations are of particular interest when considering primate neocortical evolution, as they reveal possible adaptive changes and functional modifications over the last 15-20 million years in the anterior cingulate cortex, a region that plays a major role in the regulation of many aspects of autonomic function and of certain cognitive processes. That in humans these unique neurons have been shown previously to be severely affected in the degenerative process of Alzheimer's disease suggests that some of the differential neuronal susceptibility that occurs in the human brain in the course of age-related dementing illnesses may have appeared only recently during primate evolution.
Social interaction is a cornerstone of human life, yet the neural mechanisms underlying social cognition are poorly understood. Recently, research that integrates approaches from neuroscience and social psychology has begun to shed light on these processes, and converging evidence from neuroimaging studies suggests a unique role for the medial frontal cortex. We review the emerging literature that relates social cognition to the medial frontal cortex and, on the basis of anatomical and functional characteristics of this brain region, propose a theoretical model of medial frontal cortical function relevant to different aspects of social cognitive processing.
Von Economo neurons (VENs), also known as spindle cells, have been described in layer V of the anterior cingulate (BA 24) and frontoinsular cortex (FI) of humans and other great apes. In the present study we used immunohistochemistry against two specific neuronal markers (NeuN and MAP2) in order to establish the presence of these cell types in Brodmann area 9 (BA 9) of the human prefrontal cortex. We evaluated tissue samples of eight human postmortem brains (age range 26-50) from BAs 9, 24, 4, 46, 45, 10 and 17. We identified a group of cells with similar morphology to that previously described for VENs in all specimens of BA 9 examined, albeit less frequently than in BA 24. This is the first description of this cell type in a human brain area with well developed granular layers (BA 9).
Most manual grips can be divided in precision and power grips on the basis of phylogenetic and functional considerations. We used functional magnetic resonance imaging to compare human brain activity during force production by the right hand when subjects used a precision grip and a power grip. During the precision-grip task, subjects applied fine grip forces between the tips of the index finger and the thumb. During the power-grip task, subjects squeezed a cylindrical object using all digits in a palmar opposition grasp. The activity recorded in the primary sensory and motor cortex contralateral to the operating hand was higher when the power grip was applied than when subjects applied force with a precision grip. In contrast, the activity in the ipsilateral ventral premotor area, the rostral cingulate motor area, and at several locations in the posterior parietal and prefrontal cortices was stronger while making the precision grip than during the power grip. The power grip was associated predominately with contralateral left-sided activity, whereas the precision-grip task involved extensive activations in both hemispheres. Thus our findings indicate that in addition to the primary motor cortex, premotor and parietal areas are important for control of fingertip forces during precision grip. Moreover, the ipsilateral hemisphere appears to be strongly engaged in the control of precision-grip tasks performed with the right hand.
Von Economo neurons (VENs) are a recently evolved cell type which may be involved in the fast intuitive assessment of complex situations. As such, they could be part of the circuitry supporting human social networks. We propose that the VENs relay an output of fronto-insular and anterior cingulate cortex to the parts of frontal and temporal cortex associated with theory-of-mind, where fast intuitions are melded with slower, deliberative judgments. The VENs emerge mainly after birth and increase in number until age 4 yrs. We propose that in autism spectrum disorders the VENs fail to develop normally, and that this failure might be partially responsible for the associated social disabilities that result from faulty intuition.
Cetaceans diverged from terrestrial mammals between 50 and 60 million years ago and acquired, during their adaptation to a fully aquatic milieu, many derived features, including echolocation (in odontocetes), remarkable auditory and communicative abilities, as well as a complex social organization. Whereas brain structure has been documented in detail in some odontocetes, few reports exist on its organization in mysticetes. We studied the cerebral cortex of the humpback whale (Megaptera novaeangliae) in comparison to another balaenopterid, the fin whale, and representative odontocetes. We observed several differences between Megaptera and odontocetes, such as a highly clustered organization of layer II over the occipital and inferotemporal neocortex, whereas such pattern is restricted to the ventral insula in odontocetes. A striking observation in Megaptera was the presence in layer V of the anterior cingulate, anterior insular, and frontopolar cortices of large spindle cells, similar in morphology and distribution to those described in hominids, suggesting a case of parallel evolution. They were also observed in the fin whale and the largest odontocetes, but not in species with smaller brains or body size. The hippocampal formation, unremarkable in odontocetes, is further diminutive in Megaptera, contrasting with terrestrial mammals. As in odontocetes, clear cytoarchitectural patterns exist in the neocortex of Megaptera, making it possible to define many cortical domains. These observations demonstrate that Megaptera differs from Odontoceti in certain aspects of cortical cytoarchitecture and may provide a neuromorphologic basis for functional and behavioral differences between the suborders as well as a reflection of their divergent evolution. Anat Rec Part A, 2006. (c) 2006 Wiley-Liss, Inc.
Background context
Currently dyslexia, dyspraxia, attention deficit disorder, attention deficit hyperactive disorder, obsessive compulsive disorder and Tourette's syndrome of childhood are considered as being separate disorders. There is now evidence to suggest that, on the basis of comorbidity, they should be downgraded to symptoms that will appear in syndromes of developmental delay.
Purpose
To establish that a child diagnosed by a health practitioner or educational professional as having a single disorder in fact presents symptoms of other disorders in a pattern of comorbidity.
Method
A prospective epidemiological study of 100 children attending a specialist clinic.
Results
A clear pattern of comorbidity was demonstrated. Whilst not always quantifiable, no patient was found to have one condition in isolation and comorbidity rates were found at incidences of up to 95%, representing an increase on the expected prevalence in a general population of 160–2300%.
Conclusion
The patterns of comorbidity occurred with such frequency that it would suggest that there could be an argument for the downgrading of these conditions from disorders per se to symptoms and that further investigation might suggest that the patterns of comorbidity may fit the criteria for a developmental delay syndrome.
Objective
To investigate the incidence of birth intervention/foetal distress in children with developmental delay syndromes (attention deficit disorder, attention deficit hyperactivity disorder, dyslexia, dyspraxia, obsessive compulsive disorder, Tourette's syndrome of childhood, autistic spectrum disorders).
Methodology
A population of 100 children aged 4–15 years and diagnosed with developmental delay syndrome(s) were investigated using a parental questionnaire to determine whether they had suffered any birth interventions or distress. These results were compared with an age- and gender-matched control group.
Results
On the basis of this relatively small study, significant risk of development delay syndrome(s) occurred with both foetal distress (p < 0.001) and Ventouse assisted delivery (p < 0.01).
The von Economo neurons are one of the few known specializations to hominoid cortical microcircuitry. The recent emergence of this cell type, as well as its localization to subregions of the frontal cortex, suggest its involvement in sophisticated cognitive behaviors. Studies of this cell may thus provide insights into human uniqueness and origin and may additionally be relevant to the treatment and understanding of mental illness. The first section of this thesis investigates the anatomical details of these cells, including their structure and surface receptor expression. Using a Golgi preparation of a human postmortem brain, I describe the dendritic architecture of this unique population of neurons. We found that, in contrast to layer 5 pyramidal neurons, the von Economo neurons have sparse dendritic trees with symmetric apical and basal components. This confirms that the von Economo cells in both ACC and FI share the architectural characteristics of a single population, and that this population is distinct from other layer 5 neurons. I additionally used immunohistochemistry to probe the receptor expression on these cells, and found that the von Economo neurons strongly express the dopamine D3 and D5 receptors, as well as serotonin-1b and serotonin-2b receptors. Together, these results provide the first detailed anatomical description of a neuron type unique to great apes and humans. In the second part of this thesis, I explore whether a behavioral stimulus, humor, activates the regions in which this cell occurs. Humor is a hallmark of social discourse and usually depends on the convergence of fast, intuitive assessments with a slow "re-interpretation" of the humor. Because of these characteristics, we thought it likely that humor would activate FI and ACC in addition to other regions in the brain. I used event-related fMRI to differentiate brain activity induced by the hedonic similarities and cognitive differences inherent in cartoons depicting two kinds of humor: visual humor (sight gags) and language-based humor. I found that the brain networks recruited during a humorous experience did indeed include FI and ACC, and that the profile of activation differs according to the type of humor being processed. Taken together, these projects significantly expand on our knowledge of these unusual cells, and provide a basis that allows us to hypothesize about their function. In the conclusion of this paper, we propose that the role of the von Economo neurons is to facilitate fast decision making in the context of high uncertainty, such as during social interaction.
Von Economo neurons (VENs) are a type of large, layer V spindle-shaped neurons that were previously described in humans, great apes, elephants, and some large-brained cetaceans. Here we report the presence of Von Economo neurons in the anterior cingulate (ACC), anterior insular (AI), and frontopolar (FP) cortices of small odontocetes, including the bottlenose dolphin (Tursiops truncatus), the Risso's dolphin (Grampus griseus), and the beluga whale (Delphinapterus leucas). The total number and volume of VENs and the volume of neighboring layer V pyramidal neurons and layer VI fusiform neurons were obtained by using a design-based stereologic approach. Two humpback whale (Megaptera novaeangliae) brains were investigated for comparative purposes as representatives of the suborder Mysticeti. Our results show that the distribution of VENs in these cetacean species is comparable to that reported in humans, great apes, and elephants. The number of VENs in these cetaceans is also comparable to data available from great apes, and stereologic estimates indicate that VEN volume follows in these cetacean species a pattern similar to that in hominids, the VENs being larger than neighboring layer V pyramidal cells and conspicuously larger than fusiform neurons of layer VI. The fact that VENs are found in species representative of both cetacean suborders in addition to hominids and elephants suggests that these particular neurons have appeared convergently in phylogenetically unrelated groups of mammals possibly under the influence of comparable selective pressures that influenced specifically the evolution of cortical domains involved in complex cognitive and social/emotional processes.
The anterior insular cortex (AIC) is implicated in a wide range of conditions and behaviours, from bowel distension and orgasm, to cigarette craving and maternal love, to decision making and sudden insight. Its function in the re-representation of interoception offers one possible basis for its involvement in all subjective feelings. New findings suggest a fundamental role for the AIC (and the von Economo neurons it contains) in awareness, and thus it needs to be considered as a potential neural correlate of consciousness.
Von Economo neurons (VENs), previously found in humans, all of the great ape species, and four cetacean species, are also present in African and Indian elephants. The VENs in the elephant are primarily found in similar locations to those in the other species. They are most abundant in the frontoinsular cortex (area FI) and are also present at lower density in the anterior cingulate cortex. Additionally, they are found in a dorsolateral prefrontal area and less abundantly in the region of the frontal pole. The VEN morphology appears to have arisen independently in hominids, cetaceans, and elephants, and may reflect a specialization for the rapid transmission of crucial social information in very large brains.
The human anterior cingulate cortex is distinguished by the presence of an unusual cell type, a large spindle neuron in layer Vb. This cell has been noted numerous times in the historical literature but has not been studied with modern neuroanatomic techniques. For instance, details regarding the neuronal class to which these cells belong and regarding their precise distribution along both ventrodorsal and anteroposterior axes of the cingulate gyrus are still lacking. In the present study, morphological features and the anatomic distribution of this cell type were studied using computer-assisted mapping and immunocytochemical techniques. Spindle neurons are restricted to the subfields of the anterior cingulate cortex (Brodmann's area 24), exhibiting a greater density in anterior portions of this area than in posterior portions, and tapering off in the transition zone between anterior and posterior cingulate cortex. Furthermore, a majority of the spindle cells at any level is located in subarea 24b on the gyral surface. Immunocytochemical analysis revealed that the neurofilament protein triple was present in a large percentage of these neurons and that they did not contain calcium-binding proteins. Injections of the carbocyanine dye DiI into the cingulum bundle revealed that these cells are projection neurons. Finally, spindle cells were consistently affected in Alzheimer's disease cases, with an overall loss of about 60%. Taken together, these observations indicate that the spindle cells of the human cingulate cortex represent a morphological subpopulation of pyramidal neurons whose restricted distribution may be associated with functionally distinct areas.
Finch and Sapolsky propose that the slow development of human infants and their consequent long period of de- pendency on their parents have favored the evolution of genes that retard brain senescence, specifically recently evolved variants of the apolipoprotein E gene. We examine here the probable reasons why human maturation is so slow, and the influence of this slow development on parental dependence and patterns of survival. Large brains are ex- pensive in terms of energy, anatomic complexity, and the time required to reach particular stages of postnatal matu- ration. We hypothesize that the maturational time costs arise from the fact that the brain is unique among the organs of the body in requiring a great deal of interaction with the environment (learning experience) to achieve adult compe- tence, and thus that the brain serves as a rate-limiting factor governing the maturation of the entire body. Although the brain achieves its adult size at an earlier age than the other organs of the body, it does not become structurally and functionally mature until some point after sexual maturity (30). The classical studies of developmental myelination by Flechsig (14,15) indicate that the brain matures slowly in stepwise hierarchies proceeding, for example, from the thal- amus to the primary cortical sensory areas to the higher cortical areas of the temporal, parietal, and frontal lobes. Quartz and Sejnowski (33) have proposed that the brain builds sequentially from one level to the next on the basis of experience, and thus larger brains may require more time to mature, in part because they have more levels. We have examined the time costs associated with en- larged brains by analyzing the relationships between aver- age brain size and the average times required to reach various stages of postnatal maturation, such as the eruption of various classes of teeth and reproductive maturity, in different primate species. Because both brain and develop- mental timing variables are related to body mass, we have first extracted the statistical effect of mass for each variable and then compared the residual values related to brain
We propose that the anterior cingulate cortex is a specialization of neocortex rather than a more primitive stage of cortical evolution. Functions central to intelligent behavior, that is, emotional self-control, focused problem solving, error recognition, and adaptive response to changing conditions, are juxtaposed with the emotions in this structure. Evidence of an important role for the anterior cingulate cortex in these functions has accumulated through single-neuron recording, electrical stimulation, EEG, PET, fMRI, and lesion studies. The anterior cingulate cortex contains a class of spindle-shaped neurons that are found only in humans and the great apes, and thus are a recent evolutionary specialization probably related to these functions. The spindle cells appear to be widely connected with diverse parts of the brain and may have a role in the coordination that would be essential in developing the capacity to focus on difficult problems. Furthermore, they emerge postnatally and their survival may be enhanced or reduced by environmental conditions of enrichment or stress, thus potentially influencing adult competence or dysfunction in emotional self-control and problem-solving capacity.
We report the existence of the spindle neurons in layer Vb of the anterior cingulate cortex (Brodman's area 24b) in a chimpanzee fetus (embryonic day 224), which was stillborn. About 5.3% of neuronal cells in layer Vb were the spindle neurons at this stage. The width of the spindle neurons was 10-15 microm. In layer V of the prefrontal cortex (Brodman's area 46) in the chimpanzee fetus, and in layer Vb of the cingulate cortex in adult macaque monkeys, no spindle neurons were observed. The immunoreactivity against brain-derived neurotrophic factor (BDNF) was detected only in the pyramidal neurons at this stage. These findings suggest that the existence of the spindle neurons in layer Vb of the anterior cingulate cortex and the presence of BDNF in the pyramidal neurons are intrinsically characterized during the embryonic stage of the chimpanzee.
In this study, two anatomical specializations of the brain in apes and humans are considered. One of these is a whole cortical area located in the frontal polar cortex (Brodmann's area 10), and the other is a morphologically distinctive cell type, the spindle neuron of the anterior cingulate cortex. The authors suggest that the spindle cells may relay to other parts of the brain--especially to area 10, the outcome of processing within the anterior cingulate cortex. This relay conveys the motivation to act. It particularly concerns the recognition of having committed an error that leads to the initiation of adaptive responses to these adverse events so as to reduce error commission. This capacity is related to the development of self-control as an individual matures and gains social insight. Although the anterior cingulate deals with the individual's immediate response to changing conditions, area 10 is involved in the retrieval of memories from the individual's past experience and the capacity to plan adaptive responses. The authors suggest that these neurobehavioral specializations are crucial aspects of intelligence as defined as the capacity to make adaptive responses to changing conditions. The authors further hypothesize that these specializations facilitated the evolution of the unique capacity for the intergenerational transfer of the food and information characteristic of human extended families.
Von Economo neurons (VENs) are a recently evolved cell type which may be involved in the fast intuitive assessment of complex situations. As such, they could be part of the circuitry supporting human social networks. We propose that the VENs relay an output of fronto-insular and anterior cingulate cortex to the parts of frontal and temporal cortex associated with theory-of-mind, where fast intuitions are melded with slower, deliberative judgments. The VENs emerge mainly after birth and increase in number until age 4 yrs. We propose that in autism spectrum disorders the VENs fail to develop normally, and that this failure might be partially responsible for the associated social disabilities that result from faulty intuition.
Current dissatisfaction with the limbic system concept reflects a desire to move beyond the limbic system in efforts to explain key facets of emotional functions and motivational behavior. This review promotes an anatomical viewpoint, which originated as a result of histotechnical advances. These improvements paved the way for anatomical discoveries, which in turn led to the concepts of the ventral striatopallidal system and extended amygdala. These two systems, together with the basal nucleus of Meynert and the septum-diagonal band system, serve as output channels for an expanded version of the classic limbic lobe of Broca, which contains all non-isocortical parts of the cortical mantle together with the large laterobasal-cortical amygdaloid complex. Thus defined, the limbic lobe contains all of the major cortical (e.g. orbitofrontal, cingulate and insular cortices in addition to the hippocampal formation) and cortical-like (laterobasal-cortical amygdala) structures known to be especially important for emotional and motivational functions. In their role as output channels for the limbic lobe, the basal forebrain functional-anatomical systems contribute to the establishment of a number of cortico-subcortical circuits, which provide an important part of the anatomical substrate for the elaboration of emotional functions and adaptive behavior.
The von Economo neurons are one of the few known specializations to hominoid cortical microcircuitry. Here, using a Golgi preparation of a human postmortem brain, we describe the dendritic architecture of this unique population of neurons. We have found that, in contrast to layer 5 pyramidal neurons, the von Economo neurons have sparse dendritic trees and symmetric apical and basal components. This result provides the first detailed anatomical description of a neuron type unique to great apes and humans.
Frontotemporal dementia (FTD) is a neurodegenerative disease that erodes uniquely human aspects of social behavior and emotion. The illness features a characteristic pattern of early injury to anterior cingulate and frontoinsular cortex. These regions, though often considered ancient in phylogeny, are the exclusive homes to the von Economo neuron (VEN), a large bipolar projection neuron found only in great apes and humans. Despite progress toward understanding the genetic and molecular bases of FTD, no class of selectively vulnerable neurons has been identified.
Using unbiased stereology, we quantified anterior cingulate VENs and neighboring Layer 5 neurons in FTD (n = 7), Alzheimer's disease (n = 5), and age-matched nonneurological control subjects (n = 7). Neuronal morphology and immunohistochemical staining patterns provided further information about VEN susceptibility.
FTD was associated with early, severe, and selective VEN losses, including a 74% reduction in VENs per section compared with control subjects. VEN dropout was not attributable to general neuronal loss and was seen across FTD pathological subtypes. Surviving VENs were often dysmorphic, with pathological tau protein accumulation in Pick's disease. In contrast, patients with Alzheimer's disease showed normal VEN counts and morphology despite extensive local neurofibrillary pathology.
VEN loss links FTD to its signature regional pattern. The findings suggest a new framework for understanding how evolution may have rendered the human brain vulnerable to specific forms of degenerative illness.
It has been suggested that spindle neurons, an evolutionarily unique type of neuron, might be involved in higher-order social, emotional, and cognitive functions. As such, it was hypothesized that these neurons may be particularly important to the pathophysiology of autism, a disease characterized in part by disruption of higher-order social and emotional processing. Therefore, we conducted the first stereological investigation of the number of spindle neurons in autism, using the optical fractionator technique. Our results did not provide evidence of a reduction in spindle neuron number in frontoinsular cortex in autism. However, this study provides the first quantitative stereological data on spindle neuron number in autism. Future postmortem studies with larger sample sizes will likely be critical in elucidating the spared and defective neural systems underlying the autistic phenotype.
Cetaceans diverged from terrestrial mammals between 50 and 60 million years ago and acquired, during their adaptation to a fully aquatic milieu, many derived features, including echolocation (in odontocetes), remarkable auditory and communicative abilities, as well as a complex social organization. Whereas brain structure has been documented in detail in some odontocetes, few reports exist on its organization in mysticetes. We studied the cerebral cortex of the humpback whale (Megaptera novaeangliae) in comparison to another balaenopterid, the fin whale, and representative odontocetes. We observed several differences between Megaptera and odontocetes, such as a highly clustered organization of layer II over the occipital and inferotemporal neocortex, whereas such pattern is restricted to the ventral insula in odontocetes. A striking observation in Megaptera was the presence in layer V of the anterior cingulate, anterior insular, and frontopolar cortices of large spindle cells, similar in morphology and distribution to those described in hominids, suggesting a case of parallel evolution. They were also observed in the fin whale and the largest odontocetes, but not in species with smaller brains or body size. The hippocampal formation, unremarkable in odontocetes, is further diminutive in Megaptera, contrasting with terrestrial mammals. As in odontocetes, clear cytoarchitectural patterns exist in the neocortex of Megaptera, making it possible to define many cortical domains. These observations demonstrate that Megaptera differs from Odontoceti in certain aspects of cortical cytoarchitecture and may provide a neuromorphologic basis for functional and behavioral differences between the suborders as well as a reflection of their divergent evolution.
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